WO1997041432A1 - Method for determining platelet inhibitor response - Google Patents
Method for determining platelet inhibitor response Download PDFInfo
- Publication number
- WO1997041432A1 WO1997041432A1 PCT/US1997/007356 US9707356W WO9741432A1 WO 1997041432 A1 WO1997041432 A1 WO 1997041432A1 US 9707356 W US9707356 W US 9707356W WO 9741432 A1 WO9741432 A1 WO 9741432A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- cell
- clotting
- platelet
- inhibitor
- amount
- Prior art date
Links
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/86—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving blood coagulating time or factors, or their receptors
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/483—Physical analysis of biological material
- G01N33/487—Physical analysis of biological material of liquid biological material
- G01N33/49—Blood
- G01N33/4905—Determining clotting time of blood
Definitions
- the present invention relates to a method of determining the effectiveness of antiplatelet reagents or platelet inhibitors on the mechanical activation of platelets
- the method and apparatus described performs six, four or two channel coagulation tests of which there are a number of variants
- the electromechanical assembly in the instrument which lifts and lowers the flag-plunger assembly (described in Pat No 4,599,219) in each channel ofthe assay cartridge is under software control
- the rate at which the flag-plunger assembly is lowered through the whole blood assembly can thus be controlled.
- 5,314,826 describes how the rate at which the flag-piunger assembly is lowered through a whole blood sample affects the rate at which platelets are activated
- the description of what happens in the blood sample can be described as follows Slowly lowering the flag-plunger assembly leads to the generation of low shear forces within the blood sample Under these conditions the platelets in the blood sample rapidly activate in which they expose platelet factor 3 activity and possibly release platelet factor 4 activity. Under the conditions of the assay, activation of both of these components will shorten the blood clotting time
- the ability of the platelets to rapidly activate clotting is impaired and the clotting tune becomes longer.
- the postulated mechanism is that the platelets bind to the kaolin or clotting reagent particles used the trigger contact activation Once the platelets bind to the kaolin particles, they are activated, which leads to an increase in the rate at which the blood clots.
- U.S Pat No 5,314,826 compares the clotting times of a blood sample under the two extreme conditions, maximal (or low shear force) activation and minimal (or high shear force) This is referred to as measuring platelet activity using mechanical platelet activation
- the degree of mechanical activation achieved is related to the amount of time the blood sample is subjected to this low shear force condition.
- the activation of platelets is a rate limiting step, I e. , the actual clotting times depend on how rapidly the platelets are able to activate clotting.
- any additive which can accentuate this rate limited step can be added to the test sample and the effect is even more noticeable
- heparin is added to me assay sample. Heparin inhibits other factors in coagulation so that the effect of platelets on coagulation is even more noticeable.
- Pat. No. 5,314,826 does not address the use of a mechanical activation cycle to optimize an assay for determining the impact of platelet inhibitors.
- Fig. 1 is a hypothetical graph of Percent Inhibition vs. Inhibitor Concentration.
- the present invention is embodied in a method of determining a dose response for a platelet inhibitor.
- the method includes the steps of placing a predetermined amount of heparin in each cell of a multicell test cartridge, placing an optimized amount of a clotting activator in each cell, and placing a measured amount of platelet inhibitor in each cell, the amount of inhibitor in each cell differing from the amount in each other cell.
- An aliquot of a blood sample is added to each cell, and the blood sample aliquot, clotting reagent and platelet inhibitor are mixed.
- Each cell sample is allowed to clot, and the clotting time for each cell is measured. The relative clotting times are used to calculate and determine the platelet inhibition effect of the platelet inhibitor.
- a six channel assay cartridge is selected and a predetermined amount of heparin (1-3 units/ml) is placed in each cartridge cell to enhance the sensitivity of the assay.
- An optimized amount of an activator solution, kaolin plus buffer and stabilizers, for showing the effect of platelets on an activated clotting time, is placed in the reagent portion of each cell. Amounts of 12% and 10% kaolin have been used.
- One illustrative composition is HEPES buffer, 50mM calcium chloride, .02% sodium azide as a bacteriostatic agent, and 10% kaolin, at pH 7.4. The buffer is isotonic with respect to sodium chloride.
- a platelet inhibitor is added to the reaction chambers or cells of the assay cartridge in the following concentrations:
- the actual concentrations cannot be given until a specific antiplatelet compound is tested in the system.
- X represents a low concentration of the compound with which inhibition (or an increase in the clotting time) is just noticeable.
- Factors a, b, and c represent multiple increases in the amount of the compound x added to the cells. Concentration cX is preferably an excess of the compound, in order to give maximal inhibition of platelet activation. Increasing the amount of the antiplatelet drug above this concentration will not further increase the clotting time. 4.
- the assay cartridge apparatus is programmed for an appropriate mix cycle and sample volume.
- a blood sample is drawn and aliquot volumes of the sample (0.35ml) are dispensed into each of the six cells of the assay cartridge.
- the test is initiated by injecting the contents of the reagent chamber into the reaction chamber of each test cell.
- the “mixing cycle” is run for a predetermined period of time, about 8 to 60 seconds.
- the agitator is switched to a drop rate in the high shear force mode. This optimizes the ability to detect clot formation. Clotting time is then measured for the sample in each cell.
- the test is terminated and a relative clotting time is computed wherein the clotting times of the cells containing no platelet inhibitor are used as the reference clotting time.
- the simplest calculation is to consider this zero percent inhibition, and the cell with the maximum amount or excess of the inhibitor is considered as 100% inhibition.
- the clotting times from the intermediate cells are then compared to determine the dose response.
- the purpose of the foregoing test is three-fold: 1) to determine an individual's basic response to the platelet inhibitor, 2) to monitor the presence of the platelet inhibitor, and 3) to determine the quantitative concentration of the inhibitor.
- a dose response cartridge test is performed on a patient using compound x as a specific platelet inhibitor.
- a titration curve is plotted which is used to compute a dosage of the drug which will be given to the patient.
- the test apparatus computes this dosage based on the clotting times and the program which relates to this specific drug.
- a two channel activated clotting time assay is performed. This measures whether or not the target clotting time has been achieved and is a measure of the effectiveness of the drug. If a specific concentration of the drug is desired, this may be determined by using the previous dose response curve obtained to compute the concentration of the inhibitor.
- Fig. 1 illustrates a process in which the desired degree of platelet inhibition is a 50% inhibition.
- the Y-axis is computed from the clotting times obtained using the above-described dose response assay cartridge.
- the clinician enters the 50% inhibition figure into the apparatus and the apparatus computes the information given in Fig. 1.
- the horizontal line labeled "Desired Inhibition Level” represents 50% inhibition. This line intersects the "Dose Response Curve.
- a vertical line is dropped from this point of intersection to the X-axis where the intersection of me line with the X-axis provides the concentration of inhibitor required to achieve 50% inhibition of the platelets.
- Fig. 1 is labeled in terms of cell numbers, but could also be labeled with concentrations of the inhibitor, from zero in cell 1 to the maximum (100% inhibition) in cell 6.
- the above dose response curve can be used after running a two channel assay cartridge, taking the clotting time (the Y- axis could also be given in terms of the clotting times rather than a percentage of inhibition). This is used to convert the clotting time to a concentration of the inhibitor using the same type of calculation as above.
- a third method for determining the amount of platelet drug present uses a titration assay. This requires that a chemical or antibody capable of neutralizing the inhibitor be available.
- each channel of the assay cartridge contains increasing amounts of the neutralizing agent.
- the channel where the shortest clotting time is obtained is the concentration of neutralizing agent where all of the platelet inhibitor has been neutralized. Knowing the stoichiometry between the neutralizing agent and the platelet inhibitor, the concentration of the platelet inhibitor present in the sample can be computed.
Abstract
Description
Claims
Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DE19781870T DE19781870T1 (en) | 1996-04-30 | 1997-04-30 | Method for determining platelet inhibitor responsiveness |
DE19781870.6A DE19781870B3 (en) | 1996-04-30 | 1997-04-30 | A method of determining the platelet inhibitory effect of a platelet inhibitor |
DE29723808U DE29723808U1 (en) | 1996-04-30 | 1997-04-30 | Device for determining platelet inhibitor responsiveness |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US64027796A | 1996-04-30 | 1996-04-30 | |
US08/640,277 | 1996-04-30 |
Publications (2)
Publication Number | Publication Date |
---|---|
WO1997041432A1 true WO1997041432A1 (en) | 1997-11-06 |
WO1997041432B1 WO1997041432B1 (en) | 1997-12-18 |
Family
ID=24567588
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1997/007356 WO1997041432A1 (en) | 1996-04-30 | 1997-04-30 | Method for determining platelet inhibitor response |
Country Status (2)
Country | Link |
---|---|
DE (3) | DE19781870B3 (en) |
WO (1) | WO1997041432A1 (en) |
Cited By (8)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000040963A1 (en) * | 1999-01-04 | 2000-07-13 | Medtronic, Inc. | Method for determining platelet inhibitor response |
WO2001082793A2 (en) * | 2000-04-28 | 2001-11-08 | Medtronic, Inc. | Method and device for testing a sample of fresh whole blood |
WO2001096879A2 (en) * | 2000-06-09 | 2001-12-20 | Haemoscope Corporation | Method and apparatus for monitoring anti-platelet agents |
US7179652B2 (en) | 1999-02-22 | 2007-02-20 | Haemoscope Corporation | Protocol for monitoring platelet inhibition |
US7524670B2 (en) | 2003-08-05 | 2009-04-28 | Haemoscope Corporation | Protocol and apparatus for determining heparin-induced thrombocytopenia |
US7732213B2 (en) | 1999-02-22 | 2010-06-08 | Coramed Healthcare, Inc. | Method of evaluating patient hemostasis |
US8008086B2 (en) | 1999-02-22 | 2011-08-30 | Cora Healthcare, Inc. | Protocol for monitoring direct thrombin inhibition |
US9915671B2 (en) | 2008-12-23 | 2018-03-13 | C A Casyso Ag | Cartridge device for a measuring system for measuring viscoelastic characteristics of a sample liquid, a corresponding measuring system, and a corresponding method |
Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4599219A (en) * | 1982-10-15 | 1986-07-08 | Hemotec, Inc. | Coagulation detection by plunger sensing technique |
WO1993025578A1 (en) * | 1992-06-05 | 1993-12-23 | Department Of The Army, U.S. Government | Test for quantitative thrombin time |
US5314826A (en) * | 1991-08-23 | 1994-05-24 | Medtronic Hemotec, Inc. | Platelet activation and function evaluation technique |
EP0661383A2 (en) * | 1993-12-30 | 1995-07-05 | BEHRINGWERKE Aktiengesellschaft | Method for the determination of thrombocyte aggregation |
Family Cites Families (4)
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US4671939A (en) * | 1981-07-09 | 1987-06-09 | International Technidyne Corp. | Apparatus for analyzing the influence of additive reagents upon the coagulation of blood and related methods |
US4871677A (en) * | 1985-02-25 | 1989-10-03 | Hemotec, Inc. | Method of collecting and analyzing a sample of blood when monitoring heparin therapy |
US5266462A (en) * | 1992-06-03 | 1993-11-30 | Baxter Diagnostics Inc. | Measurement of platelet activities |
GB9211966D0 (en) * | 1992-06-05 | 1992-07-15 | Univ Liverpool | Functionalisation of polymers |
-
1997
- 1997-04-30 WO PCT/US1997/007356 patent/WO1997041432A1/en active Application Filing
- 1997-04-30 DE DE19781870.6A patent/DE19781870B3/en not_active Expired - Lifetime
- 1997-04-30 DE DE19781870T patent/DE19781870T1/en active Granted
- 1997-04-30 DE DE29723808U patent/DE29723808U1/en not_active Expired - Lifetime
Patent Citations (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US4599219A (en) * | 1982-10-15 | 1986-07-08 | Hemotec, Inc. | Coagulation detection by plunger sensing technique |
US5314826A (en) * | 1991-08-23 | 1994-05-24 | Medtronic Hemotec, Inc. | Platelet activation and function evaluation technique |
WO1993025578A1 (en) * | 1992-06-05 | 1993-12-23 | Department Of The Army, U.S. Government | Test for quantitative thrombin time |
EP0661383A2 (en) * | 1993-12-30 | 1995-07-05 | BEHRINGWERKE Aktiengesellschaft | Method for the determination of thrombocyte aggregation |
Cited By (23)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2000040963A1 (en) * | 1999-01-04 | 2000-07-13 | Medtronic, Inc. | Method for determining platelet inhibitor response |
US7179652B2 (en) | 1999-02-22 | 2007-02-20 | Haemoscope Corporation | Protocol for monitoring platelet inhibition |
US8008086B2 (en) | 1999-02-22 | 2011-08-30 | Cora Healthcare, Inc. | Protocol for monitoring direct thrombin inhibition |
US7732213B2 (en) | 1999-02-22 | 2010-06-08 | Coramed Healthcare, Inc. | Method of evaluating patient hemostasis |
US7182913B2 (en) | 1999-02-22 | 2007-02-27 | Haemoscope Corporation | Sample retention apparatus for use in measuring hemostasis |
WO2001082793A2 (en) * | 2000-04-28 | 2001-11-08 | Medtronic, Inc. | Method and device for testing a sample of fresh whole blood |
WO2001082793A3 (en) * | 2000-04-28 | 2002-07-04 | Medtronic Inc | Method and device for testing a sample of fresh whole blood |
US6541262B1 (en) * | 2000-04-28 | 2003-04-01 | Medtronic, Inc. | Method and device for testing a sample of fresh whole blood |
WO2001096879A3 (en) * | 2000-06-09 | 2002-06-13 | Haemoscope Corp | Method and apparatus for monitoring anti-platelet agents |
JP2006145548A (en) * | 2000-06-09 | 2006-06-08 | Haemoscope Corp | Method and device for monitoring antiplatelet agent |
JP2004503781A (en) * | 2000-06-09 | 2004-02-05 | ヘモスコープ コーポレイション | Method and apparatus for monitoring antiplatelet agents |
CN102183665B (en) * | 2000-06-09 | 2013-08-21 | 希缪司构普公司 | Method and apparatus for monitoring anti-platelet agents |
WO2001096879A2 (en) * | 2000-06-09 | 2001-12-20 | Haemoscope Corporation | Method and apparatus for monitoring anti-platelet agents |
CN102183665A (en) * | 2000-06-09 | 2011-09-14 | 希缪司构普公司 | Method and apparatus for monitoring anti-platelet agents |
US7524670B2 (en) | 2003-08-05 | 2009-04-28 | Haemoscope Corporation | Protocol and apparatus for determining heparin-induced thrombocytopenia |
US9915671B2 (en) | 2008-12-23 | 2018-03-13 | C A Casyso Ag | Cartridge device for a measuring system for measuring viscoelastic characteristics of a sample liquid, a corresponding measuring system, and a corresponding method |
US10746750B2 (en) | 2008-12-23 | 2020-08-18 | C A Casyso Gmbh | Cartridge device for a measuring system for measuring viscoelastic characteristics of a sample liquid, a corresponding measuring system, and a corresponding method |
US11061038B2 (en) | 2008-12-23 | 2021-07-13 | C A Casyso Gmbh | Cartridge device for a measuring system for measuring viscoelastic characteristics of a sample liquid, a corresponding measuring system, and a corresponding method |
US11131680B2 (en) | 2008-12-23 | 2021-09-28 | C A Casyso Gmbh | Cartridge device for a measuring system for measuring viscoelastic characteristics of a sample liquid, a corresponding measuring system, and a corresponding method |
US11360106B2 (en) | 2008-12-23 | 2022-06-14 | C A Casyso Gmbh | Cartridge device for a measuring system for measuring viscoelastic characteristics of a sample liquid, a corresponding measuring system, and a corresponding method |
US11768211B2 (en) | 2008-12-23 | 2023-09-26 | C A Casyso Gmbh | Cartridge device for a measuring system for measuring viscoelastic characteristics of a sample liquid, a corresponding measuring system, and a corresponding method |
US11879899B2 (en) | 2008-12-23 | 2024-01-23 | C A Casyso Gmbh | Cartridge device for a measuring system for measuring viscoelastic characteristics of a sample liquid, a corresponding measuring system, and a corresponding method |
US11892459B2 (en) | 2008-12-23 | 2024-02-06 | C A Casyso Gmbh | Cartridge device for a measuring system for measuring viscoelastic characteristics of a sample liquid, a corresponding measuring system, and a corresponding method |
Also Published As
Publication number | Publication date |
---|---|
DE29723808U1 (en) | 1999-11-04 |
DE19781870T1 (en) | 2000-02-24 |
DE19781870B3 (en) | 2014-05-28 |
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