The Routine Determination of the Endogenous Thrombin Potential, First Results in Different Forms of Hyper- and Hypocoagulability

SummaryThe area under the thrombin generation curve (the endogenous thrombin potential; ETP) has been proposed as a parameter for plasma-based hypercoagulability and to monitor anticoagulant treatment. We present an ETP assay for the routine laboratory using a centrifugal analyser. Throughput is 30 samples/h, within and between run imprecision is 4-5.6%. Suitable substrates were developed for the ranges of 10-500% and 2-100% of normal.Independent of tissue factor concentration (if >4 pM), the normal value of the extrinsic ETP is 384.8 ±51.7 nM.min. The intrinsic ETP, triggered by ellagic acid, is 414 ± 41 nM.min.The ETP is decreased to 15 and 35% of normal by oral anticoagulation (INR 2.5-4.0) and by heparin administration (APTT 1.5-2.5 X control).The ETP is increased in untreated subjects with congenital antithrombin deficiency and in women using oral contraceptives. In deep vein thrombosis (phlebographically confirmed), it is increased by 29.4% (extrinsic) and 53% (intrinsic). In (angiographically assessed) coronary artery disease the increase is by 10% and 17% respectively.

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Fibrinopeptide A And Beta-Thromboglobulin Concentrations In Venous And Arterial Disorders

10.1055/s-0038-1652033 ◽

1981 ◽

Author(s):

H van Hulsteijn ◽

R M Bertina ◽

E Briët

Keyword(s):

Angina Pectoris ◽

Doppler Ultrasound ◽

Platelet Activation ◽

Thrombin Generation ◽

Fibrinopeptide A ◽

Oral Anticoagulant Treatment ◽

Vein Thrombosis ◽

The Mean ◽

Artery Disease ◽

Deep Vein

The purpose of this study was to assess the relative importance of thrombin generation and platelet activation in venous and arterial disorders. To this end Fibrinopeptide A (FPA) was used as an index of thrombin generation and Beta- thromboglobulin (BTG) as an index of platelet activation. FPA and BTG were determined by specific radioimmunoassays.In 80 controls (age 19-70, mean 41 yrs) mean FPA concentration was 0.72 ± 0.47 (ng/ml ± SD) and mean BTG concentration 28.2 ± 10.1 (ng/ml ± SD).In 51 patients with the symptoms of deep vein thrombosis (DVT) or pulmonary embolism (PE), in which these disorders were confirmed by phlebography and/or Doppler ultrasound or perfusion lungscanning, mean FPA and BTG concentrations were clearly elevated compared to mean FPA and BTG concentrations in controls and in 25 patients with the symptoms of DVT or PE in which these disorders could be excluded by the above named techniques. Heparin and phenprocoumon lowered FPA concentrations into the normal range, while the BTG concentrations remained elevated.In 20 patients with intermittent claudication, in which peripheral vascular disease (PVD) was confirmed by Doppler ultrasound mean FPA concentration did not differ from that in controls, while the mean BTG concentration was obviously elevated. This picture did not change after 2 months of phenprocoumon therapy.In 33 patients with angina pectoris in which coronary artery disease (CAD) was demonstrated by arteriography mean FPA concentration did not differ from that in 7 patients with angina pectoris in which no coronary lesions were present and in controls contrary to the mean BTG concentration, which was clearly elevated. Results in patients on phenprocoumon or acenocoumarol therapy were not different from those without oral anticoagulant treatment.So far the experimental results indicate that in venous disorders (DVT or PE) fibrin formation plays a more important role than in arterial disorders (PVD or CAD).

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Determination of a Fast Acting Plasmin Inhibitor in Plasma from Patients with Tendency of Thrombosis and Increased Fibrinolysis

10.1055/s-0039-1682716 ◽

1977 ◽

Author(s):

A-C. Teger-Nilsson ◽

H. Gyzander ◽

H. Myrwold ◽

H. Noppa ◽

R. OLsson ◽

...

Keyword(s):

Liver Cirrhosis ◽

Deep Vein Thrombosis ◽

Small Extent ◽

Vein Thrombosis ◽

Acute Deep Vein Thrombosis ◽

Deep Vein ◽

Fast Acting ◽

Plasmin Inhibitor ◽

Rapid Drop

Antiplasmin activity has been determined by means of the plasmin specific trlpeptlde substrate H-D-Vai-L-Leu-L-Lys-p-nltroanlllde (S-2251)It Is concluded that the method mainly measures the antiplasmin described by Collen and coworkers ( Thromb. Res. 7, 245, 1975), although α2-macroglobulln may interfere to a small extent. Different categories of patients with tendency to thrombosis and Increased fibrinolysis have been studied During normal mlddlesized operations antiplasmin decreased slightly, but increased postoperatively. Antiplasmin likewise decreased during deliveries, and Increased In th PuerperiumPatients with acute deep vein thrombosis had normal antiplasmin activity at the time for diagnosis, but antiplasmin Increased later during the course of eventsStreptokinase treated patients showed a pronounced and rapid drop In antiplasmin activity, which was normalized as soon as the streptokinase administration was InterruptedPatients with liver cirrhosis had lower antiplasmin activity than normals , and so had patients with disseminated Intravascular coagulation.

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Thrombin generation and venous thromboembolism

Hämostaseologie ◽

10.1055/s-0037-1616919 ◽

2008 ◽

Vol 28 (01/02) ◽

pp. 37-39 ◽

Cited By ~ 6

Author(s):

S. Eichinger

Keyword(s):

At Risk ◽

Venous Thromboembolism ◽

Thrombin Generation ◽

Recurrence Risk ◽

Hormonal Contraceptives ◽

Antithrombin Deficiency ◽

Unknown Risk ◽

Patients At Risk ◽

Recurrent Venous Thrombosis

SummaryVenous thromboembolism is a chronic and potential fatal disease. Determination of recurrence risk is time-consuming and costly, and sometimes not feasible: many patients carry more than one risk factor, the relevance of some factors with regard to risk of recurrence is unknown, and existence of thus far unknown risk factors must be considered. A laboratory assay that measures multifactorial thrombophilia would be useful to identify patients at risk of thrombosis. The process of thrombin generation is the central event of the hemostatic process. Thrombin generation is increased in patients at risk of thrombosis including those with antithrombin deficiency or those who are taking hormonal contraceptives. Risk of first and recurrent venous thrombosis is higher in patients with increased thrombin generation. Thus, by use of a simple global marker of coagulation stratification of patients according to their risk of thrombosis is possible. Future studies are needed to improve the management of patients with VTE and increased thrombin generation.

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C0179: Genetic Basis of Antithrombin Deficiency in Indian Patients with Deep Vein Thrombosis

Thrombosis Research ◽

10.1016/s0049-3848(14)50200-9 ◽

2014 ◽

Vol 133 ◽

pp. S61

Author(s):

A. Sharma ◽

T. Bhakuni ◽

R. Ranjan ◽

Mohd. Suhail Akhter ◽

R. Kumar ◽

...

Keyword(s):

Deep Vein Thrombosis ◽

Genetic Basis ◽

Antithrombin Deficiency ◽

Vein Thrombosis ◽

Indian Patients ◽

Deep Vein

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LEVELS OF FACTOR VIII (FVIII), D-DIMER AND THROMBIN GENERATION (TG) IN PATIENTS AFTER ACUTE DEEP VEIN THROMBOSIS (DVT)

Journal of Thrombosis and Haemostasis ◽

10.1111/j.1538-7836.2007.tb00697.x ◽

2007 ◽

Vol 5 ◽

pp. P-S-602-P-S-602

Author(s):

A.J. ten Cate ◽

A.W.J.H. Dielis ◽

H.M.H. Spronk ◽

R. van Oerle ◽

K. Hamulyák ◽

...

Keyword(s):

Deep Vein Thrombosis ◽

Factor Viii ◽

Thrombin Generation ◽

Vein Thrombosis ◽

Acute Deep Vein Thrombosis ◽

Deep Vein ◽

D Dimer

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Anticoagulant Response to Agkistrodon Contortrix Venom (ACV test): a New Global Test to Screen for Defects in the Anticoagulant Protein C Pathway

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650322 ◽

1996 ◽

Vol 75 (04) ◽

pp. 562-566 ◽

Cited By ~ 28

Author(s):

A Robert ◽

V Eschwège ◽

H Hameg ◽

L Drouet ◽

M-F Aillaud

Keyword(s):

Protein C ◽

Control Group ◽

Factor V ◽

Antithrombin Deficiency ◽

Global Test ◽

Vein Thrombosis ◽

Agkistrodon Contortrix ◽

Factor V Gene ◽

Deep Vein ◽

Anticoagulant Response

SummaryAs specific assays used to identify defects in the protein C (PC) anticoagulant pathway are laborious and expensive, we describe here a global test to screen for these defects. This assay is expressed as the ratio of two activated partial thomboplastin times, one in the absence and one in the presence of 0,125 U/ml of the PC activator of Agkistrodon contortrix venom (ACV). Eight of the 168 healthy volunteers of the control group exhibited an ACV ratio below the lower normal limit of 3.37 [6 subjects with the mutation Arg 506 to Gin in their factor V gene (FV R506Q) and one with PS deficiency]. 128 patients who have had at least one episode of deep-vein thrombosis were retrospectively studied. All patients carrying FV Q506R (n = 48), PC deficiency (n = 14) or combined defects, i. e. FV Q506R and PC deficiency (n = 4) or FV Q506R and PS deficiency (n = 3), had ACV ratios < 3.37. PS deficient plasmas (n = 20) exhibited ACV ratios which overlapped normal range. ACV ratios of one out of seven patients with antithrombin deficiency, and 10% of patients without identified defect in the PC anticoagulant pathway (n = 30) were < 3.37. An ACV ratio raised to 3.70 could lead to a test identifying all patients with a defect in the PC anticoagulant pathway.

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Chronic spontaneous coronary artery dissection in association with antiphospholipid syndrome presenting as stable angina

BMJ Case Reports ◽

10.1136/bcr-2018-227674 ◽

2019 ◽

Vol 12 (3) ◽

pp. e227674 ◽

Cited By ~ 1

Author(s):

Napohn Chongprasertpon ◽

Abdalla Ibrahim ◽

Michael Goggins ◽

Thomas Kiernan

Keyword(s):

Coronary Artery ◽

Antiphospholipid Syndrome ◽

Stable Angina ◽

Retinal Artery Occlusion ◽

Artery Occlusion ◽

Artery Dissection ◽

Coronary Artery Dissection ◽

Vein Thrombosis ◽

Artery Disease ◽

Deep Vein

A 52-year-old man presented to our cardiology service for an elective diagnostic coronary angiogram for risk stratification in the context of stable angina. He was diagnosed with antiphospholipid syndrome 2 years prior and had three known thrombotic episodes in the form of a stroke, retinal artery occlusion and deep vein thrombosis. Our initial differential was atherosclerotic coronary artery disease, however, coronary angiography demonstrated a dominant right coronary artery with a long segment of chronic spontaneous dissection distally but with thrombolysis in myocardial infarction III flow. He was treated medically with antianginals which rendered him asymptomatic and is currently on regular follow-up in the cardiology outpatient department.

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Abstract P596: How Common Are Microembolic Signals After Cerebrovascular Events and Are They Related to Recurrent Admissions?

Stroke ◽

10.1161/str.52.suppl_1.p596 ◽

2021 ◽

Vol 52 (Suppl_1) ◽

Author(s):

Behnam SABAYAN ◽

Simin Mahinrad ◽

Sanaz Sedaghat ◽

Eric M Liotta ◽

Farzaneh A Sorond

Keyword(s):

Cox Regression ◽

Hospital Readmissions ◽

Smoking History ◽

Vein Thrombosis ◽

Complication Risk ◽

Cerebrovascular Events ◽

History Of ◽

Artery Disease ◽

Ischemic Attack ◽

Deep Vein

Introduction: Microembolic signals (MES) identified by transcranial Doppler (TCD) reflect an ongoing embolic phenomenon with implications for the recurrence of cerebrovascular events and complications. In this study, we investigated the prevalence of MES detected after stroke or transient ischemic attack (TIA) and studied their relationship with future re-admissions. Method: This clinical cohort study is comprised of 961 consecutive patients (mean age 65 years, 59% male) admitted to Northwestern Memorial Hospital with the diagnosis of acute stroke (n: 872) or TIA (n: 89) and underwent TCD evaluation. TCD is performed within the first 48 hours of admission as a routine component of stroke etiology evaluation at our institution. After discharge, patients were followed for an average of 18 months for any hospital readmissions. Cox regression models were used to estimate risk of re-admissions in relation to MES. Results: MES were detected in 99 (10%, 95% CI; 8-12%) patients. During the follow up period, 356 patients had emergency room re-admissions. Compared to patients without MES, those with MES were younger ( p =0.007) and had longer index hospital stay ( p =0.008). Patients with MES, as compared to patients without MES, had 1.56-fold (hazard ratio 95% CI=1.15, 2.13; p =0.005) higher risk of readmission. This association was independent of age, sex, race, smoking, history of hyperlipidemia, diabetes, atrial fibrillation, history of pulmonary emboli, deep vein thrombosis, hypertension, coronary artery disease and heart failure. Conclusion: We show that MES are present in one tenth of patients admitted with stroke or TIA, and they are associated with higher risk of re-admission. These data highlight the importance of embolic signals in stroke complication risk stratification and suggest the need for prospective clinical trials targeting MES in secondary stroke risk and complication prevention.

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Routine Measurement of Endogenous Thrombin Potential (ETP) To Assess Hemostatic Function in Patients with Liver Cirrhosis.

Blood ◽

10.1182/blood.v108.11.4014.4014 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4014-4014

Author(s):

Alain P. Gadisseur ◽

Jeoffrey Schouten ◽

Sven Franque ◽

Marc Van der Planken ◽

Peter Michielsen ◽

...

Keyword(s):

Liver Cirrhosis ◽

Thrombin Generation ◽

Pearson Correlation ◽

Area Under The Curve ◽

Classification Systems ◽

Bleeding Tendency ◽

Endogenous Thrombin Potential ◽

Automated Assay ◽

The Mean

Abstract The maintenance of hemostasis through the production of most of the coagulation proteins is a basic liver function. In patients with cirrhosis of the liver the decrease in these proteins is one of the contributory factors to an increased bleeding tendency. Normally the hemostatic capacity of the liver is measured through routine clotting tests as the activated Partial Thromboplastin Time (aPTT) and Prothrombin Time (PT). In the Child classification for liver cirrhosis the coagulation as expressed by the PT is one of the determinants. Recently a test has become available which will make it possible to routinely measure the endogenous thrombin generation potential (ETP) which may be a better alternative. In this test according to the method first described by Hemker (1993) thrombin generation is continuously measured by use of a chromogenic substrate. Results are calculated as area under the curve and as a percentage of normal. We analysed 110 patients with liver cirrhosis classified according to the Child classification, 79 patients with stage A, 19 stage B and 12 stage C, without known pre-existing coagulation abnormalities like inherited bleeding disorders, or anticoagulant drugs. In these patients ETP, APTT, PT/INR, FV, FVII and FXI were measured. We used a fully automated assay for the determination of the endogenous thrombin potential (ETP) on the BCS® System (both Dade Behring, Marburg, Germany). The results for the mean PT were 81% (CI95 77 - 85) for Child A patients, 53% (CI95 44 - 63) for Child B, and 41% (CI95 33 - 50) for Child C. For the mean INR the results were 1.11 (CI95 1.08 - 1.14) for Child A patients, 1.65 (CI95 1.22 - 2.08) for Child B, and 1.82 (CI95 1.34 - 2.31) for Child C. The results for the mean normalized ETP were 0.87 (CI95 0.84 - 0.90) for Child A patients, 0.78 (CI95 0.68 - 0.88) for Child B, and 0.58 (CI95 0.51 - 0.64) for Child C (p<0.001). While the normalized ETP correlated well with both PT and INR for Child B (P<0.05) and C (p<0.01), there were significant differences within the child A patients where no significant correlation could be identified (Pearson correlation 0.203, R2=0.04, p=0.075. We conclude that the fully automated assay for the determination of the endogenous thrombin potential (ETP) on the BCS® System (both Dade Behring, Marburg, Germany) is a potentially interesting test to measure the coagulation abilities in patients with liver cirrhosis which in the future may supersede the PT/INR in classification systems for hepatic disease.

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Protein S As a Potential Treatment for FIX-Derived Deep Vein Thrombosis

Blood ◽

10.1182/blood.v126.23.2277.2277 ◽

2015 ◽

Vol 126 (23) ◽

pp. 2277-2277

Author(s):

Vijaya Satish Sekhar Pilli ◽

Willium Plautz ◽

Rinku Majumder ◽

Paolo Simioni

Keyword(s):

Deep Vein Thrombosis ◽

Thrombin Generation ◽

Conflicts Of Interest ◽

Ex Vivo ◽

Protein S ◽

Factor Ix ◽

Wild Type ◽

Vein Thrombosis ◽

Deep Vein

Abstract Background: Every year, 0.1-0.2% of the USA population experiences deep vein thrombosis (DVT). Two causes of DVT are increased Factor IX (FIX) levels and hyperactivating mutations in FIX (FIX Padua variant- R338L and Malmo variant T148A). In principle, inhibition of activated FIX (FIXa) should alleviate DVT. Previous in vitro studies demonstrated that the anticoagulant Protein S (PS) inhibits the intrinsic pathway mediated by wild type FIXa, making PS an attractive candidate to treat DVT. Aims: To establish Protein S as a remedy for FIX-mediated DVT/Padua/Malmo Methods: Anisotropy, clotting assays, thrombin generation assays, co-localization, co-immunoprecipitation, and bleeding assays. Results: We further explored the physiological relevance of the PS-FIXa interaction and PS-mediated inhibition of FIXa by ex vivo (co-immunoprecipitation) and in vivo (co-localization) studies. Because PS can inhibit FIXa in vivo, we used competitive, direct anisotropy assays and co-immunoprecipitation assays to measure the efficiency PS and hyperactive FIXa (R338L) interaction. Interestingly, the results demonstrated that FIXa R338L has lost its affinity towards PS compared with wild type FIXa. The same finding was obtained by ex vivo thrombin generation assays and FXa generation assays supplemented with various concentrations of PS. Thus, to be inhibited, hyperactive FIX requires a greater amount of PS compared with wild type FIXa. We are further confirming this finding with mouse models. Conclusion: Addition of PS to plasma inhibits both wild type and R338L FIXa and extends clotting time. Previous studies showed that the addition of PS has no significant negative effects. Thus, we conclude that PS supplementation potentially constitutes a novel and effective treatment for FIX-mediated DVT. Disclosures No relevant conflicts of interest to declare.

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