Coagulation gene polymorphisms: the benefit?

Genetic polymorphisms of coagulation factors are known risk factors for venous thrombosis (factor V Leiden, prothrombin G20210A) and candidate risk factors for arterial thrombosis. A frequently asked question is why these polymorphisms spread so extensively throughout the white populations when they are associated with these disabling and potentially life threatening conditions. Are there evolutionary advantages to be derived from a polymorphism that predisposes to thrombotic diseases? Corral and colleagues (page 2979) have investigated 201 patients with verified intracranial bleeding for the prevalence of 4 coagulation gene polymorphisms. While the prevalences of factor V Leiden, prothrombin G20210A, factor VII −323del and factor XIII V34L were those expected in the 2 control populations used, the first 3 polymorphisms were underrepresented in the patients. This suggests a benefit in being a polymorphism carrier, having protection against acquired hemorrhage.

It will be important to confirm this work with independent investigations, particularly as studies of genetic variation are prone to bias arising from admixtures, stratification, and patient selection. Additionally, even in initially large genetic studies, crucial comparison groups inevitably become small. It should also not be forgotten that polymorphisms do not directly alter disease but must act through a phenotype. When confirmation is sought of these interesting findings, the role of the clotting factors/intermediate phenotypes involved must also be explored, as the analysis of these might be equally rewarding. It is too early to speculate whether and how these findings might be translated into clinical practice: it is sobering that there is as yet not a clear patient management use for factor V Leiden in thrombosis. But the results do suggest an explanation for the presence of functional polymorphisms in coagulation genes and remind us of the delicate nature of the hemostatic balance. Furthermore, they suggest that evaluation of polymorphisms in fibrinolytic and platelet receptor genes in acquired bleeding will also be informative.