Center for Human Genetics and Laboratory Diagnostics, Dr. Klein, Dr. Rost and Colleagues

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Thrombophilia [I82.9]

OMIM numbers: 188050, 612309 (Faktor V), 176930 (Faktor II)

Dr. rer. nat. Christoph Marschall, Dipl.-Biol. Christine Schack,
Dipl.-Biol. Christina Sofeso

Scientific Background

The annual incidence for deep vein thrombosis (DVT) is 1 in 1,000. Risk factors for venous thrombosis may be genetic or acquired. Epidemiological studies have already identify several genetic risk factors for venous thrombosis; besides resistance of the coagulation factor V to activated protein C (APC), increased plasma concentration of prothrombin plays a major role.

APC resistance is the most commonly known risk factor for venous thrombosis. In 90% of all cases the genetic cause is a polymorphism in the coagulation factor V gene (c.1691G>A), resulting in arginine being substituted by glutamine in amino acid position 506. The activating factor V can therefore no longer be cleaved and inactivated sufficiently by the activated protein C. A heterozygous factor V Leiden polymorphism (rs6025) is found in 5-7% of all Caucasians and is detected in approximately a quarter of all patients suffering from thrombosis. With a prevalence of 0.02% in the general population, homozygosity for this polymorphism is very rare. Heterozygosity for the factor V Leiden polymorphism has been associated with a 5-10 times greater risk for venous thrombosis. For homozygous carriers, the individual risk for thrombosis is 50-80 times higher.

The risk for thrombosis due to the factor V Leiden polymorphism may also be increased by other genetic factors such as the prothrombin G20210A polymorphism. Prothrombin (factor II) is the precursor of thrombin, which is involved in the conversion of fibrinogen to fibrin within the coagulation cascade. A polymorphism in the nucleotide position 20210 of the 3’ untranslated region of the prothrombin gene, FII-G20210A (rs1799963), has been associated with an increased prothrombin concentration in the plasma. The consequence is hypercoagulability of the blood, which also puts the affected patients at a greater lifelong risk of thrombosis. Besides the factor V Leiden polymorphism, the prothrombin polymorphism is the second most frequent genetic risk factor. Approximately 2 % of the Western population are heterozygous carriers of this polymorphism, which increases the individual risk of thrombosis by 2-3.

There are a number of exogenous factors in addition to the genetic factors which have an impact on the individual risk of thrombosis. These factors include immobilization, smoking, pregnancy, oral contraceptives as well as age and obesity. Thrombosis prophylaxis for asymptomatic genetic carriers is currently not advised. A temporary prophylaxis may be indicated in certain risk situations such as immobilization for an extended period of time or pregnancy in combination with other risk factors. Long-term or permanent anticoagulation may be indicated in the case of severe thrombotic events or recurrences.