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.

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

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.

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.

Oral Contraceptive-Associated Thromboembolism. A Retrospective Analysis of Thrombophilic Work-out and Long Term Follow up in 57 Cases

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5348-5348
Author(s):  
Emmanouil Papadakis ◽  
Smaragda Efremidou ◽  
Haris Kartsios ◽  
Margarita Mpraimi ◽  
Kiriaki Kokoviadou ◽  
...  
Keyword(s):  
Family History ◽  
Protein C ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Apc Resistance ◽  
Increased Risk ◽  
Fv Leiden

Abstract Introduction: The increased risk of venous thrombosis in women taking oral contraceptives (OCs) has been recognized since the early 1960s. Coexistence of hereditary risk factors appears to have an additive effect. Women under OCs that carry the factor V Leiden mutation have a 35-fold increased risk of thromboembolic events compared to women without the mutation who are not on OCs. Evaluation of family and personal history is the mainstay of prophylaxis prior to OC administration, but often family thrombophilia or thromboembolic (TE) events are not reported prior to OCs prescription. Patients-Methods: Fifty-seven women with a median age of 28 (21–48) years, which suffered OC-associated TE, were studied. The median period of OC therapy prior to TE event was 2 months (0.5–60). Fifty-five of them experienced VTE while 2 suffered stroke. Leg thrombosis was the most common clinical finding [37/55 (67,2%) patients] Apart from personal and family history, Thrombophilia investigation included measurement of : serum Homocysteine, Antithrombin, Protein C and S, Lipoprotein (a), Activated Protein C (APC) resistance, antiphospholipid antibodies and lupus anticoagulant. In addition the presence of FV Leiden, FII 20210 GA mutations and MTHFR 677 CT polymorphism were determined. Results: A high prevalence of the factor V Leiden mutation was detected in the study group; 50% had APC-resistance test positive, 26 (45%) patients were found to be heterozygous and 3 (5,2%) homozygous for the FV Leiden mutation. Lp(a) elevation was observed in 19,3% and Homocysteine elevation in 15,8% of patients. In 9 women (15,8%) both family history and thrombophilic profile were negative. Serious VTE events (2 abdominal and 6 CNS thromboses) were observed only in the Leiden subgroup. During the follow up period ranging from months to 18 years, 3 women (6,25%) experienced a miscarriage and 14 suffered additional VTE events (25%) and they are currently on permanent anticoagulation. Conclusions : Universal thrombophilia screening of women prior to prescription of OCs is not advisable as it does not appear to be cost effective. However, screening certain subgroups, such as women with a known personal or family history, may be of great value. If a full thrombophilic profile can’t be performed, a mere activated protein C resistance test, that reflects the presence of the factor V Leiden mutation, may provide an easy and cheap way of identifying and consulting properly women at higher risk for VTE prior to OC use. Women with OC-associated VTE and thrombophilia carry a substantial recurrence risk that persists for years.

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

1997 ◽  
Vol 78 (03) ◽  
pp. 0993-0996 ◽  
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.

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

2011 ◽  
Vol 106 (11) ◽  
pp. 901-907 ◽  
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.

Comparison of three activated protein C resistance tests in the risk assessment of venous thrombosis in non-carriers of the factor V Leiden mutation

2006 ◽  
Vol 95 (04) ◽  
pp. 728-734 ◽  
Author(s):  
Felipe Guerrero ◽  
Catherine Arnaud ◽  
Francoise Nguyen ◽  
Bernard Boneu ◽  
Pierre Sié
Keyword(s):  
Venous Thrombosis ◽  
Protein C ◽  
Activated Protein C ◽  
Significant Risk ◽  
Factor V Leiden ◽  
Factor V ◽  
Activated Protein C Resistance ◽  
Factor V Leiden Mutation ◽  
Risk Increase ◽  
Increased Risk

SummaryActivated protein C resistance (APCR), measured using the original assay described by Dahlbäck, is a risk factor for venous thrombosis independent of the factor V Leiden (FVL) mutation. This assay is based on the activated partial thromboplastin time (APTT) after plasma exposure to activated protein C (APC).As this assay was sensitive to numerous interferences, new assays have been developed for FVL screening. The objectives of the study were to investigate the association of second generation assays for APCR with venous thrombosis in FVL non-carriers. One hundred ninety-seven subjects with a history of venous thrombosis and 211 controls were explored using 3 APCR assays, the original APTT-based assay (test A), an APTT-based assay with factorV depleted plasma pre-dilution (test B) and a direct factorX activation-based assay with the same pre-dilution (test C).We found that subjects with results in the lowest quartile of the APTT-based assays are at increased risk, compared to those in the highest quartile (test A Odds Ratio = 6.39; 95%CI 3.23–12.63; test B OR=2.72; 95%CI 1.50–4.94). There was no significant risk increase associated with test C results. After adjusting for FVIII levels, the ORs of tests A and B were similar (test A OR=3.22; 95%CI 1.47–7.08; test B OR=3.10; 95%CI 1.54–6.21). In conclusion, APTT-based assays, but not direct factor X activation-based assays, effectively detect the risk for venous thrombosis independent of FVL. Pre-dilution in factor V depleted plasma is an effective way to directly assess the risk independent of FVIII levels.

“Pseudo Homozygous” Activated Protein C Resistance due to Double Heterozygous Factor V Defects (Factor V Leiden Mutation and Type I Quantitative Factor V Defect) Associated with Thrombosis: Report of Two Cases Belonging to Two Unrelated Kindreds

1996 ◽  
Vol 75 (03) ◽  
pp. 422-426 ◽  
Author(s):  
Paolo Simioni ◽  
Alberta Scudeller ◽  
Paolo Radossi ◽  
Sabrina Gavasso ◽  
Bruno Girolami ◽  
...  
Keyword(s):  
Protein C ◽  
Dna Analysis ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Type I ◽  
Factor V ◽  
Factor V Leiden Mutation ◽  
Thrombotic Risk ◽  
Apc Resistance ◽  
Quantitative Factor

SummaryTwo unrelated patients belonging to two Italian kindreds with a history of thrombotic manifestations were found to have a double heterozygous defect of factor V (F. V), namely type I quantitative F. V defect and F. V Leiden mutation. Although DNA analysis confirmed the presence of a heterozygous F. V Leiden mutation, the measurement of the responsiveness of patients plasma to addition of activated protein C (APC) gave results similar to those found in homozygous defects. It has been recently reported in a preliminary form that the coinheritance of heterozygous F. V Leiden mutation and type I quantitative F. V deficiency in three individuals belonging to the same family resulted in the so-called pseudo homozygous APC resistance with APC sensitivity ratio (APC-SR) typical of homozygous F. V Leiden mutation. In this study we report two new cases of pseudo homozygous APC resistance. Both patients experienced thrombotic manifestations. It is likely that the absence of normal F. V, instead of protecting from thrombotic risk due to heterozygous F. V Leiden mutation, increased the predisposition to thrombosis since the patients became, in fact, pseudo-homozygotes for APC resistance. DNA-analysis is the only way to genotype a patient and is strongly recommended to confirm a diagnosis of homozygous F. V Leiden mutation also in patients with the lowest values of APC-SR. It is to be hoped that no patient gets a diagnosis of homozygous F. V Leiden mutation based on the APC-resi-stance test, especially when the basal clotting tests, i.e., PT and aPTT; are borderline or slightly prolonged.

Is APC Resistance a Risk Factor for Venous Thromboembolism in Patients over 70 Years?

2002 ◽  
Vol 88 (10) ◽  
pp. 587-591 ◽  
Author(s):  
Karine Lacut ◽  
Grégoire Le Gal ◽  
Patrick Van Dreden ◽  
Luc Bressollette ◽  
Pierre-Yves Scarabin ◽  
...  
Keyword(s):  
Risk Factor ◽  
Venous Thromboembolism ◽  
Odds Ratio ◽  
Dna Analysis ◽  
Activated Protein C ◽  
Factor V Leiden ◽  
Factor V ◽  
Apc Resistance ◽  
Increased Risk ◽  
History Of

SummaryActivated protein C (APC) resistance is the most common risk factor for venous thromboembolism (VTE). Previous studies mostly analysed patients under 70 years and reported a four-to sevenfold increased risk. This case-control study included consecutive patients referred for a clinical suspicion VTE to our medical unit: 621 patients with a well-documented diagnosis (cases) and 406 patients for which the diagnosis was ruled out and who had no personal history of VTE (controls). APC resistance related to factor V Leiden was defined by either a positive DNA analysis or a positive STA® Staclot APC-R assay. Under 70 years, APC resistance was associated with a threefold increased risk of VTE (odds ratio 3.2, 95% CI, 1.7 to 6.0), whereas in patients over 70 years, it appeared to be no longer a strong risk factor (odds ratio 0.8, 95% CI, 0.4 to 1.7). Age appeared as an effectmeasure modifier with a significant interaction (p = 0.005). Our data suggest that APC resistance is not a risk factor for VTE in elderly.

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.

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