Effect of FV-Leiden Mutation and Antiphospholipid Syndrome on Thethrombin GenerationTest.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3506-3506
Author(s):  
Ferial Peyvandi ◽  
Wolfgang Miesbach ◽  
Wolfgang Wegert ◽  
Inge Scharrer
Keyword(s):  
Antiphospholipid Syndrome ◽  
Thrombin Generation ◽  
Factor V Leiden ◽  
Coagulation Factor ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Platelet Poor Plasma ◽  
Time To Peak ◽  
Concentration Peak ◽  
Fvl Mutation

Abstract Introduction: The incidence of Factor V Leiden mutation (Arg 506 Gln) is significantly high in patients with venous and arterial thrombosis. In patients with antiphospholipid syndrome (APS), the FVL mutation may play a major role in the occurrence of thrombosis. The aim of this study was to demonstrate that an increased Endogenous Thrombin Potential (ETP) may be an important mechanism for the thrombotic risk associated with FVL and / or APS and to know if the FVL mutation would increase the risk of thrombosis in patients with APS. Additionally, we tested if fluorometric determination of ETP( area under the curve), thrombin generation velocity (PEAK) and TIME TO PEAK (time from starting to reaching the peak), is suitable to determine changes in haemostatic parameters. Methods and patients: We measured the thrombin generation in 120 patients (67F, 53M) with a median age of 40 year categorized in 3 groups of 40 patients each:(1) either heterozygous or homozygous FVL mutation (14F, 26M of whom 29 were heterozygous and 11 were homozygous) (2) presence of antiphospholipid antibodies (aPL) (20F, 20M) and (3) a combination of both (33F,7M). Three characterizing thrombin generation parameters were measured: ETP, PEAK and TIME TO PEAK. Platelet poor plasma samples (PPP) were derived from citrated blood. In a microtiter plate, we used different concentrations of TF with phospholipids after adding PRP(platelet poor plasma) and buffer. The reaction was started after adding substrate solution. Fluorometer was the Fluoroskan Ascent Type 374. Results: Using four concentrations (Innovin dilutions 1:600, 1:6.000, 1:50.000 and 1:500.000) of TF, the following results (ETP units = relative fluorescence units or RFU; PEAK units: RFU/min; TIME TO PEAK units = min) were obtained for the 3 groups: For all patients TF 1:600 median ETP, PEAK and TIME TO PEAK were taken as 100 % because less dilution gives no further increase resp. decrease in these parameters Patients with aPL: median ETP decreased from 100 % to 36,6 % (lowest TF concentration), PEAK to 34,4 % and TIME TO PEAK increased to 218 %. Patients with FVL median ETP decreased from 100 % to 2,64 % (lowest TF concentration), PEAK to 9 % and TIME TO PEAK increased to 282 %. Patients with aPl and FVL => median ETP decreased from 100 % to 33 % (lowest TF concentration), PEAK to 30,8 % and TIME TO PEAK increased to 143 %. While there was no detectable thrombin generation in aPL patients in low concentration of TF, at the two highest concentrations the thrombin generation was comparable to same concentrations in the haemostatically normal control samples(data not shown). For those affected by FVL and aPL, the threshold of detectable thrombin generation was even shifted to lower concentrations of TF, regarding a “residual activity” of about 33 % for ETP and PEAK, as for patients with FVL. In patients with APS, TF 1:50.000 caused a thrombin generation comparable to TF 1:6.000 in haemostatically normal controls, showing a shift in coagulation factor reactability. In a physiological environment this could indicate a stronger haemostatic reaction to minor vascular lesions in patients affected by factor V Leiden mutation than in those without it. Conclusion: A thrombin generation assay utilizing lower concentrations of TF as coagulation initiating agent could be usefully performed to assess thrombophilic states due to coagulation factor mutations and /or presence of antiphospholipid antibody.

The Impact of Dalteparin (Fragmin®) on Thrombin Generation in Pregnant Women with Venous Thromboembolism: Significance of the Factor V Leiden Mutation

2001 ◽  
Vol 85 (05) ◽  
pp. 782-786 ◽  
Author(s):  
Edda Eberl ◽  
Ulrich Geisen ◽  
Ralf Grossmann ◽  
Franz Keller ◽  
Schambeck Christian
Keyword(s):  
Venous Thromboembolism ◽  
Pregnant Women ◽  
Thrombin Generation ◽  
Clinical Signs ◽  
Factor V Leiden ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Asymptomatic Patients ◽  
The Impact ◽  
Fvl Mutation

SummaryHypercoagulability is observed in patients with inherited thrombophilia, e.g. factor V Leiden (FVL) mutation. Pregnancy represents a hypercoagulable state as well. This study addresses the effects of the FVL mutation on haemostatic activation during pregnancy as indicated by prothrombin fragments (F1+2). 233 pregnant women with no history of venous thromboembolism were studied. Additionally, two patient groups (25 pregnant FVL carriers and 36 pregnant women without thrombophilic diathesis) in whom low molecular weight heparin (dalteparin) was used prophylactically against rethrombosis were investigated.None of the women developed clinical signs of venous thromboembolism during pregnancy or after delivery. Untreated women exhibited substantial hypercoagulability. F1+2 levels were similar in FVL carriers and non-carriers (difference n. s.). After sufficient adjustment for anti-factor Xa activity (≥0.15; ≤0.4 U/mL), heparinized women without any thrombophilic diathesis had significantly lower levels of F1+2 than untreated pregnant women. This was evident only in the first and second trimenon (p <0.01). F1+2 levels in heparinized FVL carriers were quite similar to the levels observed in untreated pregnant women, however. In conclusion, our data support the thesis that in comparison to asymptomatic patients, thrombin generation is exaggerated in symptomatic FVL carriers. Coagulation activation during pregnancy can be reduced by dalteparin.

Coagulation Factor V Leiden Mutation Was Detected in the Patients with Activated Protein C Resistance in Thailand

1998 ◽  
Vol 80 (08) ◽  
pp. 344-345 ◽  
Author(s):  
Pasra Arnutti ◽  
Motofumi Hiyoshi ◽  
Wichai Prayoonwiwat ◽  
Oytip Nathalang ◽  
Chamaiporn Suwanasophon ◽  
...  
Keyword(s):  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Coagulation Factor ◽  
Factor V ◽  
Activated Protein C Resistance ◽  
Factor V Leiden Mutation ◽  
Coagulation Factor V

New Coagulation Factor V Gene Polymorphisms Define a Single and Infrequent Haplotype Underlying the Factor V Leiden Mutation in Mediterranean Populations and Indians

1997 ◽  
Vol 78 (03) ◽  
pp. 1037-1041 ◽  
Author(s):  
E Castoldi ◽  
B Lunghi ◽  
F Mingozzi ◽  
P Loannou ◽  
G Marchetti ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
Factor V Leiden ◽  
Coagulation Factor ◽  
Specific Factor ◽  
Mutational Event ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Mediterranean Populations ◽  
Factor V Gene ◽  
V Gene

SummaryTwo novel polymorphisms were identified in the factor V gene by direct sequencing of intronic areas. One of them, located in intron 9, is the marker closest to the Leiden mutation ever described, whereas the other, in intron 16, displays a rare allele invariantly associated to the mutation. Allele-specific amplification protocols were designed to perform extensive screenings for both polymorphic sites. The new markers were used in combination with six previously described polymorphisms to define specific factor V gene haplotypes. Haplotype investigations in 506Q homozygous thrombotic patients and normal controls showed the presence of a single haplotype underlying the factor V Leiden mutation in Mediterranean populations (among which Greek Cypriots, where the R506Q mutation is particularly frequent) and Indians. When traced in the absence of the Leiden mutation, the background haplotype was found to be present and roughly as frequent as the mutation itself in these populations. These findings indicate a single mutational event, that probably occurred outside Europe, as the cause of the Leiden mutation and provide a powerful tool to investigate its evolutionary history.

Thrombin spatial distribution determines Protein C activation during hemostasis and thrombosis

Blood ◽  
2021 ◽  
Author(s):  
Tanya T. Marar ◽  
Chelsea N. Matzko ◽  
Jie Wu ◽  
Charles Esmon ◽  
Talid Sinno ◽  
...  
Keyword(s):  
Spatial Distribution ◽  
Protein C ◽  
Thrombin Generation ◽  
Jugular Vein ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Fibrin Formation

Rebalancing of the hemostatic system by targeting endogenous anticoagulant pathways, like the Protein C system, is being tested as a means of improving hemostasis in patients with hemophilia. Recent intravital studies of hemostasis demonstrated that, in some vascular contexts, thrombin activity is sequestered to the extravascular compartment. These findings raise important questions about the context-dependent contribution of activated Protein C (aPC) to the hemostatic response since Protein C activation occurs on the surface of endothelial cells. Here, we used a combination of pharmacologic, genetic, imaging, and computational approaches to examine the relationships among thrombin spatial distribution, Protein C activation, and aPC anticoagulant function. We found that inhibition of aPC activity, either in mice harboring the Factor V-Leiden mutation or infused with an aPC blocking antibody, significantly enhanced fibrin formation and platelet activation in a microvascular injury model, consistent with aPC's role as an anticoagulant. In contrast, inhibition of aPC activity had no effect on hemostasis following penetrating injury of the mouse jugular vein. Computational studies showed that differences in blood velocity, injury size, and vessel geometry determine the localization of thrombin generation and, consequently, the extent of Protein C activation. Computational predictions were tested in vivo and showed that when thrombin generation occurred intravascularly, without penetration of the vessel wall, inhibition of aPC significantly increased fibrin formation in the jugular vein. Together, these studies show the importance of thrombin spatial distribution in determining Protein C activation during hemostasis and thrombosis.

Abstract 200: Hypercoagulabilty Panel Testing in Neonates Undergoing Cardiac Surgery

2012 ◽  
Vol 111 (suppl_1) ◽  
Author(s):  
Sirisha Emani ◽  
David Zurakowski ◽  
Christopher Baird ◽  
Frank Pigula ◽  
Trenor Cameron ◽  
...  
Keyword(s):  
Cardiac Surgery ◽  
Thrombin Generation ◽  
Factor V Leiden ◽  
Plasminogen Activator Inhibitor ◽  
Protein S ◽  
Coagulation Factors ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
C Protein ◽  
Cardiolipin Antibodies

Thrombosis is a crucial contributor of morbidity and mortality in neonates undergoing cardiac surgery. Although there is published data on several factors of the hemastatic system, there is no data correlating factor expression and/or function with thrombosis in neonates. We tested the hypothesis that hypercoagulability markers are predictive of thrombosis in neonates undergoing cardiac surgery. Sixty neonates undergoing cardiac surgery were tested for thrombin generation assay; coagulation factors; antithrombin III, protein C, protein S, and factor VIII; fibrinolytic inhibitors; thrombin-activatable fibrinolytic inhibitor, plasminogen activator inhibitor; and presence of cardiolipin antibodies by immunoassays. Factor V Leiden mutation was also tested in a few patients utilizing single nucleotide polymorphism assays. In this pilot study, thrombosis occurred in 15% of the neonates undergoing cardiac surgery. Significant risk factors associated with thrombosis were pre-mature birth, use of cardio pulmonary bypass, and single ventricle physiology. Hypercoagulability factors associated with thrombosis determined by univarent analysis were elevated thrombin generation, enhanced expression of thrombin-activatable fibrinolytic inhibitor and plasminogen activator inhibitor as well as presence of cardiolipin antibodies and factor V Leiden mutation. No correlation was observed between thrombosis and expression of coagulation factors antithrombin III, protein C, protein S, and factor VIII. Multivarient analysis has proven to show thrombin generation, thrombin-activatable fibrinolytic inhibitor, and presence of cardiolipin antibodies as multivariable predictors of thrombosis. These significant hypercoagulability markers are independent predictors of thrombosis. Thus thrombosis predictability can help in post-operative management and care for neonates undergoing cardiac surgery by regulating pro- and/or anti-coagulation therapy.

Primary antiphospholipid syndrome and factor V Leiden mutation in a young patient with non-bacterial thrombotic endocarditis and transient ischemic stroke

2005 ◽  
Vol 94 (12) ◽  
pp. 1331-1332 ◽  
Author(s):  
Konstantinos P. Letsas ◽  
Gerasimos S. Filippatos ◽  
Stavros P. Kounas ◽  
Loukas K. Pappas ◽  
Fotios Kardaras ◽  
...  
Keyword(s):  
Ischemic Stroke ◽  
Young Patient ◽  
Antiphospholipid Syndrome ◽  
Factor V Leiden ◽  
Factor V ◽  
Primary Antiphospholipid Syndrome ◽  
Factor V Leiden Mutation

 

Factor V Leiden mutation enhances fibrin formation and dissolution in vivo in a human endotoxemia model

Blood ◽  
2010 ◽  
Vol 116 (5) ◽  
pp. 801-805 ◽  
Author(s):  
Elif Elmas ◽  
Nenad Suvajac ◽  
Bernd Jilma ◽  
Hartmut Weiler ◽  
Martin Borggrefe ◽  
...  
Keyword(s):  
Degradation Products ◽  
Factor V Leiden ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Pronounced Increase ◽  
Soluble Fibrin ◽  
Fibrin Degradation Products ◽  
Endotoxemia Model ◽  
Fvl Mutation

Disseminated intravascular coagulation in sepsis is associated with microvascular thrombosis and organ dysfunction. It was expected that prothrombotic disposition such as factor V Leiden (FVL) mutation would worsen clinical outcome. Astonishingly, clinical trial and animal experimental data indicate that FVL can be associated with improved survival. This study investigated the effect of FVL on the response to endotoxin of the coagulation and fibrinolytic system in humans. Fourteen healthy male subjects without FVL and 15 healthy males with heterozygous FVL received an intravenous bolus dose of endotoxin, 2 ng/kg of body weight. Blood samples were drawn before and 1, 2, 4, 6, and 24 hours after administration of the endotoxin. Injection of endotoxin led to a more pronounced increase in soluble fibrin in patients with FVL than in controls. Patients with FVL displayed a more sustained increase in plasmin-plasmin inhibitor complex after 4, 6, and 24 hours. Patients with FVL mutation also displayed higher levels of D-dimer and fibrinogen-fibrin degradation products in plasma after 24 hours. Patients with FVL generate higher levels of soluble fibrin, which may serve as cofactor in tissue plasminogen activator–induced plasminogen activation, leading to a more sustained activation of fibrinolysis with production of more fibrinogen- and fibrin-degradation products.

scholarly journals A Case Report of Idiopathic Catastrophic Thrombotic Syndrome with Purpura Fulminans

2020 ◽  
Vol 3 (1) ◽  
Keyword(s):  
Early Recognition ◽  
Purpura Fulminans ◽  
Factor V Leiden ◽  
Coagulation Factor ◽  
Skin Lesions ◽  
Laboratory Evaluation ◽  
Caucasian Woman ◽  
Factor V ◽  
Heparin Infusion ◽  
Fvl Mutation

Background: Catastrophic thrombotic syndrome (CTS) is a rare life-threatening condition defined as rapid onset of multi-organ thrombosis affecting diverse vascular beds. Predisposing conditions include catastrophic antiphospholipid syndrome (APS), atypical thrombotic thrombocytopenic purpura (TTP), delayed heparin-induced thrombocytopenia and Trousseau syndrome. Patients who do not meet any of these criteria are diagnosed with idiopathic catastrophic thrombotic syndrome. Case description: A 44-year-old Caucasian woman with type II diabetes and hypothyroidism presented with acute onset of myalgia and extensive bruising over a period of four days. Physical exam revealed hypotension, tachycardia, and extensive purpuric and bullous skin lesions. Laboratory evaluation demonstrated microangiopathic hemolysis, thrombocytopenia, elevated D-dimer and coagulopathy suggesting disseminated intravascular coagulation (DIC) along with acute kidney injury (AKI) and transaminitis. Aggressive transfusions including packed red blood cells, fresh frozen plasma, platelets and cryoprecipitate were required to reverse her severe coagulopathy. Ultrasound showed occlusive thrombus in the left basilic vein and the greater saphenous veins bilaterally and heparin infusion was started. IV methylprednisolone, all-trans retinoic acid and doxycycline were empirically given. Workup was negative for any coagulation factor deficiency or hypercoagulable state although heterozygous factor V Leiden (FVL) mutation was found. Bone marrow biopsy was normal. Infectious and auto-immune workups were unremarkable. Skin biopsy showed diffuse intravascular thrombi but no evidence of vasculitis. Two weeks later, she developed Enterobacter bacteremia from infection of her bullous lesions. She was started on broad spectrum antibiotics and transferred to a burn unit. Eventually, her coagulopathy, bacteremia, AKI and transaminitis resolved, she was discharged with indefinite anticoagulation. Discussion: CTS presented in our patient with rapidly progressive thrombosis with consumptive coagulopathy. No obvious instigating source was found, her clinical presentation was out of proportion for the isolated heterozygous FVL mutation. Anticoagulation remained the main therapy in the acute setting and aggressive supportive care in multi-disciplinary setting to manage acute and late complications was required. Conclusion: Through this report, we emphasize the need for early recognition of CTS with this constellation of clinical findings and advocate for urgent interventions to prevent untoward outcomes.

The Factor V Leiden Mutation which Predisposes to Thrombosis Is Not Common in Patients with Antiphospholipid Syndrome

1995 ◽  
Vol 74 (04) ◽  
pp. 1029-1031 ◽  
Author(s):  
Donna Dizon-Townson ◽  
Christopher Hutchison ◽  
Robert Silver ◽  
D Ware Branch ◽  
Kenneth Ward
Keyword(s):  
Antiphospholipid Syndrome ◽  
Protein C ◽  
Restriction Analysis ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Specific Hybridization ◽  
Allele Specific ◽  
Protein Resistant

SummaryAntiphospholipid syndrome is associated with venous, arterial, and placental thrombosis, possibly through autoantibody impairment of phospholipid-dependent protein C activation. Recently, a missense mutation in the factor V gene (1691 G → A) has been identified that results in an abnormal factor V product (1). This mutation, known as the Leiden mutation, causes an amino acid substitution of glutamine for arginine at position 506 in the factor V molecule and renders the protein resistant to proteolytic inactivation by activated protein C and thus predisposes to thrombosis (2, 3). We hypothesized that some individuals with antiphospholipid syndrome may also carry the Leiden mutation, and thus have a “second hit” predisposition to thrombosis. To test this hypothesis, allele-specific hybridization and allele-specific restriction analysis were used to test for the Leiden mutation in thirty women with the antiphospholipid syndrome, 10 of whom had a history of thrombosis. None of the women were heterozygous or homozygous for the factor V mutation. We conclude that the presence of the factor V Leiden mutation is not a prerequisite for the thrombotic events in patients with antiphospholipid syndrome, due to the occurrence of thrombosis seen in patients lacking the factor V mutation.

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