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.

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Key Points Question To what extent are established cardiovascular risk factors associated with risk of venous thromboembolism (VTE)? Findings In this analysis of individual participant data from the Emerging Risk Factors Collaboration and the UK Biobank including 1.1 million participants, among a panel of several established cardiovascular risk factors, older age, smoking, and greater adiposity were consistently associated with higher VTE risk. Meaning There is overlap in at least some of the major population determinants of important venous and arterial thrombotic diseases.

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