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

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

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642720 ◽

1995 ◽

Vol 74 (01) ◽

pp. 449-453 ◽

Cited By ~ 99

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

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“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

Thrombosis and Haemostasis ◽

10.1055/s-0038-1650290 ◽

1996 ◽

Vol 75 (03) ◽

pp. 422-426 ◽

Cited By ~ 53

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.

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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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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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Evaluation of a New Assay Based on a FV-Dependent Prothrombinase Activator for the Detection of Activated Protein C Resistance Phenotype.

Blood ◽

10.1182/blood.v104.11.3994.3994 ◽

2004 ◽

Vol 104 (11) ◽

pp. 3994-3994

Author(s):

Jogin Wu ◽

Peter Quehenberger ◽

Katherine Foltyn ◽

Patricia Dillard

Keyword(s):

Protein C ◽

Tertiary Care ◽

False Negative ◽

Activated Protein C ◽

Factor V Leiden ◽

Reference Method ◽

Coagulation Cascade ◽

Factor V ◽

Resistance Phenotype ◽

Apc Resistance

Abstract Activated protein C (APC) resistance is the most frequent hereditary defect associated with deep venous thrombosis. Major cause of APC resistance phenotype is due to a point mutation of factor V (Factor V Leiden). A new clotting assay, Pefakit® APC-R Factor V Leiden (Pentapharm Ltd., Switzerland) for the detection of APC resistance phenotype was evaluated at two tertiary care hospitals, Duke University Medical Center, USA (Duke) and University of Vienna, Austria (Vienna). Samples of 242 subjects from Duke and 187 subjects from Vienna were included in the study among patients who were subjects for thormbophilia screening. The Pefakit® method is based on clotting time measurement triggered by a prothrombin activator added to a mixture of patient plasma diluted with factor V deficient plasma with and without APC. Robustness and specificity of the assay is enhanced by elimination of possible disturbing influence by factors upstream the coagulation cascade and heparin interference is precluded up to heparin level of 2 IU/ml by heparin inhibitor added to the regent. A similar, FDA approved commercial APC-R kit (COATEST of IL) was used for method comparison. Patients with elevated factor VIII (n=11), Coumadin (n=23), Lupus Anticoagulant (n-14), protein C deficient (n=7), protein S deficient (n=9), AT III (n=6) and women with pregnancy (n=9) were included in Duke study and no interference were found in phenotype. Using PCR/FRET DNA method as reference method the Pefakit® method provided 100 % sensitivity and 100 % specificity for the Vienna study and 99.0 % sensitivity and 98.6 % specificity for the Duke study and the COATEST provided 97.1 % specificity and 93.2 % sensitivity with the Duke study. Using two levels of genotype controls both studies showed similar intra and inter-assay precision (less than 6 % for the Vienna study and 9 % for the Duke study) as compared with the gold standard IL APC-R COATEST kit (less than 5 % CV). Of great interest one false positive sample from the Duke study is under investigation due to that the functional detection of the assay is supposed to detect other FV mutations leading to APC-R phenotype as well. Reasons that cause the other two false negative results for the Duke study are still unknown and under investigation. Both studies showed that the Pefakit® is simple and rebust assay. Both wild type and heterozygous groups have much higher ratio as compared with the reference method in differentiating them from homozygous phenotype. Figure Figure

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Apparent different thrombotic tendency in patients with factor V Leiden and protein C deficiency due to selection of patients

Blood ◽

10.1182/blood.v88.11.4205.bloodjournal88114205 ◽

1996 ◽

Vol 88 (11) ◽

pp. 4205-4208 ◽

Cited By ~ 1

Author(s):

RP Lensen ◽

FR Rosendaal ◽

T Koster ◽

CF Allaart ◽

H de Ronde ◽

...

Keyword(s):

Venous Thrombosis ◽

Protein C ◽

Age Of Onset ◽

Factor V Leiden ◽

Factor V ◽

Protein C Deficiency ◽

Apc Resistance ◽

Selection Of Patients ◽

Control Study ◽

Selection Of

Both activated protein C (APC) resistance and protein C deficiency are associated with an increased risk for venous thrombosis. To assess their tendencies to venous thrombosis, we compared the median age of first venous thromboembolism in patients with factor V Leiden or protein C deficiency, who were identified either within unselected consecutive cases with a first deep venous thrombosis derived from a population-based case-control study, or identified by selection of patients with a deep venous thrombosis, who were referred for thrombophilIa work-up. The median age of onset for 92 unselected APC resistant cases was 43 years and for 13 unselected protein C-deficient cases 47 years. The median age at the first thrombotic event for 28 APC- resistant members of thrombophilia families was 29 years and for 50 protein C-deficient members of thrombophilia families 31.5 years. The median age of onset for all unselected patients (n=105) was 45 years of age (range, 16 to 69 years) and the median age of onset for all selected patients from the thrombophilia families (n=78) was 30.5 years (range, 16 to 67 years). These results show that within the case-control study and the family studies, the median age of onset is very similar in patients with APC resistance and patients with protein C deficiency. This suggests that APC resistance is not less severe with respect to risk of thrombosis than (heterozygous) protein C deficiency. In conclusion, the median age at which the first thrombosis occurs mainly depends on the way the patients are identified and not on the type of thrombophilia.

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