Coagulation Factors VII and V

The blood clotting system requires precise control of factors within and outside the coagulation cascade to prevent fatal bleeding or unwanted thrombosis. One common coding sequence polymorphism (Arg/Gln353) has been found in the coagulation factor VII (F7) gene. Plasma levels of factor VII vary significantly in the general population, are associated with cardiovascular risk, and are known to be influenced by a number of different environmental factors, including sex, age, and cholesterol and triglyceride levels. The Gln variant, which occurs at a frequency of ~10% in various populations, is associated with a 20% to 25% reduction in the level of plasma factor VII activity as a result of impaired secretion (128). This relatively high frequency is suggestive of a balanced polymorphism and could indicate that the Gln variant confers some benefit, for example, protection against thrombosis, myocardial infarction, or arterial disease (129).

Another missense polymorphism of hemostatic significance is factor V Leiden. Factor V (F5) Leiden increases the risk of myocardial infarction, stroke, and venous thrombosis in men (130), and in a subgroup of patients, thrombosis is associated with coin-heritance of gene mutations that modify the factor V Leiden phenotype (131). The variant, which underlies the phenomenon of activated protein C resistance, results from the substitution of Arg506 by Gln in coagulation factor V (F5). Factor Va serves as a cofactor in the activation of prothrombin by factor Xa, and the factor V Leiden variant is relatively resistant to activated protein C-mediated inactivation. Between 1% and 7% of the Caucasian population possess the factor V Leiden mutation (132), which may therefore be regarded as a fairly frequent polymorphism with phenotypic effect. Because the factor V Leiden mutation is also associated with a relative risk of ^6.0 for venous thrombosis, this also represents a polymorphism with clinical effect. Why is this factor V variant so common? Its high frequency in the general population suggests that it confers, or has conferred, some selective advantage on its bearers. Dahlback (132) speculated that a slight hypercoagulable state associated with possession of the factor V Leiden variant might have been advantageous in certain situations, such as traumatic injury and childbirth. Consistent with this postulate, carriers of the factor V Leiden variant have a significantly reduced risk of bleeding during surgery (133) and childbirth (134), despite a higher than normal risk of fetal loss (135).

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