Activated protein C resistance as a basis for venous thrombosis

Venous thrombosis is the third most common cardiovascular 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 argmine (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 multiple-gene disorder.