Identification of the same factor V gene mutation in 47 out of 50 thrombosis-prone families with inherited resistance to activated protein C.

Abstract

Resistance to activated protein C (APC) is the most prevalent inherited cause of venous thrombosis. The APC resistance phenotype is associated with a single point mutation in the factor V gene, changing Arg' in the APC cleavage site to a Gln. We have investigated 50 Swedish families with inherited APC resistance for this mutation and found it to be present in 47 of them. Perfect cosegregation between a low APC ratio and the presence of mutation was seen in 40 families. In seven families, the co-segregation was not perfect as 12 out of 57 APC-resistant family members were found to lack the mutation. Moreover, in three families with APC resistance, the factor V gene mutation was not found, suggesting another still unidentified cause of inherited APC resistance. Of 308 investigated families members, 146 were normal, 144 heterozygotes, and 18 homozygotes for the factor V gene mutation and there were significant differences in thrombosis-free survival curves between these groups. By age 33 yr, 8% of normals, 20% of heterozygotes, and 40% of homozygotes had had manifestation of venous thrombosis. (J. Clin. Invest. 1994. 94:2521-2524.) Key words: blood coagulation * thrombophilia -protein C * protein S * factor V recently discovered in a single family (2) and is already recognized as a major cause of venous thrombosis (3-6). Intact factor V was found to correct APC resistance (7) which together with close linkage between APC resistance and the factor V gene (8, 9), suggested the molecular defect to be located in the factor V gene. A single point mutation (G to A at position 1691) has been found in many APC-resistant individuals (8)(9)(10)(11). This mutation predicts replacement of Arg5 in the APC cleavage site of factor Va with a Gln, which results in APCresistant factor Va (8,12). The prevalence in the European population of APC resistance is between 3 and 7% (3, 5).Recently, our laboratory found intact factor V to function in synergy with protein S as cofactor to APC in a purified factor VIIIa degradation system ( 13 ). This suggests the possibility of thrombophilia being the result of other factor V gene mutations causing defects in the anticoagulant function of factor V, but as yet there are no such cases described.We have previously described a large number of families with inherited APC resistance (2-3, 9). To elucidate whether the Arg5 to Gln mutation was present in all of them, or if other genetic defects may also cause or contribute to the APC resistance, 308 individuals from 50 families with inherited resistance to activated protein C were investigated. The APC resistance was found to be associated with the same factor V gene mutation in 47 of the 50 families.

Factor V Leiden and prothrombin 20210 A mutations in patients with central and branch retinal vein occlusion

“…The relative risk of deep vein thrombosis in heterozygote and homozygote carriers of factor V Leiden mutation has been reported to be 7 and 80 times higher than controls, respectively (Rosendaal et al 1995). However, the clinical presentation has varied among individuals carrying the mutation and some of them have never developed thrombosis, whereas the majority of factor V Leiden carriers who have had thrombosis also had other associated risk factors (Zö ller et al 1994). There are only a limited number of studies which have investigated the role of factor V Leiden in branch retinal vein thrombosis.…”

The factor VR506Q mutation causing APC resistance is highly prevalent amongst unselected outpatients with clinically suspected deep venous thrombosis

“…According to medical records no thromboembolic episode was observed in the 124 DVT-negative patients during 3 months of follow up. Blood sampling, preparation of genomic DNA from EDTA blood, and determination of the FV : R506Q mutation were performed as previously described [17].…”

Prevalence of activated protein C resistance and analysis of clinical profile in thromboembolic patients. A Belgian prospective study

“…In an individual patient, the most powerful clinical predictors of APC-R are a family history of thromboembolism, and male sex. As APC-R has been firmly established as an autosomal dominant trait [32], the first point is quite plausible even if it has not been found in some other studies [29]. The second finding is rather more intriguing.…”