Resistance to activated protein C, the FV: Q506 allele, and venous thrombosis (original) (raw)
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Resistance to activated protein C, the FV : Q 506 allele, and venous thrombosis
Annals of Hematology, 1996
Vitamin K-dependent protein C is an important regulator of blood coagulation. After its activation on the endothelial cell surface by thrombin bound to thrombomodulin, it cleaves and inactivates procoagulant cofactors Va and VIIIa, protein S and intact factor V working as cofactors. Until recently, genetic defects of protein C or protein S were, together with antithrombin III deficiency, the established major causes of familial venous thromboembolism, but they were found in fewer than 5-10% of patients with thrombosis. In 1993, inherited resistance to activated protein C (APC) was described as a major risk factor for venous thrombosis. It is found in up to 60% of patients with venous thrombosis. In more than 90% of cases, the molecular background for the APC resistance is a single point mutation in the factor V gene, which predicts substitution of an arginine (R) at position 506 by a glutamine (Q). Mutated factor V (FV : Q 506 ) is activated by thrombin or factor Xa in normal way, but impaired inactivation of mutated factor Va by APC results in life-long hypercoagulability. The prevalence of the FV : Q 506 allele in the general population of Western countries varies between 2 and 15%, whereas it is not found in several other populations with different ethnic backgrounds. Owing to the high prevalence of FV : Q 506 in Western populations, it occasionally occurs in patients with deficiency of protein S, protein C, or antithrombin III. Individuals with combined defects suffer more severely from thrombosis, and often at a younger age, than those with single defects, suggesting severe thrombophilia to be a multigenetic disease.
Annual Review of Medicine, 1997
▪ Inherited resistance to activated protein C (APC) was recently discovered to be a cause of familial thrombophilia and is now known to be the most common genetic risk factor for venous thrombosis. It is caused by a single point mutation in the gene for factor V, which predicts substitution of arginine (R) at position 506 with a glutamine (Q). Accordingly, the activated form of mutated factor V (FVa:Q506) is more slowly degraded by activated protein C than normal FVa (FVa:R506) is, resulting in hypercoagulability and a lifelong 5- to 10-fold increased risk of venous thrombosis. Previously known inherited hypercoagulable states, i.e. deficiencies of the anticoagulant proteins antithrombin III, protein S, and protein C, are found in fewer than 10–15% of thrombosis patients in western countries, whereas inherited APC resistance is present in 20–60% of such patients. The FV mutation is common in populations of Caucasian origin, with prevalences ranging from 1–15%, whereas it is not fo...
FAMILIAL THROMBOPHILIA Resistance to activated protein C and protein· S deficiency
Doctoral Thesis, 1996
Inherited resistance to activated protein C (APC-resistance) and protein S deficiency are associated with functional impairment of the protein C anticoagulant system, resulting in lifelong hypercoagulability and increased risk of thrombosis. APC-resistance is the most common genetic cause of thrombosis being present in 20% to 60% of thrombosis patients. A linkage study was performed in a large thrombophilic family with independent inheritance of APCresistance and protein S deficiency. APC-resistance was found to co-segregate with two neutral polymorphisms in the factor V gene. A point mutation changing Arg506 to a Gln in the factor V gene was the cause of APC-resistance in the family. The mutation (FV:Q506) is localised in one of the APC-cleavage sites of factor V, rendering mutated factor Va resistant to cleavage by activated protein C (APC). The factor V mutation was analysed in 308 members from 50 thrombosis-prone families with inherited APC-resistance. In 94% (47/50) of APC-resistant families the same factor V gene mutation was identified. The magnitude of thrombotic risk was dependent on the factor V genotype. We investigated 327 individuals in 18 thrombosis-prone families with inherited deficiency of free protein S. Deficiency of free protein S was caused by equimolar relationship between total protein S and B-chain containing isoforms of C4BP. Moreover, type I deficiency (low free and total protein S) and type III deficiency (low free but normal total protein S) coexisted in 14 out of 18 families, demonstrating the two types to be phenotypic variants of the same genetic disease. Deficiency of free protein S was a strong risk factor for thrombosis in these families. However, thrombophilia penetrance was highly variable. The FV:Q506 mutation causing APC-resistance was identified as an additional genetic risk factor in 39% (7/18) of the families. Thus, familial thrombophilia isa multiple genetic disorder. Biochemically affected family members had higher levels of prothrombin fragment Fl +2 than their normal relatives. The results demonstrate that individuals with APC-resistance or protein S deficiency have an imbalance between pro- and anti-coagulant forces, resulting in increased thrombin generation and hypercoagulability.
British Journal of Haematology, 1995
The activated protein C (APC) resistance phenotype results from a mutation at one of the cleavage sites of factor V by APC (Q506). We describe a large family with an APC resistance phenotype and without any other detectable coagulation defect, including eight subjects who had developed deep venous thrombosis (mean age of the first thrombosis episode 29 years; range 17-55 years). The factor V Q506 mutation was detected in the seven patients with thrombosis who could be tested and in 13 asymptomatic subjects (mean age 17 years; range 5-33 years). The APC resistance was detectable in only 10 heterozygotes among the 19 tested. These data suggest that, in affected families, the risk for the factor V Q506 mutation carriers to develop thrombosis may be very high and that factor V genotyping must be performed in patients with thrombosis even without any detectable APC resistance phenotype.
Arteriosclerosis, Thrombosis, and Vascular Biology, 1999
Deficiencies of antithrombin (AT), protein C (PC) or protein S (PS), and activated protein C resistance (APCR) are very well-established coagulation defects predisposing to venous thromboembolism (VTE). We performed a retrospective cohort family study to assess the risk for VTE in individuals with AT, PC, or PS deficiency, or APCR. Five hundred thirteen relatives from 9 Italian centers were selected from 233 families in which the proband had had at least 1 episode of VTE. We calculated the incidence of VTE in the whole cohort and in the subgroups after stratification by age, sex, and defect. The overall incidence of VTE (per 100 patient-years) in the group of relatives was 0.52. It was 1.07 for AT, 0.54 for PC, 0.50 for PS, 0.30 for APCR, and 0.67 in the group with a double defect. The incidence was associated with age, but not with sex. The mean age at onset was between 30 and 40 years for all the coagulation defects. Women had the peak of incidence in the age range of 21 to 40 years, earlier than men. The lifetime risk for VTE was 4.4 for AT versus APCR, 2.6 for AT versus PS, 2.2 for AT versus PC, 1.9 for PC versus APCR, and 1.6 for PS versus APCR. AT deficiency seems to have a higher risk for VTE than the other genetic defects. There is a relation between age and occurrence of thrombosis for both men and women. The latter had the peak of incidence earlier than the former.
Activated protein C resistance as a basis for venous thrombosis
The American Journal of Medicine, 1996
enous thrombosis is the third most common car-v diovascular disease after acute ischemic heart disease and stroke. A number of acquired or genetic risk factors for thrombosis have been described. Circumstantial factors such as surgery, pregnancy, malignancy, and oral contraceptive usage are well established etiologic factors associated with venous thrombosis. With the exploration of the anticoagulatory protein C system in the 1970s and 1980s and the identification of protein C and protein S deficiencies, explanations were provided for up to 10% of cases of familial thrombosis, but the real breakthrough came in 1993 with the discovery of resistance to activated protein C (APC) as a risk factor for thrombosis. Several extensive studies have shown APC resistance to be present in 20 to 60% of thrombosis patients, the wide range in reported prevalences being due to differences in selection criteria and ethnic background of the populations studied. APC resistance is by far the most common cause of inherited thrombosis, and in more than 90% of cases it is caused by a single point mutation in the large factor V gene. The mutation is a guanine-to-adenine substitution at nucleotide position 1691 of the factor V gene, resulting in the substitution of arginine (R) by glutamine (Q) at position 506 of the polypeptide chain of factor V (factor V:Q506 or factor V Leiden). Although the factor V:Q506 allele is virtually absent from several ethnic groups, its prevalence in Caucasian populations is high (2-15%). Owing to this high prevalence, APC resistance occasionally occurs in individuals with other genetic risk factors for thrombosis. In general, individuals with combined defects are characterized by a more severe thrombotic picture than are individuals with single-gene defects, thus suggesting thrombosis to be a multiplegene disorder.
Arteriosclerosis, Thrombosis, and Vascular Biology, 1999
Deficiencies of antithrombin (AT), protein C (PC) or protein S (PS), and activated protein C resistance (APCR) are very well-established coagulation defects predisposing to venous thromboembolism (VTE). We performed a retrospective cohort family study to assess the risk for VTE in individuals with AT, PC, or PS deficiency, or APCR. Five hundred thirteen relatives from 9 Italian centers were selected from 233 families in which the proband had had at least 1 episode of VTE. We calculated the incidence of VTE in the whole cohort and in the subgroups after stratification by age, sex, and defect. The overall incidence of VTE (per 100 patient-years) in the group of relatives was 0.52. It was 1.07 for AT, 0.54 for PC, 0.50 for PS, 0.30 for APCR, and 0.67 in the group with a double defect. The incidence was associated with age, but not with sex. The mean age at onset was between 30 and 40 years for all the coagulation defects. Women had the peak of incidence in the age range of 21 to 40 years, earlier than men. The lifetime risk for VTE was 4.4 for AT versus APCR, 2.6 for AT versus PS, 2.2 for AT versus PC, 1.9 for PC versus APCR, and 1.6 for PS versus APCR. AT deficiency seems to have a higher risk for VTE than the other genetic defects. There is a relation between age and occurrence of thrombosis for both men and women. The latter had the peak of incidence earlier than the former.