U.S. patent application number 13/064475 was filed with the patent office on 2011-10-06 for method for investigating the thrombocyte function of the blood.
Invention is credited to Michael Kratzer.
Application Number | 20110244508 13/064475 |
Document ID | / |
Family ID | 29285307 |
Filed Date | 2011-10-06 |
United States Patent
Application |
20110244508 |
Kind Code |
A1 |
Kratzer; Michael |
October 6, 2011 |
Method for investigating the thrombocyte function of the blood
Abstract
A method for investigating the thrombocyte function of the
blood, and particularly of platelet aggregation, wherein the
following steps are carried out: a) cross-flowing an aperture with
blood or blood components; b) determining the active radius of the
aperture depending on time and c) evaluating the time-dependent
modification of the radius as a measure for blood cell and/or
thrombocyte function.
Inventors: |
Kratzer; Michael; (Muenchen,
DE) |
Family ID: |
29285307 |
Appl. No.: |
13/064475 |
Filed: |
March 28, 2011 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10513815 |
Apr 7, 2005 |
7915049 |
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13064475 |
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Current U.S.
Class: |
435/29 |
Current CPC
Class: |
G01N 33/4905
20130101 |
Class at
Publication: |
435/29 |
International
Class: |
C12Q 1/02 20060101
C12Q001/02 |
Foreign Application Data
Date |
Code |
Application Number |
May 10, 2002 |
DE |
102 21 054.3 |
Claims
1. A method for testing the thrombocyte function of the blood, in
which there is an aperture (3), through which the blood or blood
constituents flow, said method comprising the steps of: a)
determining the effective radius of the aperture (3) as a function
of the time by measuring the drop in pressure at the aperture (3)
as a function of the time and determining the volumetric rate of
blood flow through the aperture (3) as a function of the time; b)
calculating the hemodynamically effective radius of the aperture
(3) according to the Hagen-Poiseuille law; and c) evaluating the
time-dependent change in the radius, wherein from the slope (dr/dt)
of a determined straight line (dr/dt) an angle (PTGA), which exists
between the determined straight line and the axis for the time (t),
is determined as a measure for the thrombocyte function, or an
angle (PTGA'), which exists between the determined straight line
and the axis for the radius (r), is determined as a measure for the
thrombocyte function.
2. The method as claimed in claim 1, wherein on the assumption of a
predefined blood platelet diameter, a platelet delay time is
determined from the slope of the determined straight line (dr/dt)
and the blood platelet diameter as a measure for the thrombocyte
function.
3. The method as claimed in claim 1, wherein a value (CT), at which
the aperture (3) is occluded by blood cell or thrombus formation up
to a predefined degree, is determined from the determined straight
line as a measure for the thrombocyte function.
4. The method as claimed in claim 3, wherein the value (CT) is
predetermined for a radius of the value zero.
5. The method as claimed in claim 1, wherein a selected section of
the straight line is determined by measurement, and at least one
other section of the straight line is determined by extrapolating
on the basis of the selected section of the straight line.
6. The method as claimed in claim 5, wherein the value of the
straight line at the point in time zero (t=0) is determined by
extrapolation, and the straight line is shifted by changing the
parameters in the Hagen-Poiseuille law in such a way that the value
of the radius (r) at the point in time zero (t=0) corresponds to a
predefined value (V).
7. The method as claimed in claim 1, wherein the point of
intersection (P) of two or more segments of varying slopes (dr1/dt;
dr2/dt) of straight lines determined during a measurement is
determined as a measure for certain processes in the course of
thrombus formation.
8. The method as claimed in claim 1, wherein the correlation of the
measuring points is determined with a mathematical function for the
quality control of a measurement.
9. The method as claimed in claim 8, wherein the mathematical
function is a straight line.
10. The method as claimed in claim 2, wherein a value (CT), at
which the aperture (3) is occluded by blood cell or thrombus
formation up to a predefined degree, is determined from the
determined straight line as a measure for the thrombocyte
function.
11. The method as claimed in claim 10, wherein the value (CT) is
predetermined for a radius of the value zero.
12. The method as claimed in claim 2, wherein a selected section of
the straight line is determined by measurement, and at least one
other section of the straight line is determined by extrapolating
on the basis of the selected section of the straight line.
13. The method as claimed in claim 12, wherein the value of the
straight line at the point in time zero (t=0) is determined by
extrapolation, and the straight line is shifted by changing the
parameters in the Hagen-Poiseuille law in such a way that the value
of the radius (r) at the point in time zero (t=0) corresponds to a
predefined value (V).
14. The method as claimed in claim 3, wherein a selected section of
the straight line is determined by measurement, and at least one
other section of the straight line is determined by extrapolating
on the basis of the selected section of the straight line.
15. The method as claimed in claim 14, wherein the value of the
straight line at the point in time zero (t=0) is determined by
extrapolation, and the straight line is shifted by changing the
parameters in the Hagen-Poiseuille law in such a way that the value
of the radius (r) at the point in time zero (t=0) corresponds to a
predefined value (V).
16. The method as claimed in claim 4, wherein a selected section of
the straight line is determined by measurement, and at least one
other section of the straight line is determined by extrapolating
on the basis of the selected section of the straight line.
17. The method as claimed in claim 16, wherein the value of the
straight line at the point in time zero (t=0) is determined by
extrapolation, and the straight line is shifted by changing the
parameters in the Hagen-Poiseuille law in such a way that the value
of the radius (r) at the point in time zero (t=0) corresponds to a
predefined value (V).
Description
[0001] This is a continuation application of U.S. Ser. No.
10/513,815, filed Apr. 7, 2005, and hereby claims the priority
thereof to which it is entitled.
BACKGROUND OF THE INVENTION
[0002] 1. Field of the Invention
[0003] The invention at hand has to do with a technique and
mechanism for testing the thrombocyte function in blood.
[0004] 2. Description of the Related Art
[0005] There are various mechanisms for testing the aggregation of
blood platelets or the coagulation of blood. For example, a
mechanism is based on the EP 0223244 in which the blood is
aspirated through an aperture out from a blood supply space by
means of a moveable piston in a cylinder and the pressure in the
space between the piston and the aspirated in blood is measured,
whereby the piston is driven in such a way that a target pressure
value is maintained in the space. The piston movement serves as a
measurement for the amount of blood flow.
SUMMARY OF THE INVENTION
[0006] The role of the invention at hand consists in creating a
technique and a mechanism that enable to get an exact determination
of the thrombocyte function in the blood.
[0007] This role is performed by a method for testing the
thrombocyte function in blood, whereby an aperture with blood or
blood components is flowed through, including the steps of
determining the effective radius of the aperture as a function of
time by measuring the drop in pressure at the aperture as a
function of time and determining the blood flow volume through the
aperture as a function of time; calculating the hemodynamically
effective radius of the aperture by the Hagen-Poiseuille law; and
evaluating the time-dependent change in the radius as a measure for
the blood cell and/or thrombocyte function. The present invention
also includes a mechanism for carrying out this method.
[0008] The essential advantage of the invention at hand consists in
allowing for an exact determination of the blood platelet delay
time by means of which the arterial thrombus growth is controlled
or influenced. Thus, since in accordance with the invention it
becomes possible to measure the designated blood platelets' delay
time, for the first time evidence ban be gathered on e.g. existing
disease risks, such as arterial thrombotic tendency, for example
the risk of myocardial infarction in a patient. For the first time
medications can be developed that selectively have an effect on the
blood platelet delay time to eliminate such risks.
[0009] The determination of the blood platelet delay time in a
patient's fresh blood so to speak `bedside` very quickly (without
blood thinners) and on a very small volume of blood can be arrived
at by means of a special design of the invention-related
mechanism.
[0010] With a particularly preferred design of the invention the
thrombocyte function can be determined at a very high degree of
reproducibility and preciseness fast and with only a little volume
of blood.
BRIEF DESCRIPTION OF THE DRAWINGS
[0011] Below the invention and its designs will be explained in
more detail in connection with the figures. Shown are:
[0012] FIG. 1 a mechanism for determining the blood platelet delay
time in schematic representation;
[0013] FIG. 2 a diagram for demonstrating the relationship of the
aperture diameter to the time, caused due to occlusion by the blood
platelets;
[0014] FIG. 3 a diagram for demonstrating the wall sear rate as a
function of time;
[0015] FIG. 4 a mechanism designed as a disposable part for
implementing the invention-related technique in schematic
representation; and
[0016] FIGS. 5 and 6 preferred designs of the invention.
DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0017] The following considerations and realizations led to the
inventions. A time-dependent determination of the loading of an
aperture by means of blood platelets when flowing through it
surprisingly revealed that the aperture closes in a completely
defined way, that is in accordance with the straight line depicted
in FIG. 2, whose slant 2 dr/dt yields the growth rate. When
simultaneously calculating the blood platelets' time-dependent wall
shear rate that represents a measurement for blood platelets'
transport rate, it was recognized that in time the wall shear rate
sharply rises from a low value at first in the area of the
aperture. But since the growth rate during this time remains
exactly the same, it can be inferred that a blood platelet delay
time exists that indicates that time over which the individual
blood platelets first allow an adhesion of other blood platelets.
In other words each blood platelet "determines" when, i.e. thus
after which lag in time or delay time, other platelets may adhere
to it. This blood platelet delay time in connection with certain
disease risks and with the development of medications is of primary
importance. This means that by the invention-related finding of the
mentioned rise dr/dt, i.e. therefore the blood platelet delay time,
selective evidence on disease risks, e.g. on the risk for
myocardial infarction in a patient, can be gathered and for this
reason medications can be selectively developed that influence the
blood platelet delay time.
[0018] FIG. 1 shows an existing mechanism for determining the blood
platelet delay time in schematic representation. In essence here
according to arrow 1 blood is moved out of a supply space that is
not described in any greater detail, for instance via a capillary 4
that forms a blood flow resistance stream Wc, through an aperture 3
of an aperture holder 2. The aperture 3 forms a blood flow
resistance Wa.
[0019] According to the following equation
Wa = .DELTA. P Q ( 1 ) ##EQU00001##
(Q=volume of blood flow per time) as well as according to the
Hagen-Poiseuille law
Wa = 8 l .pi. 1 r 4 ( 2 ) ##EQU00002##
by time-dependent calculation of the resistance. Wa the effective
hemodynamic radius of the aperture 3 in accordance with the
equation
r = 8 l .pi. 1 Wa 4 ( 3 ) ##EQU00003##
can be calculated and spread of time in accordance with FIG. 2.
[0020] In equations 1 through 3:
.DELTA.p designates the drop in pressure at the aperture, Wa the
flow resistance of the aperture, .mu. the viscosity of the blood
flowing through the aperture, 1 the gauge of the aperture and r the
radius of the same.
[0021] In FIG. 2 it can be seen that the opening of the aperture 3
quite definitely closes as a function of time surprisingly in
accordance with a straight line with a constant slope of
dr/dt=const) with a very high value of statistical probability:
e.g. RSq=0.982. If a platelet diameter of 2 .mu.m is assumed, a
platelet delay time of 2/0.7=2.8 sec is obtained. With a first
control person with normal platelet function a platelet delay time
of 2.77+0.32 sec. was determined. The number of measurements was
11. With a second control person the platelet delay time amounted
to 2.65+0.1 sec. with 11 measurements and a normal platelet
function as well.
[0022] Instead of the drop in pressure .DELTA.p at the aperture 3
the drop in pressure .DELTA.p' can be measured at the capillary 4
and the aperture 3, whereby then the capillary 4 flow resistance We
has to be deducted to determine the growth rate.
[0023] According to the formula:
.gamma..omega. = 4 Q .pi. r 3 ( 4 ) ##EQU00004##
the wall shear rate .gamma..omega. in the area of the aperture can
be calculated and spread in a time-dependent fashion like FIG. 3.
The result is that the platelets' transport rate on the thrombus
that is approximately proportional to the wall shear rate rates
during the measuring by the factor 4. During this rise though, just
as in FIG. 2, the thrombus growth rate remains exactly the same.
The inference is that the individual blood platelets in the area of
the aperture 3 determine in accordance with a platelet delay time
when other blood platelets may adhere to them. The blood platelet
delay time, therefore, matches the time difference between a blood
platelet's adhesion on the wall of the aperture 3 or on another
blood platelet and the adhering of an additional blood
platelet.
[0024] FIG. 4 illustrates a design of the mechanism at hand in
schematic representation, wherein blood from a blood supply space
10 is pressed or conveyed with the assistance of a piston 12
through the aperture 3 into a blood collecting space 14. The blood
supply space 10 is preferably designed in a cylinder 16 in which
the piston 12 is pushably arranged. The piston/cylinder arrangement
12, 16 can for this purpose have the shape of a blood withdrawal
syringe, wherein the blood supply space 10 is filled when
withdrawing blood from a patient's vein. After removing the
withdrawal cannula, the forward end 18 of the piston/cylinder
arrangement 12,16 can be connected with the section encompassing
the blood collection space 14 that is preferably designed as a
disposable or single use section, wherein the part of its access
opening 20 that is connectable to the piston/cylinder arrangement
12, 16 has an aperture holder 22 with the aperture 3 downstream,
through which the blood traverses from the blood supply space 10
into the blood collecting space 14 upon activation of the piston 12
in the direction of the arrow 24.
[0025] A capillary 4 (see FIG. 1) can be placed upstream to
aperture 3, as is already familiar.
[0026] To measure the pressure reduction on the aperture 3, the
disposable section can have a passage 26 that is connected to a
pressure meter mechanism in a gauge when taking readings and that
runs inside or along its wall from outside to the space upstream of
aperture 3.
[0027] One advantage here is that after withdrawing blood, for
instance at the patient's bed, the disposable section for carrying
out the technique at hand can be connected directly to the
piston/cylinder arrangement 12, 16 that serves for withdrawal of
blood and, along with the piston/cylinder arrangement 12, 16, put
into the gauge that implements the technique at hand and activates
the piston 12.
[0028] It should be pointed out that for measuring with a small
volume of blood (e.g., in pediatrics) it can be advantageous when
carrying out the technique at hand not to activate the piston 12
continuously, but rather intermittently, whereby, for example, the
movement of the piston 12 is interrupted at intervals that could be
on the order of 3 seconds.
[0029] Only one segment of the straight-line dr/dt in FIG. 2 can
also be measured, e.g., for measuring with little blood, whereby
the corresponding bleeding time can be determined by
extrapolating.
[0030] Since it is known that a straight line is to be determined,
measurements with stark deviations can be recognized as erroneous
and corrected by extrapolating in the areas of deviation.
Furthermore, it can also be sufficient to determine only a segment
of the straight line and not to determine measured areas by
extrapolating. For example, this measuring of only segments can be
carried out to save time.
[0031] Since the platelet delay time is not dependent on the
capillary resistance in the case of using a capillary, capillary
errors do not enter into the measurement, thus the measurement
precision and reliability can be enhanced.
[0032] Below a variation on the invention-related technique is
explained in more detail in connection with FIG. 5, by which is
possible a particularly advantageous, clear and significant
assessment for the user or measurement of the thrombocyte function
with a relatively small volume of blood, with short measuring times
and an even greater reproducibility.
[0033] These advantages are achieved due to the fact that by this
variation the slope of the straight-lines dr/dt is indeed
determined, yet no value CT of the bleeding time is extrapolated,
but rather an angle PTGA (Platelet Thrombus Growth Angle) that
exists between the straight line and the t-axis (see FIG. 5). This
is particularly advantageous if this angle is relatively small and
the straight line for this reason runs flat, as is the case with a
very slow thrombus formation in the aperture 3 which applies, e.g.,
to a taking of medication (for example, aspirin). In this case,
enormous fluctuations in the CT value would result by the technique
explained above even with small deviations of the slope dr/dt of
the straight line. These fluctuations are greater the farther the
CT value is removed from the t-axis zero point. In such a case, the
determination or indication of the PTGA is more significant since
it is not subjected to the designated fluctuation. Furthermore,
this PTGA can be derived very quickly from the straight-line's
slope determined at the start of a measurement by the formula
indicated below; thus the measuring time can be relatively short
and only a relatively small volume of blood is needed for
measuring.
PTGA=-(((arcTan(dr/dt))/(n/))90) (5)
Determined.
[0034] Accordingly even the PTGA' can be determined by the
formula:
PTGA'=90-PTGA (6)
and applied.
[0035] The thrombocyte function can, as already mentioned, be
quickly established by this variation of the invention at hand,
i.e., even with a small volume of blood, particularly also with
relatively long thrombus formation times in the aperture 3, as this
is possible, for example, with influences of medications, e.g.,
with the taking of aspirin. Here the values of the PTGA or the
PTGA' determined are to a certain extent comparatively significant
because they are not subjected to such great fluctuations as the CT
values determined.
[0036] A still more improved measurement is made possible with an
additional variation of the technique at hand, according to which a
fit operation is performed to compensate for changes in blood
viscosity and/or the resistance We of capillary 4 (FIG. 1). Here,
with a value t=0, the start value of the aperture opening is always
set or fitted to a pre-established defined value V (from, e.g., 150
.mu.m in FIGS. 2 and 5) in such a way that the straight line at the
beginning of a measurement is calculated by extrapolating up to the
zero point of the t-axis and the value thereby determined for t=0
is shifted to the pre-established value V. Proceeding from this
value V, the straight line is then determined and the CT value
according to FIG. 2 or the PTGA or PTGA' according to FIG. 5. In
this way the measurement data can be further enhanced because
fluctuations in viscosity or the capillary resistance are
compensated.
[0037] Below an additional variation of the technique at hand is
explained by which a quality control of the determined straight
line or the determined PTGA or PTGA' is effected. In so doing, as
indicated earlier above, it is determined how precisely the
measured values dr/dt line up on a straight line or not. With
deviations of a pre-established number of values beyond a
prescribed measure, the corresponding measurement is deemed not
processable or corrected.
[0038] With certain disease conditions or under the influence of
medication, there may be deviations from the linear relation dr/dt.
For example, in FIG. 2 by means of a pointed line is depicted that
the slope of the straight line during a measurement can change in
such a way that the straight line can encompass two segments of
varying slopes dr1/dt and dr2/dt, whereby the point of intersection
P of these segments is to be ascribed for a certain thrombus
formation that is established by a certain disease pattern. In such
cases, the point P is very significant for which reason it is
determined with the measurement.
[0039] Below an additional preferred form of implementation of the
technique at hand, shown in FIG. 6, is explained in more detail.
This essentially has a piston/cylinder arrangement 11 that
encompasses a cylinder 30 and a piston 50. The piston 50 can be
moved in the direction of the arrow 70, i.e. therefore in its axial
direction in the cylinder 30 by means of a drive that is not
illustrated in any more detail.
[0040] The piston 50 preferably has the shape of a metal part
polished on its outer surface that consists in particular of
stainless steel and possesses the shape of a lengthwise cylindrical
rod section. Between the outer surface of the piston and the inner
surface of the cylinder 30, that also preferably consists of
stainless steel, is arranged an O-ring gasket 90 that preferably
consists of a rubber material. Since the outer surface of the
piston 50 is polished between the gasket 90 and the piston 50,
there is extremely little friction so that a smooth movement of the
piston 50 in the direction of the arrow 70 is assured.
[0041] With its end away from the drive that is not illustrated in
more detail, the piston 50 extends out into a blood uptake space
110 that is established by means of a beaker-shaped vessel 130 that
is positioned tightly up against the cylinder 30 with its upper
edge area adjacent to the piston 50 with the aid of a gasket 150.
For this reason the cylinder 30 has a flange section 170 that
extends radially outwards and, on the upper edge of the vessel 130,
a flange section 190 that protrudes toward the outside radially as
well, whereby the O-ring gasket 150 is kept between the flange
sections 170 and 190 and connects the latter tightly to each other.
On the bottom 210 of the vessel 130, an aperture holder 230 is
located that holds a platelet 250 or the like with an aperture 270
arranged in it, whereby a capillary 290 led from outside through
the bottom part 210 in an inherently familiar way ends shortly
prior to the aperture 270 in such a way that out of a blood supply
space (not shown) blood that has been aspirated in through the
capillary 290 with the movement of the piston 50 in the direction
of the arrow 70 is taken in through the aperture 270 into the
uptake space 110. The aperture 270 can also be designed and
arranged in another way. For example, the end of the capillary 290
that protrudes through into the uptake space 110 can form it.
[0042] One pressure-measuring mechanism P that is not illustrated
in greater detail is connected to a passageway 310, preferably in
the wall of the cylinder 30, for measuring the pressure outside of
the blood that has been aspirated through the aperture 270 into the
uptake space 110. In this way it is achieved that the vessel 130 is
fastened to the aperture holder 230 and the capillary 290 and can
be designed as a so-called disposable part and via the gasket 150
optionally to the piston/cylinder arrangement 11 the simplest
way.
[0043] It should be pointed out that instead of determining the
drop in pressure at the aperture 3, an electrical resistance also
could be established by application of a potential difference for
determining the hemodynamic resistance of the aperture 3. The
radius of the aperture 3 that just exists can also be optically
determined.
[0044] The invention being thus described, it will be apparent that
the same may be varied in many ways. Such variations are not to be
regarded as a departure from the spirit and scope of the invention,
and all such modifications as would be recognized by one skilled in
the art are intended to be included within the scope of the
following claims.
* * * * *