U.S. patent application number 17/011817 was filed with the patent office on 2021-06-24 for plasma compositions and methods of use thereof.
The applicant listed for this patent is Cerus Corporation. Invention is credited to Richard BENJAMIN, Laurence CORASH, Elan WEINER.
Application Number | 20210187020 17/011817 |
Document ID | / |
Family ID | 1000005436293 |
Filed Date | 2021-06-24 |
United States Patent
Application |
20210187020 |
Kind Code |
A1 |
CORASH; Laurence ; et
al. |
June 24, 2021 |
PLASMA COMPOSITIONS AND METHODS OF USE THEREOF
Abstract
Provided herein are pathogen-inactivated plasma compositions and
methods for treating a disease or condition using
pathogen-inactivated plasma compositions.
Inventors: |
CORASH; Laurence; (Concord,
CA) ; BENJAMIN; Richard; (Concord, CA) ;
WEINER; Elan; (Vernon Hills, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Cerus Corporation |
Concord |
CA |
US |
|
|
Family ID: |
1000005436293 |
Appl. No.: |
17/011817 |
Filed: |
September 3, 2020 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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15770186 |
Apr 20, 2018 |
10799533 |
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PCT/US2016/058318 |
Oct 21, 2016 |
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17011817 |
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62354653 |
Jun 24, 2016 |
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62268462 |
Dec 16, 2015 |
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62245926 |
Oct 23, 2015 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 7/00 20180101; A61K
9/0019 20130101; A61K 35/16 20130101 |
International
Class: |
A61K 35/16 20060101
A61K035/16; A61P 7/00 20060101 A61P007/00; A61K 9/00 20060101
A61K009/00 |
Claims
1. A method of treating a disease or condition indicated for
treatment by plasma exchange in a subject in need thereof,
comprising administering to the subject a therapeutically effective
amount of pathogen-inactivated plasma composition by plasma
exchange, wherein the pathogen-inactivated plasma composition
comprises pathogen-inactivated cryo-poor plasma.
2. The method of claim 1, wherein the disease or condition is
indicated for treatment with albumin by plasma exchange.
3. The method of claim 1, wherein the disease or condition is other
than thrombocytopenic purpura (TTP) or hemolytic-uremic syndrome
(HUS).
4-5. (canceled)
6. The method of claim 1, wherein the disease or condition is
thrombocytopenic purpura (TTP) or hemolytic-uremic syndrome
(HUS).
7-10. (canceled)
11. The method of claim 1, wherein the pathogen-inactivated plasma
composition is administered within 5 days after thawing.
12. The method of claim 1, wherein the pathogen-inactivated plasma
composition is a lyophilized or freeze-dried plasma
composition.
13-66. (canceled)
67. The method of claim 1, wherein the plasma exchange is achieved
with a volume of the plasma composition between about 1 times and
about 1.5 times the subject's plasma volume.
68. The method of claim 1, wherein the plasma exchange is achieved
with a volume of the plasma composition comprising about 30 mL/kg,
about 40 mL/kg, about 50 mL/kg, or about 60 mL/kg patient body
weight.
69. The method of claim 1, wherein the plasma exchange is performed
at least two times.
70. The method of claim 69, wherein the plasma exchange is
performed 2-5 times.
71. The method of claim 69, wherein the plasma exchange is
performed 2-5 times within a period of two weeks.
72. The method of claim 1, wherein the pathogen-inactivated plasma
composition comprises pathogen-inactivated cryo-poor plasma
prepared from one or more units of plasma from whole blood
donation.
73. The method of claim 1, wherein the pathogen-inactivated plasma
composition comprises pathogen-inactivated cryo-poor plasma
prepared from one or more plasma units from apheresis collected
plasma.
74. The method of claim 1, wherein the pathogen-inactivated plasma
composition comprises pathogen-inactivated cryo-poor plasma
prepared from one or more units of plasma that are subjected to
pathogen inactivation within 24 hours of donation.
75. The method of claim 1, wherein the pathogen-inactivated plasma
composition comprises pathogen-inactivated cryo-poor plasma
prepared from multiple plasma units.
76. The method of claim 1, wherein the pathogen-inactivated
cryo-poor plasma is prepared from plasma that is
pathogen-inactivated by photochemical inactivation.
77. The method of claim 1, wherein the pathogen-inactivated
cryo-poor plasma is prepared from plasma that is
pathogen-inactivated with a psoralen.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application claims the priority benefit of U.S.
Provisional Application Ser. No. 62/245,926, filed Oct. 23, 2015;
62/268,462, filed Dec. 16, 2015; and 62/354,653, filed Jun. 24,
2016; each of which is incorporated herein by reference in its
entirety.
TECHNICAL FIELD
[0002] The methods described herein generally relate to the
preparation and use of plasma compositions. More particularly, the
present disclosure relates to pathogen-inactivated plasma
compositions and their use in improved treatment methods using such
compositions for therapeutic plasma exchange or infusion.
BACKGROUND
[0003] Blood collection and processing serves a critical role in
healthcare worldwide, and millions of units of donated whole blood
are collected by blood banks each year. While some whole blood
units collected from donors are stored and used for transfusion,
most whole blood is instead separated into its clinically
therapeutic components of red blood cells, platelets and plasma,
for individual storage and use in treating different medical needs
and conditions requiring one or more of the particular blood
components. Additionally, other blood derived products may be
produced through fractionation procedures, such as for example,
intravenous immunoglobulin G (IVIG), a product obtained by
fractionation of human plasma (Radosevich et al., 2010, Vox
Sanguinis, 98: 12-28).
[0004] Cryoprecipitate (also known as "cryo") is a blood product
comprising a portion of plasma rich in coagulation factors.
Cyroprecipitate, also referred to as cryoprecipitated
antihaemophilic factor (AHF), cryoprecipitated AHF, is prepared by
slow, controlled thawing of frozen plasma (e.g., whole
blood-derived fresh frozen plasma, or FFP), for example between
1.degree. and 6.degree. C. (e.g., 4.+-.2.degree. C.), which results
in the formation of a white precipitate, and then recovering the
precipitate following separation from the remaining liquid plasma
portion, such as by refrigerated centrifugation. The remaining
liquid plasma portion, also referred to herein as "supernatant" and
various other terminology, such as "cryo-poor plasma" (CPP),
"cryosupernatant", "cryoprecipitate-reduced plasma", or
"cryo-reduced plasma", is removed from the cryoprecipitate bag and
the isolated cold-insoluble precipitate is re-suspended in a
portion of the plasma (e.g., the cryo-poor plasma) left behind and
generally re-frozen within 1 hour, and stored frozen until needed
for transfusion. The cryo-poor plasma contains plasma proteins not
partitioned with the cryoprecipitate and generally is used for
plasma fractionation to produce various components (e.g., plasma
factors), as well as for certain, very limited therapeutic
applications.
[0005] Cryoprecipitate serves as a source of fibrinogen, Factor
VIII, Factor XIII, vWF, and fibronectin. This component is used in
the control of bleeding associated with fibrinogen deficiency and
to treat Factor XIII deficiency when volume considerations preclude
the use of frozen plasma and recombinant proteins are not
available. It is also indicated as second-line therapy for von
Willebrand disease and hemophilia A (Factor VIII deficiency).
[0006] In addition to the primary use of plasma in transfusions to
correct deficiencies of clotting factors or coagulopathy in
patients with active bleeding, such as for example surgery and
trauma, plasma (e.g., FFP) and plasma derived components (e.g.,
IVIG) may be used for treatment of various diseases or conditions.
For example, immunotherapy using therapeutic plasma exchange (TPE)
or intravenous immunoglobulin (IVIG) or a combination of both has
been used for treatment of a variety of diseases or conditions.
Many such the diseases or conditions have been categorized by the
American Society for Apheresis (ASFA) based on literature guidance.
TPE is a therapeutic procedure using bulk removal of plasma from
patients. In a TPE process, blood is removed and separated into
plasma and cellular components (e.g., platelets, red blood cells),
followed by mixing of the cellular components with some form of
replacement fluid, and reinfusion into the patient (Winters, 2012,
Hematology ASH Education Book 2012:7-12). TPE removes pathologic
substances such as pathologic antibodies (e.g., autoantibodies),
immune complexes, and cytokines, and may have additional
immunomodulatory effects. Because TPE involves the bulk removal of
plasma, anything circulating in the plasma will be removed, leading
to a temporary decline in normal plasma components such as factor
V, factor VII, factor VIII, factor IX, factor X, VWF and
fibrinogen. Depending on the medical indication, plasma that is
removed can be replaced with human albumin (e.g., 4%-5% in
physiologic saline) which is relatively common, or alternatively
additional plasma (e.g., fresh frozen plasma, FFP), or even the
patient's own plasma after a secondary purification procedure
(Ward, 2011, J. Clin. Apheresis 26:230-238).
[0007] There remains a need for improved compositions and methods
for treatment of various diseases and conditions through the use of
therapeutic plasma exchange or infusion.
SUMMARY
[0008] The pathogen-inactivated plasma compositions and methods
described herein are useful for the treatment of various diseases
or conditions, including, for example, in providing improved
treatment methods using such plasma compositions for therapeutic
plasma exchange or infusion.
[0009] In one aspect, the present disclosure provides a composition
comprising a cryoprecipitate suitable for infusion into a subject
at least 1 day after thawing, wherein the cryoprecipitate is
pathogen-inactivated. In some embodiments, the composition is
suitable for infusion into a subject at least 3 days after thawing.
In some embodiments, the composition is suitable for infusion into
a subject at least 5 days after thawing. In some embodiments, the
composition is suitable for infusion into a subject at least 7 days
after thawing. In some embodiments, the composition comprises less
than 80 IU of factor VIII per unit of cryoprecipitate. In some
embodiments, the composition comprises less than 50 IU of factor
VIII per unit of cryoprecipitate. In some embodiments, the
composition comprises at least 150 mg of fibrinogen per unit of
cryoprecipitate. In some embodiments, the composition further
comprises plasma of a volume between about 15 mL and about 20 mL.
In some embodiments, the composition comprises cryoprecipitate
obtained from about 600 mL of pathogen-inactivated plasma. In some
embodiments, the composition comprises a first cryoprecipitate
obtained from about 600 mL of pathogen-inactivated plasma and a
second cryoprecipitate obtained from about 600 mL of
pathogen-inactivated plasma, wherein the first and the second
cryoprecipitates are combined prior to re-freezing for storage. In
some embodiments, the composition comprises cryoprecipitate
obtained from at least about 600 mL and less than 650 mL of
pathogen-inactivated plasma. In some embodiments, the composition
comprises a first cryoprecipitate obtained from at least about 600
mL and less than 650 mL of pathogen-inactivated plasma and a second
cryoprecipitate obtained from at least about 600 mL and less than
650 mL of pathogen-inactivated plasma, wherein the first and the
second cryoprecipitates are combined prior to re-freezing for
storage. In some embodiments, the composition further comprises
plasma of a volume between about 50 mL and about 60 mL. In some
embodiments, the composition is stored at room temperature for the
at least 1 day after thawing. In some embodiments, the
cryoprecipitate has been pathogen-inactivated by photochemical
inactivation. In some embodiments, the cryoprecipitate has been
pathogen-inactivated by photoinactivation with psoralen. In some
embodiments, the psoralen is amotosalen.
[0010] In another aspect, the present disclosure provides a method
of preparing a cryoprecipitate for infusion into a subject
comprising a) preparing a cryoprecipitate from pathogen-inactivated
plasma; b) freezing the cryoprecipitate; and c) thawing the frozen
cryoprecipitate, wherein the resulting cryoprecipitate of step c)
is suitable for infusion into a subject at least 1 day after
thawing. In some embodiments, the method further comprises testing
the thawed cryoprecipitate for fibrinogen. In some embodiments, the
method does not comprise testing the thawed cryoprecipitate for
factor VIII. In some embodiments, the cryoprecipitate is prepared
from about 600 mL of pathogen-inactivated plasma. In some
embodiments, the method further comprises combining a first
cryoprecipitate prepared from about 600 mL of pathogen-inactivated
plasma and a second cryoprecipitate prepared from about 600 mL of
pathogen-inactivated plasma, wherein the first and the second
cryoprecipitates are combined prior to steps b) and c). In some
embodiments, the cryoprecipitate is prepared from at least about
600 mL and less than 650 mL of pathogen-inactivated plasma. In some
embodiments, the method further comprises combining a first
cryoprecipitate prepared from at least about 600 mL and less than
650 mL of pathogen-inactivated plasma and a second cryoprecipitate
prepared from at least about 600 mL and less than 650 mL of
pathogen-inactivated plasma, wherein the first and the second
cryoprecipitates are combined prior to steps b) and c). In some
embodiments, the resulting cryoprecipitate of step c) is suitable
for infusion into a subject at least 3 days after thawing. In some
embodiments, the resulting cryoprecipitate of step c) is suitable
for infusion into a subject at least 5 days after thawing. In some
embodiments, the resulting cryoprecipitate of step c) is suitable
for infusion into a subject at least 7 days after thawing.
[0011] In yet another aspect, the present disclosure provides a
method of infusing a cryoprecipitate into a subject comprising a)
preparing a cryoprecipitate from pathogen-inactivated plasma; b)
freezing the cryoprecipitate; c) thawing the frozen
cryoprecipitate; and d) infusing the thawed cryoprecipitate into a
subject, wherein the infusion occurs at least 1 day after thawing
the frozen cryoprecipitate. In some embodiments, the method further
comprises testing the thawed cryoprecipitate for fibrinogen. In
some embodiments, the method does not comprise testing the thawed
cryoprecipitate for factor VIII before transfusing the thawed
cryoprecipitate. In some embodiments, the cryoprecipitate is
prepared from about 600 mL of pathogen-inactivated plasma. In some
embodiments, the method further comprises combining a first
cryoprecipitate prepared from about 600 mL of pathogen-inactivated
plasma and a second cryoprecipitate prepared from about 600 mL of
pathogen-inactivated plasma, wherein the first and the second
cryoprecipitates are combined prior to step b). In some
embodiments, the cryoprecipitate is prepared from at least about
600 mL and less than 650 mL of pathogen-inactivated plasma. In some
embodiments, the method further comprises combining a first
cryoprecipitate prepared from at least about 600 mL and less than
650 mL of pathogen-inactivated plasma and a second cryoprecipitate
prepared from at least about 600 mL and less than 650 mL of
pathogen-inactivated plasma, wherein the first and the second
cryoprecipitates are combined prior to step b).
[0012] In some embodiments of any of the above embodiments, the
resulting cryoprecipitate of step c) comprises less than 80 IU of
factor VIII per unit of cryoprecipitate. In some embodiments, the
resulting cryoprecipitate of step c) comprises less than 50 IU of
factor VIII per unit of cryoprecipitate. In some embodiments of any
of the above embodiments, the resulting cryoprecipitate of step c)
comprises at least 150 mg of fibrinogen per unit of
cryoprecipitate. In some embodiments, the cryoprecipitate of step
a) further comprises plasma of a volume between about 15 mL and
about 20 mL. In some embodiments, the cryoprecipitate of step a)
further comprises plasma of a volume between about 50 mL and about
60 mL. In some embodiments of any of the above embodiments, the
plasma has been pathogen-inactivated by photochemical inactivation.
In some embodiments, the cryoprecipitate has been
pathogen-inactivated by photoinactivation with psoralen. In some
embodiments, the psoralen is amotosalen. In some embodiments of any
of the above embodiments, the subject is a human.
[0013] In still another aspect, the present disclosure provides a
kit comprising a) a container; b) a pathogen-inactivated
cryoprecipitate; and c) instructions for using the
pathogen-inactivated cryoprecipitate in an infusion into a subject,
wherein the instructions indicate that the cryoprecipitate is
suitable for infusion into the subject for up to about 5 days after
thawing.
[0014] In still another aspect, the present disclosure provides a
method of infusing a cryoprecipitate into a subject, comprising
infusing into the subject the composition of any of the above
embodiments.
[0015] In still another aspect, the present disclosure provides a
method infusing a cryoprecipitate into a subject, comprising
infusing into the subject a cryoprecipitate produced by the method
of any of the above embodiments.
[0016] In still another aspect, the present disclosure provides a
cryoprecipitate produced by the method of any of the above
embodiments.
[0017] In still another aspect, the present disclosure provides a
composition comprising a cryoprecipitate suitable for infusion into
a subject at least 1 day after thawing, wherein the cryoprecipitate
is pathogen-inactivated. In some embodiments, the composition is
suitable for infusion into a subject at least 3 days after thawing.
In some embodiments, the composition is suitable for infusion into
a subject at least 5 days after thawing. In some embodiments, the
composition comprises cryoprecipitate prepared from at least about
550 mL and less than about 650 mL of pathogen-inactivated plasma.
In some embodiments, the composition comprises cryoprecipitate
prepared from about 600 mL of pathogen-inactivated plasma. In some
embodiments, the composition comprises cryoprecipitate prepared
from 3 units of pathogen-inactivated plasma. In some embodiments,
the composition comprises a first cryoprecipitate prepared from at
least about 550 mL and less than 650 mL of pathogen-inactivated
plasma and a second cryoprecipitate prepared from at least about
550 mL and less than 650 mL of pathogen-inactivated plasma, wherein
the first and the second cryoprecipitates are combined prior to
re-freezing for storage. In some embodiments, the composition
comprises a first cryoprecipitate prepared from about 600 mL of
pathogen-inactivated plasma and a second cryoprecipitate prepared
from about 600 mL of pathogen-inactivated plasma, wherein the first
and the second cryoprecipitates are combined prior to re-freezing
for storage. In some embodiments, the composition comprises a first
cryprecipitate prepared from 3 units of pathogen-inactivated plasma
and a second cryoprecipitate prepared from 3 units of
pathogen-inactivated plasma, wherein the first and the second
cryoprecipitates are combined prior to re-freezing for storage. In
some embodiments, the composition comprises cryoprecipitate
prepared from 6 units of pathogen-inactivated plasma. In some
embodiments, the composition comprises cryoprecipitate prepared
from plasma obtained from one donor. In some embodiments, the
composition comprises cryoprecipitate prepared from plasma obtained
from 2-6 donors. In some embodiments, the composition comprises
less than 80 IU of factor VIII per unit of cryoprecipitate. In some
embodiments, the composition comprises less than 50 IU of factor
VIII per unit of cryoprecipitate. In some embodiments, the
composition comprises 80-100 IU of factor VIII per unit of
cryoprecipitate. In some embodiments, the composition comprises at
least 80 IU of factor VIII. In some embodiments, the composition
comprises 80-240 IU of factor VIII. In some embodiments, the
composition comprises 80-480 IU of factor VIII. In some
embodiments, the amount of factor VIII is determined from
cryoprecipitate sampled within about 2 hours after thawing. In some
embodiments, the amount of factor VIII is determined from
cryoprecipitate sampled about 1 day after thawing. In some
embodiments, the amount of factor VIII is determined from
cryoprecipitate sampled about 3 days after thawing. In some
embodiments, the amount of factor VIII is determined from
cryoprecipitate sampled about 5 days after thawing. In some
embodiments, the composition comprises at least 150 mg of
fibrinogen per unit of cryoprecipitate. In some embodiments, the
composition comprises at least 250 mg of fibrinogen per unit of
cryoprecipitate. In some embodiments, the composition comprises at
least 750 mg of fibrinogen. In some embodiments, the composition
comprises at least 1500 mg of fibrinogen. In some embodiments, each
unit of cryoprecipitate is prepared from 180-250 mL of
pathogen-inactivated plasma. In some embodiments, the composition
further comprises plasma of a volume between about 5 mL and about
20 mL per unit of cryoprecipitate. In some embodiments, the
composition further comprises plasma of a volume greater than about
1 mL and less than or equal to about 75 mL. In some embodiments,
the composition further comprises plasma of a volume between about
50 mL and about 60 mL. In some embodiments, the composition further
comprises plasma of a volume between about 30 mL and about 120 mL.
In some embodiments, the composition is stored at room temperature
for at least 1 day after thawing. In some embodiments, the
composition is stored at between about 2.degree. C. and about
6.degree. C. for at least 1 day after thawing. In some embodiments,
the cryoprecipitate has been pathogen-inactivated by photochemical
inactivation. In some embodiments, the cryoprecipitate has been
pathogen-inactivated by photochemical inactivation with a psoralen.
In some embodiments, the psoralen is amotosalen. In some
embodiments, the cryoprecipitate is prepared from plasma that has
been pathogen-inactivated in a first container suitable for
photochemical inactivation of the plasma under sterile conditions;
wherein the first container is coupled to a compound absorption
device (CAD) such that the pathogen-inactivated plasma can be
transferred from the first container to the CAD under sterile
conditions; and wherein the cryoprecipitate is contained within one
or more second containers, each of which is coupled to the CAD such
that the pathogen-inactivated plasma can be transferred from the
CAD to the one or more second containers under sterile conditions,
and each of which is suitable for freezing the pathogen-inactivated
plasma followed by thawing of the pathogen-inactivated plasma under
conditions that provide for the formation of the cryoprecipitate.
In some embodiments, each of the one or more second containers is
suitable for freezing the pathogen-inactivated plasma, followed by
thawing of the pathogen-inactivated plasma under conditions that
provide for the formation of the cryoprecipitate and a
cryosupernatant, followed by removal of all or a portion of the
cryosupernatant from the one or more second containers. In some
embodiments, the cryoprecipitate is prepared from plasma that has
been pathogen-inactivated in a first container suitable for
photochemical inactivation of the plasma under sterile conditions;
wherein the first container is coupled to a compound absorption
device (CAD) such that the pathogen-inactivated plasma can be
transferred from the first container to the CAD under sterile
conditions; wherein the CAD is coupled to one or more second
containers, each of which is coupled to the CAD such that the
pathogen-inactivated plasma can be transferred from the CAD to the
one or more second containers under sterile conditions; and wherein
the cryoprecipitate is contained within a third container
configured to be coupled to one or more second containers, such
that the pathogen-inactivated plasma can be transferred from the
CAD to the one or more second containers to the third container
under sterile conditions, wherein the third container is suitable
for freezing the pathogen-inactivated plasma followed by thawing of
the pathogen-inactivated plasma under conditions that provide for
the formation of the cryoprecipitate. In some embodiments, the
third container is suitable for freezing the pathogen-inactivated
plasma, followed by thawing of the pathogen-inactivated plasma
under conditions that provide for the formation of the
cryoprecipitate and a cryosupernatant, followed by removal of all
or a portion of the cryosupernatant from the third container. In
some embodiments, the composition is contained within a container
that further comprises a label indicating that the composition is
suitable for use for at least about 1 day after thawing. In some
embodiments, the composition is contained within a container that
further comprises a label indicating that the composition is
suitable for use for at least about 3 days after thawing. In some
embodiments, the composition is contained within a container that
further comprises a label indicating that the composition is
suitable for use for at least about 5 days after thawing. In some
embodiments, the cryoprecipitate is prepared from plasma other than
group O plasma.
[0018] In still another aspect, the present disclosure provides a
method of preparing a cryoprecipitate for infusion into a subject
comprising: a) preparing a cryoprecipitate from
pathogen-inactivated plasma; b) freezing the cryoprecipitate; and
c) thawing the frozen cryoprecipitate, wherein the resulting
cryoprecipitate of step c) is suitable for infusion into a subject
at least 1 day after thawing. In some embodiments, the thawed
cryoprecipitate comprises at least about 150 mg of fibrinogen per
unit of cryoprecipitate. In some embodiments, the thawed
cryoprecipitate comprises at least about 750 mg of fibrinogen. In
some embodiments, the method does not comprise determining the
level of factor VIII before infusing the thawed cryoprecipitate. In
some embodiments, the method further comprises determining the
level of factor VIII in the thawed cryoprecipitate. In some
embodiments, the cryoprecipitate is prepared from at least about
550 mL and less than about 650 mL of pathogen-inactivated plasma.
In some embodiments, the cryoprecipitate is prepared from about 600
mL of pathogen-inactivated plasma. In some embodiments, the method
further comprises combining a first cryoprecipitate prepared from
at least about 550 mL and less than about 650 mL of
pathogen-inactivated plasma and a second cryoprecipitate prepared
from at least about 550 mL and less than about 650 mL of
pathogen-inactivated plasma, wherein the first and the second
cryoprecipitates are combined prior to steps b) and c). In some
embodiments, the method further comprises combining a first
cryoprecipitate prepared from about 600 mL of pathogen-inactivated
plasma and a second cryoprecipitate prepared from about 600 mL of
pathogen-inactivated plasma, wherein the first and the second
cryoprecipitates are combined prior to steps b) and c). In some
embodiments, the method further comprises combining a first
cryprecipitate prepared from 3 units of pathogen-inactivated plasma
and a second cryoprecipitate prepared from 3 units of
pathogen-inactivated plasma, wherein the first and the second
cryoprecipitates are combined prior to steps b) and c). In some
embodiments, the resulting cryoprecipitate of step c) is suitable
for infusion into a subject at least 3 days after thawing. In some
embodiments, the resulting cryoprecipitate of step c) is suitable
for infusion into a subject at least 5 days after thawing. In
another aspect, provided herein is a method of infusing a
cryoprecipitate into a subject comprising: a) preparing a
cryoprecipitate from pathogen-inactivated plasma; b) freezing the
cryoprecipitate; c) thawing the frozen cryoprecipitate; and d)
infusing the thawed cryoprecipitate into a subject, wherein the
infusion occurs at least 1 day after thawing the frozen
cryoprecipitate. In some embodiments, the thawed cryoprecipitate
comprises at least about 150 mg of fibrinogen per unit of
cryoprecipitate. In some embodiments, the thawed cryoprecipitate
comprises at least about 750 mg of fibrinogen. In some embodiments,
the method does not comprise determining the level of factor VIII
before infusing the thawed cryoprecipitate. In some embodiments,
the method further comprises determining the level of factor VIII
in the thawed cryoprecipitate before infusing the thawed
cryoprecipitate. In some embodiments, the cryoprecipitate is
prepared from at least about 550 mL and less than about 650 mL of
pathogen-inactivated plasma. In some embodiments, the
cryoprecipitate is prepared from about 600 mL of
pathogen-inactivated plasma. In some embodiments, the method
further comprises combining a first cryoprecipitate prepared from
at least about 550 mL and less than about 650 mL of
pathogen-inactivated plasma and a second cryoprecipitate prepared
from at least about 550 mL and less than about 650 mL of
pathogen-inactivated plasma, wherein the first and the second
cryoprecipitates are combined prior to steps b) and c). In some
embodiments, the method further comprises combining a first
cryoprecipitate prepared from about 600 mL of pathogen-inactivated
plasma and a second cryoprecipitate prepared from about 600 mL of
pathogen-inactivated plasma, wherein the first and the second
cryoprecipitates are combined prior to steps b) and c). In some
embodiments, the method further comprises combining a first
cryprecipitate prepared from 3 units of pathogen-inactivated plasma
and a second cryoprecipitate prepared from 3 units of
pathogen-inactivated plasma, wherein the first and the second
cryoprecipitates are combined prior to steps b) and c). In some
embodiments, the resulting cryoprecipitate of step c) comprises
less than 80 IU of factor VIII per unit of cryoprecipitate. In some
embodiments, the resulting cryoprecipitate of step c) comprises at
least about 80 IU of factor VIII. In some embodiments, the
resulting cryoprecipitate of step c) comprises less than 50 IU of
factor VIII per unit of cryoprecipitate. In some embodiments of any
of the above embodiments, the resulting cryoprecipitate of step c)
comprises at least 150 mg of fibrinogen per unit of
cryoprecipitate. In some embodiments of any of the above
embodiments, the resulting cryoprecipitate of step c) comprises at
least 750 mg of fibrinogen. In some embodiments of any of the above
embodiments, the cryoprecipitate of step a) further comprises
plasma of a volume between about 5 mL and about 20 mL per unit of
cryoprecipitate. In some embodiments, the cryoprecipitate of step
a) further comprises plasma of a volume greater than about 1 mL and
less than or equal to about 75 mL. In some embodiments, the
cryoprecipitate of step a) further comprises plasma of a volume
between about 50 mL and about 60 mL. In some embodiments, the
cryoprecipitate of step a) further comprises plasma of a volume
between about 30 mL and about 120 mL. In some embodiments of any of
the above embodiments, the plasma has been pathogen-inactivated by
photochemical inactivation. In some embodiments, the
cryoprecipitate has been pathogen-inactivated by photochemical
inactivation with a psoralen. In some embodiments, the psoralen is
amotosalen. In some embodiments of any of the above embodiments,
the cryoprecipitate is prepared from plasma that has been
pathogen-inactivated in a first container suitable for
photochemical inactivation of the plasma under sterile conditions;
wherein the first container is coupled to a compound absorption
device (CAD) such that the pathogen-inactivated plasma can be
transferred from the first container to the CAD under sterile
conditions; and wherein the cryoprecipitate is frozen and thawed in
steps b) and c) within one or more second containers, each of which
is coupled to the CAD such that the pathogen-inactivated plasma can
be transferred from the CAD to the one or more second containers
under sterile conditions, and each of which is suitable for
freezing the pathogen-inactivated plasma followed by thawing of the
pathogen-inactivated plasma under conditions that provide for the
formation of the cryoprecipitate. In some embodiments, each of the
one or more second containers is suitable for freezing the
pathogen-inactivated plasma, followed by thawing of the
pathogen-inactivated plasma under conditions that provide for the
formation of the cryoprecipitate and a cryosupernatant, followed by
removal of all or a portion of the cryosupernatant from the one or
more second containers. In some embodiments, the cryoprecipitate is
prepared from plasma that has been pathogen-inactivated in a first
container suitable for photochemical inactivation of the plasma
under sterile conditions; wherein the first container is coupled to
a compound absorption device (CAD) such that the
pathogen-inactivated plasma can be transferred from the first
container to the CAD under sterile conditions; and wherein the
cryoprecipitate is frozen and thawed in steps b) and c) within a
third container configured to be coupled to one or more second
containers, such that the pathogen-inactivated plasma can be
transferred from the CAD to the one or more second containers to
the third container under sterile conditions, wherein the third
container is suitable for freezing the pathogen-inactivated plasma
followed by thawing of the pathogen-inactivated plasma under
conditions that provide for the formation of the cryoprecipitate.
In some embodiments, the third container is suitable for freezing
the pathogen-inactivated plasma, followed by thawing of the
pathogen-inactivated plasma under conditions that provide for the
formation of the cryoprecipitate and a cryosupernatant, followed by
removal of all or a portion of the cryosupernatant from the third
container. In some embodiments of any of the above embodiments, the
subject is a human.
[0019] In still another aspect, the present disclosure provides a
kit comprising: a) a container; b) a pathogen-inactivated
cryoprecipitate; and c) instructions for using the
pathogen-inactivated cryoprecipitate in an infusion into a subject,
wherein the instructions indicate that the cryoprecipitate is
suitable for infusion into the subject for up to about 5 days after
thawing.
[0020] In still another aspect, the present disclosure provides a
kit comprising: a) a container; b) a pathogen-inactivated
cryoprecipitate; and c) a label indicating that the
pathogen-inactivated cryoprecipitate is suitable for use for up to
about 5 days after thawing.
[0021] In still another aspect, the present disclosure provides a
method of infusing a cryoprecipitate into a subject, comprising
infusing into the subject the composition of any of the above
embodiments.
[0022] In still another aspect, the present disclosure provides a
method of infusing a cryoprecipitate into a subject, comprising
infusing into the subject a cryoprecipitate produced by any of the
above embodiments.
[0023] In still another aspect, the present disclosure provides a
cryoprecipitate produced by any of the above embodiments.
[0024] In still another aspect, the present disclosure provides a
method of preparing a pooled cryosupernatant for infusion into a
subject comprising: a) freezing at least a first
pathogen-inactivated plasma and a second pathogen-inactivated
plasma, wherein the first and the second pathogen-inactivated
plasmas each have a volume of at least about 550 mL and less than
about 650 mL; b) thawing the first pathogen-inactivated plasma
under conditions that provide for the formation of a first
precipitate and a first supernatant, and thawing the second
pathogen-inactivated plasma under conditions that provide for the
formation of a second precipitate and a second supernatant; c)
separating the first and the second supernatants from the first and
the second precipitates to form a first cryosupernatant and a
second cryosupernatant; and d) combining the first and the second
cryosupernatants to form a pooled cryosupernatant. In some
embodiments, the first and the second pathogen-inactivated plasmas
each have a volume of about 600 mL. In some embodiments, step a)
further comprises freezing at least a third pathogen-inactivated
plasma and a fourth pathogen-inactivated plasma, wherein the third
and the fourth pathogen-inactivated plasmas each have a volume of
at least about 550 mL and less than 650 mL; step b) further
comprises thawing the third pathogen-inactivated plasma under
conditions that provide for the formation of a third precipitate
and a third supernatant, and thawing the fourth
pathogen-inactivated plasma under conditions that provide for the
formation of a fourth precipitate and a fourth supernatant; step c)
further comprises separating the third and the fourth supernatants
from the third and the fourth precipitates to form a third
cryosupernatant and a fourth cryosupernatant; the pooled
cryosupernatant formed in step d) is a first pooled supernatant,
and step d) further comprises combining the third and the fourth
cryosupernatants to form a second pooled cryosupernatant; and the
method further comprises e) combining the first pooled
cryosupernatant and the second pooled cryosupernatant. In some
embodiments, the third and the fourth pathogen-inactivated plasmas
each have a volume of about 600 mL. In some embodiments, the first
and/or the second pathogen-inactivated plasma have been
pathogen-inactivated by photochemical inactivation. In some
embodiments, the one or more of the first, second, third, and
fourth pathogen-inactivated plasmas have been pathogen-inactivated
with a psoralen. In some embodiments, the psoralen is amotosalen.
In some embodiments, one or more of the first, second, third, and
fourth pathogen-inactivated plasmas have been pathogen-inactivated
in a first container suitable for photochemical inactivation of
plasma under sterile conditions, wherein the first container is
coupled to a compound absorption device (CAD) such that the
pathogen-inactivated plasma can be transferred from the first
container to the CAD under sterile conditions. In some embodiments,
one or more of the first, second, third, and fourth
pathogen-inactivated plasmas is frozen in step a) and thawed in
step b) within one or more second containers, each of which is
coupled to the CAD such that the pathogen-inactivated plasma can be
transferred from the CAD to the one or more second containers under
sterile conditions, and each of which is suitable for freezing the
pathogen-inactivated plasma followed by thawing of the
pathogen-inactivated plasma under conditions that provide for the
formation of the cryoprecipitate. In some embodiments, one or more
of the first, second, third, and fourth pathogen-inactivated
plasmas is frozen in step a) and thawed in step b) within a third
container configured to be coupled to the one or more second
containers, such that the pathogen-inactivated plasma can be
transferred from the CAD to the one or more second containers to
the third container under sterile conditions, wherein the third
container is suitable for freezing the pathogen-inactivated plasma
followed by thawing of the pathogen-inactivated plasma under
conditions that provide for the formation of the cryoprecipitate.
In some embodiments, one or more of the first, second, third, and
fourth supernatants is separated from one or more of the first,
second, third, and fourth precipitates in step c) within one or
more fourth containers, each of which is configured to be coupled
to the one or more second containers or to the third container such
that the supernatant can be transferred from the one or more second
containers or the third container to the one or more fourth
containers under sterile conditions to afford a
pathogen-inactivated cryosupernatant contained within the one or
more fourth containers and a pathogen-inactivated cryoprecipitate
contained within the one or more second containers or the third
container.
[0025] In still another aspect, the present disclosure provides a
method of infusing a cryosupernatant into a subject, comprising
infusing into the subject a cryosupernatant produced by the method
of any of the above embodiments.
[0026] In still another aspect, the present disclosure provides a
processing set for preparing a pathogen-inactivated
cryoprecipitate, comprising a) a first container within which one
or more units of a plasma can be photochemically inactivated in the
presence of a psoralen under sterile conditions; b) a compound
absorption device (CAD) coupled to the first container such that
the one or more units of plasma can be transferred from the first
container to the compound absorption device under sterile
conditions; and c) one or more second containers, each of which is
coupled to the compound absorption device such that the one or more
units of plasma can be transferred from the compound absorption
device to the one or more second containers under sterile
conditions to provide pathogen-inactivated plasma suitable for
infusion into a subject, wherein the one or more second containers
is suitable for freezing the pathogen-inactivated plasma followed
by thawing of the pathogen-inactivated plasma under conditions that
provide for the formation of a precipitate and a supernatant. In
some embodiments, each of the one or more second containers is
suitable for freezing the pathogen-inactivated plasma, followed by
thawing of the pathogen-inactivated plasma under conditions that
provide for the formation of the cryoprecipitate and a
cryosupernatant, followed by removal of all or a portion of the
cryosupernatant from the one or more second containers.
[0027] In still another aspect, the present disclosure provides a
processing set for preparing a pathogen-inactivated
cryoprecipitate, comprising a) a first container within which one
or more units of a plasma can be photochemically inactivated in the
presence of a psoralen under sterile conditions; b) a compound
absorption device (CAD) coupled to the first container such that
the one or more units of plasma can be transferred from the first
container to the compound absorption device under sterile
conditions; c) one or more second containers, each of which is
coupled to the compound absorption device such that the one or more
units of plasma can be transferred from the compound absorption
device to the one or more second containers under sterile
conditions to provide pathogen-inactivated plasma suitable for
infusion into a subject; and d) a third container, which is
configured to be coupled to the one or more second containers such
that the pathogen-inactivated plasma can be transferred from the
one or more second containers to the third container under sterile
conditions, wherein the third container is suitable for freezing
the pathogen-inactivated plasma followed by thawing of the
pathogen-inactivated plasma under conditions that provide for the
formation of a precipitate and a supernatant. In some embodiments,
the third container is suitable for freezing the
pathogen-inactivated plasma, followed by thawing of the
pathogen-inactivated plasma under conditions that provide for the
formation of the cryoprecipitate and a cryosupernatant, followed by
removal of all or a portion of the cryosupernatant from the third
container. In some embodiments, the processing set further
comprises an additional container suitable for mixing the one or
more units of plasma with a pathogen inactivation compound, wherein
the additional container is coupled to the first container such
that the one or more units of plasma in admixture with the
pathogen-inactivating compound can be transferred from the
additional container to the first container under sterile
conditions. In some embodiments, the processing set further
comprises one or more fourth containers, each of which is
configured to be coupled to the one or more second containers or to
the third container such that the supernatant can be transferred
from the one or more second containers or the third container to
the one or more fourth containers under sterile conditions to
provide a pathogen-inactivated cryosupernatant contained within the
one or more fourth containers and a pathogen-inactivated
cryoprecipitate contained within the one or more second containers
or the third container. In some embodiments, the third container is
coupled to the one or more second containers such that the
supernatant can be transferred from the one or more second
containers to the third container under sterile conditions to
afford a pathogen-inactivated cryosupernatant contained within the
third container and a pathogen-inactivated cryoprecipitate
contained within the one or more second containers. In some
embodiments, the third container is configured to be coupled to the
one or more second containers such that the pathogen-inactivated
plasma can be transferred from the one or more second containers to
the third container under sterile conditions; wherein the third
container is suitable for freezing the pathogen-inactivated plasma
followed by thawing of the pathogen-inactivated plasma under
conditions that provide for the formation of a precipitate and a
supernatant; and wherein each of the one or more fourth containers
is configured to be coupled to the third container such that the
supernatant can be transferred from the third container to the one
or more fourth containers under sterile conditions to afford a
pathogen-inactivated cryosupernatant contained within the one or
more fourth containers and a pathogen-inactivated cryoprecipitate
contained within the third container.
[0028] In still another aspect, the present disclosure provides a
method of preparing a cryoprecipitate for infusion into a subject
comprising: a) preparing a cryoprecipitate from
pathogen-inactivated plasma; and b) freezing the cryoprecipitate;
wherein the cryoprecipitate is suitable for infusion into the
subject for up to about 5 days after thawing. In some embodiments,
the cryoprecipitate is prepared from at least about 550 mL and less
than about 650 mL of pathogen-inactivated plasma. In some
embodiments, the cryoprecipitate is prepared from about 600 mL of
pathogen-inactivated plasma. In some embodiments, the method
further comprises combining a first cryoprecipitate prepared from
at least about 550 mL and less than about 650 mL of
pathogen-inactivated plasma and a second cryoprecipitate prepared
from at least about 550 mL and less than about 650 mL of
pathogen-inactivated plasma, wherein the first and the second
cryoprecipitates are combined prior to step b). In some
embodiments, the first cryoprecipitate is prepared from about 600
mL of pathogen-inactivated plasma, and wherein the second
cryoprecipitate is prepared from about 600 mL of
pathogen-inactivated plasma. In some embodiments, the method
further comprises combining a first cryprecipitate prepared from 3
units of pathogen-inactivated plasma and a second cryoprecipitate
prepared from 3 units of pathogen-inactivated plasma, wherein the
first and the second cryoprecipitates are combined prior to step
b).
[0029] In still another aspect, the present disclosure provides a
method of treating a disease or condition indicated for treatment
by plasma exchange in a subject in need thereof, comprising
administering to the subject a therapeutically effective amount of
pathogen-inactivated plasma composition by plasma exchange. In some
embodiments, the disease or condition is indicated for treatment
with albumin by plasma exchange. In some embodiments, the disease
or condition is a disease or condition set forth in the present
disclosure. In some embodiments, the disease or condition is
Guillain-Barre syndrome, chronic inflammatory demyelinating
polyneuropathy, myasthenia gravis, a paraproteinemic
polyneuropathy, Goodpasture's syndrome, or cryoglobulinemia. In
some embodiments, the disease or condition is other than
thrombocytopenic purpura (TTP) or hemolytic-uremic syndrome (HUS).
In some embodiments, the disease or condition is burn shock
resuscitation. In some embodiments, the pathogen-inactivated plasma
composition comprises pathogen-inactivated plasma that has not been
previously frozen. In some embodiments, the pathogen-inactivated
plasma composition comprises pathogen-inactivated frozen plasma. In
some embodiments, the pathogen-inactivated plasma composition
comprises pathogen-inactivated fresh frozen plasma. In some
embodiments, the pathogen-inactivated plasma composition comprises
pathogen-inactivated cryo-poor plasma. In some embodiments, the
disease or condition is thrombocytopenic purpura (TTP) or
hemolytic-uremic syndrome (HUS). In some embodiments, the plasma
exchange is achieved with a volume of the plasma composition
similar to the subject's plasma volume. In some embodiments, the
plasma exchange is achieved with a volume of the plasma composition
between about 1 times and about 1.5 times the subject's plasma
volume. In some embodiments, the plasma exchange is achieved with a
volume of the plasma composition comprising about 40 mL/kg patient
body weight. In some embodiments, the plasma exchange is achieved
with a volume of the plasma composition comprising about 60 mL/kg
patient body weight. In some embodiments, the plasma exchange is
performed at least two times. In some embodiments, the plasma
exchange is performed 2-5 times. In some embodiments, the plasma
exchange is performed 2-5 times within a period of two weeks. In
some embodiments, the plasma exchange is performed 2-5 times within
a period of one week.
[0030] In still another aspect, the present disclosure provides a
method of treating a disease or condition indicated for treatment
by infusion with intravenous immunoglobulin in a subject in need
thereof, comprising administering to the subject a therapeutically
effective amount of pathogen-inactivated plasma composition by
plasma exchange. In some embodiments, the disease or condition is a
disease or condition set forth in the present disclosure. In some
embodiments, the disease or condition is Guillain-Barre syndrome,
myasthenia gravis, polymyositis, dermatomyositis, or chronic
inflammatory demyelinating polyneuropathy. In some embodiments, the
disease or condition is other than thrombocytopenic purpura (TTP)
or hemolytic-uremic syndrome (HUS). In some embodiments, the
pathogen-inactivated plasma composition comprises
pathogen-inactivated plasma that has not been previously frozen. In
some embodiments, the pathogen-inactivated plasma composition
comprises pathogen-inactivated frozen plasma. In some embodiments,
the pathogen-inactivated plasma composition comprises
pathogen-inactivated fresh frozen plasma. In some embodiments, the
pathogen-inactivated plasma composition comprises
pathogen-inactivated cryo-poor plasma. In some embodiments, the
plasma exchange is achieved with a volume of the plasma composition
similar to the subject's plasma volume. In some embodiments, the
plasma exchange is achieved with a volume of the plasma composition
between about 1 times and about 1.5 times the subject's plasma
volume. In some embodiments, the plasma exchange is achieved with a
volume of the plasma composition comprising about 40 mL/kg patient
body weight. In some embodiments, the plasma exchange is achieved
with a volume of the plasma composition comprising about 60 mL/kg
patient body weight. In some embodiments, the plasma exchange is
performed at least two times. In some embodiments, the plasma
exchange is performed 2-5 times. In some embodiments, the plasma
exchange is performed 2-5 times within a period of two weeks. In
some embodiments, the plasma exchange is performed 2-5 times within
a period of one week. In some embodiments, the disease or condition
is thrombocytopenic purpura (TTP) or hemolytic-uremic syndrome
(HUS).
[0031] In still another aspect, the present disclosure provides a
method of treating a disease or condition set forth in the present
disclosure. In some embodiments, the present disclosure provides a
method of treating a disease or condition selected from the group
consisting of Guillain-Barre syndrome, myasthenia gravis,
polymyositis, dermatomyositis and chronic inflammatory
demyelinating polyneuropathy in a subject, comprising administering
to a subject in need thereof a therapeutically effective amount of
pathogen-inactivated plasma composition by plasma exchange. In some
embodiments, the pathogen-inactivated plasma composition comprises
pathogen-inactivated plasma that has not been previously frozen. In
some embodiments, the pathogen-inactivated plasma composition
comprises pathogen-inactivated frozen plasma. In some embodiments,
the pathogen-inactivated plasma composition comprises
pathogen-inactivated fresh frozen plasma. In some embodiments, the
pathogen-inactivated plasma composition comprises
pathogen-inactivated cryo-poor plasma. In some embodiments, the
plasma exchange is achieved with a volume of the plasma composition
similar to the subject's plasma volume. In some embodiments, the
plasma exchange is achieved with a volume of the plasma composition
between about 1 times and about 1.5 times the subject's plasma
volume. In some embodiments, the plasma exchange is achieved with a
volume of the plasma composition comprising about 40 mL/kg patient
body weight. In some embodiments, the plasma exchange is achieved
with a volume of the plasma composition comprising about 60 mL/kg
patient body weight. In some embodiments, the plasma exchange is
performed at least two times. In some embodiments, the plasma
exchange is performed 2-5 times. In some embodiments, the plasma
exchange is performed 2-5 times within a period of two weeks. In
some embodiments, the plasma exchange is performed 2-5 times within
a period of one week.
[0032] In still another aspect, the present disclosure provides a
method of treating thrombocytopenic purpura (TTP) or
hemolytic-uremic syndrome (HUS) in a subject, comprising
administering to a subject in need thereof a therapeutically
effective amount of a pathogen-inactivated plasma composition. In
some embodiments, the composition is administered by plasma
exchange. In some embodiments, the pathogen-inactivated plasma
composition comprises pathogen-inactivated cryo-poor plasma. In
still another aspect, the present disclosure provides a method of
treating thrombocytopenic purpura (TTP) or hemolytic-uremic
syndrome (HUS) in a subject, comprising administering to a subject
in need thereof a therapeutically effective amount of a
pathogen-inactivated plasma composition by plasma exchange, wherein
the pathogen-inactivated plasma composition comprises
pathogen-inactivated cryo-poor plasma. In some embodiments, the
pathogen-inactivated plasma composition is administered within 1
day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after
thawing. In some embodiments, the plasma exchange is achieved with
a volume of the plasma composition similar to the subject's plasma
volume. In some embodiments, the plasma exchange is achieved with a
volume of the plasma composition between about 1 times and about
1.5 times the subject's plasma volume. In some embodiments, the
plasma exchange is achieved with a volume of the plasma composition
comprising about 40 mL/kg patient body weight. In some embodiments,
the plasma exchange is achieved with a volume of the plasma
composition comprising about 60 mL/kg patient body weight. In some
embodiments, the plasma exchange is performed at least two times.
In some embodiments, the plasma exchange is performed 2-5 times. In
some embodiments, the plasma exchange is performed 2-5 times within
a period of two weeks. In some embodiments, the plasma exchange is
performed 2-5 times within a period of one week.
[0033] In still another aspect, the present disclosure provides a
method of treating a solid organ transplant recipient to prevent an
immune-mediated solid organ transplant rejection, comprising
administering to the transplant recipient a therapeutically
effective amount of a pathogen-inactivated plasma composition by
plasma exchange, wherein the plasma exchange is prior to the
transplant procedure. In some embodiments, the immune-mediated
transplant rejection is an antibody-mediated transplant rejection.
In some embodiments, the antibody-mediated transplant rejection is
an IgG-mediated transplant rejection. In some embodiments, the
solid organ transplant is an ABO-incompatible solid organ
transplant. In some embodiments, the solid organ transplant is an
HLA-incompatible solid organ transplant. In some embodiments, the
solid organ transplant is a renal (e.g., kidney) transplant. In
some embodiments, the kidney is obtained from a living donor. In
some embodiments, the solid organ transplant is a cardiac (e.g.,
heart) transplant. In some embodiments, the solid organ transplant
is a liver transplant. In some embodiments, the method of treating
a solid organ transplant recipient is a method of desensitization
to the transplant. In some embodiments, the pathogen-inactivated
plasma composition comprises pathogen-inactivated plasma that has
not been previously frozen. In some embodiments, the
pathogen-inactivated plasma composition comprises
pathogen-inactivated frozen plasma. In some embodiments, the
pathogen-inactivated plasma composition comprises
pathogen-inactivated fresh frozen plasma. In some embodiments, the
pathogen-inactivated plasma composition comprises
pathogen-inactivated cryo-poor plasma. In some embodiments, the
pathogen-inactivated plasma composition is administered within 1
day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after
thawing. In some embodiments, the plasma exchange is achieved with
a volume of the plasma composition similar to the subject's plasma
volume. In some embodiments, the plasma exchange is achieved with a
volume of the plasma composition between about 1 times and about
1.5 times the subject's plasma volume. In some embodiments, the
plasma exchange is achieved with a volume of the plasma composition
comprising about 40 mL/kg patient body weight. In some embodiments,
the plasma exchange is achieved with a volume of the plasma
composition comprising about 60 mL/kg patient body weight. In some
embodiments, the plasma exchange is performed at least two times
prior to the transplant procedure. In some embodiments, the plasma
exchange is performed 2-15 times prior to the transplant procedure.
In some embodiments, the method further comprises administering to
the transplant recipient a therapeutically effective amount of
pathogen-inactivated plasma composition by plasma exchange after
the transplant procedure. In some embodiments, the plasma exchange
is performed at least two times after the transplant procedure. In
some embodiments, the plasma exchange is performed 2-5 times after
the transplant procedure.
[0034] In some embodiments of any of the above embodiments, the
pathogen-inactivated plasma composition is administered within 1
day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after
thawing. In some embodiments of any of the above embodiments, the
pathogen-inactivated plasma composition is a lyophilized or
freeze-dried plasma composition. In some embodiments, the
pathogen-inactivated plasma composition is administered within 1
day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after
reconstitution.
[0035] In still another aspect, the present disclosure provides a
method of fluid resuscitation in a subject suffering from burns,
comprising administering to a subject in need thereof a
therapeutically effective amount of a pathogen-inactivated plasma
composition. In some embodiments, the subject is suffering from
major burns comprising at least 20% of total body surface area. In
some embodiments, the method of fluid resuscitation is a method of
burn shock resuscitation. In some embodiments, endothelial
permeability, endothelial dysfunction and/or vascular
hyperpermeability is reduced by administration of the
pathogen-inactivated plasma composition. In some embodiments,
administration of the pathogen-inactivated plasma composition
results in decreased subject mortality. In some embodiments, the
pathogen-inactivated plasma composition comprises
pathogen-inactivated frozen plasma. In some embodiments, the
pathogen-inactivated plasma composition comprises
pathogen-inactivated fresh frozen plasma. In some embodiments, the
pathogen-inactivated plasma composition comprises
pathogen-inactivated cryo-poor plasma. In some embodiments, the
pathogen-inactivated plasma composition is administered within 1
day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after
thawing. In some embodiments, the pathogen-inactivated plasma
composition is a lyophilized or freeze-dried plasma composition. In
some embodiments, the pathogen-inactivated plasma composition is
administered within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days,
or 7 days after reconstitution. In some embodiments, about 1 mL to
about 5 mL per kg body weight per % total burn surface area (TBSA)
of the pathogen-inactivated plasma composition is administered to
the subject. In some embodiments, a volume of the
pathogen-inactivated plasma composition sufficient to achieve an
increase in blood pressure to at least about 50 mmHg is
administered to the subject. In some embodiments, a volume of the
pathogen-inactivated plasma composition sufficient to achieve an
increase in blood pressure to at least about 100 mmHg is
administered to the subject. In some embodiments, the
pathogen-inactivated plasma composition is administered to the
subject within about 24 hours, within about 20 hours, within about
16 hours, within about 12 hours, within about 10 hours, within
about 8 hours, within about 6 hours, within about 5 hours, within
about 4 hours, within about 3 hours, within about 2 hours or within
about 1 hours after the onset of burns or medical diagnosis
thereof. In some embodiments, pathogen-inactivated plasma
composition is administered to the subject over a time period of
about 24 hours. In some embodiments, pathogen-inactivated plasma
composition is administered to the subject in multiple infusions
over a time period of about 24 hours.
[0036] In still another aspect, the present disclosure provides a
method of treating a subject suffering from burns or a trauma, the
method comprising: administering to a subject in need thereof a
therapeutically effective amount of a pathogen-inactivated plasma
composition. In some embodiments, the subject is suffering from
burns. In some embodiments, the subject is suffering from blunt
trauma. In some embodiments, the subject is suffering from
penetrating trauma. In some embodiments, the subject is suffering
from hemorrhage. In some embodiments, the subject is suffering from
internal hemorrhage. In some embodiments, the method is a method of
fluid resuscitation. In some embodiments, the method reduces
hemorrhage in the subject. In some embodiments, the method reduces
hemorrhagic shock in the subject. In some embodiments, endothelial
permeability is reduced in the subject. In some embodiments, the
method reduces or prevents trauma-induced endotheliopathy in the
subject. In some embodiments, the infusion or treatment results in
decreased subject mortality.
[0037] In still another aspect, the present disclosure provides a
method of resuscitation from hemorrhagic shock in a subject
suffering from burns or a trauma, comprising administering to the
subject a therapeutically effective amount of a
pathogen-inactivated plasma composition. In some embodiments, the
subject is suffering from burns. In some embodiments, the subject
is suffering from blunt trauma. In some embodiments, the subject is
suffering from penetrating trauma. In some embodiments, the subject
is suffering from internal hemorrhage. In some embodiments, the
method reduces hemorrhage in the subject. In some embodiments,
endothelial permeability is reduced in the subject. In some
embodiments, the method reduces or prevents trauma-induced
endotheliopathy in the subject. In some embodiments, the method
reduces or prevents traumatic coagulopathy in the subject. In some
embodiments, the treatment results in decreased subject
mortality.
[0038] In some embodiments of any of the above embodiments, the
pathogen-inactivated plasma composition comprises
pathogen-inactivated frozen plasma. In some embodiments, the
pathogen-inactivated plasma composition comprises
pathogen-inactivated fresh frozen plasma. In some embodiments of
any of the above embodiments, the pathogen-inactivated plasma
composition comprises pathogen-inactivated cryo-poor plasma. In
some embodiments of any of the above embodiments, the
pathogen-inactivated plasma composition is administered within 1
day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after
thawing. In some embodiments of any of the above embodiments, the
pathogen-inactivated plasma composition is a lyophilized or
freeze-dried plasma composition. In some embodiments, the
pathogen-inactivated plasma composition is administered within 1
day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after
reconstitution. In some embodiments of any of the above
embodiments, the pathogen-inactivated plasma composition is first
administered less than 24 hours after the onset of trauma. In some
embodiments of any of the above embodiments, administration of the
pathogen-inactivated plasma composition is followed by
administration of at least one additional intravenous fluid.
[0039] In still another aspect, the present disclosure provides a
method for preparing pathogen-inactivated cryo-poor plasma, the
method comprising:
a) photochemically inactivating one or more units of plasma in the
presence of a psoralen, wherein the photochemical inactivation is
performed under sterile conditions in a first container containing
the one or more units of plasma; b) transferring under sterile
conditions the one or more units of plasma from the first container
to a compound absorption device (CAD) coupled to the first
container; c) transferring under sterile conditions the one or more
units of plasma from the CAD to two or more second containers
coupled to the CAD to provide pathogen-inactivated plasma; d)
transferring under sterile conditions the pathogen-inactivated
plasma from the two or more second containers to a third container
coupled to the two or more second containers; e) freezing the
pathogen-inactivated plasma followed by thawing of the
pathogen-inactivated plasma under conditions that provide for the
formation of a cryoprecipitate and pathogen-inactivated cryo-poor
plasma; f) transferring the pathogen-inactivated cryo-poor plasma
to a at least a first of the two or more second containers; and g)
transferring the cryoprecipitate to a second of the two or more
second containers. In some embodiments, at least a portion of the
pathogen-inactivated cryo-poor plasma is transferred to each of at
least two second containers in step f), and wherein the
cryoprecipitate is transferred to a third second container in step
g). In some embodiments, prior to step g), the cryoprecipitate is
resuspended in about 80 mL to about 120 mL of pathogen-inactivated
cryo-poor plasma. In some embodiments, prior to step g), the
cryoprecipitate is resuspended in about 100 mL of
pathogen-inactivated cryo-poor plasma.
[0040] In still another aspect, the present disclosure provides a
method for infusing pathogen-inactivated cryo-poor plasma into a
subject, comprising infusing into a subject in need thereof a
therapeutically effective amount of a pathogen-inactivated
cryo-poor plasma prepared by the method of any one of the above
embodiments. In some embodiments, the subject is suffering from one
or more of burns, blunt trauma, penetrating trauma, and hemorrhage.
In some embodiments, the infusion results in fluid resuscitation of
the subject. In some embodiments, infusing the pathogen-inactivated
cryo-poor plasma into a subject is by therapeutic plasma exchange.
In some embodiments, the subject in need thereof is a subject
suffering from thrombocytopenic purpura (TTP) or hemolytic-uremic
syndrome (HUS). In some embodiments, the method further comprises,
prior to the infusion: 1) freezing the pathogen-inactivated
cryo-poor plasma; and 2) thawing the pathogen-inactivated cryo-poor
plasma. In some embodiments, the pathogen-inactivated cryo-poor
plasma is infused into the subject within 1 day, 2 days, 3 days, 4
days, 5 days, 6 days, or 7 days after thawing.
[0041] In still another aspect, the present disclosure provides a
pathogen-inactivated plasma composition according to any of the
above embodiments for use in treating a disease or condition
indicated for treatment by plasma exchange in a subject in need
thereof. In still another aspect, the present disclosure provides a
use of a pathogen-inactivated plasma composition according to any
of the above embodiments in the manufacture of a medicament for
treating a disease or condition indicated for treatment by plasma
exchange in a subject in need thereof
[0042] In still another aspect, the present disclosure provides a
pathogen-inactivated plasma composition according to any of the
above embodiments for use in treating a disease or condition
indicated for treatment by infusion with intravenous immunoglobulin
in a subject in need thereof. In still another aspect, the present
disclosure provides a use of a pathogen-inactivated plasma
composition according to any of the above embodiments in the
manufacture of a medicament for treating a disease or condition
indicated for treatment by infusion with intravenous immunoglobulin
in a subject in need thereof.
[0043] In still another aspect, the present disclosure provides a
pathogen-inactivated plasma composition according to any of the
above embodiments for use in treating a disease or condition
selected from the group consisting of Guillain-Barre syndrome,
myasthenia gravis, polymyositis, dermatomyositis and chronic
inflammatory demyelinating polyneuropathy in a subject. In still
another aspect, the present disclosure provides a use of a
pathogen-inactivated plasma composition according to any of the
above embodiments in the manufacture of a medicament for treating a
disease or condition selected from the group consisting of
Guillain-Barre syndrome, myasthenia gravis, polymyositis,
dermatomyositis and chronic inflammatory demyelinating
polyneuropathy in a subject.
[0044] In still another aspect, the present disclosure provides a
pathogen-inactivated plasma composition comprising
pathogen-inactivated cryo-poor plasma according to any of the above
embodiments for use in treating thrombocytopenic purpura (TTP) or
hemolytic-uremic syndrome (HUS) in a subject. In still another
aspect, the present disclosure provides a use of a
pathogen-inactivated plasma composition comprising
pathogen-inactivated cryo-poor plasma according to any of the above
embodiments in the manufacture of a medicament for treating
thrombocytopenic purpura (TTP) or hemolytic-uremic syndrome (HUS)
in a subject.
[0045] In still another aspect, the present disclosure provides a
pathogen-inactivated plasma composition according to any of the
above embodiments for use in treating a solid organ transplant
recipient to prevent an immune-mediated solid organ transplant
rejection. In still another aspect, the present disclosure provides
a use of a pathogen-inactivated plasma composition according to any
of the above embodiments in the manufacture of a medicament for
treating a solid organ transplant recipient to prevent an
immune-mediated solid organ transplant rejection.
[0046] In still another aspect, the present disclosure provides a
pathogen-inactivated plasma composition according to any of the
above embodiments for use in treating a subject suffering from a
trauma. In still another aspect, the present disclosure provides a
use of a pathogen-inactivated plasma composition according to any
of the above embodiments in the manufacture of a medicament for
treating a subject suffering from a trauma. In some embodiments,
the subject is suffering from burns.
[0047] In still another aspect, the present disclosure provides a
pathogen-inactivated plasma composition according to any of the
above embodiments for use in resuscitation from hemorrhagic shock
in a subject suffering from a trauma. In still another aspect, the
present disclosure provides a use of a pathogen-inactivated plasma
composition according to any of the above embodiments in the
manufacture of a medicament for resuscitation from hemorrhagic
shock in a subject suffering from a trauma.
[0048] In still another aspect, the present disclosure provides a
pathogen-inactivated plasma composition according to any of the
above embodiments for use in fluid resuscitation in a subject
suffering from burns. In still another aspect, the present
disclosure provides a use of a pathogen-inactivated plasma
composition according to any of the above embodiments in the
manufacture of a medicament for fluid resuscitation in a subject
suffering from burns.
[0049] In still another aspect, the present disclosure provides a
pathogen-inactivated plasma composition according to any of the
above embodiments for use in burn shock resuscitation in a subject.
In still another aspect, the present disclosure provides a use of a
pathogen-inactivated plasma composition according to any of the
above embodiments in the manufacture of a medicament for burn shock
resuscitation in a subject.
[0050] It is to be understood that one, some, or all of the
properties of the various embodiments described herein may be
combined to form other embodiments. These and other aspects will
become apparent to one of skill in the art. These and other
embodiments are further described by the detailed description that
follows.
BRIEF DESCRIPTION OF THE DRAWINGS
[0051] FIG. 1A shows an exemplary processing kit in accordance with
some embodiments. Dotted components are optional.
[0052] FIG. 1B shows an exemplary processing kit in accordance with
some embodiments. Dotted components are optional.
[0053] FIG. 1C shows an exemplary processing kit in accordance with
some embodiments. Dotted components are optional.
[0054] FIG. 2A shows an exemplary processing kit in accordance with
some embodiments. Dotted components are optional.
[0055] FIG. 2B shows an exemplary processing kit in accordance with
some embodiments. Dotted components are optional.
[0056] FIG. 2C shows an exemplary processing kit in accordance with
some embodiments. Dotted components are optional.
[0057] FIG. 3A shows an exemplary processing kit in accordance with
some embodiments. Dotted components are optional.
[0058] FIG. 3B shows an exemplary processing kit in accordance with
some embodiments. Dotted components are optional.
[0059] FIG. 4 depicts combining two separate cryoprecipitate
preparations in accordance with some embodiments.
[0060] FIG. 5 shows an exemplary processing kit in accordance with
some embodiments. Dotted components are optional.
[0061] FIG. 6 shows an exemplary processing kit in accordance with
some embodiments. Dotted components are optional.
DETAILED DESCRIPTION
[0062] The term "cryoprecipitate" refers to a blood product
produced by controlled thawing of frozen plasma (e.g., whole
blood-derived fresh frozen plasma, apheresis derived plasma) to
form a precipitate comprising one or more coagulation factors
including without limitation fibrinogen, Factor VIII, Factor XIII,
vWF, and/or fibronectin. Such cryoprecipitate may be recovered from
the liquid plasma portion, for example, by refrigerated
centrifugation. A cryoprecipitate may be resuspended in any
suitable volume of plasma after recovery. Methods for preparing a
cryoprecipitate are well known in the art and provided throughout
the present disclosure.
[0063] The term "plasma" refers to any plasma blood product known
in the art. In some embodiments, plasma refers to whole
blood-derived fresh frozen plasma. In some embodiments, plasma
refers to one or more plasma units from a whole blood donation
(e.g., approximately 180-250 mL volume each). In some embodiments,
plasma refers to one or more plasma units from an apheresis blood
donation (may be up to approximately 700-800 mL each). In some
embodiments, plasma refers to a single unit. In some embodiments,
plasma may be pooled from multiple units. In some embodiments,
plasma may contain one or more additional components, including,
without limitation, one or more pathogen-inactivation compounds
and/or byproducts of a pathogen-inactivation process.
[0064] The terms "cryo-poor plasma", "cryosupernatant" and
"cryo-reduced plasma" refer to the supernatant recovered after
subjecting thawed frozen plasma (e.g., fresh frozen plasma, FFP) to
a cryoprecipitation process, and separating the liquid supernatant
from the precipitated plasma components or factors
(cryoprecipitate). The cryo-poor plasma (CPP) supernatant generally
contains reduced levels of various plasma components or factors
(e.g., factor VIII, factor XIII, vWF, fibrinogen) that were
precipitated and removed during the preparation of
cryoprecipitate.
[0065] The term "suitable for infusion" refers to any blood product
(e.g., a cryoprecipitate) able to be used for an infusion (e.g., a
transfusion) into a subject (e.g., a human patient) according to
medical judgement. In some embodiments, suitability refers to
having sufficient biological activity for its intended use, i.e.,
for use where a transfusion of human coagulation factors is
indicated, including, without limitation, control of bleeding
associated with fibrinogen deficiency, treating Factor XIII
deficiency, treating Factor VIII deficiency, treating von
Willebrand disease, maintenance of hemostasis, treating
disseminated intravascular coagulation (DIC) or high volume
hemorrhage, and/or making fibrin sealant. In some embodiments,
suitability refers to having sufficient safety, e.g., that the
product has undergone a treatment that improves product safety
(e.g., pathogen inactivation) and/or demonstrates satisfactory
performance with respect to one or more safety-related measurements
(such as viral or bacterial titer). Photochemical inactivation of
pathogens in blood product units using amotosalen and UVA light as
described herein is well established to provide such a blood
product (e.g., cryoprecipitate) that is suitable for transfusion
into humans. In some embodiments, suitability refers to meeting one
or more standards (e.g., having a level of a biological activity or
a biological component, a safety criterion, and the like)
established by an accrediting agency or regulatory body that
governs infusion practices, such as the AABB.
[0066] "Pathogen-inactivated" as used herein describes a blood
product (e.g., a cryoprecipitate or plasma) that has undergone
processing (e.g., by the methods described herein) to inactivate
pathogens that may be present. It is understood that a
pathogen-inactivated cryoprecipitate may include a cryoprecipitate
that has itself undergone pathogen inactivation, or a
cryoprecipitate made from a pathogen-inactivated blood product
(e.g., plasma, whole blood, and the like). It is further understood
that the process does not necessarily inactivate completely all
pathogens that may be present, but substantially reduces the amount
of one or more pathogens to significantly reduce the risk of a
transfusion-associated disease. The inactivation of a pathogen may
be assayed by measuring the number of infective pathogens (e.g.,
virus or bacteria) in a certain volume, and the level of
inactivation is typically represented by the log reduction in the
infectivity of the pathogen, or log reduction in titer. Methods of
assaying log reduction in titer, and measurements thereof for
pathogen inactivation are known in the art. Methods of assaying log
reduction in titer, and measurements thereof for pathogen
inactivation are described, for example, in U.S. Pat. No.
7,655,392, the disclosure of which is hereby incorporated by
reference as it relates to assays for pathogen inactivation. As
such, for any given pathogen, known amounts can be added to a test
unit of cryoprecipitate or plasma to assess how much inactivation
results from the process, where typically the pathogen inactivation
process results in at least about 1 log reduction in titer, or
about 2 log, about 3 log, about 4 log, or at least about 5 log
reduction in titer. While the methods as described herein are
applicable to any pathogen-inactivation treatment, it is desirable
that the pathogen-inactivation treatment is capable of inactivating
a variety of pathogens to at least 1 log reduction in titer,
including a pathogen selected from the group consisting of HIV-1,
HBV, HCV, HTLV-1, HTLV-2, West Nile virus, Escherichia coli,
Klebsiella pneumoniae, Yersinia enterocolitica, Staphylococcus
epidermidis, Staphylococcus aureus, Treponema pallidum, Borrelia
burgdorferi, Plasmodium falciparum, Trypanosoma cruzi, and Babesia
microti.
[0067] The term "pathogen inactivation compound" means any suitable
compound, such as a small organic compound, that can be used to
inactivate a pathogen that may be present in a blood product such
as cryoprecipitate or plasma. A "photoactivated pathogen
inactivation compound" is a suitable compound that requires some
level of light (e.g., ultraviolet light) in order to sufficiently
inactivate a pathogen. Such compounds are preferred in the
inactivation of pathogens in blood products such as cryoprecipitate
or plasma as they provide control over the inactivation process.
Such photoactivated pathogen inactivation compounds described
herein include psoralens, isoalloxazines, alloxazines,
phthalocyanines, phenothiazines, and porphyrins, where these terms
are understood to encompass a general class of compounds, i.e. the
core compound and suitable derivatives thereof. For example,
psoralens or a psoralen generally describes the psoralen core
compound and any derivative thereof (e.g. amotosalen),
isoalloxazines or an isoalloxazine generally describes the
isoalloxazine core and any derivative thereof (e.g. riboflavin),
and so forth. Such derivatives comprise the core compound structure
as well as additional substituents on the core. Descriptions of
such compounds include any salts thereof.
[0068] The term "amotosalen" means the compound
3-(2-aminoethoxymethyl)-2,5,9-trimethylfuro[3,2-g]chromen-7-one and
any salts thereof. The compound may also be referred to as
3-[(2-aminoethoxy)methyl]-2,5,9-trimethyl-7H-furo[3,2-G][1]benzopyran-7-o-
ne-hydrochloride. The compound may also be referred to as
4'-(4-amino-2-oxa)butyl-4,5',8-trimethyl psoralen. Where the
inactivation of blood products such as cryoprecipitate or plasma
includes adding amotosalen HCl (the HCl salt of amotosalen) to a
unit of blood product, the removal of this compound from the unit
is not limited to the removal of amotosalen HCl, as the amotosalen
can be present in solution as other salts or as the free base. As
used in the methods described herein, removal of amotosalen means
removal of the compound in any form, e.g. as the free base or as
any salt, as measured by the assays described herein. Treatment or
processing of blood products by amotosalen inactivation refers to
combining a blood product (e.g., unit of cryoprecipitate or plasma,
individual unit, pooled) with amotosalen and illuminating with a
suitable dose of UVA light in order to inactivate pathogens that
may be present. In some embodiments, amotosalen-inactivated
cryoprecipitate has been pathogen inactivated, or the plasma from
which the cryoprecipitate has been produced has been pathogen
inactivated, according to commercial methods, or by similar
methods.
[0069] The term "under sterile conditions" as used herein refers to
maintaining the sterility of the system, for example by connection
of two bags from a blood processing set, or refers to a means by
which the process does not introduce contamination. For example, as
used in the methods described herein, a source unit of blood
product such as cryoprecipitate or plasma comprising a tubing for
connection to a processing set or container of pathogen
inactivation compound comprising a similar tubing may be joined
under sterile condition by methods known in the art, for example
using a sterile connecting device, which acts to melt or weld the
tubing together to provide a sterile flow path between the two
containers. Similarly, when methods described herein describe
sealing off such tubing, the sealing is done under sterile
conditions, for example using a tubing welder.
[0070] A "blood-collection bag" can be any bag used for collecting
blood from a donor as known in the art. Blood collected in a
blood-collection bag that is not attached to other bags may be
centrifuged to separate the blood into blood components. Then, the
blood-collection bag is sterile docked to a number of satellite
bags that corresponds to the number of blood products it has been
determined to manufacture from the whole blood. Blood in a
blood-collection bag may be processed, such as by centrifuging
and/or freezing, in the blood-collection bag before separation into
satellite bags, or the blood may be transferred (by gravity or by
pumping) from the blood-collection bag to a blood-processing
bag.
[0071] A "blood-processing bag" is any such bag known in the art,
other than the blood-collection bag, used for processing blood. The
blood-processing bag may be pre-connected to the blood-collection
bag or attached to the blood-collection bag through sterile
docking. Blood transferred to a blood-processing bag may be
centrifuged. Prior to centrifuging or immediately after
centrifuging, the blood-processing bag is sterile docked to a
number of satellite bags that corresponds to the number of blood
products it has been determined to manufacture from the whole
blood.
Blood Collection and Cryoprecipitate/Cryo-Poor Plasma
Preparation
[0072] Whole blood for use in the preparation of cryoprecipitate
and cryo-poor plasma as described herein may be collected by a
variety of procedures known in the art. One of the most common
blood collection techniques, is the "manual" collection of whole
blood from healthy donors. As commonly understood and as used
herein, manual collection refers to a collection method where whole
blood is allowed to drain from the donor and into a collection
container without the use of external pumps or similar devices.
This is in contrast to so-called automated procedures where blood
is withdrawn from a donor and further processed by an instrument
that typically includes a processing or separation device and pumps
for moving blood or blood components into and out of the device.
Automated cell separation systems may be used to collect plasma
from a donor by an apheresis procedure (e.g., plasmapheresis),
while returning other blood components to the donor. Apheresis
collected plasma also may be used for the preparation of
cryoprecipitate and cryo poor plasma using the methods and kits
provided herein.
[0073] In some embodiments, plasma of the present disclosure
includes plasma frozen within 8 hours of donation or subjected to a
pathogen inactivation process within 8 hours of donation and then
frozen (e.g., fresh frozen plasma, FFP), or plasma frozen within 24
hours of donation or subjected to a pathogen inactivation process
within 24 hours of donation and then frozen (e.g., PF24). In some
embodiments, plasma of the present disclosure includes liquid
plasma (e.g., never frozen plasma) subjected to a pathogen
inactivation process and not frozen for storage and then thawed
prior to the initiation of the cryoprecipitation freeze/thaw
process. In some embodiments, plasma refers to one or more plasma
units from a whole blood donation (e.g., approximately 180-250 mL
volume each). In some embodiments, plasma refers to one or more
plasma units from an apheresis blood donation (e.g., apheresis
collected plasma) (may be up to approximately 700-800 mL each).
[0074] Regardless of whether the blood collection technique is
manual or automated, withdrawing blood from the donor typically
includes inserting a vein access device, such as a needle, into the
donor's arm (and, more specifically, the donor's vein) and
withdrawing blood from the donor through the needle. The
"venipuncture" needle typically has attached to it, one end of a
plastic tube that provides a flow path for the blood. The other end
of the plastic tube terminates in one or more pre-attached plastic
blood containers or bags for collecting the blood. The needle,
tubing and containers make up a blood collection set which is
pre-sterilized and disposed of after a single use. The sterile
blood collection container typically serves as the primary
container for initial separation of blood components (e.g.,
separation of plasma from red blood cells and platelets).
[0075] The blood collection container and plastic tubing may also
include a volume of a liquid anticoagulant, while in the automated
technique, a separate container of anticoagulant may be provided
from which the anticoagulant is metered into the flow path and
mixed with the incoming whole blood. Anticoagulant is required
because of the tendency of blood to clot and adhere to the walls of
the plastic surfaces which it. Exemplary anticoagulants are well
known in the art and may include, but are not limited to, an
anticoagulant citrate phosphate dextrose (CPD) solution, an
anticoagulant citrate phosphate double dextrose (CP2D) solution, an
anticoagulant citrate phosphate dextrose adenine (CPDA) solution
(e.g., CPDA-1), an acid citrate dextrose (ACD) solution (e.g.,
ACD-A), and an anticoagulant sodium citrate 4% w/v solution.
[0076] Blood may be identified or characterized with respect to one
or more parameters, such as for example, hematocrit. Such
identification or characterization is typically prior to or shortly
after blood collection, but prior to subjecting the collected whole
blood to further processing, such as according to the methods
provided herein. In addition, at or near the time of collection and
prior to transfusion to a patient, tests may be performed for
determining blood type and the presence of pathogens such as virus,
bacteria and/or other foreign substances in the donor's blood. Such
testing generally requires obtaining a sample of the donor's blood.
Generally sampling of blood may be before, during or after
donation, but without compromising the sterility of the system
and/or the collected blood product. For example, samples may be
commonly obtained by finger stick, heel stick or venipuncture. In
the case where blood for hemoglobin testing is gathered with a
capillary stick, a single-use sterile lancet may be used. Another
well-known technique is to simply withdraw or collect the blood
remaining in the flow path of the collection set after donation.
This involves removing the needle from the donor, inserting the
needle into a vacuum sealed sampling vial or tube and allowing the
blood from the flow path to drain into the vial. Another
alternative is to clamp off the flow path near the collection
container and divert the blood being withdrawn from the donor to a
collection (sampling) vial or tube. This procedure may employ a
particular type of disposable tubing set having a pre-attached
sampling site on the main flow path. Blood at or near the sampling
site may be obtained by piercing the sampling site with a
separately provided needle or other piercing device, and attaching
a sampling vial thereto. To minimize the risk that the incoming
blood will be exposed to the outside environment, the sample is
typically collected after completion of the blood donation.
Alternatively, some collection bags or collection sets include
diversion pouches to sequester a portion (e.g., the first 20 ml) of
blood collected. Another example of a blood sampling system is
described in U.S. Pat. No. 5,167,656, which describes blood
collection sets with an enlarged sample collection portion included
in the flow path. Blood for sampling is collected in the enlarged
portion by clamping off the flow path near the collection container
and allowing the enlarged tubing portion to fill with blood.
[0077] Plasma useful for cryoprecipitate preparation and cryo-poor
supernatant as described herein may be recovered from whole blood
by a variety of procedures known in the art. For example, plasma
may be recovered by centrifuging whole blood at low speed (e.g.,
approximately 1000-3000 rpm for approximately 10-20 minutes,
optionally under refrigeration), followed by recovery of the plasma
fraction. In some embodiments, the plasma may be depleted of
platelets (e.g., by centrifugation at higher speeds and/or longer
times within the above ranges, such as approximately 2000-3000 rpm
for approximately 15-20 minutes, or approximately 5000.times.g).
Plasma may also be separated from whole blood by higher speed
centrifugation, such as for example 5000.times.g for 10 min at
4.degree. C. Plasma collected by apheresis methods (e.g.,
plasmapheresis) are also well known in the art.
[0078] Methods for producing cryoprecipitate and cryo-poor plasma
from plasma are well known in the art and described and exemplified
herein. Typically individual units of whole blood derived plasma
used for preparation of cryoprecipitate are frozen within 8 hours
of donation and the frozen plasma (e.g., whole blood-derived fresh
frozen plasma, FFP) may be thawed in a temperature controlled
apparatus, such as a water bath. The present disclosure also
contemplates that whole blood derived plasma frozen within 24 hours
of donation (e.g., PF24) and plasma produced by apheresis (e.g.,
frozen with 8 hours, frozen within 24 hours) may be used. In
certain embodiments, previously collected plasma frozen for storage
(e.g., FFP, PF24), may be thawed and, if desired combined (e.g.,
pooled), prior to initiating a cryoprecipitation freeze/thaw
process. For thawing, the temperature may be sufficiently low
(e.g., at approximately 4.degree. C., or between about 1.degree. C.
and about 6.degree. C.) so as to result in a controlled, gradual
thawing. For example, the thawing may take place over a total time
of between about 4 hours and about 7-8 hours, 8-10 hours, or
overnight. As discussed in greater detail supra, individual units
(e.g., 200 mL units, as defined by an accepted standard such as
AABB) of plasma may be used to produce a cryoprecipitate and/or
cryo-poor plasma, or more than one individual unit (e.g., 200 mL
units) of plasma may be pooled to produce a cryoprecipitate and/or
cryo-poor plasma (e.g., 550-650 mL of plasma). For pooled plasma, a
larger suitable bag such as a 1000 mL PVC bag (e.g., a Fenwal
transfer pack) or any blood product compatible bag of sufficient
volume (e.g., 800 mL, 600 mL) may be used to produce the
cryoprecipitate and/or cryo-poor plasma. In some embodiments, the
total thaw time may be dependent on the volume of plasma; e.g., a
200-250 mL unit of plasma may thaw for approximately 4.5 hours,
whereas 550-650 mL of plasma may take approximately 6.5 hours.
After thawing, the plasma may be centrifuged, e.g., under
refrigeration (such as at approximately 4.degree. C.) for
approximately 10-15 minutes at approximately 4200 rcf (optionally
with a slow stop) to separate the cryoprecipitate from the
cryo-poor plasma (cryosupernatant). The cryoprecipitate may be
separated from the cryo-poor plasma, e.g., by inversion to remove
the cryo-poor plasma, or through use of a plasma expressor to
remove the cryo-poor plasma, with the cryo-poor plasma collected by
transfer into one or more separate containers
[0079] In some embodiments, cryoprecipitate and/or cryo-poor plasma
may be frozen after production. As the cryoprecipitate may be
derived from plasma that has itself been frozen, "re-freezing" the
cryoprecipitate as used herein refers to freezing a cryoprecipitate
after producing the cryoprecipitate (e.g., after the initial plasma
freezing step, after the precipitation step). Advantageously, this
allows the cryoprecipitate to be stored for later use. In some
embodiments, cryoprecipitate may be stored at about -18.degree. C.
or lower (e.g., according to AABB standards).
[0080] After freezing (and optional frozen storage),
cryoprecipitate and/or cryo-poor plasma may be thawed. Methods for
thawing frozen cryoprecipitate and/or cryo-poor plasma are well
known in the art. As a non-limiting example, cryoprecipitate and/or
cryo-poor plasma may be thawed in a plasma thawer (e.g., those
commercially available from Helmer Scientific). In some
embodiments, cryoprecipitate and/or cryo-poor plasma may be thawed
at about 35.degree. C. In some embodiments, cryoprecipitate and/or
cryo-poor plasma may be thawed for approximately 5-10 minutes. In
some embodiments, after thawing, the cryoprecipitate may be mixed,
e.g., by agitation. In some embodiments, cryoprecipitate may be
allowed to thaw for two or more intervals, which may optionally be
separated by one or more mixing steps. In some embodiments,
cryoprecipitate may be thawed for approximately 5-10 minutes,
mixed, and allowed to continue thawing for approximately 5-10
minutes.
[0081] In some embodiments, cryoprecipitate and/or cryo-poor plasma
may be lyophilized or freeze-dried. Freeze-dried and lyophilized
blood product compositions are known in the art. For example,
freeze-dried plasma (FDP) and lyophilized plasma have been used in
patients suffering from traumatic injury (see, e.g., Inaba, K.
(2011) J. Trauma 70:S57-8 and Sailliol, A. et al. (2013)
Transfusion 53 Suppl 1:65S-71S).
[0082] For each of the parameters set forth in the methods provided
herein, techniques for determination or measurement of the
parameters are well known in the art.
Cryoprecipitate and Cryo-Poor Plasma Compositions
[0083] Described infra are various exemplary parameters and
properties that may characterize a cryoprecipitate (or a
composition comprising a cryoprecipitate) and/or cryo-poor plasma
of the present disclosure. It will be appreciated by one of skill
in the art that these exemplary characteristics and embodiments may
be combined in any number or combination, unless otherwise
indicated by context. These exemplary characteristics and
embodiments may be combined with any of the other embodiments or
aspects described elsewhere herein in any number or combination,
unless otherwise indicated by context.
[0084] Certain aspects of the present disclosure relate to
compositions comprising a cryoprecipitate suitable for infusion
into a subject. As disclosed herein, these compositions are
suitable for infusion into a subject for a longer duration after
thawing (e.g., thawing after frozen cryoprecipitate storage) than
is currently prescribed by existing guidelines (e.g., the
compositions have an extended period before expiry after thawing).
Such compositions may find use, inter alia, in treatments (e.g.,
infusions) related to control of bleeding associated with
fibrinogen deficiency, treating Factor XIII deficiency, treating
von Willebrand disease, maintenance of hemostasis, treating
disseminated intravascular coagulation (DIC) or high volume
hemorrhage, and/or making fibrin sealant.
[0085] Certain aspects of the present disclosure relate to
compositions comprising a cryo-poor plasma suitable for infusion
into a subject. Such compositions may find use, inter alia, in
improved treatment methods using such compositions for therapeutic
plasma exchange or infusion for indications, such as, but not
limited to trauma and/or burns.
[0086] In some embodiments, a cryoprecipitate (or a composition
comprising a cryoprecipitate) or cryo-poor plasma is suitable for
infusion into a subject at least 6 hours, at least 12 hours, at
least 24 hours, at least 36 hours, at least 48 hours, at least 60
hours, at least 72 hours, at least 84 hours, at least 96 hours, at
least 108 hours, at least 120 hours, at least 132 hours, at least
144 hours, at least 156 hours, or at least 168 hours after thawing.
In some embodiments, a cryoprecipitate or cryo-poor plasma is
suitable for infusion into a subject within 6 hours, within 12
hours, within 24 hours, within 36 hours, within 48 hours, within 60
hours, within 72 hours, within 84 hours, within 96 hours, within
108 hours, within 120 hours, within 132 hours, within 144 hours,
within 156 hours, or within 168 hours after thawing. In some
embodiments, the cryoprecipitate or cryo-poor plasma is suitable
for infusion into a subject for a number of hours after thawing
that is less than about any of the following numbers of hours: 168,
156, 144, 132, 120, 108, 96, 84, 72, 60, 48, 36, 24, or 12. In some
embodiments, the cryoprecipitate is or cryo-poor plasma suitable
for infusion into a subject for a number of hours after thawing
(e.g., after thawing and resuspension of the cryoprecipitate) that
is greater than about any of the following numbers of hours: 0,
0.25, 0.5, 1, 2, 3, 4, 5, 6, 12, 24, 36, 48, 60, 72, 84, 96, 108,
120, 132, 144, or 156. That is, the number of hours after thawing
for which the cryoprecipitate or cryo-poor plasma is suitable for
infusion into a subject may be any number of hours within a range
having an upper limit of 168, 156, 144, 132, 120, 108, 96, 84, 72,
60, 48, 36, 24, or 12 hours and an independently selected lower
limit of 0, 0.25, 0.5, 1, 2, 3, 4, 5, 6, 12, 24, 36, 48, 60, 72,
84, 96, 108, 120, 132, 144, or 156 hours, wherein the upper limit
is greater than the lower limit. In some embodiments, the
cryoprecipitate is suitable for infusion into a subject immediately
after thawing and resuspension of the cryoprecipitate (e.g., 0
hours after thawing). In some embodiments, the cryoprecipitate or
cryo-poor plasma may be suitable for infusion into a subject for
about 0 to about 168 hours, about 0 to about 144 hours, about 0 to
about 120 hours after thawing, about 0 to about 96 hours after
thawing, about 0 to about 72 hours after thawing, or about 0 to
about 48 hours after thawing. In some embodiments, the
cryoprecipitate may be suitable for infusion into a subject for
about 6 to about 168 hours, about 6 to about 144 hours, or about 6
to about 120 hours after thawing. In some embodiments, the
cryoprecipitate may be suitable for infusion into a subject for
about 12 to about 168 hours, about 12 to about 144 hours, or about
12 to about 120 hours after thawing. In some embodiments, the
cryoprecipitate may be suitable for infusion into a subject for
about 24 to about 168 hours, about 24 to about 144 hours, or about
24 to about 120 hours after thawing. In some embodiments, the
cryoprecipitate may be suitable for infusion into a subject for
about 36 to about 168 hours, about 36 to about 144 hours, or about
36 to about 120 hours after thawing. In some embodiments, the
cryoprecipitate may be suitable for infusion into a subject for
about 48 to about 168 hours, about 48 to about 144 hours, or about
48 to about 120 hours after thawing.
[0087] In some embodiments, a cryoprecipitate (or a composition
comprising a cryoprecipitate) or cryo-poor plasma is suitable for
infusion into a subject at least 1 day, at least 2 days, at least 3
days, at least 4 days, at least 5 days, at least 6 days, or at
least 7 days after thawing. In some embodiments, the
cryoprecipitate or cryo-poor plasma is suitable for infusion into a
subject within 1 day, within 2 days, within 3 days, within 4 days,
within 5 days, within 6 days, or within 7 days after thawing. In
some embodiments, a cryoprecipitate or cryo-poor plasma is suitable
for infusion into a subject for a number of days after thawing that
is less than about any of the following numbers of days: 7, 6, 5,
4, 3, or 2. In some embodiments, the cryoprecipitate or cryo-poor
plasma is suitable for infusion into a subject for a number of days
after thawing (e.g., after thawing and resuspension of the
cryoprecipitate) that is greater than about any of the following
numbers of days: 0, 1, 2, 3, 4, 5, or 6. In some embodiments, the
cryoprecipitate or cryo-poor plasma is suitable for infusion into a
subject immediately after thawing and resuspension of the
cryoprecipitate (e.g., 0 days after thawing). That is, the number
of days after thawing for which the cryoprecipitate or cryo-poor
plasma is suitable for infusion into a subject may be any number of
days within a range having an upper limit of 7, 6, 5, 4, 3, or 2
days and an independently selected lower limit of 0, 1, 2, 3, 4, 5,
or 6 days, wherein the upper limit is greater than the lower limit.
In some embodiments, the cryoprecipitate or cryo-poor plasma may be
suitable for infusion into a subject for about 0 to about 7 days,
about 0 to about 6 days, about 0 to about 5 days, about 0 to about
4 days, about 0 to about 3 days, or about 0 to about 2 days after
thawing. In some embodiments, the cryoprecipitate or cryo-poor
plasma may be suitable for infusion into a subject for about 1 to
about 7 days, about 1 to about 6 days, or about 1 to about 5 days
after thawing. In some embodiments, the cryoprecipitate or
cryo-poor plasma may be suitable for infusion into a subject for
about 2 to about 7 days, about 2 to about 6 days, or about 2 to
about 5 days after thawing.
[0088] In some embodiments, a cryoprecipitate (or a composition
comprising a cryoprecipitate) or cryo-poor plasma is stored at room
temperature after thawing, e.g., for the interval between thawing
and use (e.g., in an infusion). In some embodiments, a
cryoprecipitate (or a composition comprising a cryoprecipitate) or
cryo-poor plasma is stored at between about 2.degree. C. and about
25.degree. C. after thawing, e.g., for the interval between thawing
and use (e.g., in an infusion). In some embodiments, a
cryoprecipitate (or a composition comprising a cryoprecipitate) or
cryo-poor plasma is stored at between about 20.degree. C. and about
24.degree. C. after thawing, e.g., for the interval between thawing
and use (e.g., in an infusion). In some embodiments, a
cryoprecipitate (or a composition comprising a cryoprecipitate) or
cryo-poor plasma is stored at about 22.degree. C. after thawing,
e.g., for the interval between thawing and use. In some
embodiments, a cryoprecipitate (or a composition comprising a
cryoprecipitate) or cryo-poor plasma is stored at 2.degree. C. and
about 6.degree. C. after thawing, e.g., for the interval between
thawing and use (e.g., in an infusion). In some embodiments, a
cryoprecipitate (or a composition comprising a cryoprecipitate) or
cryo-poor plasma is stored after thawing, e.g., for the interval
between thawing and use (e.g., in an infusion) according to
standards set by AABB, the American Red Cross or another
accrediting, regulatory, or standard-setting agency.
[0089] It is well known in the art that different types of blood
donations containing plasma may have different associated volumes.
The volume of plasma obtained from a whole blood donation may vary,
depending upon, for example, the volume of whole blood collected,
the size of the collection bag (e.g., 450 mL, 500 mL), the donor
percent hematocrit and processing conditions (e.g., centrifugation
conditions). For example, in certain embodiments, a whole blood
donation typically yields an approximately 180-250 mL (e.g.,
approximately 200 mL) unit of plasma (e.g., whole blood derived
plasma), whereas the volume of plasma from a single apheresis
donation or sample (e.g., apheresis collected plasma) may yield
from about 200 mL up to approximately 700-800 mL, depending on a
variety of factors including donor size (e.g., body weight). In
some embodiments, a cryoprecipitate (or a composition comprising a
cryoprecipitate) and/or cryo-poor plasma of the present disclosure
may be obtained or prepared from about 180 mL or 200 mL to about
250 mL or 300 mL or 325 mL of plasma. For example, the
cryoprecipitate and/or cryo-poor plasma may be obtained from one
approximately 200 mL unit (e.g., AABB defined unit, AABB unit
volume) volume of plasma, such as from a single whole blood
donation. In other embodiments, a cryoprecipitate (or a composition
comprising a cryoprecipitate) and/or cryo-poor plasma of the
present disclosure may be obtained from at least about 300 mL, at
least about 400 mL, at least about 500 mL, or at least about 600 mL
or more of plasma. In other embodiments, a cryoprecipitate (or a
composition comprising a cryoprecipitate) and/or cryo-poor plasma
of the present disclosure may be obtained from at least about 300
mL, at least about 400 mL, at least about 500 mL, or at least about
600 mL or more of plasma. In other embodiments, a cryoprecipitate
(or a composition comprising a cryoprecipitate) of the present
disclosure may be obtained from at least about 550 mL and less than
650 mL of plasma. In some embodiments, a cryoprecipitate (or a
composition comprising a cryoprecipitate) and/or cryo-poor plasma
of the present disclosure may be obtained from at least about 570
mL and less than about 620 mL of plasma. In some embodiments, a
cryoprecipitate (or a composition comprising a cryoprecipitate)
and/or cryo-poor plasma of the present disclosure may be obtained
from at least about 600 mL and less than about 650 mL of plasma. In
certain embodiments, a cryoprecipitate (or a composition comprising
a cryoprecipitate) and/or cryo-poor plasma of the present
disclosure may be obtained from about 600 mL of plasma. For
example, a cryoprecipitate and/or cryo-poor plasma may be obtained
from pooling multiple AABB unit volumes of plasma (e.g., to yield
550-650 mL), a single apheresis sample (e.g., having 550-650 mL or
more), or from pooling multiple cryoprecipitates or cryo-poor
plasmas obtained from different samples of plasma.
[0090] As such, in some embodiments, a cryoprecipitate (or a
composition comprising a cryoprecipitate) and/or cryo-poor plasma
of the present disclosure may contain cryoprecipitate and cryo-poor
plasma, respectively, obtained or prepared from one donor. In other
embodiments, a cryoprecipitate (or a composition comprising a
cryoprecipitate) of the present disclosure and/or cryo-poor plasma
may contain cryoprecipitate and/or cryo-poor plasma, respectively,
obtained or prepared from more than one donor (e.g., prepared from
more than one plasma donation, prepared from more than one plasma
unit). In some embodiments, a cryoprecipitate (or a composition
comprising a cryoprecipitate) and/or cryo-poor plasma of the
present disclosure may contain cryoprecipitate and/or cryo-poor
plasma, respectively, obtained or prepared from 2-12 donors. In
some embodiments, a cryoprecipitate (or a composition comprising a
cryoprecipitate) and/or cryo-poor plasma of the present disclosure
may contain cryoprecipitate and/or cryo-poor plasma, respectively,
prepared from plasma obtained from 2-6 donors. For example, in some
embodiments, a cryoprecipitate (or a composition comprising a
cryoprecipitate) and/or cryo-poor plasma of the present disclosure
may contain cryoprecipitate and/or cryo-poor plasma, respectively,
prepared from plasma obtained from 1, 2, 3, 4, 5, or 6 donors. In
some embodiments, a cryoprecipitate (or a composition comprising a
cryoprecipitate) and/or cryo-poor plasma of the present disclosure
may contain cryoprecipitate and/or cryo-poor plasma, respectively,
obtained or prepared from 7-12 donors. For example, in some
embodiments, a cryoprecipitate (or a composition comprising a
cryoprecipitate) and/or cryo-poor plasma of the present disclosure
may contain cryoprecipitate and/or cryo-poor plasma, respectively,
prepared from plasma obtained from 7, 8, 9, 10, 11 or 12
donors.
[0091] In some embodiments, a cryoprecipitate composition and/or
cryo-poor plasma of the present disclosure may contain more than
one cryoprecipitate (e.g., individual cryoprecipitate preparations)
and/or cryo-poor plasma, respectively. For example, in some
embodiments, a cryoprecipitate composition and/or cryo-poor plasma
of the present disclosure may contain a first cryoprecipitate
and/or cryo-poor plasma, respectively, obtained from
pathogen-inactivated plasma and a second cryoprecipitate and/or
cryo-poor plasma, respectively, obtained from pathogen-inactivated
plasma. In some embodiments, a cryoprecipitate composition and/or
cryo-poor plasma of the present disclosure may contain a first
cryoprecipitate and/or cryo-poor plasma, respectively, obtained
from 2 units of pathogen-inactivated plasma and a second
cryoprecipitate and/or cryo-poor plasma, respectively, obtained
from 2 units of pathogen-inactivated plasma. In some embodiments, a
cryoprecipitate composition and/or cryo-poor plasma of the present
disclosure may contain a first cryoprecipitate and/or cryo-poor
plasma, respectively, obtained from 3 units of pathogen-inactivated
plasma and a second cryoprecipitate and/or cryo-poor plasma,
respectively, obtained from 3 units of pathogen-inactivated plasma.
In some embodiments, the first and the second cryoprecipitates
and/or cryo-poor plasma are combined prior to re-freezing for
storage. In some embodiments, the first and the second
cryoprecipitates and/or cryo-poor plasma are combined prior to use
(e.g., in an infusion), and/or prior to storage at room temperature
or under refrigeration. In some embodiments, a cryoprecipitate
composition and/or cryo-poor plasma of the present disclosure may
contain pathogen-inactivated plasma pooled from at least 3, at
least 4, at least 5, or at least 6 units of pathogen-inactivated
plasma. In some embodiments, a cryoprecipitate composition and/or
cryo-poor plasma of the present disclosure may contain
pathogen-inactivated plasma pooled from at least 7, at least 8, at
least 9, at least 10, at least 11, or at least 12 units of
pathogen-inactivated plasma. In some embodiments, a cryoprecipitate
composition and/or cryo-poor plasma of the present disclosure may
contain pathogen-inactivated plasma pooled from at least 7, at
least 8, at least 9, at least 10, at least 11, or at least 12 units
of pathogen-inactivated plasma. In certain embodiments, a
cryoprecipitate composition and/or cryo-poor plasma of the present
disclosure may contain pathogen-inactivated plasma pooled from at
least 3 units of pathogen-inactivated plasma. In certain
embodiments, a cryoprecipitate composition and/or cryo-poor plasma
of the present disclosure may contain pathogen-inactivated plasma
pooled from at least 6 units of pathogen-inactivated plasma.
[0092] In some embodiments, a cryoprecipitate composition of the
present disclosure may be generated from plasma that has not been
subject to pathogen inactivation, then the cryoprecipitate itself
may be subjected to pathogen-inactivation (and, optionally, frozen
for storage after pathogen inactivation). In some embodiments, the
pathogen inactivated cryoprecipitate may be stored at 2-25.degree.
C. (e.g., 2-6.degree. C., 20-24.degree. C.) until use for infusion.
In some embodiments, a cryoprecipitate may be prepared from plasma
and subsequently subjected to pathogen inactivation. In some
embodiments, the plasma has not been subject to pathogen
inactivation. In some embodiments, multiple cryoprecipitate
preparations made from plasma (e.g., plasma that has not been
subject to pathogen inactivation) may be pooled together, then
subject to pathogen inactivation. Advantageously, this enables the
pathogen inactivation of a large volume of cryoprecipitate (e.g., a
pooled cryoprecipitate composition) in one step and/or one
container. In other embodiments, multiple cryoprecipitate
preparations prepared from plasma (e.g., plasma that has not been
subject to pathogen inactivation) may be subject to pathogen
inactivation, then pooled together. In some embodiments, the
pathogen-inactivated cryoprecipitate (e.g., pooled cryoprecipitate)
is frozen for storage. Any desired volume of cryoprecipitate may be
subject to pathogen inactivation and optionally pooled (e.g.,
before or after pathogen inactivation). For example, in some
embodiments, at least two, at least three, at least four, at least
five, at least six, at least seven, at least eight, at least nine,
at least 10, at least 11, or at least 12 preparations or units of
cryoprecipitate may be pooled together, e.g., before or after
pathogen inactivation. In some embodiments, the cryoprecipitate is
prepared from at least about 550 mL and less than about 650 mL of
plasma. In some embodiments, the cryoprecipitate is prepared by
pooling two or more cryoprecipitate units (e.g., before or after
pathogen inactivation), each cryoprecipitate unit having been
prepared from at least about 550 mL and less than about 650 mL of
plasma. In some embodiments, the cryoprecipitate is prepared by
pooling two or more, three or more, four or more, five or more, six
or more, seven or more, eight or more, nine or more, ten or more,
eleven or more, or twelve or more cryoprecipitate units (e.g.,
before or after pathogen inactivation), each cryoprecipitate unit
having been prepared from at least about 150 mL and less than about
250 mL of plasma, e.g., about 200 mL of plasma. In some
embodiments, the cryoprecipitate is prepared by pooling two or
more, three or more, four or more, five or more, six or more, seven
or more, eight or more, nine or more, ten or more, eleven or more,
or twelve or more cryoprecipitate units (e.g., before or after
pathogen inactivation), each cryoprecipitate unit having been
prepared from a whole blood derived plasma unit.
[0093] In some embodiments, a cryoprecipitate composition of the
present disclosure may contain a first cryoprecipitate obtained or
prepared from at least about 550 mL and less than 650 mL of
pathogen-inactivated plasma, and a second cryoprecipitate obtained
or prepared from at least about 550 mL and less than 650 mL of
pathogen-inactivated plasma. In some embodiments, a cryoprecipitate
composition of the present disclosure may contain a first
cryoprecipitate obtained or prepared from at least about 570 mL and
less than 620 mL of pathogen-inactivated plasma, and a second
cryoprecipitate obtained or prepared from at least about 570 mL and
less than 620 mL of pathogen-inactivated plasma. In some
embodiments, a cryoprecipitate composition of the present
disclosure may contain a first cryoprecipitate obtained or prepared
from at least about 600 mL and less than 650 mL of
pathogen-inactivated plasma, and a second cryoprecipitate obtained
or prepared from at least about 600 mL and less than 650 mL of
pathogen-inactivated plasma. In certain embodiments, a
cryoprecipitate composition of the present disclosure may contain a
first cryoprecipitate obtained or prepared from about 600 mL of
pathogen-inactivated plasma, and a second cryoprecipitate obtained
or prepared from about 600 mL of pathogen-inactivated plasma. In
some embodiments, a cryoprecipitate composition of the present
disclosure may contain a first cryoprecipitate obtained or prepared
from at least about 150 mL and less than about 250 mL of
pathogen-inactivated plasma, and a second cryoprecipitate obtained
or prepared from at least about 150 mL and less than about 250 mL
of pathogen-inactivated plasma. Individual cryoprecipitates may be
combined or pooled after cryoprecipitate production but prior to
use and/or re-freezing for storage, and/or individual plasma
samples may be combined or pooled prior to cryoprecipitate
production.
[0094] In some embodiments, a cryoprecipitate may be part of a
composition containing plasma at a specific volume. For example,
cryoprecipitate is typically resuspended in a volume of plasma
remaining after cryoprecipitate production (e.g., some amount of
leftover plasma after production of the cryoprecipitate). This
volume may then be used or frozen for storage as described
herein.
[0095] In some embodiments, a composition comprising a
cryoprecipitate of the present disclosure includes plasma (e.g.,
cryo-poor plasma) of a volume that is less than about any of the
following volumes (in mL): 150, 140, 130, 120, 110, 100, 90, 80,
76, 75, 74, 73, 72, 71, 70, 69, 68, 67, 66, 65, 64, 63, 62, 61, 60,
59, 58, 57, 56, 55, 54, 53, 52, 51, 50, 45, 40, 35, 30, 25, 20, 19,
18, 17, 16, 15, 14, 13, 12, 11, 10, 9, 8, 7, or 6. In some
embodiments, a composition comprising a cryoprecipitate of the
present disclosure includes plasma of a volume that is greater than
about any of the following volumes (in mL): 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 51, 52,
53, 54, 55, 56, 57, 58, 59, or 60. That is, the composition
comprising a cryoprecipitate of the present disclosure may include
plasma of any volume within a range having an upper limit of 150,
140, 130, 120, 110, 100, 90, 80, 76, 75, 74, 73, 72, 71, 70, 69,
68, 67, 66, 65, 64, 63, 62, 61, 60, 59, 58, 57, 56, 55, 54, 53, 52,
51, 50, 45, 40, 35, 30, 25, 20, 19, 18, 17, 16, 15, 14, 13, 12, 11,
10, 9, 8, 7, or 6 mL and an independently selected lower limit of
5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30,
35, 40, 45, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, or 60 mL,
wherein the upper limit is greater than the lower limit. In some
embodiments, a composition comprising a cryoprecipitate of the
present disclosure includes between about 5 mL and about 25 mL of
plasma, about 5 mL and about 20 mL of plasma, about 10 mL to about
20 mL of plasma, or about 15 mL to about 20 mL of plasma. In other
embodiments, a composition comprising a cryoprecipitate of the
present disclosure includes between about 30 mL and about 150 mL,
between about 75 mL and about 150 mL, between about 30 mL and about
75 mL of plasma, between about 40 mL and about 75 mL of plasma,
between about 50 mL and about 75 mL of plasma, between about 60 mL
and about 75 mL of plasma, between about 50 mL and about 70 mL of
plasma, between about 50 mL and about 65 mL of plasma, between
about 50 mL and about 60 mL of plasma, between about 55 mL to about
70 mL of plasma, between about 55 mL to about 65 mL of plasma,
between about 55 mL to about 60 mL of plasma, or between about 60
mL and about 70 mL of plasma. In other embodiments, a composition
comprising a cryoprecipitate of the present disclosure includes
greater than about 1 mL and less than or equal to about 75 mL of
plasma, or greater than about 5 mL and less than or equal to about
75 mL of plasma. In some embodiments, a composition comprising a
cryoprecipitate of the present disclosure includes about 10 mL,
about 20 mL, about 30 mL, about 40 mL, about 50 mL, about 60 mL,
about 70 mL, about 80 mL, about 90 mL, about 100 mL, about 110 mL,
about 120 mL or about 130 mL of plasma. In some embodiments, the
aforementioned plasma volumes comprise the plasma volumes following
resuspension of the cryoprecipitate.
[0096] In some embodiments, the specific volume of plasma may
depend upon the amount of cryoprecipitate (e.g., depend upon the
amount of plasma used to produce the cryoprecipitate). In some
embodiments, for cryoprecipitate obtained from one AABB unit volume
of plasma (e.g., 200 mL), the volume of plasma in the composition
may be from about 5 mL to about 25 mL, from about 5 mL to about 20
mL, from about 10 mL to about 20 mL or from about 15 mL to about 20
mL, or any other comparable range as described above. In some
embodiments, for cryoprecipitate obtained from more than one AABB
unit volume of plasma (e.g., 550-650 mL), or for a pool of multiple
cryoprecipitate preparations (e.g., each having been obtained from
about 200 mL of plasma), the volume of plasma in the composition
may be from about 15 mL to about 75 mL, from about 15 mL to about
60 mL, from about 30 mL to about 75 mL, from about 30 mL to about
60 mL, from about 30 mL to about 40 mL, 40 mL to about 70 mL, from
about 45 mL to about 65 mL, from about 50 mL to about 60 mL, or any
other comparable range as described above. In certain embodiments,
the volume of plasma in the composition may be less than or equal
to about 75 mL. In some embodiments, for cryoprecipitate obtained
by combining two or more cryoprecipitate preparations, each made
from more than one AABB unit volume of plasma (e.g., each being
550-650 mL, for an aggregate total of 1100-1300 mL), the volume of
plasma in the composition may be from about 30 mL to about 150 mL,
from about 30 mL to about 120 mL, from about 60 mL to about 120 mL,
from about 90 mL to about 120 mL, from about 50 mL to about 100 mL,
from about 60 mL to about 90 mL, from about 60 mL to about 75 mL
from about 50 mL to about 75 mL, or about 75 mL. In certain
embodiments, the volume of plasma in the composition obtained by
combining two or more cryoprecipitate preparations may be less than
or equal to about 75 mL.
[0097] As described herein and well known in the art, a
cryoprecipitate or cryoprecipitate composition or cryo-poor plasma
of the present disclosure may be tested for the amount and/or
activity of one or more components, including without limitation
fibrinogen, Factor VIII, Factor XIII, and/or vWF. In some
embodiments, this testing refers to a measurement taken from an
individual sample. In other embodiments, it refers to an average
based on measurements taken from multiple samples (e.g., random
samples of sufficient number to provide a statistically significant
sampling). Often, multiple cryoprecipitate compositions (units) may
be thawed during a particular period of production (e.g., 1 month
of production) and tested to yield a measurement that is held to be
representative of those units that were not tested. Similarly,
multiple cryo-poor plasma compositions (units) may be thawed during
a particular period of production (e.g., 1 month of production) and
tested to yield a measurement that is held to be representative of
those units that were not tested. The un-tested or non-tested
samples may then be used in a treatment, such as an infusion.
Therefore, "testing" as used herein refers to testing a particular
cryoprecipitate and/or cryo-poor plasma composition, or it refers
to testing other cryoprecipitate and/or cryo-poor plasma
compositions in a defined cross-section of cryoprecipitate and/or
cryo-poor plasma compositions (e.g., in which a measurement of one
or more individual samples or average of measurements is held to be
representative of a cryoprecipitate and/or cryo-poor plasma
composition that was not tested). In some embodiments, a
cryoprecipitate or cryoprecipitate composition or cryo-poor plasma
of the present disclosure may be tested prior to re-freezing and/or
storage. In some embodiments, a cryoprecipitate or cryoprecipitate
composition or cryo-poor plasma of the present disclosure may be
tested after thawing. In some embodiments, a cryoprecipitate or
cryoprecipitate composition or cryo-poor plasma of the present
disclosure may be tested before use, e.g., in an infusion. As used
herein, the terms "testing" and "determining," including
grammatical derivatives thereof, may be used interchangeably.
Therefore, "determining" as used herein refers to determining an
amount of an analyte of interest (including without limitation
fibrinogen, Factor VIII, Factor XIII, and/or vWF) in a particular
cryoprecipitate and/or cryo-poor plasma composition, or it refers
to determining an amount of the analyte of interest in other
cryoprecipitate and/or cryo-poor plasma compositions in a defined
cross-section of cryoprecipitate and/or cryo-poor plasma
compositions (e.g., in which a measurement of one or more
individual samples or average of measurements is held to be
representative of a cryoprecipitate and/or cryo-poor plasma
composition that was not tested, such as a plurality of
cryoprecipitate and/or cryo-poor plasma compositions produced by
the same methods and/or produced in the same location or general
time frame, e.g., within 30 days).
[0098] It will be appreciated by one of skill in the art that a
cryoprecipitate or cryoprecipitate composition or cryo-poor plasma
of the present disclosure may be tested at one or more times (e.g.,
after thawing) for the amount and/or activity of one or more
components, including without limitation fibrinogen, Factor VIII,
Factor XIII, and/or vWF. For example, a cryoprecipitate or
cryoprecipitate composition or cryo-poor plasma of the present
disclosure may be tested shortly after thawing (e.g., within 2
hours of thawing, within 6 hours of thawing), and/or a
cryoprecipitate or cryoprecipitate composition or cryo-poor plasma
of the present disclosure may be tested at or shortly preceding the
time of infusion or the time of expiry post-thaw, which, in some
embodiments described herein, may occur up to about 1 day, up to
about 2 days, up to about 3 days, up to about 4 days, up to about 5
days, or up to about 7 days after thawing. It is to be understood
that any of the exemplary amounts of cryoprecipitate or
cryoprecipitate composition or cryo-poor plasma components
described herein (e.g., fibrinogen, Factor VIII, Factor XIII,
and/or vWF) refers to an amount tested or determined shortly after
thawing (e.g., within 2 hours of thawing, within 6 hours of
thawing) or an amount tested at or shortly preceding the time of
infusion or the time of expiry post-thaw (e.g., up to about 1 day,
up to about 2 days, up to about 3 days, up to about 4 days, up to
about 5 days, or up to about 7 days after thawing).
[0099] In some embodiments, a cryoprecipitate or cryoprecipitate
composition or cryo-poor plasma of the present disclosure may be
tested for Factor VIII. Various assays for measuring Factor VIII
are known in the art, including without limitation the chromogenic
assay, the one-stage clotting or activated partial thromboplastin
time (APTT) assay, and the two-stage clotting or activated partial
thromboplastin time (APTT) assay. Without wishing to be bound to
theory, it is thought that cryoprecipitate having less than a
particular amount of Factor VIII, e.g., an AABB standard for Factor
VIII such as 80 IU per unit, may advantageously be used for the
treatment of many conditions, including without limitation control
of bleeding associated with fibrinogen deficiency, treating Factor
XIII deficiency, treating von Willebrand disease, maintenance of
hemostasis, treating disseminated intravascular coagulation (DIC)
or high volume hemorrhage, and/or making fibrin sealant.
Advantageously, this cryoprecipitate, preferably containing
pathogen inactivated plasma, may be suitable for infusion after a
greater duration post-thawing than, e.g., recommended by current
AABB standards (such as less than 6 hours).
[0100] In some embodiments, a cryoprecipitate or cryoprecipitate
composition or cryo-poor plasma of the present disclosure contains
less than about 80, less than about 75, less than about 70, less
than about 65, less than about 60, less than about 55, less than
about 50, less than about 45, less than about 40, less than about
35, less than about 30, less than about 25, less than about 20,
less than about 15, or less than about 10 IU of Factor VIII per
unit of cryoprecipitate (e.g., per unit of cryoprecipitate derived
from about 200 mL of plasma) or cryo-poor plasma. In some
embodiments, a composition comprising a cryoprecipitate or
cryo-poor plasma of the present disclosure includes Factor VIII at
an amount that is less than about any of the following amounts (in
IU, either absolute or per unit of cryoprecipitate): 480, 450, 400,
350, 300, 250, 225, 200, 175, 150, 125, 100, 95, 90, 85, 80, 75,
70, 65, 60, 55, 50, 45, 40, 35, 30, 25, 20, or 15. In some
embodiments, a composition comprising a cryoprecipitate or
cryo-poor plasma of the present disclosure includes Factor VIII at
an amount that is greater than about any of the following amounts
(in IU, either absolute or per unit of cryoprecipitate): 10, 15,
20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95,
100, 125, 150, 175, 200, or 225. That is, the composition
comprising a cryoprecipitate or cryo-poor plasma of the present
disclosure may include Factor VIII at any amount within a range
having an upper limit of 480, 450, 400, 350, 300, 250, 225, 200,
175, 150, 125, 100, 95, 90, 85, 80, 75, 70, 65, 60, 55, 50, 45, 40,
35, 30, 25, 20, or 15 IU and an independently selected lower limit
of 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85,
90, 95, 100, 125, 150, 175, 200, or 225 IU, wherein the upper limit
is greater than the lower limit. In other embodiments, a
cryoprecipitate or cryoprecipitate composition of the present
disclosure contains at least 80 IU of Factor VIII per unit (e.g.,
200 mL unit, per unit of cryoprecipitate derived from about 200 mL
of plasma) of cryoprecipitate. In some embodiments, a
cryoprecipitate or cryoprecipitate composition of the present
disclosure contains at least 80 IU of Factor VIII. In some
embodiments, a cryoprecipitate or cryoprecipitate composition of
the present disclosure contains 80-100 IU of Factor VIII per unit
(e.g., 200 mL unit, per unit of cryoprecipitate derived from about
200 mL of plasma) of cryoprecipitate. Factor VIII content of a
cryoprecipitate or cryoprecipitate composition of the present
disclosure may be expressed per unit volume (e.g., per unit of
cryoprecipitate derived from about 200 mL of plasma), or as an
absolute amount. In some embodiments, a cryoprecipitate or
cryoprecipitate composition of the present disclosure contains less
than about 80 IU or less than about 50 IU of Factor VIII per unit
(e.g., 200 mL unit, per unit of cryoprecipitate derived from about
200 mL of plasma) of cryoprecipitate at the time of thawing (e.g.,
within about 1 hour or within about 2 hours of thawing). In some
embodiments, a cryoprecipitate or cryoprecipitate composition of
the present disclosure contains less than about 80 IU or less than
about 50 IU of Factor VIII per unit of cryoprecipitate at or
shortly preceding the infusion (e.g., up to about 1 day, up to
about 3 days, up to about 5 days, or up to about 7 days after
thawing). In some embodiments, a cryoprecipitate or cryoprecipitate
composition of the present disclosure contains less than about 80
IU of Factor VIII at or shortly preceding the infusion (e.g., up to
about 1 day, up to about 3 days, up to about 5 days, or up to about
7 days after thawing). In some embodiments, a cryoprecipitate or
cryoprecipitate composition of the present disclosure contains at
least about 80 IU of Factor VIII at or shortly preceding the
infusion (e.g., up to about 1 day, up to about 3 days, up to about
5 days, or up to about 7 days after thawing). In some embodiments,
a cryoprecipitate or cryoprecipitate composition of the present
disclosure contains 80-100 IU of Factor VIII at or shortly
preceding the infusion (e.g., up to about 1 day, up to about 3
days, up to about 5 days, or up to about 7 days after thawing). In
some embodiments, a cryoprecipitate or cryoprecipitate composition
of the present disclosure contains comprises about 80-240 IU (e.g.,
total IU) of Factor VIII at or shortly preceding the infusion
(e.g., up to about 1 day, up to about 3 days, up to about 5 days,
or up to about 7 days after thawing). In some embodiments, a
cryoprecipitate or cryoprecipitate composition of the present
disclosure contains comprises about 80-480 IU (e.g., total IU) of
Factor VIII at or shortly preceding the infusion (e.g., up to about
1 day, up to about 3 days, up to about 5 days, or up to about 7
days after thawing). In some embodiments, an amount of factor VIII
is determined from cryoprecipitate sampled within about 2 hours,
within about 6 hours, within about 1 day, within about 2 days,
within about 3 days, within about 4 days, or within about 5 days
after thawing.
[0101] In some embodiments, a composition contains cryoprecipitate
prepared from at least about 550 mL and less than about 650 mL of
pathogen-inactivated plasma. In some embodiments, a composition
contains two or more cryoprecipitates, each of the two or more
cryoprecipitates prepared from at least about 150 mL and less than
about 250 mL of plasma, e.g., about 200 mL of plasma. In some
embodiments, cryoprecipitate prepared from at least about 550 mL
and less than about 650 mL of pathogen-inactivated plasma contains
between about 80 and about 200 IU of Factor VIII, e.g., at or
shortly preceding the infusion (e.g., up to about 1 day, up to
about 3 days, up to about 5 days, or up to about 7 days after
thawing). For example, in some embodiments, cryoprecipitate
prepared from at least about 550 mL and less than about 650 mL of
pathogen-inactivated plasma contains between about 80 and about 200
IU of Factor VIII at the time of thawing (e.g., within about 1 hour
or within about 2 hours of thawing). In some embodiments,
cryoprecipitate prepared from at least about 550 mL and less than
about 650 mL of pathogen-inactivated plasma contains between about
80 and about 200 IU of Factor VIII as determined within about 2
hours, within about 6 hours, within about 1 day, within about 2
days, within about 3 days, within about 4 days, or within about 5
days after thawing.
[0102] In some embodiments, a composition contains a first
cryoprecipitate prepared from at least about 550 mL and less than
about 650 mL of pathogen-inactivated plasma and a second
cryoprecipitate prepared from at least about 550 mL and less than
about 650 mL of pathogen-inactivated plasma. In some embodiments, a
composition containing two cryoprecipitates, each prepared from at
least about 550 mL and less than about 650 mL of
pathogen-inactivated plasma, contains between about 160 and about
400 IU of Factor VIII, e.g., at or shortly preceding the infusion
(e.g., up to about 1 day, up to about 3 days, up to about 5 days,
or up to about 7 days after thawing). For example, in some
embodiments, a composition containing two cryoprecipitates, each
prepared from at least about 550 mL and less than about 650 mL of
pathogen-inactivated plasma, contains between about 160 and about
400 IU of Factor VIII at the time of thawing (e.g., within about 1
hour or within about 2 hours of thawing). In some embodiments, a
composition containing two cryoprecipitates, each prepared from at
least about 550 mL and less than about 650 mL of
pathogen-inactivated plasma, contains between about 160 and about
400 IU of Factor VIII as determined within about 2 hours, within
about 6 hours, within about 1 day, within about 2 days, within
about 3 days, within about 4 days, or within about 5 days after
thawing.
[0103] In some embodiments, a cryoprecipitate or cryoprecipitate
composition or cryo-poor plasma of the present disclosure may be
tested for fibrinogen. Various assays for measuring fibrinogen are
known in the art, including without limitation the Clauss method,
prothrombin time-derived assays, immunological assays, and
gravimetric assays. In some embodiments, a cryoprecipitate or
cryoprecipitate composition or cryo-poor plasma of the present
disclosure contains an amount of fibrinogen meeting AABB standards.
In some embodiments, a cryoprecipitate or cryoprecipitate
composition or cryo-poor plasma of the present disclosure contains
at least about 100, at least about 150, at least about 200, at
least about 250, or at least about 300 mg of fibrinogen per unit of
cryoprecipitate (e.g., per unit of cryoprecipitate derived from
about 200 mL of plasma). In some embodiments, a composition
comprising a cryoprecipitate or cryo-poor plasma of the present
disclosure includes fibrinogen at an amount that is less than about
any of the following amounts (in mg, either absolute or per unit of
cryoprecipitate): 2500, 2000, 1800, 1500, 1200, 750, 700, 650, 600,
550, 500, 450, 400, 350, 300, 250, 200, or 150. In some
embodiments, a composition comprising a cryoprecipitate or
cryo-poor plasma of the present disclosure includes fibrinogen at
an amount that is greater than about any of the following amounts
(in mg, either absolute or per unit of cryoprecipitate): 140, 150,
200, 250, 300, 350, 400, 450, 500, 550, 600, 650, 700, 750, 800,
850, 900, 1000, 1100, 1200, or 1500. That is, the composition
comprising a cryoprecipitate or cryo-poor plasma of the present
disclosure may include fibrinogen at any amount within a range
having an upper limit of 2500, 2000, 1800, 1500, 1200, 750, 700,
650, 600, 550, 500, 450, 400, 350, 300, 250, 200, or 150 mg and an
independently selected lower limit of 140, 150, 200, 250, 300, 350,
400, 450, 500, 550, 600, 650, 700, 140, 150, 200, 250, 300, 350,
400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 1000, 1100,
1200, or 1500 mg, wherein the upper limit is greater than the lower
limit. In some embodiments, a cryoprecipitate or cryoprecipitate
composition or cryo-poor plasma of the present disclosure contains
at least about 250 mg or at least about 150 mg of fibrinogen per
unit of cryoprecipitate (e.g., per unit of cryoprecipitate derived
from about 200 mL of plasma) or cryo-poor plasma at the time of
thawing (e.g., within about 1 hour or within about 2 hours of
thawing). In some embodiments, a cryoprecipitate or cryoprecipitate
composition or cryo-poor plasma of the present disclosure contains
at least about 250 mg or at least about 150 mg of fibrinogen per
unit of cryoprecipitate (e.g., per unit of cryoprecipitate derived
from about 200 mL of plasma) or cryo-poor plasma at or shortly
preceding the infusion (e.g., up to about 1 day, up to about 3
days, up to about 5 days, or up to about 7 days after thawing). In
some embodiments, a cryoprecipitate or cryoprecipitate composition
or cryo-poor plasma of the present disclosure contains at least
about 250 mg or at least about 150 mg of fibrinogen at the time of
thawing (e.g., within about 1 hour or within about 2 hours of
thawing). In some embodiments, a cryoprecipitate or cryoprecipitate
composition or cryo-poor plasma of the present disclosure contains
at least about 750 mg of fibrinogen (e.g., total mg of fibrinogen)
at or shortly preceding the infusion (e.g., up to about 1 day, up
to about 3 days, up to about 5 days, or up to about 7 days after
thawing). In some embodiments, a cryoprecipitate or cryoprecipitate
composition or cryo-poor plasma of the present disclosure contains
at least about 750 mg of fibrinogen (e.g., total mg of fibrinogen)
at the time of thawing (e.g., within about 1 hour or within about 2
hours of thawing). In some embodiments, an amount of fibrinogen is
determined from cryoprecipitate sampled within about 2 hours,
within about 6 hours, within about 1 day, within about 2 days,
within about 3 days, within about 4 days, or within about 5 days
after thawing.
[0104] In some embodiments, a composition contains cryoprecipitate
prepared from at least about 550 mL and less than about 650 mL of
pathogen-inactivated plasma. In some embodiments, a composition
contains two or more cryoprecipitates, each of the two or more
cryoprecipitates prepared from at least about 150 mL and less than
about 250 mL of plasma, e.g., about 200 mL of plasma. In some
embodiments, cryoprecipitate prepared from at least about 550 mL
and less than about 650 mL of pathogen-inactivated plasma contains
between about 700 mg and about 1000 mg of fibrinogen, e.g., at or
shortly preceding the infusion (e.g., up to about 1 day, up to
about 3 days, up to about 5 days, or up to about 7 days after
thawing). For example, in some embodiments, cryoprecipitate
prepared from at least about 550 mL and less than about 650 mL of
pathogen-inactivated plasma contains between about 700 mg and about
1000 mg of fibrinogen at the time of thawing (e.g., within about 1
hour or within about 2 hours of thawing). In some embodiments,
cryoprecipitate prepared from at least about 550 mL and less than
about 650 mL of pathogen-inactivated plasma contains between about
700 mg and about 1000 mg of fibrinogen as determined within about 2
hours, within about 6 hours, within about 1 day, within about 2
days, within about 3 days, within about 4 days, or within about 5
days after thawing.
[0105] In some embodiments, a composition contains a first
cryoprecipitate prepared from at least about 550 mL and less than
about 650 mL of pathogen-inactivated plasma and a second
cryoprecipitate prepared from at least about 550 mL and less than
about 650 mL of pathogen-inactivated plasma. In some embodiments, a
composition containing two cryoprecipitates, each prepared from at
least about 550 mL and less than about 650 mL of
pathogen-inactivated plasma, contains between about 1400 mg and
about 2000 mg of fibrinogen, e.g., at or shortly preceding the
infusion (e.g., up to about 1 day, up to about 3 days, up to about
5 days, or up to about 7 days after thawing). For example, in some
embodiments, a composition containing two cryoprecipitates, each
prepared from at least about 550 mL and less than about 650 mL of
pathogen-inactivated plasma, contains between about 1400 mg and
about 2000 mg of fibrinogen at the time of thawing (e.g., within
about 1 hour or within about 2 hours of thawing). In some
embodiments, a composition containing two cryoprecipitates, each
prepared from at least about 550 mL and less than about 650 mL of
pathogen-inactivated plasma, contains between about 1400 mg and
about 2000 mg of fibrinogen as determined within about 2 hours,
within about 6 hours, within about 1 day, within about 2 days,
within about 3 days, within about 4 days, or within about 5 days
after thawing.
[0106] In some embodiments, a cryoprecipitate or cryoprecipitate
composition of the present disclosure may be tested for vWF.
Various assays for measuring vWF (such as vWF:RCo and vWF:Ag
assays) are known in the art, including without limitation vWF
ELISA, platelet agglutination, flow cytometry, and latex
immunoassays. In some embodiments, a cryoprecipitate or
cryoprecipitate composition of the present disclosure contains an
amount of vWF meeting AABB standards. In some embodiments, a
cryoprecipitate or cryoprecipitate composition of the present
disclosure contains at least about 80, at least about 90, at least
about 100, at least about 110, at least about 120, at least about
130, at least about 140, or at least about 150 IU of vWF per unit
of cryoprecipitate (e.g., per unit of cryoprecipitate derived from
about 200 mL of plasma). In some embodiments, a composition
comprising a cryoprecipitate of the present disclosure includes vWF
at an amount that is less than about any of the following amounts
(in IU, either absolute or per unit of cryoprecipitate): 450, 400,
350, 300, 250, 200, 150, 140, 130, 120, 110, 100, or 90. In some
embodiments, a composition comprising a cryoprecipitate of the
present disclosure includes vWF at an amount that is greater than
about any of the following amounts (in IU, either absolute or per
unit of cryoprecipitate): 80, 90, 100, 110, 120, 130, 140, 150,
200, 250, 300, 350, or 400. That is, the composition comprising a
cryoprecipitate of the present disclosure may include vWF at any
amount within a range having an upper limit of 450, 400, 350, 300,
250, 200, 150, 140, 130, 120, 110, 100, or 90 IU and an
independently selected lower limit of 80, 90, 100, 110, 120, 130,
140, 150, 200, 250, 300, 350, or 400 IU, wherein the upper limit is
greater than the lower limit. In some embodiments, a
cryoprecipitate or cryoprecipitate composition of the present
disclosure contains at least about 100 IU or at least about 150 IU
of vWF per unit of cryoprecipitate at the time of thawing (e.g.,
within about 1 hour or within about 2 hours of thawing). In some
embodiments, a cryoprecipitate or cryoprecipitate composition of
the present disclosure contains at least about 100 IU or at least
about 150 IU of vWF per unit of cryoprecipitate at or shortly
preceding the infusion (e.g., up to about 1 day, up to about 3
days, up to about 5 days, or up to about 7 days after thawing).
[0107] In some embodiments, a cryoprecipitate or cryoprecipitate
composition of the present disclosure may be tested for Factor
XIII. Various assays for measuring Factor XIII are known in the
art, including without limitation the Berichrom assay, the clot
solubility assay, and a Factor XIII ELISA. In some embodiments, a
cryoprecipitate or cryoprecipitate composition of the present
disclosure contains an amount of Factor XIII meeting AABB
standards. In some embodiments, a cryoprecipitate or
cryoprecipitate composition of the present disclosure contains at
least about 40, at least about 50, at least about 60, at least
about 70, at least about 80, at least about 90, or at least about
100 IU of Factor XIII per unit of cryoprecipitate (e.g., per unit
of cryoprecipitate derived from about 200 mL of plasma). In some
embodiments, a composition comprising a cryoprecipitate of the
present disclosure includes Factor XIII at an amount that is less
than about any of the following amounts (in IU, either absolute or
per unit of cryoprecipitate): 300, 275, 250, 225, 200, 175, 150,
125, 100, 90, 80, 70, 60, or 50. In some embodiments, a composition
comprising a cryoprecipitate of the present disclosure includes
Factor XIII at an amount that is greater than about any of the
following amounts (in IU, either absolute or per unit of
cryoprecipitate): 40, 50, 60, 70, 80, 90, 100, 125, 150, 175, 200,
225, 250, or 275. That is, the composition comprising a
cryoprecipitate of the present disclosure may include Factor XIII
at any amount within a range having an upper limit of 300, 275,
250, 225, 200, 175, 150, 125, 100, 90, 80, 70, 60, or 50 IU and an
independently selected lower limit of 40, 50, 60, 70, 80, 90, 100,
125, 150, 175, 200, 225, 250, or 275 IU, wherein the upper limit is
greater than the lower limit. In some embodiments, a
cryoprecipitate or cryoprecipitate composition of the present
disclosure contains at least about 100 IU or at least about 150 IU
of Factor XIII per unit of cryoprecipitate at the time of thawing
(e.g., within about 1 hour or within about 2 hours of thawing). In
some embodiments, a cryoprecipitate or cryoprecipitate composition
of the present disclosure contains at least about 100 IU or at
least about 150 IU of Factor XIII per unit of cryoprecipitate at or
shortly preceding the infusion (e.g., up to about 1 day, up to
about 3 days, up to about 5 days, or up to about 7 days after
thawing).
[0108] Any of the above amounts of cryoprecipitate or cryo-poor
plasma components may be combined in any number or combination
described herein. For example, in some embodiments, a
cryoprecipitate or cryoprecipitate composition or cryo-poor plasma
of the present disclosure contains less than about 80 IU or less
than about 50 IU of Factor VIII per unit of cryoprecipitate or
cryo-poor plasma and at least about 250 mg or at least about 150 mg
of fibrinogen per unit of cryoprecipitate or cryo-poor plasma at
the time of thawing (e.g., within about 1 hour or within about 2
hours of thawing). In some embodiments, a cryoprecipitate or
cryoprecipitate composition or cryo-poor plasma of the present
disclosure contains less than about 80 IU or less than about 50 IU
of Factor VIII per unit of cryoprecipitate or cryo-poor plasma and
at least about 250 mg or at least about 150 mg of fibrinogen per
unit of cryoprecipitate or cryo-poor plasma at or shortly preceding
the infusion (e.g., up to about 1 day, up to about 3 days, up to
about 5 days, or up to about 7 days after thawing).
[0109] In some embodiments, a cryoprecipitate, cryoprecipitate
composition, and/or cryo-poor plasma of the present disclosure may
be prepared from plasma other than group O plasma, e.g., group A,
B, and/or AB plasma. In some embodiments, a cryoprecipitate,
cryoprecipitate composition, and/or cryo-poor plasma of the present
disclosure may be prepared from plasma of more than one ABO type.
In some embodiments, a cryoprecipitate, cryoprecipitate
composition, and/or cryo-poor plasma of the present disclosure may
be prepared from A, B, and AB type plasma.
[0110] In some embodiments, a cryoprecipitate, cryoprecipitate
composition, and/or cryo-poor plasma of the present disclosure may
be contained in a container of the present disclosure. In some
embodiments, the container further comprises a label indicating
that the composition is suitable for use (e.g., suitable for
infusion) for up to about 1 day, 2 days, 3 days, 4 days, 5 days, 6
days, or 7 days after thawing.
[0111] Further provided herein is a cryoprecipitate produced by any
of the methods of the present disclosure, e.g., including one or
more of the aspects and features described above in any order or
combination.
Cryoprecipitate and/or Cryo-Poor Plasma Kits or Articles of
Manufacture
[0112] In some embodiments, a cryoprecipitate, cryoprecipitate
composition, and/or cryo-poor plasma of the present disclosure, or
one produced by the methods of the present disclosure, may be
packaged in a kit or article of manufacture. In some embodiments, a
kit or article of manufacture may include a container, a
pathogen-inactivated cryoprecipitate and/or cryo-poor plasma, and
instructions for using the pathogen-inactivated cryoprecipitate
and/or cryo-poor plasma. In some embodiments, a kit or article of
manufacture may include a container, a pathogen-inactivated
cryoprecipitate and/or cryo-poor plasma, and a label indicating
that the pathogen-inactivated cryoprecipitate and/or cryo-poor
plasma is suitable for use for up to about 1 day, up to about 2
days, up to about 3 days, up to about 4 days, up to about 5 days,
up to about 6 days, or up to about 7 days after thawing. In some
embodiments, a kit or article of manufacture may further include
any other material or device useful in a treatment (e.g., a
transfusion), including without limitation one or more containers,
tubing, sterilizing agents or equipment, cannulae, syringes, and
the like.
[0113] In some embodiments, the instructions may be for using the
pathogen-inactivated cryoprecipitate and/or cryo-poor plasma in an
infusion into a subject. In some embodiments, the instructions may
indicate an expiry date of the cryoprecipitate and/or cryo-poor
plasma, e.g., a date by which the cryoprecipitate and/or cryo-poor
plasma should be used in a treatment (e.g., an infusion) after
thawing. In some embodiments, the instructions may indicate that
the cryoprecipitate and/or cryo-poor plasma is suitable for
infusion into the subject for up to about 1 day, up to about 2
days, up to about 3 days, up to about 4 days, up to about 5 days,
up to about 6 days, or up to about 7 days after thawing. In some
embodiments, the instructions may indicate that the cryoprecipitate
and/or cryo-poor plasma is suitable for infusion into the subject
for up to about 6 hours, up to about 12 hours, up to about 24
hours, up to about 36 hours, up to about 48 hours, up to about 60
hours, up to about 72 hours, up to about 84 hours, up to about 96
hours, up to about 108 hours, up to about 120 hours, up to about
132 hours, up to about 144 hours, up to about 156 hours, or up to
about 168 hours after thawing.
Cryoprecipitate and/or Cryo-Poor Plasma Methods
[0114] Certain aspects of the present disclosure relate to methods
of preparing a cryoprecipitate and/or cryo-poor plasma for infusion
into a subject. Certain aspects of the present disclosure relate to
methods of infusing a cryoprecipitate and/or cryo-poor plasma into
a subject. It is to be understood that any of the cryoprecipitate,
cryoprecipitate compositions, and/or cryo-poor plasma of the
present disclosure may find use in any of the methods described
herein. It is to be understood that any of the features or aspects
of cryoprecipitate, cryoprecipitate compositions, and/or cryo-poor
plasma of the present disclosure described herein may find use in
any of the methods described herein in any combination.
[0115] In some embodiments, the methods of preparing a
cryoprecipitate and/or cryo-poor plasma for infusion into a subject
and/or methods of infusing a cryoprecipitate and/or cryo-poor
plasma into a subject may include preparing a cryoprecipitate,
cryoprecipitate composition, and/or cryo-poor plasma of the present
disclosure from pathogen-inactivated plasma. Any of the exemplary
methods of preparing a cryoprecipitate and/or cryo-poor plasma from
plasma (e.g., pathogen-inactivated plasma) described herein (e.g.,
supra), or any methods of preparing a cryoprecipitate and/or
cryo-poor plasma from plasma known in the art, may be used. Any of
the exemplary methods of pathogen inactivating plasma described
herein (e.g., infra), or any methods of pathogen inactivating
plasma known in the art, may be used to generate the
pathogen-inactivated plasma.
[0116] In some embodiments, the methods of preparing a
cryoprecipitate and/or cryo-poor plasma for infusion into a subject
and/or methods of infusing a cryoprecipitate and/or cryo-poor
plasma into a subject may include freezing a cryoprecipitate,
cryoprecipitate composition, and/or cryo-poor plasma of the present
disclosure, e.g., as described supra or as is known in the art.
[0117] In some embodiments, the methods of preparing a
cryoprecipitate and/or cryo-poor plasma for infusion into a subject
and/or methods of infusing a cryoprecipitate and/or cryo-poor
plasma into a subject may include thawing a frozen cryoprecipitate,
cryoprecipitate composition, and/or cryo-poor plasma of the present
disclosure, e.g., as described supra or as is known in the art. In
some embodiments, the thawed cryoprecipitate, cryoprecipitate
composition, and/or cryo-poor plasma may be suitable for infusion
into a subject as described herein for at least about 1 day, at
least about 2 days, at least about 3 days, at least about 4 days,
at least about 5 days, at least about 6 days, or at least about 7
days after thawing. In some embodiments, the thawed
cryoprecipitate, cryoprecipitate composition, and/or cryo-poor
plasma may be suitable for infusion into a subject as described
herein for at least about 6 hours, at least about 12 hours, at
least about 24 hours, at least about 36 hours, at least about 48
hours, at least about 60 hours, at least about 72 hours, at least
about 84 hours, at least about 96 hours, at least about 108 hours,
at least about 120 hours, at least about 132 hours, at least about
144 hours, at least about 156 hours, or at least about 168 hours
after thawing.
[0118] In some embodiments, the methods of preparing a
cryoprecipitate for infusion into a subject and/or methods of
infusing a cryoprecipitate into a subject may include testing the
thawed cryoprecipitate (e.g., testing one or more representative
random cryoprecipitate preparations) for Factor VIII, e.g., as
described herein or known in the art. In some embodiments, the
thawed cryoprecipitate may be tested for Factor VIII prior to
infusion. In some embodiments, the thawed cryoprecipitate may have
been tested for Factor VIII prior to freezing. In other
embodiments, the methods of preparing a cryoprecipitate for
infusion into a subject and/or methods of infusing a
cryoprecipitate into a subject may exclude testing the thawed
cryoprecipitate for Factor VIII. In some embodiments, the methods
of preparing a cryoprecipitate for infusion into a subject and/or
methods of infusing a cryoprecipitate into a subject may include
testing the thawed cryoprecipitate for fibrinogen, but exclude
testing for Factor VIII.
[0119] In some embodiments, the methods of preparing a
cryoprecipitate for infusion into a subject and/or methods of
infusing a cryoprecipitate into a subject may include testing the
thawed cryoprecipitate (e.g., testing one or more representative
random cryoprecipitate preparations) for fibrinogen, e.g., as
described herein or known in the art. In some embodiments, the
thawed cryoprecipitate may be tested for fibrinogen prior to
infusion. In some embodiments, the thawed cryoprecipitate may have
been tested for fibrinogen prior to freezing. In other embodiments,
the methods of preparing a cryoprecipitate for infusion into a
subject and/or methods of infusing a cryoprecipitate into a subject
may exclude testing the thawed cryoprecipitate for fibrinogen.
[0120] In some embodiments, the methods of preparing a
cryoprecipitate and/or cryo-poor plasma for infusion into a subject
and/or methods of infusing a cryoprecipitate and/or cryo-poor
plasma into a subject may include a cryoprecipitate and/or
cryo-poor plasma made from about 600 mL of pathogen-inactivated
plasma, from at least about 550 mL and less than 650 mL of
pathogen-inactivated plasma, from at least about 570 mL and less
than 620 mL of pathogen-inactivated plasma, or from at least about
600 mL and less than 650 mL of pathogen-inactivated plasma. Such a
cryoprecipitate and/or cryo-poor plasma may be obtained, e.g., from
pooling multiple unit volumes of plasma (e.g., 200 mL unit volumes,
AABB unit volumes, to yield 550-650 mL), or from pooling multiple
cryoprecipitates and/or cryo-poor plasma obtained from different
samples of plasma. Individual cryoprecipitates and/or cryo-poor
plasma may be combined or pooled after cryoprecipitate/cryo-poor
plasma production but prior to re-freezing for storage, and/or
individual plasma samples may be combined or pooled prior to use,
storage at room temperature or under refrigeration, and/or
cryoprecipitate production. In some embodiments, two or more
cryoprecipitates and/or cryo-poor plasma may be combined prior to
using, storing, and/or freezing the cryoprecipitate and/or
cryo-poor plasma. In some embodiments, two or more cryoprecipitates
and/or cryo-poor plasma may be combined after freezing the
cryoprecipitate and/or cryo-poor plasma but prior to infusion.
[0121] In some embodiments, the methods of the present disclosure
may further comprise infusing a cryoprecipitate or cryoprecipitate
composition of the present disclosure into a subject. Methods of
infusing a cryoprecipitate into a subject are well known in the
art. In some embodiments, the cryoprecipitate may be infused at a
rate of about 1 mL, about 2 mL, about 3 mL, about 4 mL, about 5 mL,
about 6 mL, about 7 mL, about 8 mL, about 9 mL, or about 10 mL per
minute, or for a total duration of about 30 minutes to about 4
hours. In some embodiments, a pool of cryoprecipitates (e.g.,
equivalent to 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 units) may be
infused. In some embodiments, the infusion is sufficient to raise
the subject's fibrinogen level by an amount from about 30 mg/dL to
about 60 mg/dL, e.g., by about 40 mg/dL. In some embodiments, the
infusion is a transfusion. Further description of cryoprecipitate
infusion dosing, response, indications, and preparation may be
found, e.g., in the American Red Cross Compendium of Transfusion
Practice Guidelines, the disclosure of which is hereby incorporated
by reference as it relates to cryoprecipitate infusion dosing,
response, indications, and preparation.
[0122] Further disclosed herein are methods for preparing a
cryoprecipitate and/or cryo-poor plasma for infusion into a
subject. In some embodiments, the methods include preparing a
cryoprecipitate and/or cryo-poor plasma from pathogen-inactivated
plasma (e.g., as described herein) and freezing the cryoprecipitate
and/or cryo-poor plasma. In some embodiments, the methods include
preparing a cryoprecipitate a and/or cryo-poor plasma,
respectively, from pathogen-inactivated plasma (e.g., as described
herein) and storing the cryoprecipitate and/or cryo-poor plasma at
room temperature or under refrigeration before using in an
infusion. In some embodiments, the cryoprecipitate and/or cryo-poor
plasma, respectively, is suitable for infusion into the subject for
up to about 1 day, 2 days, 3 days, 4 days, 5 days 6 days, or 7 days
after thawing, as described herein. In some embodiments, the
cryoprecipitate and/or cryo-poor plasma is prepared from at least
about 550 mL and less than about 650 mL of pathogen-inactivated
plasma of the present disclosure. In certain embodiments, the
cryoprecipitate and/or cryo-poor plasma is prepared from about 600
mL of pathogen-inactivated plasma of the present disclosure.
[0123] In some embodiments, the methods further include combining a
first cryoprecipitate and/or cryo-poor plasma, respectively,
prepared from at least about 150 mL and less than about 250 mL
(e.g., about 200 mL) of pathogen-inactivated plasma of the present
disclosure and a second cryoprecipitate and/or cryo-poor plasma,
respectively, prepared from at least about 150 mL and less than
about 250 mL (e.g., about 200 mL) of pathogen-inactivated plasma of
the present disclosure. In some embodiments, the methods further
include combining a first cryoprecipitate and/or cryo-poor plasma,
respectively, prepared from at least about 550 mL and less than
about 650 mL of pathogen-inactivated plasma of the present
disclosure and a second cryoprecipitate and/or cryo-poor plasma,
respectively, prepared from at least about 550 mL and less than
about 650 mL of pathogen-inactivated plasma of the present
disclosure. In some embodiments, the first and the second
cryoprecipitates and/or cryo-poor plasma, respectively, are
combined prior to freezing the cryoprecipitate and/or cryo-poor
plasma. In certain embodiments, the first cryoprecipitate and/or
cryo-poor plasma, respectively, is prepared from about 600 mL of
pathogen-inactivated plasma of the present disclosure, and the
second cryoprecipitate and/or cryo-poor plasma, respectively, is
prepared from about 600 mL of pathogen-inactivated plasma of the
present disclosure.
[0124] In some embodiments, the methods further include combining a
first cryoprecipitate and/or cryo-poor plasma, respectively,
prepared or obtained from 1-3 (e.g., 3) units of
pathogen-inactivated plasma of the present disclosure and a second
cryoprecipitate and/or cryo-poor plasma, respectively, prepared or
obtained from 1-3 (e.g., 3) units of pathogen-inactivated plasma of
the present disclosure. In some embodiments, the first and the
second cryoprecipitates and/or cryo-poor plasma are combined prior
to freezing the cryoprecipitate.
[0125] In any of the methods of the present disclosure, the subject
may be a human. In other embodiments, the subject may be a
veterinary subject.
Cryoprecipitate and/or Cryo-Poor Plasma Processing
[0126] Cryoprecipitate and/or cryo-poor plasma processing and the
handling of blood products typically involves the use of blood
compatible bag systems, which are well known in the art, as
described, for example, in U.S. Pat. Nos. 5,405,343, 7,025,877, and
8,439,889, the disclosures of which are incorporated by reference
herein for the disclosure of blood handling bags and systems. In
general, a blood handling system includes more than one plastic
container, typically plastic bags, where the bags are integrally
connected with plastic tubing. Some of the containers described
herein include such plastic bags as are known in the storage and
handling of blood products, including cryoprecipitates. Blood
handling bags typically can be designed to hold various volumes of
fluid, including, but not limited to, volumes ranging from 50 mL to
2 liters, for example having up to a 1 liter capacity, up to a 1.5
liter capacity, or up to a 2 liter capacity. Examples of common
blood-collection bags include such bags with volumes of 350 mL, 450
mL and 500 mL, among others. It is understood that when a method
refers to a bag, it includes any such plastic bags used in blood
handling. Where such bags are referred to as "removal bag",
"product bag", "transfer bag", "collection bag," or "illumination
bag", it is understood that these bags are typical blood handling
bags, or are similar to such bags in nature. Plastic bags suitable
for use according to the present disclosure include for example,
those comprising PL2410, as well as other suitable plastics known
in the art. Plastic bag materials include polyvinyl chloride,
polyolefins, ethylene vinyl acetate, ethylene vinyl acetate blended
with other plastics, and the like.
[0127] As described herein, where tubing is described as connecting
e.g. two bags of a processing set, it is understood that the tubing
may be joined at some point therebetween by another component of
the connection between the two bags. For example, a removal bag
connected to a product bag by tubing includes wherein the tubing
comprises a filter between the two bags, i.e. the tubing is divided
by a filter such that fluid flows from one bag to the other through
the tubing and filter. In one example, tubing connecting a removal
bag and a product bag can include a filter to remove any loose
particles from fluid flowing from the removal device to the product
bag, i.e. the tubing is divided by, or interrupted by the filter
between the bags. Such filters are designed to remove any small
particles that may come off of the removal device, while allowing
platelets to pass through the filter. The tubing between bags
allows for fluid to flow from one bag to another, which can be
blocked to prevent the flow until necessary, e.g. as part of the
processing the fluid in one bag may be prevented from flowing to
the next bag until required for the next step in a process. As such
an openable seal, such as a clamp, plug, valve or the like is
included in or on the tubing connecting the bags, where the clamp,
plug, valve or the like can be selectively opened as required, for
example to transfer the fluid from one bag to the next. In certain
preferred embodiments, the tubing between bags comprises a
breakable seal, such as a breakable valve, whereupon breaking the
breakable seal allows for the blood solution to flow between the
bags through the tubing. It is understood that the breakable seal
is contained within the connection between containers, such that
sterility of the system is maintained. It is also understood that a
tubing comprising a filter, or a breakable seal, includes where the
tubing may be interrupted by the filter or the seal, for example
the tubing runs from one bag and is connected to the filter or seal
(an incoming portion of the tubing), and the tubing continues from
another portion of the filter or seal to another bag (an outgoing
portion of the tubing). In such a configuration, fluid flows from
the first bag, through the incoming portion of the tubing, through
the filter or seal, and through the outgoing portion of the tubing
and into the other bag.
[0128] Different bags within a blood bag system can be used for
different steps of a process. For example, a system of bags to be
used for the pathogen inactivation of a unit of cryoprecipitate or
plasma can include a container with pathogen inactivation compound
contained within, a bag for receiving the unit of cryoprecipitate
or plasma and a pathogen inactivation compound (e.g. an
illumination bag), a bag for the illumination of the unit of
cryoprecipitate or plasma when the pathogen inactivation method
includes illumination (e.g., an illumination bag, and typically the
same bag to receive the unit of cryoprecipitate or plasma and
pathogen inactivation compound), a bag for the removal of pathogen
inactivation compounds and/or by-products thereof from the treated
unit of cryoprecipitate or plasma (e.g., referred to as a removal
bag), and one or more bags for containing the final cryoprecipitate
or plasma product, i.e. the pathogen inactivated cryoprecipitate or
plasma unit that has the concentration of the inactivation compound
and/or by-products thereof reduced to below a desired
concentration, which is ready for use, can be stored for later use
(e.g., referred to as a product bag), or in the case of plasma can
be used to generate a cryoprecipitate. Each bag in the system is
typically made up of a plastic material. For example, the container
for containing a solution of pathogen inactivation compound can be
made of a suitable plastic such as PL2411 (Baxter Healthcare), or
other plastics such as polyvinyl chloride, polyolefins, ethylene
vinyl acetate, ethylene vinyl acetate blended with other plastics,
and the like. This container is also overwrapped with a material
that is impermeable to light of a wavelength that will activate the
photoactive pathogen inactivation compound (for example suitable
plastic such as PL2420, Baxter Healthcare). The illumination bag
for a photoactivated pathogen inactivation compound requires a
clear, durable thermoplastic material that is translucent to light
of the selected wavelength. Suitable plastics that are translucent
to light in the UVA wavelength range include polyvinyl chloride,
polyolefins, ethylene vinyl acetate, ethylene vinyl acetate blended
with other plastics, or other blends of thermoplastic polymers.
Such suitable plastics include PL2410 (Baxter Healthcare) and PL732
(Baxter Healthcare). Similar materials may be used to make the
removal bag and the product bag. The product bags include those
made of PL2410. Suitable bag materials are discussed, for example,
in PCT publication number WO 2003078023, and U.S. Pat. No.
7,025,877, the disclosures of which are hereby incorporated by
reference as it relates to such bag materials and related
materials. In all cases, the materials used in preparing the
processing set have to be sterilizable by known methods such as
steam and gamma or electron beam radiation used to ensure sterility
of the processing set. While these are exemplary materials for
making the bags, the methods described herein are applicable to
processes using any suitable bag material as would be readily
available to one skilled in the art, and can also be used with
containers other than bags. The bags used for illumination,
removal, and storage are also designed to allow for gases such as
oxygen and carbon dioxide to go into and out of the blood bag, so
that the blood products therein have adequate oxygen supply and
carbon dioxide levels during the processing and storage.
Pathogen Inactivation
[0129] Blood products, including cryoprecipitate, cryo-poor plasma,
or plasma blood products such frozen plasma (e.g., FFP, PF24), may
contain pathogens, or may be contaminated with pathogens during
processing. As such, it is desirable to subject such blood products
to a process in order to reduce the risk of transfusion-transmitted
diseases. In some embodiments, plasma may be subjected to one or
more treatments to inactivate pathogens (i.e., pathogen
inactivation, pathogen reduction). In some embodiments, the
pathogen-inactivated plasma may then be used to produce a
cryoprecipitate and a cryo-poor plasma, as described herein. In
some embodiments, cryoprecipitate and/or cryo-poor plasma may be
subjected to one or more treatments to inactivate pathogens (i.e.,
pathogen inactivation, pathogen reduction).
[0130] Various methods are available to mitigate the risk of
transfusion-associated disease transmission in cryoprecipitate,
cryo-poor plasma or plasma-containing blood products. Aside from
screening and detection of pathogens and subsequent elimination of
contaminated blood products, processes that incorporate treatments
to inactivate pathogens (i.e., pathogen inactivation, pathogen
reduction) that may be present are available. Ideally, such a
process results in the inactivation of a broad range of pathogens
such as viruses, bacteria and parasites that may be present in the
blood product. In certain embodiments, the method of pathogen
inactivation is based on a solvent/detergent process to treat
plasma (OCTAPLAS, Octapharma; Solheim et al., 2000, Transfusion,
40:84-90). In certain embodiments, the method of pathogen
inactivation is a methylene blue process to treat plasma
(THERAFLEX-MB, MacoPharma; Garwood et al., 2003, Transfusion
43:1238-1247). In certain embodiments, the method of pathogen
inactivation is based on a riboflavin/UV light process to treat
plasma (MIRASOL, TerumoBCT; Hornsey et al., 2009, Transfusion
49:2167-2172). In certain embodiments, the method of pathogen
inactivation requires addition of an amount of pathogen
inactivation compound to a unit of cryoprecipitate or plasma. For
example, pathogen inactivation may involve the addition of a low
molecular weight compound, such as for example a psoralen (e.g.,
amotosalen) that inactivates various pathogens (INTERCEPT Blood
System, Cerus Corporation; Mintz et al., 2006, Transfusion
46:1693-1704).
[0131] In some embodiments, pathogen inactivation may involve
photochemical inactivation (e.g., photoinactivation), which
involves the addition of a photosensitizer that, when activated by
illumination using light of suitable wavelengths, will inactivate a
variety of pathogens that may be present. Two such methods include
the addition of amotosalen or riboflavin to the blood product, with
subsequent illumination with UV light. Other methods include
illumination with UV light without addition of a photosensitizer,
as well as illumination with other photoactive compounds, including
psoralen derivatives other than amotosalen, isoalloxazines other
than riboflavin, alloxazines, dyes such as phthalocyanines,
phenothiazine dyes (e.g. methylene blue, azure B, azure C,
thionine, toluidine blue), porphyrin derivatives (e.g.
dihematoporphyrin ether, hematoporphyrin derivatives,
benzoporphyrin derivatives, alkyl-substituted sapphyrin), and
merocyanine 540 (Prodouz et al., Blood Cells 1992, 18(1):101-14;
Sofer, Gail, BioPharm, August 2002).
[0132] In some embodiments, the pathogen inactivation is carried
out using an INTERCEPT.RTM. Blood System (Cerus), such as the
INTERCEPT.RTM. Blood System for Plasma. The INTERCEPT.RTM. Blood
System is well known in the art as a system for pathogen
inactivation, with widespread adoption in European blood centers
and FDA approval in the United States. For greater description of
the INTERCEPT.RTM. Blood System and pathogen inactivation methods
and compositions related thereto, see, e.g., U.S. Pat. Nos.
5,399,719, 5,556,993, 5,578,736, 5,585,503, 5,593,823, 5,625,079,
5,654,443, 5,712,085, 5,871,900, 5,972,593, 6,004,741, 6,004,742,
6,017,691, 6,194,139, 6,218,100, 6,503,699, 6,544,727, 6,951,713,
7,037,642, and 7,611,831; and PCT publication numbers WO
1995000141, WO 1996014739, WO 1997021346, WO 1998030327, WO
1999034914, and WO1999034915, the disclosures of each of which are
hereby incorporated by reference as they relate to pathogen
inactivation in blood products.
[0133] As described above, plasma or cryoprecipitate or cryo-poor
plasma may be subjected to pathogen inactivation. An exemplary
process for using the INTERCEPT.RTM. Blood System to pathogen
inactivate plasma is as follows. A sample of plasma (e.g.,
containing one or more than one plasma units, AABB units) in the
illumination container may be brought into contact with amotosalen
from the amotosalen container (e.g., by connecting through tubing
and breaking the amotosalen container cannula to release the
amotosalen). After sealing the illumination container, it may be
illuminated with UV according to manufacturer's protocols. Once
illuminated, the plasma may be transferred through tubing into one
or more storage containers through a compound adsorption device
(CAD). Optionally, if more than one storage container of plasma is
to be pooled, they may be pooled into a larger blood bag (e.g., a
600-650 mL bag for three plasma units, e.g., 200 mL units, AABB
plasma units; such as a 600 mL PVC transfer pack). Cryoprecipitate
may then be prepared (e.g., in the larger blood bag) as described
herein. Liquid plasma may then be removed, e.g., by draining into
one or more bags. Optionally, more than one cryoprecipitate sample
may be produced; if so, the individual cryoprecipitates samples may
be combined in a single container through use of a sterile
dock/tubing. Cryoprecipitate may then be frozen and stored. It will
be understood by one of skill in the art that alternative steps,
combinations of steps, and order of steps may be followed.
[0134] In some embodiments, plasma or cryoprecipitate or cryo-poor
plasma may be pathogen-inactivated in a container (e.g., a blood
bag or other container described herein) suitable for photochemical
inactivation of plasma under sterile conditions. This container may
be coupled to a CAD (e.g., as described and/or referenced above)
such that plasma can be transferred from the container to the CAD
under sterile conditions. In some embodiments, the CAD may further
be coupled to one or more second containers, such that the plasma
can be transferred from the CAD to the one or more second
containers under sterile conditions. For example, one 600 mL PVC
transfer pack or other larger blood bag may be used for a single
second container, or more than one (e.g., three) smaller blood bags
(e.g., sized for one AABB unit) may be used as second containers.
The one or more second containers may be suitable for freezing
pathogen-inactivated plasma followed by thawing the
pathogen-inactivated plasma under conditions that provide for the
formation of cryoprecipitate. In some embodiments, a third
container may be coupled to the one or more second containers, such
that the pathogen-inactivated plasma can be transferred from the
CAD to the one or more second containers to the third container
under sterile conditions. The third container may be suitable for
freezing pathogen-inactivated plasma followed by thawing the
pathogen-inactivated plasma under conditions that provide for the
formation of cryoprecipitate. For example, pathogen-inactivated
plasma from multiple (e.g., three) second containers may be
transferred to and combined within a larger third container (e.g.,
a 600-650 mL bag) for subsequent cryoprecipitate preparation.
[0135] Other pathogen inactivation systems include, for example,
those described in PCT publication numbers WO 2012071135; WO
2012018484; WO 2003090794; WO 2003049784; WO 1998018908; WO
1998030327; WO 1996008965; WO 1996039815; WO 1996039820; WO
1996040857; WO 1993000005; US patent application number US
20050202395; and U.S. Pat. Nos. 8,296,071 and 6,548,242, the
disclosures of which are hereby incorporated by reference as they
relate to pathogen inactivation in blood products. Where addition
of a compound to the blood product is used for pathogen
inactivation, whether the method requires illumination or not, in
some instances it is desirable to remove any residual pathogen
inactivation compound or by-product thereof.
[0136] Some pathogen inactivation methods may require the use of a
removal device, i.e. a device for reducing the concentration of
pathogen inactivation compound, such as a small organic compound,
and by-products thereof, in a unit of cryoprecipitate or plasma
while substantially maintaining a desired biological activity of
the cryoprecipitate or plasma. In some instances, the removal
device comprises porous adsorbent particles in an amount sufficient
to reduce the pathogen inactivation compound to below a desired
concentration, wherein the adsorbent particles have an affinity for
the pathogen inactivation compound, where it is understood that
such adsorbent particle can be selected to best adsorb the compound
or compounds to be removed, with minimal effect on components that
should not be removed or damaged by contact with the adsorbent
particle. A variety of adsorbent particles are known, including
generally particles made from any natural or synthetic material
capable of interacting with compounds to be removed, including
particulates made of natural materials such as activated carbon,
silica, diatomaceous earth, and cellulose, and synthetic materials
such as hydrophobic resins, hydrophilic resins or ion exchange
resins. Such synthetic resins include, for example, carbonaceous
materials, polystyrene, polyacrylic, polyacrylic ester, cation
exchange resin, and polystyrene-divinylbenzene. Detailed
description of such removal devices suitable for use in the methods
as described herein can be found in PCT publication numbers WO
1996040857, WO 1998030327, WO 1999034914, and WO 2003078023, the
disclosures of which are hereby incorporated by reference with
respect to the discussion of such removal devices and the adsorbent
particles and other materials used to prepare such devices.
Exemplary adsorbent particles include, but are not limited to,
Amberlite (Rohm and Haas) XAD-2, XAD-4, XAD-7, XAD-16, XAD-18,
XAD-1180, XAD-1600, XAD-2000, XAD-2010; Amberchrom (Toso Haas)
CG-71m, CG-71c, CG-161m, CG161c; Diaion Sepabeads (Mitsubishi
Chemicals) HP20, SP206, SP207, SP850, HP2MG, HP20SS, SP20MS; Dowex
(Dow Chemical) XUS-40285, XUS-40323, XUS-43493 (also referred to as
Optipore V493 (dry form) or Optipore L493 (hydrated form)),
Optipore V503, Optipore SD-2; Hypersol Macronet (Purolite) MN-100,
MN-102, MN-150, MN-152, MN-170, MN-200, MN-202, MN-250, MN-252,
MN-270, MN-300, MN-400, MN-500, MN-502, Purosorb (Purolite) PAD
350, PAD 400, PAD 428, PAD 500, PAD 550, PAD 600, PAD 700, PAD 900,
and PAD 950. The material used to form the immobilized matrix
comprises a low melting polymer, such as nylon, polyester,
polyethylene, polyamide, polyolefin, polyvinyl alcohol, ethylene
vinyl acetate, or polysulfone. In one example, the adsorbent
particles immobilized in a matrix are in the form of a sintered
medium. While it is understood that the methods and devices
described herein encompass removal devices as are known in the art,
such methods and devices may be exemplified using the removal
device of an amotosalen inactivated blood product as is
commercially available. Some such removal devices contain Hypersol
Macronet MN-200 adsorbent contained within a sintered matrix, where
the sintered matrix comprises PL2410 plastic as a binder. In one
instance, the removal device comprises Hypersol Macronet MN-200
adsorbent in a sintered matrix comprising PL2410, wherein the
Hypersol Macronet MN-200 is in an amount of about 5 g dry weight
equivalent.
[0137] As various resins may require different processing when used
to make the removal devices useful in the methods and devices as
described herein, comparison of amounts of adsorbent resins
described herein, unless otherwise indicated, are comparison of the
dry weight of the resin. For example, the resins are dried to
<5% water prior to processing, and the equivalent of the dry
weight of adsorbent is used in comparing amounts of resin in use.
For example, Hypersol Macronet MN-200 is processed to stabilize the
adsorbent, or what is typically referred to as wetting the
adsorbent, so as to be directly usable upon contact with a blood
product unit. Such a wetted sample may include, for example, about
50% glycerol or other suitable wetting agent. In some embodiments,
the adsorbent resin is a polystyrene-divinylbenzene resin. In some
embodiments, the polystyrene-divinylbenzene resin is Hypersol
Macronet MN-200. In some embodiments, the adsorbent is contained
within a sintered matrix, wherein the sintered matrix comprises
PL2410 binder. In some embodiments, Hypersol Macronet MN-200
adsorbent is contained within a sintered matrix to provide a
removal device.
Cryosupernatant Preparation
[0138] It will be appreciated by one of skill in the art that, in
the process of generating a cryoprecipitate or cryoprecipitate
composition, a cryosupernatant (e.g., cryo-poor plasma,
cryo-reduced plasma) of the present disclosure is also produced or
formed. Such cryosupernatant may have medical uses of interest,
such as infusion into a patient.
[0139] As such, disclosed herein are methods of preparing a
cryo-poor plasma (e.g., pooled cryo-poor plasma, pooled
cryosupernatant) for infusion into a subject. In some embodiments,
the methods comprise combining at least a first plasma and a second
plasma, and subjecting the combined (e.g., pooled) plasma to a
pathogen inactivation process and freezing. In some embodiments,
the at least first and second plasmas have a combined volume of at
least about 550 mL and less than about 650 mL. In some embodiments,
the methods comprise freezing at least a first pathogen-inactivated
plasma and a second pathogen-inactivated plasma. In some
embodiments, the first and the second pathogen-inactivated plasmas
have a combined volume of at least about 550 mL and less than about
650 mL. In some embodiments, the first and the second
pathogen-inactivated plasmas each have a volume of at least about
550 mL and less than about 650 mL. In some embodiments, the first
and the second pathogen-inactivated plasmas have a combined volume
of about 600 mL. In some embodiments, the first and the second
pathogen-inactivated plasmas each have a volume of about 600 mL. In
some embodiments, three units (e.g., AABB plasma units) may be
used.
[0140] In some embodiments, the first and the second
pathogen-inactivated plasmas may then be thawed under conditions
that provide for the formation of cryoprecipitates (e.g., as
described herein). In some embodiments, each cryoprecipitate may
then be separated from the corresponding cryosupernatant. In some
embodiments, the two cryosupernatants may then be combined to form
a pooled cryosupernatant.
[0141] In some embodiments, two pooled cryosupernatants (prepared,
e.g., as described above) may be combined. For example, two pooled
cryosupernatants may be combined, where each of the pooled
cryosupernatants is obtained from pooling cryosupernatants obtained
from pathogen-inactivated plasmas totaling at least about 550 mL
and less than about 650 mL, e.g., as described above. As such, in
some embodiments, a pooled cryosupernatant may be obtained from
1100-1300 mL of pathogen-inactivated plasma.
[0142] In some embodiments, plasma or cryoprecipitate or cryo-poor
plasma may be pathogen-inactivated in a container (e.g., a blood
bag or other container described herein) suitable for photochemical
inactivation of plasma under sterile conditions. This container may
be coupled to a CAD (e.g., as described and/or referenced above)
such that plasma can be transferred from the container to the CAD
under sterile conditions. In some embodiments, this container may
be coupled to an additional (e.g., upstream) container suitable for
mixing the one or more units of plasma with a pathogen-inactivating
compound (e.g., as described and/or referenced herein). In some
embodiments, the additional container is coupled to the first
container such that the one or more units of plasma in admixture
with the pathogen-inactivating compound can be transferred from the
additional container to the first container under sterile
conditions. In some embodiments, the CAD may further be coupled to
one or more second containers, such that the plasma can be
transferred from the CAD to the one or more second containers under
sterile conditions. For example, one 600 mL PVC transfer pack or
other larger blood bag may be used for a single second container,
or more than one (e.g., three) smaller blood bags (e.g., sized for
one AABB unit) may be used as second containers. The one or more
second containers may be suitable for freezing pathogen-inactivated
plasma followed by thawing the pathogen-inactivated plasma under
conditions that provide for the formation of cryoprecipitate. In
some embodiments, a third container may be coupled to the one or
more second containers, such that the pathogen-inactivated plasma
can be transferred from the CAD to the one or more second
containers to the third container under sterile conditions. The
third container may be suitable for freezing pathogen-inactivated
plasma followed by thawing the pathogen-inactivated plasma under
conditions that provide for the formation of cryoprecipitate. For
example, pathogen-inactivated plasma from multiple (e.g., three)
second containers may be transferred to and combined within a
larger third container (e.g., a 600-650 mL bag) for subsequent
cryoprecipitate preparation. In some embodiments,
pathogen-inactivated cryo-poor plasma can be transferred from the
third container to a first of the two or more second containers,
and the precipitate can be transferred from the third container to
a second of the two or more second containers. In some embodiments
(e.g., when three or more second containers are used), the
pathogen-inactivated cryo-poor plasma is transferred from the third
container to each of two second containers and the precipitate is
transferred from the third container to a third second container.
In some embodiments, the precipitate (e.g., the precipitate in the
third second container) is resuspended in about 80 mL to about 120
mL of pathogen-inactivated plasma (e.g., in about 100 mL of
pathogen-inactivated plasma), where the pathogen-inactivated plasma
used for resuspension is optionally pathogen-inactivated cryo-poor
plasma from the third container.
[0143] In some embodiments, cryosupernatant may be separated from
cryoprecipitate in one or more fourth containers (e.g., one or more
600-650 mL bags). In some embodiments, the one or more fourth
containers may be configured to be coupled to one or more second
containers or a third container, as described above, such that the
supernatant can be transferred from the one or more second
containers or the third container to the one or more fourth
containers under sterile conditions to afford a
pathogen-inactivated cryosupernatant contained within the one or
more fourth containers and a pathogen-inactivated cryoprecipitate
contained within the one or more second containers or the third
container.
[0144] In some embodiments, a therapeutically effective amount of
pathogen-inactivated cryo-poor plasma is administered to a subject.
In some embodiments, the subject is suffering from one or more of
burns, blunt trauma, penetrating trauma, and hemorrhage. In some
embodiments, the administration results in fluid resuscitation of
the subject.
[0145] In some embodiments, prior to administering the
pathogen-inactivated cryo-poor plasma to a subject, the
pathogen-inactivated cryo-poor plasma is frozen (e.g., for frozen
storage) and thawed (e.g., from frozen storage). In some
embodiments, the pathogen-inactivated cryo-poor plasma is
administered within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days,
or 7 days after thawing.
[0146] Further disclosed herein are methods for infusing a
pathogen-inactivated plasma composition (e.g., frozen plasma, fresh
frozen plasma, PF24, apheresis plasma, cryo-poor plasma,
cryosupernatant) of the present disclosure into a subject.
Use of Plasma Compositions
[0147] Pathogen-inactivated plasma compositions of the present
disclosure may be used for treating a variety of diseases and
conditions. The pathogen-inactivated plasma compositions may
include for example a pathogen-inactivated frozen plasma (e.g.,
whole blood collected plasma), such as a fresh frozen plasma (e.g.,
FFP) or a plasma frozen within 24 hr (e.g., PF24), a
pathogen-inactivated apheresis collected plasma, and/or a plasma
supernatant from a cryoprecipitate process (e.g., cryosupernatant,
cryo-poor plasma). For example, pathogen-inactivated plasma
compositions of the present disclosure may be used for treating a
disease or condition indicated for treatment by plasma exchange
(e.g., therapeutic plasma exchange) in a subject in need thereof,
for example by administering to the subject a therapeutically
effective amount of the pathogen-inactivated plasma composition by
plasma exchange. In certain embodiments, the disease or condition
is indicated for treatment with albumin by plasma exchange.
Pathogen-inactivated plasma compositions of the present disclosure
may also be used for treating a disease or condition indicated for
treatment by intravenous infusion with immunoglobulin (e.g.,
intravenous immunoglobulin infusion, IVIG) in a subject in need
thereof, for example by administering to the subject a
therapeutically effective amount of the pathogen-inactivated plasma
composition by plasma exchange. In certain embodiments,
pathogen-inactivated plasma compositions of the present disclosure
may be used for treating a disease or condition that is
contra-indicated for treatment with a plasma (e.g., frozen plasma,
FFP, cryo-poor plasma), for example by administering a
therapeutically effective amount of the pathogen-inactivated plasma
composition to a subject suffering from the disease or condition by
plasma exchange. In some embodiments, a pathogen-inactivated plasma
composition of the present disclosure is administered to a subject
within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days
after thawing (e.g., from frozen storage).
[0148] Pathogen-inactivated plasma compositions of the present
disclosure also may be used for treating a neurologic disease or
condition. Non-limiting examples of neurologic diseases or
conditions include, for example, Guillain-Barre syndrome, chronic
inflammatory demyelinating polyneuropathy (CIDP), myasthenia
gravis, paraproteinemic polyneuropathy (e.g., polyneuropathy
associated with paraproteinaemias, paraproteinemic demyelinating
neuropathy), PANDAS, Lambert-Eaton myasthenic syndrome, acute
exacerbation of multiple sclerosis, chronic focal encephalitis
and/or neuromyelitis optica.
[0149] Pathogen-inactivated plasma compositions of the present
disclosure also may be used for treating a hematologic disease or
condition. Non-limiting examples of hematologic diseases or
conditions include, for example, hyperviscosity syndromes (e.g.,
paraproteinaemias, hyperviscosity in monoclonal gamopathies),
cryoglobulinaemia (e.g., severe/symptomatic), haemopoietic stem
cell transplantation (e.g., ABO-incompatible haemopoietic stem cell
transplantation), pure red cell aplasia, cold agglutinin disease
(e.g., life-threatening cold agglutinin disease), myeloma with cast
nephropathy, red cell alloimmunisation in pregnancy, alloimmune
thrombocytopenia and/or hemolytic disease of the newborn. Other
non-limiting examples of hematologic diseases or conditions
include, for example, thrombotic thrombocytopenic purpura (TTP) and
hemolytic uremic syndrome (e.g., HUS, atypical hemolytic uremic
syndrome, autoantibody to factor H).
[0150] Pathogen-inactivated plasma compositions of the present
disclosure also may be used for treating a renal disease or
condition. Non-limiting examples of renal diseases or conditions
include, for example, Goodpasture's syndrome, antineutrophil
cytoplasmic antibody (ANCA)-associated rapidly progressive
glomerulonephritis, recurrent focal segmental glomerular sclerosis
and/or antibody-mediated renal transplant rejection.
[0151] Pathogen-inactivated plasma compositions of the present
disclosure also may be used for treating a metabolic disease or
condition. Non-limiting examples of metabolic diseases or
conditions include, for example, familial hypercholesterolaemia
(e.g., homozygous), Wilson's disease (e.g., fulminant) and/or
Refsum's disease.
[0152] Pathogen-inactivated plasma compositions of the present
disclosure also may be used for treating an immunologic disease or
condition. Non-limiting examples of immunologic diseases or
conditions include, for example, catastrophic antiphospholipid
syndrome and/or cerebral systemic lupus erythematosus (SLE).
[0153] Pathogen-inactivated plasma compositions of the present
disclosure may be used for treating one or more of the following
diseases or conditions, whereby a therapeutically effective amount
of the pathogen-inactivated plasma composition is administered to a
subject in need thereof by plasma exchange (e.g., therapeutic
plasma exchange): Guillain-Barre syndrome, chronic inflammatory
demyelinating polyneuropathy (e.g., CIDP, chronic inflammatory
demyelinating polyradiculoneuropathy), myasthenia gravis,
paraproteinemic polyneuropathy (e.g., polyneuropathy associated
with paraproteinaemias, paraproteinemic demyelinating neuropathy),
polyneuropathy associated with monoclonal gammopathy of
undetermined significance (MGUS), PANDAS (Pediatric Autoimmune
Neuropsychiatric Disorders Associated with Streptococcal
Infections), hyperviscosity syndromes (e.g., paraproteinaemias,
hyperviscosity in monoclonal gamopathies), cryoglobulinaemia (e.g.,
severe, symptomatic), Goodpasture's syndrome, antineutrophil
cytoplasmic antibody (ANCA)-associated rapidly progressive
glomerulonephritis, recurrent focal segmental glomerular sclerosis,
antibody-mediated renal transplant rejection, familial
hypercholesterolaemia (e.g., homozygous), Wilson's disease (e.g.,
fulminant Wilson's disease), Lambert-Eaton myasthenic syndrome,
acute exacerbation of multiple sclerosis, chronic focal
encephalitis, neuromyelitis optica, haemopoietic stem cell
transplantation (e.g., ABO-incompatible haemopoietic stem cell
transplantation), pure red cell aplasia, cold agglutinin disease
(e.g., life-threatening cold agglutinin disease), hemolytic uremic
syndrome (e.g., HUS, atypical hemolytic uremic syndrome,
autoantibody to factor H), thrombotic thrombocytopenic purpura
(TTP), myeloma with cast nephropathy, red cell alloimmunisation in
pregnancy, catastrophic antiphospholipid syndrome, systemic lupus
erythematosus (e.g., cerebral systemic lupus erythematosus, SLE),
Refsum's disease, alloimmune thrombocytopenia, hemolytic disease of
the newborn, Kawasaki disease, toxic epidermal necrolysis, Stevens
Johnson syndrome (SJS), autoimmune haemolytic anaemia, clotting
(e.g., coagulation) factor inhibitors, haemophagocytic syndrome,
post-transfusion purpura, chronic inflammatory demyelinating
polyradiculoneuropathy, inflammatory myelopathies, multifocal motor
neuropathy, Rasmussen syndrome (e.g., Rasmussen encephalitis),
stiff person syndrome, autoimmune congenital heart block,
autoimmune uveitis, immunobullous diseases, necrotising
staphylococcal sepsis, Clostridium difficile colitis (e.g., severe,
recurrent), staphylococcal or streptococcal toxic shock syndrome,
immune-mediated solid organ transplant rejection (e.g., treating or
preventing antibody-mediated rejection after solid organ
transplantation, treating or preventing ABO-incompatible solid
organ transplant rejection, treating or preventing HLA-incompatible
solid organ transplant rejection, desensitization to solid organ
transplant), Wegener's granulomatosis, cryoglobulinemia, focal
segmental glomerulosclerosis (e.g., recurrent), thrombotic
microangiopathy (TMA) (e.g., drug-associated TMA), B-cell chronic
lymphocytic leukemia (CLL), multifocal motor neuropathy (MMN),
asthma, treatment or prevention of acute graft versus host disease
(GVHD) and/or infection after allogeneic bone marrow transplant
(BMT), myositis (e.g., dermatomyositis, polymyositis), CMV induced
pneumonitis in solid organ transplantation (SOT), rheumatoid
arthritis, Lambert-Eaton myasthenic syndrome (LEMS), Still's
disease, vasculitides, bacterial infection in pediatric HIV (e.g.,
prevention), inclusion body myositis (IBM), acute disseminated
encephalomyelitis, cardiomyopathy (e.g., dilated cardiomyopathy,
idiopathic dilated cardiomyopathy), Henoch-Schonlein purpura (e.g.,
HSP, anaphylactoid purpura, purpura rheumatica), hyperleukocytosis,
nephrogenic systemic fibrosis, paraneoplastic neurological
syndromes, Sydenham's chorea, scleroderma, sudden sensorineural
hearing loss, acute liver failure, aplastic anemia, burn shock
resuscitation, cardiac transplant (e.g., treating or preventing
ABO-incompatible cardiac transplant rejection, treating or
preventing HLA-incompatible cardiac transplant rejection,
desensitization to transplant), heparin-induced thrombocytopenia,
hypertriglyceridemic pancreatitis, liver transplant (e.g., treating
or preventing ABO-incompatible liver transplant rejection, treating
or preventing HLA-incompatible liver transplant rejection,
desensitization to transplant), lung allograft rejection, pemphigus
vulgaris, poisoning, overdose, envenomation, renal transplant
(e.g., treating or preventing ABO-incompatible renal transplant
rejection, treating or preventing HLA-incompatible renal transplant
rejection, desensitization to transplant), thyroid storm, sepsis
(e.g., sepsis with multi-organ failure), immune complex rapidly
progressive glomerulonephritis.
[0154] In certain embodiments, pathogen-inactivated plasma
compositions of the present disclosure may be used for treating a
disease or condition selected from the group consisting of
Guillain-Barre syndrome, chronic inflammatory demyelinating
polyneuropathy (e.g., CIDP, chronic inflammatory demyelinating
polyradiculoneuropathy), myasthenia gravis, paraproteinemic
polyneuropathy (e.g., polyneuropathy associated with
paraproteinaemias, paraproteinemic demyelinating neuropathy),
polyneuropathy associated with monoclonal gammopathy of
undetermined significance (MGUS), PANDAS (Pediatric Autoimmune
Neuropsychiatric Disorders Associated with Streptococcal
Infections), hyperviscosity syndromes (e.g., paraproteinaemias,
hyperviscosity in monoclonal gamopathies), cryoglobulinaemia (e.g.,
severe, symptomatic), Goodpasture's syndrome, antineutrophil
cytoplasmic antibody (ANCA)-associated rapidly progressive
glomerulonephritis, recurrent focal segmental glomerular sclerosis,
antibody-mediated renal transplant rejection, familial
hypercholesterolaemia (e.g., homozygous), Wilson's disease (e.g.,
fulminant Wilson's disease), Lambert-Eaton myasthenic syndrome,
acute exacerbation of multiple sclerosis, chronic focal
encephalitis, neuromyelitis optica, haemopoietic stem cell
transplantation (e.g., ABO-incompatible haemopoietic stem cell
transplantation), pure red cell aplasia, cold agglutinin disease
(e.g., life-threatening cold agglutinin disease), myeloma with cast
nephropathy, red cell alloimmunisation in pregnancy, catastrophic
antiphospholipid syndrome, systemic lupus erythematosus (e.g.,
cerebral systemic lupus erythematosus, SLE), Refsum's disease,
alloimmune thrombocytopenia, hemolytic disease of the newborn,
Kawasaki disease, toxic epidermal necrolysis, Stevens Johnson
syndrome (SJS), autoimmune haemolytic anaemia, clotting (e.g.,
coagulation) factor inhibitors, haemophagocytic syndrome,
post-transfusion purpura, chronic inflammatory demyelinating
polyradiculoneuropathy, inflammatory myelopathies, multifocal motor
neuropathy, Rasmussen syndrome (e.g., Rasmussen encephalitis),
stiff person syndrome, autoimmune congenital heart block,
autoimmune uveitis, immunobullous diseases, necrotising
staphylococcal sepsis, Clostridium difficile colitis (e.g., severe,
recurrent), staphylococcal or streptococcal toxic shock syndrome,
immune-mediated solid organ transplant rejection (e.g., treating or
preventing antibody-mediated rejection after solid organ
transplantation, treating or preventing ABO-incompatible solid
organ transplant rejection, treating or preventing HLA-incompatible
solid organ transplant rejection, desensitization to solid organ
transplant), Wegener's granulomatosis, cryoglobulinemia, focal
segmental glomerulosclerosis (e.g., recurrent), thrombotic
microangiopathy (TMA) (e.g., drug-associated TMA), B-cell chronic
lymphocytic leukemia (CLL), multifocal motor neuropathy (MMN),
asthma, treatment or prevention of acute graft versus host disease
(GVHD) and/or infection after allogeneic bone marrow transplant
(BMT), myositis (e.g., dermatomyositis, polymyositis), CMV induced
pneumonitis in solid organ transplantation (SOT), rheumatoid
arthritis, Lambert-Eaton myasthenic syndrome (LEMS), Still's
disease, vasculitides, bacterial infection in pediatric HIV (e.g.,
prevention), inclusion body myositis (IBM), acute disseminated
encephalomyelitis, cardiomyopathy (e.g., dilated cardiomyopathy,
idiopathic dilated cardiomyopathy), Henoch-Schonlein purpura (e.g.,
HSP, anaphylactoid purpura, purpura rheumatica), hyperleukocytosis,
nephrogenic systemic fibrosis, paraneoplastic neurological
syndromes, Sydenham's chorea, scleroderma, sudden sensorineural
hearing loss, acute liver failure, aplastic anemia, burn shock
resuscitation, cardiac transplant (e.g., treating or preventing
ABO-incompatible cardiac transplant rejection, treating or
preventing HLA-incompatible cardiac transplant rejection,
desensitization to transplant), heparin-induced thrombocytopenia,
hypertriglyceridemic pancreatitis, liver transplant (e.g., treating
or preventing ABO-incompatible liver transplant rejection, treating
or preventing HLA-incompatible liver transplant rejection,
desensitization to transplant), lung allograft rejection, pemphigus
vulgaris, poisoning, overdose, envenomation, renal transplant
(e.g., treating or preventing ABO-incompatible renal transplant
rejection, treating or preventing HLA-incompatible renal transplant
rejection, desensitization to transplant), thyroid storm, sepsis
(e.g., sepsis with multi-organ failure), immune complex rapidly
progressive glomerulonephritis.
[0155] In certain embodiments, pathogen-inactivated plasma
compositions of the present disclosure may be used for treating
hemolytic uremic syndrome (e.g., HUS, atypical hemolytic uremic
syndrome, autoantibody to factor H) or thrombotic thrombocytopenic
purpura (TTP). For example, in some embodiments, the disclosure
provides a method of treating thrombocytopenic purpura (TTP) or
hemolytic-uremic syndrome (HUS) in a subject, comprising
administering to a subject in need thereof a therapeutically
effective amount of pathogen-inactivated plasma composition. In
some embodiments, the pathogen-inactivated plasma composition
comprises pathogen-inactivated cryo-poor plasma. In some
embodiments, the pathogen-inactivated plasma composition is
administered by plasma exchange.
[0156] Treatment with a pathogen-inactivated plasma composition of
the present disclosure may be accomplished by administering a
therapeutically effective amount of the pathogen-inactivated plasma
by plasma exchange (e.g., therapeutic plasma exchange) to a subject
in need thereof. In certain embodiments, a pathogen-inactivated
plasma composition of the present disclosure may be administered in
conjunction with (e.g., concurrently with, consecutively with,
after) the administration of immunoglobulin by intravenous infusion
(e.g., intravenous immunoglobulin infusion, IVIG).
[0157] Therapeutic plasma exchange is a treatment process well
known in the art, whereby blood is separated into plasma and
cellular components, followed by mixing of the cellular components
with a replacement fluid and reinfusion into the patient (Winters,
2012, Hematology ASH Education Book 2012:7-12). TPE is generally an
automated process performed using commercially available apheresis
(e.g., plasmapheresis) devices, which can be divided into two broad
categories: those that use filters to separate the plasma from the
cellular components based on size, and those that use
centrifugation to separate components based on density.
[0158] A plasma exchange using a plasma composition of the present
disclosure may be performed using a variety of pathogen-inactivated
plasma composition volumes, such as for example volumes of the
plasma composition greater than to about equal to (e.g., 1-2 times,
1-1.5 times) or less than to about equal to (e.g., 0.5-1 times) the
subject's plasma volume. For example, in certain embodiments plasma
exchange may be achieved with a volume of the plasma composition
similar to the subject's plasma volume. Alternatively or in
addition, plasma exchange may be achieved with a volume of the
plasma composition more than the subject's plasma volume. For
example, plasma exchange may be achieved with a volume of the
plasma composition about 1 times, about 1.1 times, about 1.2 times,
about 1.3 times, about 1.4 times, about 1.5 times, about 1.6 times,
about 1.7 times, about 1.8 times, about 1.9 times, or about 2 times
the subject's plasma volume. Alternatively or in addition, plasma
exchange may be achieved with a volume of the plasma composition
less than the subject's plasma volume. For example, plasma exchange
may be achieved with a volume of the plasma composition about 0.9
times, about 0.8 times, about 0.7 times, about 0.6 times or about
0.5 times less than the subject's plasma volume. Plasma exchange
volumes may also be indicated as volume per patient weight. For
example, plasma exchange may be achieved with a volume of the
plasma composition comprising about 20 mL/kg, about 25 mL/kg, about
30 mL/kg, about 35 mL/kg, about 40 mL/kg, about 45 mL/kg, about 50
mL/kg, about 55 mL/kg, about 60 mL/kg, about 65 mL/kg, about 70
mL/kg, about 75 mL/kg or about 80 mL/kg patient body weight.
[0159] A plasma exchange of the present disclosure may be performed
one time or more than one time, for example, the plasma exchange
may be performed at least two times, at least three times, at least
four times or at least five times or more. In certain embodiments,
the plasma exchange is performed 2-5 times. When multiple plasma
exchanges (e.g., 2-5 plasma exchanges) are used, the multiple
plasma exchanges may be performed within a defined period of time.
For example, a plasma exchange may be performed 2-5 times within a
period of 4 weeks, within a period or three weeks, within a period
of two weeks or within a period of one week. In certain
embodiments, five plasma exchanges are performed within a period of
4 weeks, within a period or three weeks, within a period of two
weeks or within a period of one week. In certain embodiments, four
plasma exchanges are performed within a period of 4 weeks, within a
period or three weeks, within a period of two weeks or within a
period of one week. In certain embodiments, three plasma exchanges
are performed within a period of 4 weeks, within a period or three
weeks, within a period of two weeks or within a period of one week.
In certain embodiments, two plasma exchanges are performed within a
period of 4 weeks, within a period or three weeks, within a period
of two weeks or within a period of one week.
[0160] Certain aspects of the present disclosure relate to methods
of treating a subject suffering from a trauma. In some embodiments,
the methods include administering to the subject a therapeutically
effective amount of a pathogen-inactivated plasma composition of
the present disclosure. For example, in some embodiments, the
subject is suffering from burns (including without limitation major
burns, e.g., .gtoreq.20% of total body surface area), blunt trauma,
or penetrating trauma. In some embodiments, the subject is
suffering from hemorrhage, e.g., internal hemorrhage.
[0161] Certain aspects of the present disclosure relate to methods
of treating a subject suffering from burns. In some embodiments,
the methods include administering to the subject a therapeutically
effective amount of a pathogen-inactivated plasma composition of
the present disclosure. For example, in some embodiments, the burns
include major burns, e.g., .gtoreq.20% of total body surface
area.
[0162] In some embodiments, the methods include fluid
resuscitation. In some embodiments, the methods reduce hemorrhage,
hemorrhagic shock, and/or endothelial permeability in the subject.
In some embodiments, the methods reduce or prevent traumatic
coagulopathy in the subject. In some embodiments, treatment with a
method of the present disclosure results in decreased subject
mortality (e.g., increased survival rate).
[0163] Certain aspects of the present disclosure relate to methods
of resuscitation from hemorrhagic shock in a subject suffering from
a trauma, e.g., hemorrhagic shock. In some embodiments, the methods
include administering to the subject a therapeutically effective
amount of a pathogen-inactivated plasma composition of the present
disclosure. In some embodiments, the subject is suffering from
internal hemorrhage.
[0164] Certain aspects of the present disclosure relate to methods
of resuscitation suffering from burns. In some embodiments, the
methods include administering to the subject a therapeutically
effective amount of a pathogen-inactivated plasma composition of
the present disclosure. For example, in some embodiments, the burns
include major burns, e.g., .gtoreq.20% of total body surface
area.
[0165] In some embodiments, the methods reduce hemorrhage and/or
endothelial permeability in the subject. In some embodiments, the
methods reduce or prevent trauma-induced endotheliopathy and/or
traumatic coagulopathy in the subject. In some embodiments,
treatment with a method of the present disclosure results in
decreased subject mortality (e.g., increased survival rate).
[0166] In some embodiments, a therapeutically effective amount of a
pathogen-inactivated plasma composition comprising
pathogen-inactivated frozen plasma is administered to a subject. In
some embodiments, the pathogen-inactivated plasma composition
comprises pathogen-inactivated fresh frozen plasma. In some
embodiments, the pathogen-inactivated plasma composition comprises
pathogen-inactivated cryo-poor plasma as described herein.
[0167] In some embodiments, a pathogen-inactivated plasma
composition of the present disclosure is administered after
freezing, optional storage, and thawing. For example, in some
embodiments, a pathogen-inactivated plasma composition of the
present disclosure is administered within 1 day, 2 days, 3 days, 4
days, 5 days, 6 days, or 7 days after thawing (e.g., post-storage
thawing as described herein). In other embodiments, the
pathogen-inactivated plasma composition is a lyophilized or
freeze-dried plasma composition. For example, in some embodiments,
a pathogen-inactivated plasma composition of the present disclosure
is administered within 1 day, 2 days, 3 days, 4 days, 5 days, 6
days, or 7 days after reconstitution. In some embodiments, a
pathogen-inactivated plasma composition of the present disclosure
is first administered less than 24 hours after the onset of trauma
(e.g., an event which resulted in trauma).
[0168] Treatment of trauma in a subject using a
pathogen-inactivated plasma composition of the present disclosure
may be performed using a variety of volumes. For example, in
certain embodiments the volume of the plasma composition
administered (e.g., infused) may comprise a volume required to
achieve an increase in blood pressure (e.g., systolic blood
pressure) to a desired level, such as for example, to at least 50
mmHg, at least 55 mmHg, at least 60 mmHg, at least 65 mmHg, at
least 70 mmHg, at least 75 mmHg, at least 80 mmHg, at least 85
mmHg, at least 90 mmHg, at least 95 mmHg, or at least 100 mmHg. In
certain embodiments, additional volumes of the plasma composition
may be administered to maintain the blood pressure at a desired
level, such as any of the aforementioned levels. Alternatively or
in addition, the volume of plasma composition administered may
comprise the volume required to achieve and/or maintain a palpable
pulse (e.g., radial pulse), for example a palpable pulse of a
desired strength (e.g., such that it is no longer faint or weak) as
determined by medical personnel. In some embodiments,
administration of the plasma composition is in conjunction with one
or more other medically accepted bleeding control procedures.
[0169] Alternatively or in addition, in subjects suffering from
burns, such as for example, major burns (e.g., burns.gtoreq.20% of
total body surface area, TBSA), the volume of a
pathogen-inactivated plasma composition administered may be
calculated prior to administration, for example, based on the
subject's weight and the % TBSA of the burns. For example, the
volume of plasma administered may be in a range of about 1-5 mL per
kg subject body weight per % burn TBSA (mL/kg/% burn), about 2-5
mL/kg/% burn, about 2-4 mL/kg/% burn, about 2-3 mL/kg/% burn, or
about 3-4 mL/kg/% burn, or about 1 mL/kg/% burn, about 2 mL/kg/%
burn, about 3 mL/kg/% burn, about 4 mL/kg/% burn, or about 5
mL/kg/% burn.
[0170] Alternatively or in addition, the volume of a
pathogen-inactivated plasma composition of the present disclosure
may be titrated as an amount to maintain renal perfusion to obtain
a target urinary output, such as for example about 0.5 ml/kg/hr for
adults or about 1 ml/kg/hr for young pediatric patients.
[0171] Administration of a pathogen-inactivated plasma composition
of the present disclosure may be about 1 hour, about 2 hours, about
3 hours, about 4 hours, about 5 hours, about 6 hours, about 8
hours, about 10 hours, about 12 hours, about 16 hours, about 20
hours, about 24 hours, about 36 hours, about 48 hours, about 72
hours, about 96 hours or about 120 hours after the onset of trauma
(e.g., medical diagnosis of trauma, event which resulted in onset
of trauma). Alternatively or in addition, administration of a
pathogen-inactivated plasma composition may be initiated within
(e.g., less than) about 24 hours, within about 20 hours, within
about 16 hours, within about 12 hours, within about 10 hours,
within about 8 hours, within about 6 hours, within about 5 hours,
within about 4 hours, within about 3 hours, within about 2 hours or
within about 1 hours after the onset of trauma.
[0172] Administration of a desired volume of a pathogen-inactivated
plasma composition of the present disclosure may be achieved by
administering more than one unit of a pathogen-inactivated plasma
composition. For example, at least two, at least three, at least
four, at least 5 or more units many be administered to the subject.
Administration of the desired volume occur over a desired time
period, such as for example, over a period of about 1 hour, about 2
hours, about 3 hours, about 4 hours, about 6 hours, about 8 hours,
about 10 hours, about 12 hours, about 16 hours, about 20 hours, or
about 24 hours or more. In certain embodiments, administration of a
desired volume may be divided between two time periods, such as for
example, half of the desired volume within 8 hours of trauma onset
and the other half within 24 hours of trauma onset.
[0173] In some embodiments, administration of a
pathogen-inactivated plasma composition of the present disclosure
is followed by administration of at least one additional
intravenous fluid. Suitable intravenous fluids are known in the art
and can include, without limitation, colloid such as albumin or
starch, or crystalloid such as Ringer's lactate or Hartmann
solution.
Processing Sets
[0174] Certain aspects of the present disclosure relate to
processing sets. The processing sets of the present disclosure may
find use, inter alia, in preparing a pathogen-inactivated
cryoprecipitate, e.g., as described herein.
[0175] In some embodiments, a processing set of the present
disclosure includes a first container within which a psoralen of
the present disclosure can be photoactivated in the presence of one
or more units of plasma under sterile conditions (e.g., as
described and/or referenced herein). In some embodiments, the
processing set further includes a compound absorption device (CAD)
coupled to the first container such that the one or more units of
plasma can be transferred from the first container to the compound
absorption device under sterile conditions. In some embodiments,
the processing set further includes one or more second containers.
In some embodiments, each of the one or more second containers is
coupled to the compound absorption device such that the one or more
units of plasma can be transferred from the compound absorption
device to the one or more second containers under sterile
conditions, e.g., to provide pathogen-inactivated plasma suitable
for infusion into a subject. As non-limiting examples, the one or
more second containers could include one 600 mL PVC transfer pack
or other larger blood bag, or more than one (e.g., three) smaller
blood bags (e.g., sized for one AABB unit). In some embodiments,
the one or more second containers are suitable for freezing the
pathogen-inactivated plasma followed by thawing of the
pathogen-inactivated plasma under conditions that provide for the
formation of a precipitate and a supernatant.
[0176] In some embodiments, a processing set of the present
disclosure further includes a third container. In some embodiments,
the third container is configured to be coupled to the one or more
second containers such that the pathogen-inactivated plasma can be
transferred from the one or more second containers to the third
container under sterile conditions. In some embodiments, the third
container is suitable for freezing the pathogen-inactivated plasma
followed by thawing of the pathogen-inactivated plasma under
conditions that provide for the formation of a precipitate and a
supernatant. In some embodiments, the third container may be e.g.,
a 600-650 mL bag.
[0177] In some embodiments, a processing set of the present
disclosure further includes one or more fourth containers. In some
embodiments, the one or more fourth containers are configured to be
coupled to the one or more second containers as described above or
to the third container as described above such that the supernatant
can be transferred from the one or more second containers or the
third container to the one or more fourth containers under sterile
conditions, e.g., to afford a pathogen-inactivated cryosupernatant
of the present disclosure contained within the one or more fourth
containers and a pathogen-inactivated cryoprecipitate of the
present disclosure contained within the one or more second
containers or the third container. In some embodiments, the fourth
container is suitable for storage of a pathogen-inactivated
cryoprecipitate of the present disclosure under conditions in which
the pathogen-inactivated cryoprecipitate is frozen. In some
embodiments, two or more fourth containers are used. The two or
more fourth containers may be configured to be coupled to one
another while each of the two or more fourth containers contains
pathogen-inactivated cryoprecipitate such that the cryoprecipitate
contained within the two or more fourth containers can be combined
in one of the two or more fourth containers. In some embodiments, a
fourth container may be e.g., a 600-650 mL bag. Non-limiting
examples of processing sets of the present disclosure are as
follows.
[0178] In some embodiments, a processing set includes a first
container within which a psoralen can be photoactivated in the
presence of one or more units of plasma under sterile conditions; a
compound absorption device (CAD) coupled to the first container
such that the plasma can be transferred from the first container to
the compound absorption device under sterile conditions; one or
more second containers, each of which is coupled to the compound
absorption device such that the plasma can be transferred from the
compound absorption device to the one or more second containers
under sterile conditions to provide pathogen-inactivated plasma
suitable for infusion into a subject; and a third container, which
is configured to be coupled to the one or more second containers
such that the pathogen-inactivated plasma can be transferred from
the one or more second containers to the third container under
sterile conditions. In some embodiments, the one or more second
containers are suitable for freezing the pathogen-inactivated
plasma followed by thawing of the pathogen-inactivated plasma under
conditions that provide for the formation of a precipitate and a
supernatant. In some embodiments, the third container is coupled to
the one or more second containers such that the supernatant can be
transferred from the one or more second containers to the third
container under sterile conditions to afford a pathogen-inactivated
cryosupernatant contained within the third container and a
pathogen-inactivated cryoprecipitate contained within the one or
more second containers.
[0179] In other embodiments, a processing set includes a first
container within which a psoralen can be photoactivated in the
presence of one or more units of plasma under sterile conditions; a
compound absorption device (CAD) coupled to the first container
such that the plasma can be transferred from the first container to
the compound absorption device under sterile conditions; one or
more second containers, each of which is coupled to the compound
absorption device such that the plasma can be transferred from the
compound absorption device to the one or more second containers
under sterile conditions to provide pathogen-inactivated plasma
suitable for infusion into a subject; a third container, which is
configured to be coupled to the one or more second containers such
that the pathogen-inactivated plasma can be transferred from the
one or more second containers to the third container under sterile
conditions; and one or more fourth containers, each of which is
configured to be coupled to the third container such that the
supernatant can be transferred from the third container to the one
or more fourth containers under sterile conditions to afford a
pathogen-inactivated cryosupernatant contained within the one or
more fourth containers and a pathogen-inactivated cryoprecipitate
contained within the third container. In some embodiments, the
third container is suitable for freezing the pathogen-inactivated
plasma followed by thawing of the pathogen-inactivated plasma under
conditions that provide for the formation of a precipitate and a
supernatant.
[0180] Further non-limiting examples of processing sets are
illustrated in FIGS. 1A-3B. Exemplary processing set 100 shown in
FIG. 1A includes optional plasma bag 102 containing the donor
plasma to be pathogen inactivated, container 104 that contains a
pathogen inactivation compound (PIC, e.g., a psoralen), and bag 106
for photoactivation of the plasma (e.g., a first container of the
present disclosure). Photoactivation bag 106 is coupled to CAD 108
through tubing 110, which allows for the transfer of plasma after
photoactivation to the CAD. CAD 108 in turn is coupled to three
smaller blood bags 112, 114, and 116 (e.g., second containers of
the present disclosure) through tubing 118, which allows the plasma
to pass through the CAD (e.g., to remove free photoproducts and/or
unreacted pathogen inactivation compound) before being collected in
the smaller blood bags. Optional larger bag 122 for freezing the
plasma to form cryoprecipitate (e.g., a third container of the
present disclosure) and optional larger bag 124 for separating the
cryoprecipitate from the cryosupernatant (e.g., a fourth container
of the present disclosure), which may be sterile docked (e.g.,
using sterile connect 126) to the tubing between the CAD 108 and
the three-way lead 120 of tubing 118 after collection of the PI
plasma in the three bags, are also depicted.
[0181] An alternative configuration for processing set 100 is shown
in FIG. 1B, where the cryoprecipitate is separated from the
cryosupernatant by flowing the cryosupernatant from sterile-docked
third container 122 back into the three smaller bags 112, 114, and
116 (e.g., second containers of the present disclosure), rather
than into the optional fourth container 124.
[0182] In other embodiments, the cryoprecipitate is separated from
the cryosupernatant by flowing the cryosupernatant from
sterile-docked third container 122 back into smaller bags 112 and
114. The cryoprecipitate in 122 may then be resuspended in a small
volume of cryo-poor plasma supernatant (e.g., about 100 mL) and
transferred to smaller bag 116, resulting in two smaller bags 112
and 114 containing cryo-poor plasma (CPP) and smaller bag 116
containing resuspended cryoprecipitate.
[0183] Another alternative configuration for processing set 100 is
shown in FIG. 1C. This configuration includes optional container
128 that is sterile connected or docked with third container 122
through sterile connect 130. This configuration allows two
cryosupernatant preparations made from pathogen-inactivated plasma
(e.g., prepared in 122 and 128) to be combined.
[0184] The exemplary processing set 200 shown in FIG. 2A, includes
optional plasma bag 202 containing the donor plasma to be pathogen
inactivated, container 204 that contains a pathogen inactivation
compound (PIC), photoactivation bag 206, and CAD 208 coupled to
photoactivation bag 206 with tubing 210 as described above, and
additionally a pre-attached (e.g., integrated) third container 222.
After collection of the pathogen-inactivated plasma in the three
bags 212, 214, and 216, the three units of PI plasma are pooled by
transferring into larger bag 222 (e.g., a third container of the
present disclosure) for freezing to form cryoprecipitate and for
separating cryoprecipitate from the cryosupernatant. As shown in
FIG. 2B, cryosupernatant bag 224 (e.g., a fourth container of the
present disclosure) may be used to collect the cryosupernatant
after freezing (this is depicted as an optional component in FIG.
2A). This cryosupernatant bag may be connected to the larger
freezing bag via tubing with common tubing clamp 226. An
alternative configuration is shown in FIG. 2C, where the
cryoprecipitate is separated from the cryosupernatant by flowing
the cryosupernatant back into the three smaller bags 212, 214, and
216 (e.g., second containers of the present disclosure) using
tubing 228, rather than into the fourth container 224 shown in FIG.
2B.
[0185] The exemplary processing set 300 shown in FIG. 3A includes
optional plasma bag 302 containing the donor plasma to be pathogen
inactivated, container 304 that contains a pathogen inactivation
compound (PIC), photoactivation bag 306, and CAD 308 coupled to
photoactivation bag 306 with tubing 310 as described above.
However, in this example, a single, larger (e.g., 800 mL) bag 312
(e.g., a third container of the present disclosure) replaces the
three smaller bags (e.g., 212, 214, and 216). This bag 312 may be
used for pathogen-inactivated plasma collection after
photoactivation, as well as freezing/thawing for production of
cryoprecipitate. The optional bag for cryosupernatant (e.g., 314)
also depicted could be a pre-attached (e.g., integrated) part of
the set with clamp 316 or alternatively sterile docked after PI
plasma collection. In FIG. 3B, this cryosupernatant bag 314 (e.g.,
a fourth container of the present disclosure) is an integral part
of set 300 coupled to the cryoprecipitate bag 312 (e.g., via tubing
and a tubing clamp 316) and used to collect the
cryosupernatant.
[0186] In any of the processing sets of the present disclosure, the
first container (e.g., 106, 206, and/or 306) and the CAD (e.g.,
108, 208, and/or 308) may be separated in a sterile manner from the
rest of the components, such as the PI plasma and cryoprecipitate
containers (e.g., 112, 114, 116, 212, 214, 216, and/or 312), e.g.,
before freezing.
[0187] As described herein, in some embodiments, two or more
cryoprecipitate preparations of the present disclosure can be
combined or pooled. Exemplary technique 400 for this pooling is
shown in FIG. 4. Containers 402 and 404 contain a first and a
second cryoprecipitate preparation, respectively. They are combined
in FIG. 4 by sterile docking, e.g., using sterile connect 406. The
technique illustrated in FIG. 4 may be applied to any of the
cryoprecipitate preparations described herein, e.g., the
cryoprecipitate preparations made from pathogen-inactivated plasma
contained in containers 122, 222, and/or 312.
[0188] Exemplary processing set 500 is shown in FIG. 5. Integrated
processing set 500 allows for the production and combining or
pooling of two larger cryoprecipitate preparations, e.g., as
described herein. Processing set 500 includes one or more optional
plasma containers (e.g., as shown by optional plasma container
502). Container(s) 502 is coupled to container 504, which contains
a pathogen inactivation compound (PIC). Pathogen-inactivated plasma
is then split into first and second photoactivation bags 506 and
508 (respectively), which in turn are coupled to first and second
CADs 510 and 512 (respectively). CADs 510 and 512 are then coupled
to first and second bags 514 and 516 (respectively), which are used
for pathogen-inactivated plasma collection after photoactivation,
as well as freezing/thawing for production of cryoprecipitate. For
example, in some embodiments, 514 and/or 516 are larger (e.g., 800
mL) bags (e.g., third containers of the present disclosure),
similar to bag 312 described above. Bag 514 is connected (e.g.,
through tubing 518) to cryosupernatant bags 520, 522, and 524
(e.g., fourth containers of the present disclosure) for collection
of cryo-poor plasma. Similarly, bag 516 is connected (e.g., through
tubing 528) to cryosupernatant bags 530, 532, and 534 (e.g., fourth
containers of the present disclosure) for collection of cryo-poor
plasma. In some embodiments, bags 514 and 516 are themselves
connected via tubing 526, e.g., to allow the pathogen-inactivated
cryoprecipitate preparations contained therein to be combined or
pooled.
[0189] Exemplary processing set 600 is shown in FIG. 6. Integrated
processing set 600 represents another configuration that allows for
the production and combining or pooling of two larger
cryoprecipitate preparations, e.g., as described herein. Processing
set 600 includes one or more optional plasma containers (e.g., as
shown by optional plasma container 602). Container(s) 602 is
coupled to container 604, which contains a pathogen inactivation
compound (PIC). Container 604 is then coupled to mixing container
606, which is used to contain the plasma/PIC mixture (optionally,
as depicted in FIG. 6, container 602 may be coupled directly to
mixing container 606 without 604 as an intermediary). The
plasma/PIC mixture is then split into first and second
photoactivation bags 608 and 610 (respectively). After
photoactivation, the split plasma/PIC mixtures are then passed
through CAD 612 and into bag 614, which is used for
pathogen-inactivated plasma collection after photoactivation, as
well as freezing/thawing for production of cryoprecipitate. In some
embodiments, bag 614 is a larger (e.g., 800 mL) bag (e.g., a third
container of the present disclosure), similar to bag 312 described
above. One or more cryosupernatant bags (e.g., bags 616, 618, 620,
622, 624, and 626) are connected to bag 614 for collection of
cryo-poor plasma.
[0190] It is to be understood that any of the processing sets of
the present disclosure may be used in any of the methods of the
present disclosure, or used to contain and/or process any of the
plasma compositions, including for example the cryoprecipitates,
cryoprecipitate compositions, and/or cryo-poor plasmas
(cryosupernatants) of the present disclosure.
[0191] The disclosure is illustrated further by the following
examples, which are not to be construed as limiting the disclosure
in scope or spirit to the specific procedures described in
them.
EXAMPLES
Example 1: Preparation of Pathogen Inactivated Cryoprecipitate and
Cryo-Poor Plasma
[0192] Multiple blood group O negative units of liquid plasma units
from the day of draw were pooled and split to obtain multiple
plasma units for processing, each with a final volume 585 to 650
mL. Pathogen inactivation and preparation of cryoprecipitate and
cryo-poor plasma was undertaken with the pooled plasma units. The
plasma was subjected to photochemical pathogen inactivation using
the commercially available INTERCEPT Blood System for Plasma (Cerus
Corporation). In the case of four of the pooled units subjected to
INTERCEPT treatment, the pathogen inactivated plasma collected in
the 3 storage bags of the INTERCEPT processing set (see e.g., 112,
114, and 116 in FIG. 1B) was transferred to a sterile-docked
(sterile-connected), single 1000 mL transfer bag (see e.g., 122 in
FIG. 1B) as large volume unit preparations. Two other of the pooled
units subjected to INTERCEPT treatment were maintained in the 3
storage bags as smaller volume individual "single unit"
preparations. The pathogen inactivated plasma units were then
frozen at -30.degree. C. for use in the preparation of
cryoprecipitate and cryo-poor plasma.
[0193] For preparing cryoprecipitate and cryo-poor plasma, units
were thawed in a temperature controlled 4.degree. C. water bath,
with a total thaw time of approximately 6 hr 30 minute for the
large cryo units and 4 hr 30 min for the single cryo units. The
thawed units were centrifuged for 12 minutes at 4.degree. C. at
4200 rcf, with a slow deceleration. The cryo-poor supernatants were
removed from the cryoprecipitates by transferring out of the 1000
mL transfer bag, while maintaining a small amount of plasma for
re-suspension of the cryoprecipitates. Following resuspension, the
cryoprecipitate units were frozen for storage at -30.degree. C.
[0194] The frozen, stored cryoprecipitate units were thawed in a
Helmer plasma thawer set at 35.degree. C., with the cryoprecipitate
full dissolved with no visible particulate matter. Thawed units
were stored in a temperature controlled cabinet at 22.degree. C.,
with samples removed at defined intervals of <2 hr, 6 hr, 24 hr
and 5 days for analytical testing. Samples were tested for Factor
VIII (FVIII) and Fibrinogen (FIB), with resulting data in Table
1.
TABLE-US-00001 TABLE 1 Fibrinogen and Factor VIII in
cryoprecipitate preparations. 2 hr 6 hr 24 hr 5 days Large volume
(n = 4), 60.2 .+-. 4.9 mL Cryo FIB 492.7 .+-. 70.7 498.7 .+-. 74.0
501.3 .+-. 61.46 482.9 .+-. 74.8 (mg) Cryo FIB 181.2 .+-. 24.3
183.5 .+-. 26.6 184.4 .+-. 21.22 177.6 .+-. 26.7 (mg/unit*) Cryo
FVIII 182.6 .+-. 37.9 176.3 .+-. 26.9 177.6 .+-. 73.4 145.7 .+-.
37.5 (IU) Cryo FVIII 67.2 .+-. 13.7 64.9 .+-. 9.6 65.2 .+-. 26.6
53.6 .+-. 13.5 (IU/unit*) Single unit (n = 2), 24.1 .+-. 11.5 mL
Cryo FIB 315.4 .+-. 49.1 315.5 .+-. 38.8 301.2 .+-. 35.4 274.2 .+-.
55.3 (mg) Cryo FIB 192.6 .+-. 4.2 183.5 .+-. 26.6 184.4 .+-. 3.1
167.0 .+-. 11.4 (mg/unit*) Cryo FVIII 94.5 .+-. 32.5 89.2 .+-. 40.0
82.4 .+-. 33.0 69.3 .+-. 40.0 (IU) Cryo FVIII 57.0 .+-. 12.2 53.4
.+-. 17.3 49.5 .+-. 13.5 41.1 .+-. 19.0 (IU/unit*) *Based on AABB
unit volume of 200 mL
Example 2: Preparation of Pathogen Inactivated Cryoprecipitate and
Cryo-Poor Plasma
[0195] Multiple plasma units obtained from blood group A donors
were pooled to obtain plasma preparations with volumes of about 650
mL each (e.g., large volume). Pathogen inactivation and preparation
of cryoprecipitate and cryo-poor plasma was undertaken with the
pooled plasma units. The plasma was subjected to photochemical
pathogen inactivation using the commercially available INTERCEPT
Blood System for Plasma (Cerus Corporation), to yield three
individual pathogen-inactivated plasma (PI plasma) units from each
pool. The three PI plasma units (3 containers, see e.g., 112, 114,
and 116 in FIG. 1B) generated from each INTERCEPT processing set
were combined by transferring into a sterile-docked, single 600 mL
transfer bag (see e.g., 122 in FIG. 1B) and frozen at -30.degree.
C. for use in the preparation of cryoprecipitate and cryo-poor
plasma.
[0196] For preparing cryoprecipitate and cryo-poor plasma, pooled
units were thawed in a temperature controlled 4.degree. C. water
bath, with a total thaw time of approximately 6 hr 15 minutes. The
thawed units were centrifuged for 12 minutes at 4.degree. C. at
4200 rcf, with a slow deceleration. The cryo-poor plasma
supernatants were removed from the cryoprecipitates by transfer
into the three previous containers, 60 mL of the plasma (i.e.,
cryo-poor plasma) added back to the cryoprecipitate for
re-suspension, and the cryoprecipitate units were frozen for
storage at -30.degree. C.
[0197] The frozen, stored cryoprecipitate units were thawed in a
Helmer plasma thawing system at 37.degree. C., with the
cryoprecipitate fully dissolved with no visible particulate matter.
Thawed units were stored in a temperature controlled cabinet at
22.degree. C., with samples removed at defined intervals at least
through day 5 post-thaw for analytical testing of Factor VIII
(FVIII) and Fibrinogen (FIB), with resulting data in Table 2:
TABLE-US-00002 TABLE 2 Fibrinogen and Factor VIII in
cryoprecipitate preparations. <2 hr 6 hr 24 hr 48 hr Cryo FIB
(mg) Cryo prep 1 960.5 926.5 942.0 937.8 Cryo prep 2 661.4 676.0
670.0 683.3 Cryo FVIII (IU) Cryo prep 1 273.8 277.6 277.9 188.1
Cryo prep 2 252.9 260.8 248.9 174.2
Example 3: Preparation of PI Cryoprecipitate and Cryo-Poor
Plasma
[0198] Pathogen inactivated (PI) cryoprecipitate and cryo-poor
plasma supernatant were prepared as three large volume (647.+-.2
mL) input pools of 2-3 units of ABO matched whole blood derived
plasma in CPD anticoagulant within 8 hr of draw.
[0199] The pooled plasma was subjected to photochemical pathogen
inactivation using amotosalen and UVA, with the commercially
available INTERCEPT Blood System for Plasma. Baseline samples were
collected prior to INTERCEPT treatment, and pathogen inactivation
was performed according to the manufacturer's package insert. The
three PI plasma units (3 containers, see e.g., 112, 114, and 116 in
FIG. 1B) generated from each INTERCEPT processing set were combined
by sealing above the connection, sterilely connecting a 600 mL
transfer bag (see e.g., 122 in FIG. 1B), and transferring by
gravity flow. After sampling, pathogen inactivated plasma
preparations were subjected to rapid freezing and stored at
-30.degree. C. for use in the preparation of cryoprecipitate.
[0200] For preparing cryoprecipitate, the frozen plasma was thawed
in a 4.degree. C. water bath within approximately 12 hr, and
centrifuged at 4,000.times.g for 12 min to sediment the
cryoprecipitate. The cryo-poor plasma was removed using a plasma
expressor and transferred back into the three plasma bags of the
INTERCEPT processing set, leaving approximately 60 mL of the plasma
(i.e., cryo-poor plasma) for resuspension of the cryoprecipitate.
The cryoprecipitate bag and CPP bags were separated and sealed
using a tubing sealer, and frozen at -30.degree. C. for
storage.
[0201] For characterization, the frozen cryoprecipitate and
cryosupernatants were thawed at 37.degree. C. in a QuickThaw.TM.
Plasma Thawing System (Helmer, Noblesville, Ind.) and held at room
temperature (22.degree. C., 2 units) or refrigerated (4.degree. C.,
1 unit) for sterile sampling at times 0 hr, 6 hr, 24 hr, day 3 and
day 5 post-thaw for analytical testing. In vitro assays for
cryoprecipitate and cryo-poor plasma supernatant characterization
included total fibrinogen and Factor VIII, as measured on diluted
samples, using an AMAX coagulation analyzer. Table 3 includes total
fibrinogen and Factor FVIII content for each of the three
cryoprecipitate preparations.
TABLE-US-00003 TABLE 3 Fibrinogen and Factor VIII in
cryoprecipitate preparations. 0 hr 6 hr 24 hr D 3 D 5 Cryo FIB (mg)
Cryo prep 1 (22.degree. C.) 901 857 887 ND 887 Cryo prep 2
(22.degree. C.) 788 908 ND 771 995 Cryo prep 3 (4.degree. C.) 772
896 969 ND 907 Cryo FVIII (IU) Cryo prep 1 (22.degree. C.) 278 319
280 ND 286 Cryo prep 2 (22.degree. C.) 319 347 ND 268 229 Cryo prep
3 (4.degree. C.) 316 307 322 ND 218 ND: not determined.
[0202] Fibrinogen and Factor VIII were also determined for the
cryo-poor plasma by the same method. At time 0 hr, fibrinogen
content was 772 mg, 746 mg and 736 mg total for preps 1, 2 and 3,
respectively. Also, at time 0 hr, FVIII content was 54, 46 and 70
IU total for preps 1, 2 and 3, respectively. Thrombin generation
activity was also determined by standard methodologies and found to
be at high levels.
Example 4: Preparation of PI Cryoprecipitate and Cryo-Poor
Plasma
[0203] Pathogen inactivated (PI) cryoprecipitate and cryo-poor
plasma supernatant were prepared as large volume (585 to 650 mL)
input of whole blood derived FFP, whole blood derived PF24 or
apheresis plasma (apheresis FFP) obtained from blood group A, B
and/or O donors. Six replicates were prepared from pools of 5 to 6
iso-group units of whole blood derived plasma collected in CP2D
anticoagulant to yield approximately 1700 mL. The pooled plasma was
split into two components (target 625 mL.+-.25 mL, FFP and PF24)
and stored at room temperature for up to 8 hr (FFP) or 24 hr (PF24)
prior to subjecting the plasma to photochemical pathogen
inactivation using the commercially available INTERCEPT Blood
System, and freezing. Two units were maintained as untreated
controls without pathogen inactivation (target 215-235 mL, FFP and
PF24). Additionally, six replicates of apheresis plasma were
collected in ACD anticoagulant from a maximum of two iso-group
donors and split into two components: one (target 625+25 mL) which
was stored at room temperature for up to 8 hr prior to subjecting
the plasma to pathogen inactivation and freezing, and the other
maintained as untreated control. Baseline samples were collected
prior to INTERCEPT treatment, and pathogen inactivation was
performed according to the manufacturer's package insert. The three
PI plasma units (3 containers, see e.g., 112, 114, and 116 in FIG.
1B) generated from each INTERCEPT processing set were combined by
transferring into a sterile-connected, single 800 mL transfer bag
(Terumo) (see e.g., 122 in FIG. 1B) and frozen for use in the
preparation of cryoprecipitate. Controls were frozen without
pathogen inactivation treatment.
[0204] For preparing cryoprecipitate, the combined frozen plasma
was thawed in a temperature controlled 2-6.degree. C. refrigerator,
with a total thaw time of approximately 24 hr. The thawed plasma
was centrifuged to sediment the cryoprecipitate, and the cryo-poor
plasma supernatants were removed from the cryoprecipitate using a
plasma expressor and transferred into the three previous
containers, leaving sufficient plasma (i.e., the cryo-poor plasma)
to result in about 60 mL of resuspended cryoprecipitate, the
cryoprecipitate bag then was separated from the three cryo-poor
plasma bags using a tube sealer, and the cryoprecipitate and CPP
units frozen for storage.
[0205] For characterization, the frozen cryoprecipitate and CPP
cryosupernatants were thawed at 37.degree. C. in a QuickThaw.TM.
Plasma Thawing System (Helmer, Noblesville, Ind.) and held at room
temperature (20-24.degree. C.) for sterile sampling at times 0, 24
and 120 hours post-thaw for analytical testing. In vitro assays for
cryoprecipitate and/or CPP cryosupernatant include a panel of
coagulation parameters (e.g., PT, aPTT, thrombin generation),
coagulation factors and hemostatic system proteins (e.g.,
fibrinogen, Factors II, V, VII, VIII (VIII:C), IX, X, XI, XIII,
vWF, ADAMTS-13), and other proteins and markers and/or function
(e.g., antithrombin III, Protein C, Protein S, Alpha-2-PI,
thrombin-antithrombin complexes, Factor VIIa, NAPTT, C3a, Ig's,
ROTEM).
[0206] Analysis of FVIII, FXIII and fibrinogen was performed using
an AMAX Destiny Plus coagulation analyzer and Stago Diagnostic
reagents. The following Tables 4 and 5 include total fibrinogen and
FVIII at times 0, 24 and 120 hours post-thaw for containers of
cryoprecipitate product prepared from whole blood derived FFP,
whole blood derived PF24 and apheresis derived FFP, with ABO blood
types as listed, and support an extended post-thaw expiry for
cryoprecipitate as disclosed herein.
TABLE-US-00004 TABLE 4 Total fibrinogen content (mg) after
post-thaw storage. Plasma Unit t = 0 t = 24 hr t = 120 hr WBD FFP
Group O Average 758 786 793 SD 192.4 229.8 183.8 WBD FFP Group A
Average 767 827 794 SD 91.0 52.7 81.6 WBD FFP All groups Average
762 806 794 SD 134.7 150.8 127.2 PF24 Group O Average 762 768 775
SD 150.5 183.1 196.7 PF24 Group A Average 693 682 695 SD 77.0 97.3
64.5 PF24 All groups Average 728 725 735 SD 113.5 139.5 138.1 Aph
FFP Group O Average 923 914 963 SD 195.3 281.2 239.1 Aph FFP Group
A and B Average 954 1041 1052 SD 17.2 93.4 100.7 Aph FFP All groups
Average 942 978 1008 SD 99.9 186.1 158.3
TABLE-US-00005 TABLE 5 Total Factor VIII content (IU) after
post-thaw storage. Plasma Unit t = 0 t = 24 hr t = 120 hr WBD FFP
Group O Average 178 158 138 SD 50.7 46.8 5.1 WBD FFP Group A
Average 226 195 204 SD 30.7 34.9 45.5 WBD FFP All groups Average
202 176 171 SD 45.7 42.2 46.2 PF24 Group O Average 197 175 168 SD
14.7 12.6 6.5 PF24 Group A Average 197 211 243 SD 14.7 14.1 32.7
PF24 All groups Average 197 193 206 SD 13.2 23.3 45.9 Aph FFP Group
O Average 184 72 67 SD 52.4 16.8 18.8 Aph FFP Group A and B Average
269 110 100 SD 65.9 48.8 29.0 Aph FFP All groups Average 235 91 83
SD 70.8 37.0 27.6
[0207] Factor V, Factor VII, Factor VIII, Factor IX, Factor X,
Factor XI and Fibrinogen content were determined for each of the
six cryo-poor plasma supernatants obtained from the apheresis
derived FFP, with the following average total content for the six
samples: Factor V (464.4 IU; SD 38.1), Factor VII (465.4 IU; SD
55.4), Factor VIII (91.9 IU; SD 32.8), Factor IX (464.7 IU; SD
54.6), Factor X (494.8 IU; SD 10.7), Factor XI (507.8 IU; SD 67.5),
and Fibrinogen (975.7 mg; SD 107.6).
[0208] For additional CPP preparations, multiple whole blood
derived plasma collections were pooled and split into 625 mL
components, and subjected to photochemical pathogen inactivation
using INTERCEPT Blood System for Plasma. In one study comparing two
commercially available transfer bags, the three PI plasma units (3
containers, see e.g., 112, 114, and 116 in FIG. 1B) generated from
each INTERCEPT processing set were combined by transferring into a
sterile-connected, single 750 mL or 800 mL transfer bags (see e.g.,
122 in FIG. 1B) and frozen at -30.degree. C. for use in the
preparation of cryoprecipitate.
[0209] For preparing cryoprecipitate and CPP, the bags containing
frozen pathogen-inactivated plasma were thawed in a 4.degree. C.
water bath for approximately 5 hr. The thawed plasma was
centrifuged to sediment the cryoprecipitate, and the cryo-poor
plasma supernatants were removed from the cryoprecipitate and
transferred back into two of the three previous containers (see
e.g., bags 112 and 114 in FIG. 1B), leaving approximately 100 mL of
plasma (i.e., the cryo-poor plasma) to resuspend the
cryoprecipitate, which was then transferred back into the third of
the three previous containers (see e.g., bag 116 in FIG. 1B), and
the cryoprecipitate and CPP units were frozen for storage.
[0210] Subsequent analysis of fibrinogen and Factor VIII levels in
the cryo-poor plasma indicated high levels of fibrinogen, but no
significant different between materials produced using either of
the two transfer bags.
[0211] Similarly, additional CPP preparations were prepared from
multiple units of whole blood derived plasma that were pooled by
combining into a sterile connected 600 mL transfer bag, to obtain
pooled plasmas with a volume of 585-650 mL. The pooled plasma was
subjected to photochemical pathogen inactivation using INTERCEPT
Blood System for Plasma per manufacturer's instructions and as
described above. The three resulting PI plasma units (3 containers,
see e.g., 112, 114, and 116 in FIG. 1B) generated from each
INTERCEPT processing set were combined by transferring into a
sterile-connected, single 600 mL transfer bag (see e.g., 122 in
FIG. 1B), frozen in a blast freezer and transferred to a storage
freezer at .ltoreq.-25.degree. C. for use in the preparation of
cryoprecipitate.
[0212] For preparing cryoprecipitate and CPP, the bags containing
frozen pathogen-inactivated plasma were thawed in a 2-6.degree. C.
refrigerator for 20-24 hr, and centrifuged to sediment the
cryoprecipitate. The cryo-poor plasma supernatants (.about.550 mL)
were removed from the cryoprecipitate and transferred back into two
of the three previous containers (see e.g., bags 112 and 114 in
FIG. 1B), leaving approximately 50 mL of plasma (i.e., the
cryo-poor plasma) to resuspend the cryoprecipitate, which was then
transferred back into the third of the three previous containers
(see e.g., bag 116 in FIG. 1B). Approximately 50 mL of CPP was
transferred back into the 600 mL transfer bag to wash and collect
residual cryoprecipitate and then transferred into and combined
with the initial cryoprecipitate. This process yielded one
container of cryoprecipitate (.about.100 mL) and two containers of
cryo-poor plasma (.about.250 mL each). The CPP units and
cryoprecipitate were frozen for storage. Analysis of five cryo-poor
plasma preparations found a fibrinogen content of 288.+-.37 mg and
a Factor VIII content of 42.+-.14 IU.
Example 5: PI Cryoprecipitate from Two Cryo Preparations
[0213] Pathogen inactivated cryoprecipitate compositions of the
present disclosure may be combined to yield a cryoprecipitate
composition with higher levels of desired factors, such as for
example fibrinogen and Factor VIII. More specifically, a first
cryoprecipitate is prepared from a large volume input of
approximately 600 mL of FFP (e.g., 2-3 units, pooled) that is
subjected to pathogen inactivation (e.g., INTERCEPT Blood System),
as described in Example 2 above and illustrated in FIG. 1B.
Following sedimentation of the cryoprecipitate, the cryo-poor
supernatant is transferred back into the three containers for
storage, leaving sufficient plasma for resuspension of the
cryoprecipitate in approximately 35 mL. In addition, a second
cryoprecipitate is prepared from a large volume input of
approximately 600 mL of FFP (e.g., 2-3 units, pooled) of the same
ABO type as the first cryoprecipitate and subjected to pathogen
inactivation treatment in a similar manner. The container with the
second cryoprecipitate is separated from the three cryo-poor plasma
bags using a tube sealer, prior to combining with the first
cryoprecipitate (FIG. 1C). The second cryoprecipitate (labeled Cryo
"freeze" #2) is connected using a sterile connecting device to the
container with the first cryoprecipitate, which has also been
separated from its corresponding three cryo-poor plasma bags, and
the two cryoprecipitate preparations combined by transfer prior to
re-freezing or storage at room temperature for use.
Example 6: Pathogen-Inactivated Cryo-Poor Plasma for Guillain-Barre
Syndrome
[0214] Pathogen-inactivated plasma compositions of the present
disclosure may be used for treatment of Guillain-Barre syndrome.
More specifically, for example, to evaluate the use of
pathogen-inactivated cryo-poor plasma of the present disclosure in
therapeutic plasma exchange for treatment of Guillain-Barre
syndrome, a randomized, double-blind clinical study is performed,
comparing pathogen-inactivated cryo-poor plasma and intravenous
immunoglobulin. Study volunteers diagnosed are enrolled within two
weeks of the start of symptoms at 100 subjects per group. For the
pathogen-inactivated cryo-poor plasma treatment group, subjects
receive multiple plasma exchanges (e.g., five) over a two week
period, each as a 50 mL/kg exchange. For the IVIG treatment group,
subjects receive five daily infusions of IVIG (e.g., GAMMAGARD,
Baxter) at 0.4 gm/kg body weight/day.
[0215] Subjects are monitored over a period of 12 months for
clinical adverse events and the following primary measure of
efficacy: Proportion of patients with more than 1 grade improvement
in Hughes Functional Grade (FG) at 28 days. Additional secondary
measures of efficacy as measured at 28 days and later points (e.g.,
6 months) include days required for 1 grade improvement of FG, days
required for 2 grade improvement of FG, changes in activity of
daily living (ADL), and one or more of hand dynamometer, Visual
Analog Pain Scale, McGill Pain Questionnaire-Short Form,
Neuromuscular Functional Assessment Index, Jebsen-Taylor Hand
Function Test, Minnesota Rate of Manipulation and Manual Dexterity
Tests, Walk Test and Center for Epidemiological Studies Depression
Scale (CES-D).
Example 7: Pathogen-Inactivated Plasma for CIDP
[0216] Pathogen-inactivated plasma compositions of the present
disclosure may be used for treatment of chronic inflammatory
demyelinating polyneuropathy (CIDP). More specifically, for
example, pathogen-inactivated cryo-poor plasma compositions of the
present disclosure are used in therapeutic plasma exchange for the
treatment of CIDP. Briefly, CIDP is a peripheral nerve disease of
presumed autoimmune etiology that may include both humoral and
cell-mediated immune responses. CIDP patients receive ten plasma
exchange treatments over five weeks with 40-50 mL/kg plasma
exchanged. Therapeutic response is measured by improvement or
stabilization in neurological symptoms. Clinical outcomes are
assessed during and after the treatment period using one or more of
the Inflammatory Neuropathy Cause and Treatment (INCAT) score,
maximum grip strength, the Medical Research Council (MRC) sum
score, the Rasch-built Overall Disability Scale (R-ODS), and/or
electrophysiological evaluations (see e.g., Dyck, et al., 1994,
Ann. Neurol. 3:838-845).
[0217] INCAT Score. The INCAT score and changes in the score from
baseline are determined. The INCAT disability score ranges from 0
to 10 and is the sum of arm and leg disability each rated between 0
and 5 (where arm=0 indicates `no upper limb problems` and arm=5
indicates `inability to use either arm for any purposeful
movement`, and leg=0 indicates `walking not affected`, and leg=5
indicates `restricted to wheelchair, unable to stand and walk a few
steps with help`). Thus, a higher INCAT disability score indicates
greater disability. Negative values for change in INCAT score
indicate improvement, with a more negative value indicating greater
improvement compared with the value at baseline. Improvement is
defined as an INCAT score decrease by at least 1 point.
[0218] Maximum Grip Strength. The mean maximum grip strength of the
dominant hand and changes from baseline are determined. Positive
values for change in maximum grip strength indicate improvement.
Improvement is defined as improvement by at least 8 kPa.
[0219] Medical Research Council Sum Scale (MRC). The MRC sum score
and changes from baseline are determined. The 80-point MRC sum
score is the sum of scores for eight bilateral (left and right
side) muscle groups, each rated between 0 (no visible contraction)
to 5 (normal movement). A higher MRC sum score indicates greater
muscle contraction/limb movement. Positive values for change in MRC
sum score indicate improvement, with a more positive value
indicating greater muscle contraction/limb movement compared with
the value at baseline.
Example 8: Pathogen-Inactivated Plasma for Renal
Transplantation
[0220] Pathogen-inactivated plasma compositions of the present
disclosure may be used in conjunction with solid organ
transplantation. For example, pathogen-inactivated cryo-poor plasma
compositions are used for a therapeutic plasma exchange regimen in
conjunction with ABO-incompatible kidney transplantation to reduce
circulating antibody (e.g., IgG) that may contribute to transplant
rejection. More specifically, in one example, transplant patients
receiving an ABO-incompatible kidney from a living donor are
subjected to a preconditioning regimen of multiple therapeutic
plasma exchange (TPE) treatments before transplant to reduce ABO
antibody (e.g., anti-A, anti-B) titers to a desired level, such as
for example to pre-transplant titers of less than 16. TPE
treatments are performed daily prior to transplant using accepted
plasma exchange methods known in the art and as described herein,
with the number of TPE treatments based on the initial ABO antibody
titers. For example, in one embodiment, two TPE treatments are used
for an initial antibody titer of 16, three TPE treatments for an
initial titer of 32, four TPE treatment for an initial titer of 64,
five TPE treatments for an initial titer of 128, seven TPE
treatments for an initial titer of 256, nine TPE treatments for an
initial titer of 512, eleven TPE treatments for an initial titer of
1024, and fifteen or more TPE treatment for an initial titer of
>1024. The pathogen-inactivated plasma compositions used for TPE
treatment may be obtained from plasma donors seropositive for
cytomegalovirus (CMV).
[0221] On the day of transplant, high risk patients may be
subjected to splenectomy and/or anti-CD20 therapy. Following the
kidney transplant procedure, the patients are subjected to one or
more additional daily TPE treatments (e.g., two, three) with the
pathogen-inactivated plasma to reduce the risk of antibody
rebound.
Example 9: Pathogen-Inactivated Plasma for Burn Resuscitation
[0222] Pathogen-inactivated plasma compositions of the present
disclosure may be used for fluid resuscitation in a subject
suffering from burns (e.g., burn shock resuscitation). More
specifically, in one example, a subject suffering from major burns
representing approximately 25% of total body surface area (TBSA) is
infused with ABO-matched pathogen-inactivated cryo-poor plasma
prepared as described above. Infusion of the CPP is initiated based
on an amount calculated as 3 mL of CPP per kg body weight per %
TBSA, with half of the amount infused within the first 8 hours.
Resuscitation with the cryo-poor plasma is continued as guided by
titration to maintain a urine output of about 1.0 ml/kg/hour.
[0223] All references, including publications, patent applications,
and patents, cited herein are hereby incorporated by reference to
the same extent as if each reference were individually and
specifically indicated to be incorporated by reference and were set
forth in its entirety herein.
[0224] The use of the terms "a" and "an" and "the" and similar
referents (especially in the context of the following claims) are
to be construed to cover both the singular and the plural, unless
otherwise indicated herein or clearly contradicted by context. The
terms "comprising," "having," "including," and "containing" are to
be construed as open-ended terms (i.e., meaning "including, but not
limited to,") unless otherwise noted. Wherever an open-ended term
is used to describe a feature or element, it is specifically
contemplated that a closed-ended term can be used in place of the
open-ended term without departing from the spirit and scope of the
disclosure. Recitation of ranges of values herein are merely
intended to serve as a shorthand method of referring individually
to each separate value falling within the range, unless otherwise
indicated herein, and each separate value is incorporated into the
specification as if it were individually recited herein. All
methods described herein can be performed in any suitable order
unless otherwise indicated herein or otherwise clearly contradicted
by context. The use of any and all examples, or exemplary language
(e.g., "such as") provided herein, is intended merely to better
illuminate the description and does not pose a limitation on the
scope of the description unless otherwise claimed. No language in
the specification should be construed as indicating any non-claimed
element as essential to the practice of the compositions, methods,
and kits disclosed herein.
[0225] Preferred embodiments are described herein. Variations of
those preferred embodiments may become apparent to those working in
the art upon reading the foregoing description. It is expected that
skilled artisans will be able to employ such variations as
appropriate, and the practice of the compositions, methods, and
kits described herein otherwise than as specifically described
herein. Accordingly, the compositions, methods, and kits described
herein include all modifications and equivalents of the subject
matter recited in the claims appended hereto as permitted by
applicable law. Moreover, any combination of the above-described
elements in all possible variations thereof is encompassed by the
description unless otherwise indicated herein or otherwise clearly
contradicted by context.
LIST OF EMBODIMENTS
[0226] Embodiment 1. A method of treating a disease or condition
indicated for treatment by plasma exchange in a subject in need
thereof, comprising administering to the subject a therapeutically
effective amount of pathogen-inactivated plasma composition by
plasma exchange. [0227] Embodiment 2. The method of embodiment 1,
wherein the disease or condition is indicated for treatment with
albumin by plasma exchange. [0228] Embodiment 3. The method of
embodiment 1 or embodiment 2, wherein the disease or condition is
Guillain-Barre syndrome, chronic inflammatory demyelinating
polyneuropathy, myasthenia gravis, a paraproteinemic
polyneuropathy, Goodpasture's syndrome, or cryoglobulinemia. [0229]
Embodiment 4. The method of embodiment 1 or embodiment 2, wherein
the disease or condition is other than thrombocytopenic purpura
(TTP) or hemolytic-uremic syndrome (HUS). [0230] Embodiment 5. The
method of embodiment 1 or embodiment 2, wherein the disease or
condition is burn shock resuscitation. [0231] Embodiment 6. The
method of any one of embodiments 1-5, wherein the
pathogen-inactivated plasma composition comprises
pathogen-inactivated frozen plasma. [0232] Embodiment 7. The method
of embodiment 6, wherein the pathogen-inactivated plasma
composition comprises pathogen-inactivated fresh frozen plasma.
[0233] Embodiment 8. The method of any one of embodiments 1-5,
wherein the pathogen-inactivated plasma composition comprises
pathogen-inactivated cryo-poor plasma. [0234] Embodiment 9. The
method of embodiment 8, wherein the disease or condition is
thrombocytopenic purpura (TTP) or hemolytic-uremic syndrome (HUS).
[0235] Embodiment 10. A method of treating a disease or condition
indicated for treatment by infusion with intravenous immunoglobulin
in a subject in need thereof, comprising administering to the
subject a therapeutically effective amount of pathogen-inactivated
plasma composition by plasma exchange. [0236] Embodiment 11. The
method of embodiment 10, wherein the disease or condition is
Guillain-Barre syndrome, myasthenia gravis, polymyositis,
dermatomyositis, or chronic inflammatory demyelinating
polyneuropathy. [0237] Embodiment 12. The method of embodiment 10,
wherein the disease or condition is other than thrombocytopenic
purpura (TTP) or hemolytic-uremic syndrome (HUS). [0238] Embodiment
13. The method of any one of embodiments 10-12, wherein the
pathogen-inactivated plasma composition comprises
pathogen-inactivated frozen plasma. [0239] Embodiment 14. The
method of embodiment 13, wherein the pathogen-inactivated plasma
composition comprises pathogen-inactivated fresh frozen plasma.
[0240] Embodiment 15. The method of any one of embodiments 10-12,
wherein the pathogen-inactivated plasma composition comprises
pathogen-inactivated cryo-poor plasma. [0241] Embodiment 16. The
method of embodiment 15, wherein the disease or condition is
thrombocytopenic purpura (TTP) or hemolytic-uremic syndrome (HUS).
[0242] Embodiment 17. A method of treating a disease or condition
selected from the group consisting of Guillain-Barre syndrome,
myasthenia gravis, polymyositis, dermatomyositis and chronic
inflammatory demyelinating polyneuropathy in a subject, comprising
administering to a subject in need thereof a therapeutically
effective amount of pathogen-inactivated plasma composition by
plasma exchange. [0243] Embodiment 18. The method of embodiment 17,
wherein the pathogen-inactivated plasma composition comprises
pathogen-inactivated frozen plasma. [0244] Embodiment 19. The
method of embodiment 18, wherein the pathogen-inactivated plasma
composition comprises pathogen-inactivated fresh frozen plasma.
[0245] Embodiment 20. The method of embodiment 17, wherein the
pathogen-inactivated plasma composition comprises
pathogen-inactivated cryo-poor plasma. [0246] Embodiment 21. The
method of any one of embodiments 1-20, wherein the
pathogen-inactivated plasma composition is administered within 1
day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after
thawing. [0247] Embodiment 22. The method of any one of embodiments
1-20, wherein the pathogen-inactivated plasma composition is a
lyophilized or freeze-dried plasma composition. [0248] Embodiment
23. The method of embodiment 22, wherein the pathogen-inactivated
plasma composition is administered within 1 day, 2 days, 3 days, 4
days, 5 days, 6 days, or 7 days after reconstitution. [0249]
Embodiment 24. A method of treating thrombocytopenic purpura (TTP)
or hemolytic-uremic syndrome (HUS) in a subject, comprising
administering to a subject in need thereof a therapeutically
effective amount of a pathogen-inactivated plasma composition by
plasma exchange, wherein the pathogen-inactivated plasma
composition comprises pathogen-inactivated cryo-poor plasma. [0250]
Embodiment 25. A method of treating a solid organ transplant
recipient to prevent an immune-mediated solid organ transplant
rejection, comprising administering to the transplant recipient a
therapeutically effective amount of a pathogen-inactivated plasma
composition by plasma exchange, wherein the plasma exchange is
prior to the transplant procedure. [0251] Embodiment 26. The method
of embodiment 25, wherein the immune-mediated transplant rejection
is an antibody-mediated transplant rejection. [0252] Embodiment 27.
The method of embodiment 26, wherein the antibody-mediated
transplant rejection is an IgG-mediated transplant rejection.
[0253] Embodiment 28. The method of any one of embodiments 25-26,
wherein the solid organ transplant is an ABO-incompatible solid
organ transplant. [0254] Embodiment 29. The method of any one of
embodiments 25-26, wherein the solid organ transplant is an
HLA-incompatible solid organ transplant. [0255] Embodiment 30. The
method of any one of embodiments 25-29, wherein the solid organ
transplant is a kidney transplant. [0256] Embodiment 31. The method
of embodiment 30, wherein the kidney is obtained from a living
donor. [0257] Embodiment 32. The method of any one of embodiments
25-31, wherein the pathogen-inactivated plasma composition
comprises pathogen-inactivated frozen plasma. [0258] Embodiment 33.
The method of embodiment 32, wherein the pathogen-inactivated
plasma composition comprises pathogen-inactivated fresh frozen
plasma. [0259] Embodiment 34. The method of any one of embodiments
25-31, wherein the pathogen-inactivated plasma composition
comprises pathogen-inactivated cryo-poor plasma. [0260] Embodiment
35. The method of any one of embodiments 25-34, wherein the
pathogen-inactivated plasma composition is administered within 1
day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after
thawing. [0261] Embodiment 36. The method of any one of embodiments
25-31, wherein the pathogen-inactivated plasma composition is a
lyophilized or freeze-dried plasma composition. [0262] Embodiment
37. The method of embodiment 36, wherein the pathogen-inactivated
plasma composition is administered within 1 day, 2 days, 3 days, 4
days, 5 days, 6 days, or 7 days after reconstitution. [0263]
Embodiment 38. The method of any one of embodiments 1-37, wherein
the plasma exchange is achieved with a volume of the plasma
composition similar to the subject's plasma volume. [0264]
Embodiment 39. The method of any one of embodiments 1-37, wherein
the plasma exchange is achieved with a volume of the plasma
composition between about 1 times and about 1.5 times the subject's
plasma volume. [0265] Embodiment 40. The method of any one of
embodiments 1-37, wherein the plasma exchange is achieved with a
volume of the plasma composition comprising about 40 mL/kg patient
body weight. [0266] Embodiment 41. The method of any one of
embodiments 1-37, wherein the plasma exchange is achieved with a
volume of the plasma composition comprising about 60 mL/kg patient
body weight. [0267] Embodiment 42. The method of any one of
embodiments 1-41, wherein the plasma exchange is performed at least
two times. [0268] Embodiment 43. The method of embodiment 42,
wherein the plasma exchange is performed 2-5 times. [0269]
Embodiment 44. The method of embodiment 42 or embodiment 43,
wherein the plasma exchange is performed 2-5 times within a period
of two weeks. [0270] Embodiment 45. The method of embodiment 42 or
embodiment 43, wherein the plasma exchange is performed 2-5 times
within a period of one week. [0271] Embodiment 46. The method of
any one of embodiments 25-45, wherein the plasma exchange is
performed at least two times prior to the transplant procedure.
[0272] Embodiment 47. The method of embodiment 46, wherein the
plasma exchange is performed 2-15 times prior to the transplant
procedure. [0273] Embodiment 48. The method of any one of
embodiments 25-47, further comprising administering to the
transplant recipient a therapeutically effective amount of
pathogen-inactivated plasma composition by plasma exchange after
the transplant procedure. [0274] Embodiment 49. The method of
embodiment 48, wherein the plasma exchange is performed at least
two times after the transplant procedure. [0275] Embodiment 50. A
method of fluid resuscitation in a subject suffering from burns,
comprising administering to a subject in need thereof a
therapeutically effective amount of a pathogen-inactivated plasma
composition. [0276] Embodiment 51. The method of embodiment 50,
wherein the subject is suffering from major burns comprising at
least 20% of total body surface area. [0277] Embodiment 52. The
method of embodiment 50 or embodiment 51, wherein the method of
fluid resuscitation is a method of burn shock resuscitation. [0278]
Embodiment 53. The method of any one of embodiments 50-52, wherein
endothelial permeability, endothelial dysfunction and/or vascular
hyperpermeability is reduced by administration of the
pathogen-inactivated plasma composition. [0279] Embodiment 54. The
method of any one of embodiments 50-53, wherein administration of
the pathogen-inactivated plasma composition results in decreased
subject mortality. [0280] Embodiment 55. The method of any one of
embodiments 50-54, wherein the pathogen-inactivated plasma
composition comprises pathogen-inactivated frozen plasma. [0281]
Embodiment 56. The method of embodiment 55, wherein the
pathogen-inactivated plasma composition comprises
pathogen-inactivated fresh frozen plasma. [0282] Embodiment 57. The
method of any one of embodiments 50-54, wherein the
pathogen-inactivated plasma composition comprises
pathogen-inactivated cryo-poor plasma. [0283] Embodiment 58. The
method of any one of embodiments 50-57, wherein the
pathogen-inactivated plasma composition is administered within 1
day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after
thawing. [0284] Embodiment 59. The method of any one of embodiments
50-54, wherein the pathogen-inactivated plasma composition is a
lyophilized or freeze-dried plasma composition. [0285] Embodiment
60. The method of embodiment 59, wherein the pathogen-inactivated
plasma composition is administered within 1 day, 2 days, 3 days, 4
days, 5 days, 6 days, or 7 days after reconstitution. [0286]
Embodiment 61. The method of any one of embodiments 50-60, wherein
about 1 mL to about 5 mL per kg body weight per % total burn
surface area (TBSA) of the pathogen-inactivated plasma composition
is administered to the subject. [0287] Embodiment 62. The method of
any one of embodiments 50-60, wherein a volume of the
pathogen-inactivated plasma composition sufficient to achieve an
increase in blood pressure to at least about 50 mmHg is
administered to the subject. [0288] Embodiment 63. The method of
embodiment 62, wherein a volume of the pathogen-inactivated plasma
composition sufficient to achieve an increase in blood pressure to
at least about 100 mmHg is administered to the subject. [0289]
Embodiment 64. The method of any one of embodiments 50-63, wherein
the pathogen-inactivated plasma composition is administered to the
subject within about 24 hours, within about 20 hours, within about
16 hours, within about 12 hours, within about 10 hours, within
about 8 hours, within about 6 hours, within about 5 hours, within
about 4 hours, within about 3 hours, within about 2 hours or within
about 1 hours after the onset of burns or medical diagnosis
thereof. [0290] Embodiment 65. The method of any one of embodiments
50-64, wherein pathogen-inactivated plasma composition is
administered to the subject over a time period of about 24 hours.
[0291] Embodiment 66. The method of embodiment 65, wherein
pathogen-inactivated plasma composition is administered to the
subject in multiple infusions over a time period of about 24 hours
[0292] Embodiment 67. A method of treating a subject suffering from
burns or a trauma, the method comprising: administering to a
subject in need thereof a therapeutically effective amount of a
pathogen-inactivated plasma composition. [0293] Embodiment 68. The
method of embodiment 67, wherein the subject is suffering from
burns. [0294] Embodiment 69. The method of embodiment 67, wherein
the subject is suffering from blunt trauma. [0295] Embodiment 70.
The method of embodiment 67, wherein the subject is suffering from
penetrating trauma. [0296] Embodiment 71. The method of any one of
embodiments 67-70, wherein the subject is suffering from
hemorrhage. [0297] Embodiment 72. The method of embodiment 71,
wherein the subject is suffering from internal hemorrhage. [0298]
Embodiment 73. The method of any one of embodiments 67-72, wherein
the method is a method of fluid resuscitation. [0299] Embodiment
74. The method of any one of embodiments 67-73, wherein the method
reduces hemorrhage in the subject. [0300] Embodiment 75. The method
of any one of embodiments 67-74, wherein the method reduces
hemorrhagic shock in the subject. [0301] Embodiment 76. The method
of any one of embodiments 67-74, wherein endothelial permeability
is reduced in the subject. [0302] Embodiment 77. The method of any
one of embodiments 67-74, wherein the method reduces or prevents
trauma-induced endotheliopathy in the subject. [0303] Embodiment
78. The method of any one of embodiments 67-74, wherein the method
reduces or prevents traumatic coagulopathy in the subject. [0304]
Embodiment 79. The method of any one or embodiments 67-78, wherein
the infusion or treatment results in decreased subject mortality.
[0305] Embodiment 80. A method of resuscitation from hemorrhagic
shock in a subject suffering from burns or a trauma, comprising
administering to the subject a therapeutically effective amount of
a pathogen-inactivated plasma composition. [0306] Embodiment 81.
The method of embodiment 80, wherein the subject is suffering from
burns. [0307] Embodiment 82. The method of embodiment 80, wherein
the subject is suffering from blunt trauma. [0308] Embodiment 83.
The method of embodiment 80, wherein the subject is suffering from
penetrating trauma. [0309] Embodiment 84. The method of any one of
embodiments 80-83, wherein the subject is suffering from internal
hemorrhage. [0310] Embodiment 85. The method of any one of
embodiments 80-84, wherein the method reduces hemorrhage in the
subject.
[0311] Embodiment 86. The method of any one of embodiments 80-85,
wherein endothelial permeability is reduced in the subject. [0312]
Embodiment 87. The method of any one of embodiments 80-85, wherein
the method reduces or prevents trauma-induced endotheliopathy in
the subject. [0313] Embodiment 88. The method of any one of
embodiments 80-85, wherein the method reduces or prevents traumatic
coagulopathy in the subject. [0314] Embodiment 89. The method of
any one or embodiments 80-88, wherein the treatment results in
decreased subject mortality. [0315] Embodiment 90. The method of
any one of embodiments 67-89, wherein the pathogen-inactivated
plasma composition comprises pathogen-inactivated frozen plasma.
[0316] Embodiment 91. The method of embodiment 90, wherein the
pathogen-inactivated plasma composition comprises
pathogen-inactivated fresh frozen plasma. [0317] Embodiment 92. The
method of any one of embodiments 67-89, wherein the
pathogen-inactivated plasma composition comprises
pathogen-inactivated cryo-poor plasma. [0318] Embodiment 93. The
method of any one of embodiments 67-92, wherein the
pathogen-inactivated plasma composition is administered within 1
day, 2 days, 3 days, 4 days, 5 days, 6 days, or 7 days after
thawing. [0319] Embodiment 94. The method of any one of embodiments
67-89, wherein the pathogen-inactivated plasma composition is a
lyophilized or freeze-dried plasma composition. [0320] Embodiment
95. The method of embodiment 94, wherein the pathogen-inactivated
plasma composition is administered within 1 day, 2 days, 3 days, 4
days, 5 days, 6 days, or 7 days after reconstitution. [0321]
Embodiment 96. The method of any one of embodiments 67-95, wherein
the pathogen-inactivated plasma composition is first administered
less than 24 hours after the onset of trauma. [0322] Embodiment 97.
The method of any one of embodiments 67-96, wherein administration
of the pathogen-inactivated plasma composition is followed by
administration of at least one additional intravenous fluid. [0323]
Embodiment 98. A method for preparing pathogen-inactivated
cryo-poor plasma, the method comprising: [0324] a) photochemically
inactivating one or more units of plasma in the presence of a
psoralen, wherein the photochemical inactivation is performed under
sterile conditions in a first container containing the one or more
units of plasma; [0325] b) transferring under sterile conditions
the one or more units of plasma from the first container to a
compound absorption device (CAD) coupled to the first container;
[0326] c) transferring under sterile conditions the one or more
units of plasma from the CAD to two or more second containers
coupled to the CAD to provide pathogen-inactivated plasma; [0327]
d) transferring under sterile conditions the pathogen-inactivated
plasma from the two or more second containers to a third container
coupled to the two or more second containers; [0328] e) freezing
the pathogen-inactivated plasma followed by thawing of the
pathogen-inactivated plasma under conditions that provide for the
formation of a cryoprecipitate and pathogen-inactivated cryo-poor
plasma; [0329] f) transferring the pathogen-inactivated cryo-poor
plasma to a at least a first of the two or more second containers;
and [0330] g) transferring the cryoprecipitate to a second of the
two or more second containers. [0331] Embodiment 99. The method of
embodiment 98, wherein at least a portion of the
pathogen-inactivated cryo-poor plasma is transferred to each of at
least two second containers in step f), and wherein the
cryoprecipitate is transferred to a third second container in step
g). [0332] Embodiment 100. The method of embodiment 98 or
embodiment 99, wherein, prior to step g), the cryoprecipitate is
resuspended in about 80 mL to about 120 mL of pathogen-inactivated
cryo-poor plasma. [0333] Embodiment 101. The method of embodiment
100, wherein, prior to step g), the cryoprecipitate is resuspended
in about 100 mL of pathogen-inactivated cryo-poor plasma. [0334]
Embodiment 102. A method for infusing pathogen-inactivated
cryo-poor plasma into a subject, comprising infusing into a subject
in need thereof a therapeutically effective amount of a
pathogen-inactivated cryo-poor plasma prepared by the method of any
one of embodiments 98-101. [0335] Embodiment 103. The method of
embodiment 102, wherein the subject is suffering from one or more
of burns, blunt trauma, penetrating trauma, and hemorrhage. [0336]
Embodiment 104. The method of embodiment 102 or embodiment 103,
wherein the infusion results in fluid resuscitation of the subject.
[0337] Embodiment 105. The method of embodiment 102, wherein
infusing the pathogen-inactivated cryo-poor plasma into a subject
is by therapeutic plasma exchange. [0338] Embodiment 106. The
method of embodiment 105, wherein the subject in need thereof is a
subject suffering from thrombocytopenic purpura (TTP) or
hemolytic-uremic syndrome (HUS). [0339] Embodiment 107. The method
of any one of embodiments 102-106, further comprising, prior to the
infusion: [0340] 1) freezing the pathogen-inactivated cryo-poor
plasma; and [0341] 2) thawing the pathogen-inactivated cryo-poor
plasma. [0342] Embodiment 108. The method of embodiment 107,
wherein the pathogen-inactivated cryo-poor plasma is infused into
the subject within 1 day, 2 days, 3 days, 4 days, 5 days, 6 days,
or 7 days after thawing.
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