Genotype of proband and thrombophilia screening

In this issue of Blood, Bucciarelli et al¹  report on the risk for venous thrombosis (VT) among family members of heterozygous and homozygous carriers of 2 common polymorphisms, F5 rs6025 and F2 rs1799963, commonly known as the factor V Leiden (FVL) and the prothrombin (FII) gene G20210A (PT20210A) polymorphisms, respectively. F5 rs6025 yields an arginine to glutamine shift at position 506 of the mature factor V molecule, an important cleavage site for its inactivation by activated protein C, leading to slower inactivation of factor V and prolonged activation of coagulation,²  whereas F2 rs1799963 occurs in a regulatory region of the prothrombin gene that results in higher levels of prothrombin in plasma.³  As they lead to increased clotting factor activity or level, both are labeled “gain-of-function” polymorphisms to differentiate them from the mutations or polymorphisms that occur in the coagulation inhibitor genes, such as the antithrombin, protein C, and protein S genes, resulting in reduced activity or deficiency or “loss-of-function”.

The FVL and PT20210A polymorphisms are prevalent in Caucasians and are found in 2% to 8% and 1% to 3% of European populations, respectively, but are rare among individuals of African and Asian descent.⁴  FVL increases the risk for a first VT by 3% to 5% and PT20210A by 2% to 3%,⁵  but they only marginally increase the risk for recurrent VT.⁶  Family members are at increased risk,⁷  and a recent study suggested that the risk was higher if the proband presented with VT, rather than other clinical presentations.⁸  The genotype of the proband could also be of importance, as homozygotes have a several-fold higher risk for VT compared with heterozygotes.

Bucciarelli et al also addressed this issue and investigated 192 kindreds with a total of 886 relatives with at least a single member being homozygous for either of the polymorphisms. The incidence of VT among family members was higher when the proband was heterozygous compared with being homozygous. The researchers confirmed that family members of probands presenting with VT had increased risk compared with other clinical presentations. Overall, family members of probands with heterozygous polymorphisms and who presented with VT had a 4-fold increased risk compared with family members of homozygous probands without VT. Using population statistics, Bucciarelli et al found that family members of homozygous probands without VT had an incidence rate of VT similar to that of the general population, but that the incidence was 4.5-fold higher compared with the general population among family members of heterozygous probands with VT.

The implication of these findings is that screening of family members may be limited to family members with a proband who is heterozygous for either the FVL or the PT20210A polymorphisms and who presents with VT, but this should be tested in prospective studies.