Resistance to Activated Protein C and Factor V Leiden as Risk Factors for Venous Thrombosis

1995 ◽  
Vol 74 (01) ◽  
pp. 449-453 ◽  
Author(s):  
Rogier M Bertina ◽  
Pieter H Reitsma ◽  
Frits R Rosendaal ◽  
Jan P Vandenbroucke
Keyword(s):  
Risk Factors ◽  
Venous Thrombosis ◽  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Factor V

scholarly journals High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance) [see comments]

Blood ◽  
1995 ◽  
Vol 85 (6) ◽  
pp. 1504-1508 ◽  
Author(s):  
FR Rosendaal ◽  
T Koster ◽  
JP Vandenbroucke ◽  
PH Reitsma
Keyword(s):  
Venous Thrombosis ◽  
Protein C ◽  
Absolute Risk ◽  
Thrombotic Event ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Coagulation Factor ◽  
Factor V ◽  
Increased Risk ◽  
The Absolute

Resistance to activated protein C (APC) is a common inherited risk factor for venous thrombosis, which is associated with a mutation in coagulation factor V (factor V Leiden). We investigated the risk of venous thrombosis in individuals homozygous for this abnormality. We determined the factor V Leiden genotype in 471 consecutive patients aged less than 70 years with a first objectively confirmed deep-vein thrombosis and in 474 healthy controls. We found 85 heterozygous and seven homozygous individuals among the cases with thrombosis and 14 heterozygous individuals among the control subjects. The expected number of homozygous individuals among the controls was calculated from Hardy-Weinberg equilibrium and estimated at 0.107 (allele frequency, 1.5%). Whereas the relative risk was increased sevenfold for heterozygous individuals, it was increased 80-fold for homozygous individuals. These patients experienced their thrombosis at a much younger age (31 v 44 years). The homozygous individuals were predominantly women, most likely due to the effect of oral contraceptives. Because of the increased risk of thrombosis with age, the absolute risk becomes most pronounced in older patients, both for heterozygous and homozygous individuals. For the homozygous individuals, the absolute risk may become several percentage points per year. This implies that most individuals homozygous for factor V Leiden will experience at least one thrombotic event in their lifetime.

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

Blood ◽  
1998 ◽  
Vol 91 (4) ◽  
pp. 1140-1144 ◽  
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.

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

2011 ◽  
Vol 154 (2) ◽  
pp. 241-247 ◽  
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

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

Blood ◽  
2014 ◽  
Vol 124 (9) ◽  
pp. 1531-1538 ◽  
Author(s):  
Farida Omarova ◽  
Shirley Uitte de Willige ◽  
Paolo Simioni ◽  
Robert A. S. Ariëns ◽  
Rogier M. Bertina ◽  
...  
Keyword(s):  
Risk Factor ◽  
Venous Thrombosis ◽  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Factor V ◽  
Common Risk Factor ◽  
Apc Resistance ◽  
Key Points

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.

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

Blood ◽  
1999 ◽  
Vol 93 (4) ◽  
pp. 1271-1276 ◽  
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.

The HR2 Haplotype of Factor V: Effects on Factor V Levels, Normalized Activated Protein C Sensitivity Ratios and the Risk of Venous Thrombosis

2000 ◽  
Vol 83 (04) ◽  
pp. 577-582 ◽  
Author(s):  
Joan Guasch ◽  
Pieter Kamphuisen ◽  
Hans Vos ◽  
Frits Rosendaal ◽  
Rogier Bertina ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Compound Heterozygous ◽  
Factor V ◽  
Vein Thrombosis ◽  
Increased Risk ◽  
V Antigen ◽  
Deep Vein

SummaryWe studied the HR2 haplotype of the factor V gene in a case-control study for venous thrombosis including 474 patients with a first deep-vein thrombosis and 474 age- and sex-matched healthy controls (Leiden Thrombophilia Study, LETS). We investigated both the original His1299Arg (A4070G) polymorphism and the Met385Thr (T1328C) polymorphism. This latter polymorphism, located in exon 8 (heavy chain), is always present in the HR2 haplotype, but also occurs on its own in a His1299 (wt) background. The HR2 haplotype was not associated with an increased risk of venous thrombosis (OR = 1.2, 95% confidence interval: 0.8-2.0). We did not find an association between the HR2 haplotype and a reduced sensitivity for activated protein C (APC) in non-carriers of factor V Leiden (FVL). However, in compound heterozygous FVL/HR2 carriers the sensitivity for APC was reduced. The HR2 haplotype was also associated with reduced factor V antigen levels in both patients and controls. Sequence analysis of the promoter region of factor V in HR2 homozygotes did not reveal any sequence variations that could explain the reduced FV levels. Our results show that the HR2 haplotype is not associated with an increased risk of venous thrombosis or with a reduced sensitivity for APC in non-FVL carriers. However, the HR2 haplotype is associated with a reduced sensitivity for APC in carriers of FVL and with reduced factor V antigen levels.

No interaction between factor V Leiden and hyperhomocysteinemia or MTHFR 677TT genotype in venous thrombosis

2007 ◽  
Vol 97 (01) ◽  
pp. 32-37 ◽  
Author(s):  
Miranda Keijzer ◽  
George Borm ◽  
Henk Blom ◽  
Gerard Bos ◽  
Frits Rosendaal ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Interaction Effect ◽  
Protein C ◽  
Meta Analysis ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Factor V ◽  
Multiplicative Interaction ◽  
Interaction Term ◽  
Large Case

SummaryHomocysteine may have a thrombogenic effect through inhibition of inactivation of factor Va by activated protein C. Because factor V Leiden also leads to resistance of factor V to activated protein C, it would be possible that both factors show interaction for the risk of venous thrombosis. This has been reported in some studies, but not in others. We performed a meta-analysis to investigate a possible interaction between factor V Leiden and hyperhomocysteinemia, including 825 subjects with venous thrombosis and 2,109 controls, for the risk of venous thrombosis. In addition, we assessed a possible interaction between factor V Leiden and MTHFR 677TT genotype (the most common genetic determinant of homocysteine levels), including 2,547 subjects with venous thrombosis and 4,327 controls. We also investigated the interaction effect of factor V Leiden and hyperhomocysteinemia in a large case-only study using data of the VITRO study, including 2,077 subjects with first-time venous thrombosis. The meta-analysis yielded no evidence for additive or multiplicative interaction between factor V Leiden and hyperhomocysteinemia [relative excess risk due to interaction (RERI) –1.77 (95%CI –8.61 to 5.08) and multiplicative interaction term 0.86 (95%CI 0.35 to 2.14)].The case-only study also showed no interaction effect [0.58 (95%CI 0.29 to 1.16)]. Also the metaanalysis on factor V Leiden and MTHFR 677TT yielded no evidence of interaction; RERI 0.13 (95%CI –3.60 to 3.86) and multiplicative interaction term 1.23 (95%CI 0.72 to 2.11). Both the meta-analyses of published studies and a large case-only study did not show evidence for interaction between factor V Leiden and hyperhomocysteinemia for risk of venous thrombosis.

The factor VIII D1241E polymorphism is associated with decreased factor VIII activity and not with activated protein C resistance levels

2005 ◽  
Vol 93 (03) ◽  
pp. 453-456 ◽  
Author(s):  
Daniela Scanavini ◽  
Cristina Legnani ◽  
Barbara Lunghi ◽  
Federico Mingozzi ◽  
Gualtiero Palareti ◽  
...  
Keyword(s):  
Venous Thrombosis ◽  
Factor Viii ◽  
Protein C ◽  
Large Population ◽  
Specific Interaction ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Factor V ◽  
Thrombotic Risk ◽  
Sensitivity Ratio

SummaryElevated factor VIII (FVIII) levels are a recognized risk factor for venous thrombosis. Recently, family studies suggested that the G allele of the 3951C/G (D1241E) FVIII polymorphism is associated to lower FVIII activity. We investigated in case-control studies both biological effects (FVIII levels and activated protein C sensitivity ratio) and clinical associations (venous thromboembolism) of the D1241E change. Among 145 healthy and 150 thrombotic women, not carriers of known thrombophilic defects, the 1241E allele was associated with 11% reduced (t-test, P< 0.05) FVIII levels. The effect on activated protein C sensitivity ratio was not statistically significant. Carriership of the 1241E allele, potentially conferring protection from thrombosis, was found in 22.8% of controls and in 15.3% of cases. In an additional cohort of factor V Leiden carriers (n=283), carriership of the 1241E allele was 25.2% among 143 asymptomatic subjects and 17.1% among 140 thrombotic patients. Our data do not indicate a specific interaction with factor V Leiden. These genotype distributions suggest a mild protective effect from venous thrombosis conferred by 1241E FVIII, masked by other genetic and/or environmental components, and detectable only in very large population studies. Our findings point toward the presence of genetic determinant of coagulation factor levels with a biologically significant role, but with a poor predictive value to estimate thrombotic risk beyond established risk factors.

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