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

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

Blood ◽

10.1182/blood-2014-02-554055 ◽

2014 ◽

Vol 124 (9) ◽

pp. 1531-1538 ◽

Cited By ~ 8

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.

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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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Advances in Understanding Mechanisms of Thrombophilic Disorders

Hämostaseologie ◽

10.1055/s-0040-1701612 ◽

2020 ◽

Vol 40 (01) ◽

pp. 012-021

Author(s):

Björn Dahlbäck

Keyword(s):

Risk Factor ◽

Genetic Risk ◽

Protein C ◽

Activated Protein C ◽

Protein S ◽

Medical Problem ◽

Factor V ◽

Apc Resistance ◽

Thrombosis Risk ◽

Increased Risk

AbstractVenous thromboembolism constitutes a major medical problem afflicting millions of individuals worldwide each year. Its pathogenesis is multifactorial, involving both environmental and genetic risk factors. The most common genetic risk factor known to date is a mutation in the factor V (FV) gene (R506Q or FV Leiden), which impairs the normal regulation of FV by activated protein C (APC). APC is an important regulator of blood coagulation, cleaving and inactivating not only FV/FVa but also activated factor VIII (FVIIIa). In FVa, APC cleaves several sites, Arg506 (R506) being one of them. The R506Q mutation results in the APC resistance phenotype and a lifelong hypercoagulable state. A prothrombin gene mutation is another relatively frequent thrombosis risk factor, whereas deficiencies of the anticoagulant proteins antithrombin, protein C, or protein S are less common. As a result of the high prevalence of FV and prothrombin mutations in the general population, combinations of genetic defects are relatively common. Such individuals have highly increased risk of thrombosis.

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State-of-the-Art Review: Activated Protein C Resistance: Clinical Implications

Clinical and Applied Thrombosis/Hemostasis ◽

10.1177/107602969700300103 ◽

1997 ◽

Vol 3 (1) ◽

pp. 25-32 ◽

Cited By ~ 7

Author(s):

Bengt Zöller ◽

Andreas Hillarp ◽

Björn Dahlbäck

Keyword(s):

Risk Factors ◽

Venous Thrombosis ◽

Protein C ◽

Activated Protein C ◽

Protein S ◽

Factor V ◽

Thrombotic Risk ◽

Western Countries ◽

Apc Resistance ◽

Increased Risk

The discovery of inherited resistance to activated protein C (APC) as a major risk factor for venous thrombosis has dramatically improved our understanding of the pathogenesis of venous thrombosis. In a majority of cases, APC resistance is associated with a single point mutation in the factor V gene (FV) that results in substitution of arginine, R, at position 506 by glutamine, Q. (FV:Q506). The mutation renders factor Va partially resistant to degradation by APC. A functional APC resistance test, which includes predilution of the patient plasma with factor V-deficient plasma, is found to be 100% sensitive and specific for the presence of FV:Q506 and is useful as a screening assay. Carriers of the FV:Q506 allele have increased thrombin generation, resulting in hypercoagulability and a lifelong increased risk of venous thrombosis. In Western countries, APC resistance due to the FV mutation is present in 20-60% of thrombosis patients and in 1-15% of healthy controls, whereas the mutation is virtually absent from ethnic groups other than Caucasians. This may explain the high incidence of venous thrombosis in Western countries. The thrombotic risk in APC-resistant individuals may be further increased by other genetic defects, e.g., protein C or protein S deficiency, and by exposure to circumstantial risk factors, e.g., oral contraceptives, pregnancy, immobilization, and surgery. The question is thus raised as to whether general screening for APC resistance before circumstantial risk factors occur is warranted in Western countries. Key Words: Factor V—APC resistance-Protein C-Protein S—Thrombosis—Mutation.

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

Thrombosis and Haemostasis ◽

10.1055/s-0037-1613260 ◽

2002 ◽

Vol 88 (10) ◽

pp. 587-591 ◽

Cited By ~ 8

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.

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

Blood ◽

10.1182/blood.v85.6.1504.bloodjournal8561504 ◽

1995 ◽

Vol 85 (6) ◽

pp. 1504-1508 ◽

Cited By ~ 648

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.

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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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