Genetic heterogeneity in hereditary thrombophilia

Venous thromboembolism is a multifactorial disease that depends on variable combinations of acquired and genetic risk factors. The genetic risk factors include loss-of-function mutations in the genes that encode proteins with clot-restraining function, and gain-of-function mutations in procoagulant factors. The loss-of-function mutations are heterogeneous and comprise any mutation that impairs gene function. On the whole, these mutations are rare, with fewer than 1/200--500 individuals affected. This low prevalence in the population is probably caused by the loss of mutant alleles from the gene pool through critically ill homozygous subjects. The gain-of-function mutations in procoagulant proteins differ from the loss-of-function mutations in at least three important respects: these are more homogeneous (factor V Leiden and PT 20210), homozygous individuals are relatively mildly affected, and these are relatively prevalent (3--15%) in Caucasian populations.