Fibrinogen γ′ increases the sensitivity to activated protein C in normal and factor V Leiden plasma

Key Points Fibrinogen, and particularly fibrinogen γ′, counteracts plasma APC resistance, the most common risk factor for venous thrombosis. The C-terminal peptide of the fibrinogen γ′ chain inhibits protein C activation, but still improves the response of plasma to APC.

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A Reduced Sensitivity for Activated Protein C in the Absence of Factor V Leiden Increases the Risk of Venous Thrombosis

Blood ◽

10.1182/blood.v93.4.1271 ◽

1999 ◽

Vol 93 (4) ◽

pp. 1271-1276 ◽

Cited By ~ 202

Author(s):

Marieke C.H. de Visser ◽

Frits R. Rosendaal ◽

Rogier M. Bertina

Keyword(s):

Risk Factor ◽

Confidence Interval ◽

Venous Thrombosis ◽

Protein C ◽

Activated Protein C ◽

Factor V Leiden ◽

Factor V ◽

Factor V Leiden Mutation ◽

Apc Resistance ◽

Increased Risk

Abstract Activated protein C (APC) resistance caused by the factor V Leiden mutation is associated with an increased risk of venous thrombosis. We investigated whether a reduced response to APC, not due to the factor V point mutation, is also a risk factor for venous thrombosis. For this analysis, we used the Leiden Thrombophilia Study (LETS), a case-control study for venous thrombosis including 474 patients with a first deep-vein thrombosis and 474 age- and sex-matched controls. All carriers of the factor V Leiden mutation were excluded. A dose-response relationship was observed between the sensitivity for APC and the risk of thrombosis: the lower the normalized APC sensitivity ratio, the higher the associated risk. The risk for the lowest quartile of normalized APC-SR (<0.92), which included 16.5% of the healthy controls, compared with the highest quartile (normalized APC-SR > 1.05) was greater than fourfold increased (OR = 4.4; 95% confidence interval, 2.9 to 6.6). We adjusted for VIII:C levels, which appeared to affect our APC resistance test. The adjusted (age, sex, FVIII:C) odds ratio for the lowest quartile was 2.5 (95% confidence interval, 1.5 to 4.2). So, after adjustment for factor VIII levels, a reduced response to APC remained a risk factor. Our results show that a reduced sensitivity for APC, not caused by the factor V Leiden mutation, is a risk factor for venous thrombosis.

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A Reduced Sensitivity for Activated Protein C in the Absence of Factor V Leiden Increases the Risk of Venous Thrombosis

Blood ◽

10.1182/blood.v93.4.1271.404k22_1271_1276 ◽

1999 ◽

Vol 93 (4) ◽

pp. 1271-1276 ◽

Cited By ~ 1

Author(s):

Marieke C.H. de Visser ◽

Frits R. Rosendaal ◽

Rogier M. Bertina

Keyword(s):

Risk Factor ◽

Confidence Interval ◽

Venous Thrombosis ◽

Protein C ◽

Activated Protein C ◽

Factor V Leiden ◽

Factor V ◽

Factor V Leiden Mutation ◽

Apc Resistance ◽

Increased Risk

Activated protein C (APC) resistance caused by the factor V Leiden mutation is associated with an increased risk of venous thrombosis. We investigated whether a reduced response to APC, not due to the factor V point mutation, is also a risk factor for venous thrombosis. For this analysis, we used the Leiden Thrombophilia Study (LETS), a case-control study for venous thrombosis including 474 patients with a first deep-vein thrombosis and 474 age- and sex-matched controls. All carriers of the factor V Leiden mutation were excluded. A dose-response relationship was observed between the sensitivity for APC and the risk of thrombosis: the lower the normalized APC sensitivity ratio, the higher the associated risk. The risk for the lowest quartile of normalized APC-SR (<0.92), which included 16.5% of the healthy controls, compared with the highest quartile (normalized APC-SR > 1.05) was greater than fourfold increased (OR = 4.4; 95% confidence interval, 2.9 to 6.6). We adjusted for VIII:C levels, which appeared to affect our APC resistance test. The adjusted (age, sex, FVIII:C) odds ratio for the lowest quartile was 2.5 (95% confidence interval, 1.5 to 4.2). So, after adjustment for factor VIII levels, a reduced response to APC remained a risk factor. Our results show that a reduced sensitivity for APC, not caused by the factor V Leiden mutation, is a risk factor for venous thrombosis.

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Factor V Cambridge: A New Mutation (Arg306→Thr) Associated With Resistance to Activated Protein C

Blood ◽

10.1182/blood.v91.4.1140 ◽

1998 ◽

Vol 91 (4) ◽

pp. 1140-1144 ◽

Cited By ~ 165

Author(s):

David Williamson ◽

Karen Brown ◽

Roger Luddington ◽

Caroline Baglin ◽

Trevor Baglin

Keyword(s):

Venous Thrombosis ◽

Cleavage Site ◽

Protein C ◽

Activated Protein C ◽

Factor V Leiden ◽

Factor V ◽

Degree Relative ◽

Prothrombinase Complex ◽

Apc Resistance ◽

The Common

AbstractA new factor V mutation associated with resistance to activated protein C and thrombosis (factor V Cambridge, Arg306→Thr) was found in one patient from a carefully selected group of 17 patients with venous thrombosis and confirmed APC resistance in the absence of the common Gln506 mutation. The Arg306 mutation was also present in a first degree relative who also had APC resistance. Other potential causes of APC resistance, such as a mutation at the Arg679 site and the factor V HR2 haplotype, were excluded. Subsequent screening of 585 patients with venous thromboembolism and 226 blood donors did not show any other individual with this mutation. Factor VThr306 is the first description of a mutation affecting the Arg306 APC cleavage site and is the only mutation, other than factor V Leiden (Arg506→Gln), that has been found in association with APC resistance. This finding confirms the physiologic importance of the Arg306 APC-cleavage site in the regulation of the prothrombinase complex. It also supports the concept that APC resistance and venous thrombosis can result from a variety of genetic mutations affecting critical sites in the factor V cofactor.

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Resistance to activated protein C is a risk factor for pregnancy-related venous thrombosis in the absence of the F5 rs6025 (factor V Leiden) polymorphism

British Journal of Haematology ◽

10.1111/j.1365-2141.2011.08712.x ◽

2011 ◽

Vol 154 (2) ◽

pp. 241-247 ◽

Cited By ~ 9

Author(s):

Astrid Bergrem ◽

Anders Erik Astrup Dahm ◽

Anne Flem Jacobsen ◽

Marie-Christine Mowinckel ◽

Leiv Sandvik ◽

...

Keyword(s):

Risk Factor ◽

Venous Thrombosis ◽

Protein C ◽

Activated Protein C ◽

Factor V Leiden ◽

Factor V

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Resistance to activated protein C caused by the R506Q mutation in the gene for factor V is a common risk factor for venous thrombosis

Journal of Internal Medicine ◽

10.1111/joim.1997.242.s740.1 ◽

1997 ◽

Vol 242 ◽

pp. 1-8 ◽

Cited By ~ 7

Author(s):

B. DAHLBÄCK

Keyword(s):

Risk Factor ◽

Venous Thrombosis ◽

Protein C ◽

Activated Protein C ◽

Factor V ◽

Common Risk Factor

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Female Gender and Resistance to Activated Protein C (FV:Q506) as Potential Risk Factors for Thrombosis after Elective Hip Arthroplasty

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657675 ◽

1997 ◽

Vol 78 (03) ◽

pp. 0993-0996 ◽

Cited By ~ 19

Author(s):

P J Svensson ◽

G Benoni ◽

H Fredin ◽

O Bjӧrgell ◽

P Nilsson ◽

...

Keyword(s):

Risk Factor ◽

Venous Thrombosis ◽

Protein C ◽

Activated Protein C ◽

Female Gender ◽

Prolonged Treatment ◽

Factor V ◽

Apc Resistance ◽

Increased Risk ◽

Postoperative Thrombosis

SummaryResistance to activated protein C (APC) caused by the R506Q mutation in factor V is the most common inherited risk factor for venous thrombosis. To elucidate whether APC-resistance is a risk factor for venous thrombosis after elective total hip replacement, the association between APC-resistance (presence of FV:Q506 allele) and postoperative thrombosis was investigated in patients (n = 198) randomised to received short (during hospitalisation, n = 100) or prolonged prophylaxis (three weeks after hospitalisation, n = 98) with low molecular weight heparin (LMWH). Among APC-resistant individuals receiving short prophylaxis, 7/10 developed thrombosis as compared to 2/12 receiving long prophylaxis (p <0.0179). Odds ratio for association between APC-resistance and thrombosis in the short prophylaxis group was 4.2 (CI 95% 1.02-17.5) (p <0.0465). Among those receiving prolonged, prophylaxis, there was no increased incidence of thrombosis associated with APC-resistance. Two unexpected observations were made. One was that APC-resistance was much more common in women (19/109) than in men (3/89) (p <0.001). The other was that even women without APC-resistance were much more thrombosis-prone than men. Thus, 24/48 of women with normal FV genotype and short prophylaxis developed thrombosis vs 8/42 among men, p = 0.002. The increased risk of thrombosis associated with female gender and APC-resistance was neutralised by the prolonged treatment. In conclusion, among patients receiving short prophylaxis, female gender was found to be a strong risk factor for venous thrombosis. Even though APC-resistance appeared to be a risk factor for postoperative thrombosis, the uneven distribution of APC-resistance between men and women, taken together with the increased risk of thrombosis among women, precluded valid conclusions to be drawn about the association between APC-resistance and an increased risk of thrombosis. Our results suggest that prolonged prophylaxis with LMWH after hip surgery is more important for women than for men.

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Thrombin generation and activated protein C resistance in the absence of factor V Leiden correlates with the risk of recurrent venous thromboembolism in women aged 18–65 years

Thrombosis and Haemostasis ◽

10.1160/th11-04-0254 ◽

2011 ◽

Vol 106 (11) ◽

pp. 901-907 ◽

Cited By ~ 8

Author(s):

Svetlana Tchaikovski ◽

Margareta Holmström ◽

Jan Rosing ◽

Katarina Bremme ◽

Gerd Lärfars ◽

...

Keyword(s):

Risk Factor ◽

Protein C ◽

Thrombin Generation ◽

Activated Protein C ◽

Factor V Leiden ◽

Peak Height ◽

Factor V ◽

Risk Of Recurrence ◽

Apc Resistance ◽

Increased Risk

SummaryIdentification of patients at high risk of recurrence after a first event of venous thromboembolism (VTE) remains difficult. Resistance to activated protein C (APC) is a known risk factor for VTE, but data on the risk of recurrence is controversial. We wanted to investigate whether APC resistance in the absence of factor V Leiden, determined with global coagulation test such as the thrombin generation assay, could be used as a marker for increased risk of recurrent VTE among women 18–65 years old after a first event of VTE. In a cohort of 243 women with a first event of VTE, plasma was collected after discontinuation of anticoagulant treatment and the patients were followed up for 46 months (median). Thrombin generation was measured via calibrated automated thrombography, at 1 pM and 10 pM of tissue factor (TF). In women without factor V Leiden (n=117), samples were analysed in the absence and in the presence of APC. Increase in ETP (endogenous thrombin potential) and peak height analysed in the presence of APC correlated significantly with higher risk of recurrence. At 1 pM, peak height correlated with increased risk of recurrence. In conclusion, high thrombin generation in the presence of APC, in women after a first event of VTE is indicative for an increased risk of a recurrence. We also found that thrombin generation at low TF (1 pM) is correlated with the risk of recurrence. Our data suggest that APC resistance in the absence of factor V Leiden is a risk factor for recurrent VTE.

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