WO2001007070A1 - Method for measuring coagulant factor activity in whole blood - Google Patents

Method for measuring coagulant factor activity in whole blood Download PDF

Info

Publication number: WO2001007070A1
Authority: WO; WIPO (PCT)
Prior art keywords: inhibitor; whole blood; blood; sample; factor
Prior art date: 1999-07-23

Application number

PCT/US2000/020118

Other languages

English (en)

French (fr)

Inventor

Nigel Mackman

John J. Mcdonnell

Original Assignee

The Scripps Research Institute

Coagulation Diagnostics, Inc.

Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)

1999-07-23

Filing date

2000-07-24

Publication date

2001-02-01

2000-07-24 Application filed by The Scripps Research Institute, Coagulation Diagnostics, Inc. filed Critical The Scripps Research Institute

2000-07-24 Priority to KR1020027000975A priority Critical patent/KR20020042622A/ko

2000-07-24 Priority to CA002378898A priority patent/CA2378898A1/en

2000-07-24 Priority to AU63697/00A priority patent/AU6369700A/en

2000-07-24 Priority to JP2001511953A priority patent/JP2003505678A/ja

2000-07-24 Priority to EP00950617A priority patent/EP1212073A4/en

2001-02-01 Publication of WO2001007070A1 publication Critical patent/WO2001007070A1/en

Links

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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
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
- C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
- C12Q1/56—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving blood clotting factors, e.g. involving thrombin, thromboplastin, fibrinogen

Definitions

disease prevention More specifically, it relates to diagnostic methods and test kits for
risk for clot formation would help rule in or rule out thrombotic events and
Blood may also clot too slowly, or not at all, which can lead to bleeding or
hemophilias are examples of inheritable
hemophilia A The best known of the inherited disorders of coagulation are hemophilia A and
hemophilia may not be evident until later in life.
Treatment of hemophilias generally consists of transfusions of concentrates of
DIC Disseminated intravascular coagulation
Blood clotting is a complex process involving multiple initiators, cascades of
insoluble fibrin strands or a clot For example, clot formation may be detected
the measurement of clotting time may be made immediately on freshly drawn
blood without added anticoagulants can be used without added anticoagulants.
the clotting time measurement is initiated by adding a calcium salt to reverse the effect of the
PT PT
APTT activated partial thromboplastin time
thrombotic event also may be performed by measuring the level of soluble fibrin or
warfarin would be improved if the coagulability of whole blood, rather than plasma
anticoagulants modulates coagulability through cellular as well as soluble (plasma)
tissue plasminogen activator protein a procoagulant protein called tissue
Factor III also known as Factor III, which is a transmembrane glycoprotein present on the
monocytes surface of circulating cell known as monocytes. Tissue factor is also found in
tissue factor has been found on circulating cells and vesicles in plasma from
the level of tissue factor activity in whole blood is a diagnostically useful
Tissue factor must form an active complex with a plasma clotting factor
prothrombinase complex active procoagulant
thrombin cleaves fibrinogen to produce fibrin, which forms a clot.
modified recalcification time is measured for a blood sample.
immunomodulator creates a condition that simulates disease or trauma, thus
present invention provides another important assessment of tissue factor by providing
TF tissue factor pathway inhibitor
plasma can be determined by the degree of correction obtained when the plasma is
the patient's plasma is compared to the correction obtained by known concentrations
hypocoagulability i.e. pathologically slow blood clotting
coagulation cascade such as F 1.2 prothrombin fragment, D-dimer, soluble fibrin and
the present invention provides a method to rapidly assess the overall
the sample is whole blood
the resulting clotting time represents the overall coagulant
Figure 1 is a diagram showing the central role of monocyte TF during the
Thrombin activates platelets, which form a thrombogenic surface for the prothrombinase complex (Xa: Va). Fibrinogen is
Figure 2 shows the detection of exogenously added TF in whole blood through
Figure 3 shows the effect of anti-TF antibodies on re-calcified whole blood
anti-TF antibodies blocked the LPS-mediated reduction in the re-calcified whole
Figure 4 shows the effect of recombinant TF on the re-calcified whole blood
Figure 5a shows the clotting times for cells isolated from blood and mixed
Figure 5b shows the effect of an inhibitory anti-Factor XI antibody (100
Figure 5c shows the effect of corn trypsin inhibitor (CTI) (32 ⁇ g/mL) added to
Figure 6a shows the effect of unfractionated heparin (0-0.1 U/ml) on the
Figure 6b shows the effect of low molecular weight heparin (LMWH; 0-0.25
Figure 6c shows the effect of hirudin (0-0.1 U/ml) on the clotting time of LPS-
Figure 7 compares the re-calcified whole blood clotting times of patients with
heart attack for example, stroke, coronary artery disease, deep vein thrombosis, and
erythematosus, and infection may predispose patients to undergo adverse clotting
prothrombotic pathways to predominate and intensify, as compared with the
the soluble (plasma) portion of blood as well as that provided by the cellular portion.
prothrombin Traditional measures of clotting or blood coagulability, for example, prothrombin
PT active partial thromboplastin time
APTT active partial thromboplastin time
example is the contribution of tissue factor to blood coagulability. As described
tissue factor is an initiator and modulator of blood coagulation, and may be
Elevated levels are associated with pathologic states.
pathologic states present in the blood. Elevated levels are associated with pathologic states.
tissue factor other components present in or on the cellular components of blood may also modulate blood coagulability and also contribute to the propensity for blood
the method of the invention involves measuring whole
tissue factor in contrast to the above-mentioned modified recalcif ⁇ cation time test
tissue factor which in turn influences the coagulant
the method of the present invention does not measure
the method of the present invention may be performed with fresh whole
a blood sample may be collected in the presence of an anticoagulant
the anticoagulant will block the
the inhibitor may be added, and then
the anticoagulant in the blood sample must be reversed at the time that blood
coagulability or clotting time is measured. This is accomplished by the addition of a
reactivate the clotting process is referred to as the recalcification time.
Any inhibitor of a procoagulant or anticoagulant is suitable for use in the
Suitable inhibitors include, among other things, antibodies or
the analogue is a peptide.
Suitable inhibitors are known to those skilled
tissue factor exhibiting sufficient affinity for tissue factor may be used as the inhibitor of TF:Factor
VD10 and VIC 12 are antibodies to VD10 and VIC 12 are antigens.
the concentration of the antibody or combination of antibodies in the reagent is provided so that it may be easily added to the blood sample to
the inhibitor is Factor VIlai, which is a
Determination of clotting time by the methods of the invention may also be
modulators of the clotting process contemplated for use in the present invention
procoagulants such as thrombin, platelet activating factor, fibrinogen, kaolin,
anticoagulant activity useful as modulators of the clotting process of the present
inventions include protein C, protein S, antithrombin III, thrombomodulin, tissue
coagulant activity of blood may also be used as modulators in the invention.
cancer cell extracts and amniotic fluid may serve as modulators.
the invention is not limited to any particular method of measuring clotting.
reagents that initiate clotting or affect clotting times may be
TEG thrombelastograph
CTEG computerized thrombelastograph
SONOCLOTTM and CTEG are capable of recording changes in the coagulation
HEMOCHRONTM system International Technidyne Corp., which uses a precision
the assays may be performed directly with a fresh blood sample.
the necessary reagents, such as an antibody, may be preloaded into the coagulation
the blood is first collected with an
anticoagulant that binds calcium ions, such as citrate, oxalate, EDTA, etc., and the
anticoagulants may result when blood collection is performed in the presence of a
milliliter of citrated blood is prepared with control antibody or protein control.
control versus the sample containing inhibitor (antibody) is used diagnostically to
a test kit is provided for determining
Tissue factor also known as Factor III, is responsible for initiating the Tissue factor
Tissue factor is primarily present in the monocytes of
Certain disease states may predispose a person's monocytes to be
the present invention may be used to assess hypercoagulability by detecting
tissue factor whole blood assay described in this example involves a test
Control vial + high positive TF control 250 to 350 seconds
Control vial + low positive TF control 650 to 750 seconds
Figure 2 shows the detection of exogenously added TF
This example describes a lipopolysaccharide-stimulation test procedure on the
Hemochron instrument that assesses the production of TF in whole blood in response
citrate/CTI blood collection tubes provided in the kit. Blood should be analyzed
tissue factor whole blood assay described in this example involves a test
CTI com trypsin inhibitor
the Vacutainer tube should contain at least 4.5 ml of
Vials are color-coded by their cap: either a clear cap (for control mAb), a
patient sample will require four tubes, one of each color. Store at 2-8° C.
Tissue factor monoclonal antibody in tris buffered saline (pH 7.4) 1 mg/ml BSA.
Sample preparation Place one clear vial, one white vial, one yellow vial, and one
Analyzer automatically calculates the clotting time. The test should be allowed to run for at least 20 minutes to obtain additional raw data, even though the tone will
vial type (clear, white, yellow, or blue) patient
sources of error for each group include:
Blood donor subjects were drawn from a healthy, normal population of the
NNSA nonsteroidal anti-inflammatory drags
SonoclotTM Coagulation and Platelet Function Analyzer (Sienco, Inc., Wheat Ridge,
the clotting time is derived by
LPS lipopolysaccharide
Inhibitory anti-human TF monoclonal antibodies significantly prolonged the clotting
Factor Vll-deficient plasma may be due to differences between fresh plasma versus
an inhibitory anti-Factor Xla antibody significantly prolonged the clotting
heparin shows greater antithrombin activity relative to its anti-Factor Xa activity (5).
the LMWHs have antithrombin activity that is low, compared with their
Hirudin selectively inhibits thrombin (6).
LPS-stimulated blood prolonged the clotting times in a dose-dependent manner.
thrombosis potential differences between bivalirudin and hirudin. Am. J.

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Molecular Biology (AREA)
Immunology (AREA)
Biomedical Technology (AREA)
Urology & Nephrology (AREA)
Microbiology (AREA)
Biotechnology (AREA)
General Health & Medical Sciences (AREA)
Analytical Chemistry (AREA)
Physics & Mathematics (AREA)
Organic Chemistry (AREA)
Biochemistry (AREA)
Zoology (AREA)
Wood Science & Technology (AREA)
General Physics & Mathematics (AREA)
Medicinal Chemistry (AREA)
Proteomics, Peptides & Aminoacids (AREA)
Food Science & Technology (AREA)
Pathology (AREA)
Cell Biology (AREA)
Biophysics (AREA)
Genetics & Genomics (AREA)
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Investigating Or Analysing Biological Materials (AREA)

PCT/US2000/020118 1999-07-23 2000-07-24 Method for measuring coagulant factor activity in whole blood WO2001007070A1 (en)

Priority Applications (5)

Application Number	Priority Date	Filing Date	Title
KR1020027000975A KR20020042622A (ko)	1999-07-23	2000-07-24	전혈내 응고 인자 활성을 측정하는 방법
CA002378898A CA2378898A1 (en)	1999-07-23	2000-07-24	Method for measuring coagulant factor activity in whole blood
AU63697/00A AU6369700A (en)	1999-07-23	2000-07-24	Method for measuring coagulant factor activity in whole blood
JP2001511953A JP2003505678A (ja)	1999-07-23	2000-07-24	全血の凝固因子活性を測定する方法
EP00950617A EP1212073A4 (en)	1999-07-23	2000-07-24	Method for measuring coagulant factor activity in whole blood

Applications Claiming Priority (2)

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US14514099P	1999-07-23	1999-07-23
US60/145,140		1999-07-23

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EP (1)	EP1212073A4 (ko)
JP (1)	JP2003505678A (ko)
KR (1)	KR20020042622A (ko)
CN (1)	CN1368886A (ko)
AU (1)	AU6369700A (ko)
CA (1)	CA2378898A1 (ko)
WO (1)	WO2001007070A1 (ko)

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- 2000-07-24 CN CN00810751A patent/CN1368886A/zh active Pending
- 2000-07-24 EP EP00950617A patent/EP1212073A4/en not_active Withdrawn
- 2000-07-24 KR KR1020027000975A patent/KR20020042622A/ko not_active Withdrawn
- 2000-07-24 WO PCT/US2000/020118 patent/WO2001007070A1/en not_active Application Discontinuation
- 2000-07-24 CA CA002378898A patent/CA2378898A1/en not_active Abandoned
- 2000-07-24 AU AU63697/00A patent/AU6369700A/en not_active Abandoned
- 2000-07-24 JP JP2001511953A patent/JP2003505678A/ja active Pending

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EP1337660A4 (en) *	2000-10-27	2005-08-17	Bio Merieux Inc	METHOD FOR DETERMINING GLOBAL COAGULABILITY AND HEMOSTATIC POTENTIAL
WO2002079375A1 (en) *	2001-03-30	2002-10-10	Coagulation Diagnostics, Incorporated	Rapid assessment of coagulation activity in whole blood
WO2006084648A1 (de)	2005-02-08	2006-08-17	Csl Behring Gmbh	Methode zur differenzierung von faktor xiii- gegenüber fibrinogen- mangelzuständen unter einsatz thrombelastographischer techniken
AU2006212471B2 (en) *	2005-02-08	2011-02-24	Wolfgang Korte	Method for differentiating a XIII factor and fibrinogen deficiency states by means of thrombelastographic engineering
US7939288B2 (en)	2005-02-08	2011-05-10	Csl Behring Gmbh	Method for differentiating between factor XIII deficiency states and fibrinogen deficiency states by means of thrombelastographic techniques
US8574849B2 (en)	2007-10-03	2013-11-05	The University Of Vermont And State Agriculture College	Methods of detection of factor XIa and tissue factor
US9873720B2 (en)	2008-12-19	2018-01-23	Baxalta GmbH	TFPI inhibitors and methods of use
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US9018167B2 (en)	2010-03-19	2015-04-28	Baxter International Inc.	TFPI inhibitors and methods of use
US11793855B2 (en)	2010-03-19	2023-10-24	Takeda Pharmaceutical Company Limited	TFPI inhibitors and methods of use
US10800816B2 (en)	2012-03-21	2020-10-13	Baxalta GmbH	TFPI inhibitors and methods of use
US10337048B2 (en)	2013-06-28	2019-07-02	Roche Diagnostics Operations, Inc.	Methods for universal determination of anticoagulant activity
US11650196B2 (en)	2017-01-06	2023-05-16	Sony Corporation	Blood coagulation system analysis apparatus, blood coagulation system analysis system, blood coagulation system analysis method, blood coagulation system analysis program, blood loss prediction apparatus, blood loss prediction system, blood loss prediction method, and blood loss prediction program
RU2750839C1 (ru) *	2020-05-18	2021-07-05	Общество с ограниченной ответственностью "Меднорд-Техника" (ООО "Меднорд-Т")	Устройство и способ экспресс-оценки агрегационной активности форменных элементов крови

Also Published As

Publication number	Publication date
CN1368886A (zh)	2002-09-11
EP1212073A4 (en)	2003-09-03
KR20020042622A (ko)	2002-06-05
JP2003505678A (ja)	2003-02-12
CA2378898A1 (en)	2001-02-01
AU6369700A (en)	2001-02-13
EP1212073A1 (en)	2002-06-12

Publication	Publication Date	Title
EP1212073A1 (en)	2002-06-12	Method for measuring coagulant factor activity in whole blood
Brummel‐Ziedins et al.	2004	Thrombin generation: phenotypic quantitation
Laffan et al.	2012	Investigation of haemostasis
US5525477A (en)	1996-06-11	Method for diagnosing blood clotting disorders
US6403381B1 (en)	2002-06-11	Inhibition of coagulation in blood and blood products
US20030064414A1 (en)	2003-04-03	Rapid assessment of coagulation activity in whole blood
US6245573B1 (en)	2001-06-12	Rapid assessment of the coagulant activity of blood
Lippi et al.	2009	Milestones and perspectives in coagulation and hemostasis
US5525478A (en)	1996-06-11	Soluble thrombomodulin-based one-stage assay for vitamin-K dependent coagulation-inhibiting proteins
Simpson et al.	2011	Simultaneous thrombin and plasmin generation capacities in normal and abnormal states of coagulation and fibrinolysis in children and adults
EP2235542B1 (en)	2016-07-27	Diagnostic in vitro method for assessing von willebrand disease and increased bleeding risk associated with von willebrand disease and acquired or congenital disorders of platelet function
CA2623142C (en)	2016-01-19	Methods for a global assay of coagulation and fibrinolysis
JP3248621B2 (ja)	2002-01-21	血栓症リスクのテスト
CA2155503C (en)	2008-10-14	A method for detecting defects in protein c/protein s mediated blood clotting
Hoffmann et al.	1988	Automated nephelometry of fibrinogen: analytical performance and observations during thrombolytic therapy.
Laffan et al.	2006	17 Investigation of a thrombotic tendency
Ruberto et al.	2021	Chronic intravascular coagulation in liver cirrhosis predicts a high hemorrhagic risk.
Cellai et al.	2010	Assessment of fibrinolytic activity by measuring the lysis time of a tissue factor-induced clot: a feasibility evaluation
Kato et al.	2022	Differences in the composition of activated partial thromboplastin time (aptt) reagents affect clot waveform analysis
RU2835822C1 (ru)	2025-03-04	Способ определения антикоагулянтного потенциала плазмы крови для диагностики предтромботических состояний
RU2835822C9 (ru)	2025-03-27	Способ определения антикоагулянтного потенциала плазмы крови для диагностики предтромботических состояний
Herskovits et al.	2008	Comparison of Russell viper venom–based and activated partial thromboplastin time–based screening assays for resistance to activated protein C
US11630101B2 (en)	2023-04-18	Method for diagnosing anomalies in the coagulation of blood
De Metz et al.	1987	Use of a centrifugal analyzer for a chromogenic prothrombin time, a chromogenic activated partial thromboplastin time and a kinetic fibrinogen assay in a routine hospital laboratory
Laffan et al.	2006	16 Investigation of haemostasis

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