Inherited Thrombophilia Classification – Epidemiology – Pathophysiology

Haema 2014; 5(1):1-13

by Vasileia Garypidou, Sofia Vakalopoulou

2nd Department of Propaedeutic Internal Medicine, Aristoteleio University of Thessaloniki, Hippokration Hospital, Thessaloniki, Greece

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The term thrombophilia was first indroduced by Egeberg in 1965, when he reported a family with remarkable tendency to venous thrombosis because of a deficiency in the natural anticoagulant antithrombin. At present the term is generally used to describe a laboratory abnormality (most often in the coagulation system) that increases the tendency mainly to venous thromboembolism. Thrombophilic abnormalities can be inherited or acquired. Following Egeberg’s discovery several much more frequent inherited defects have been identified and studied. The causes of inherited thrombophilia include a group of definitely inherited disorders arising from a variety of genetic defects, as the deficiencies of natural anticoagulants (antithrombin, protein C and protein S), factor V Leiden, G20210A prothrombin mutation and a second group with multifactorial and at least partly inherited disorders, as the elevated levels of factor VIIι and mild hyperhomocysteinemia. Overall incidence of inherited thrombophilia estimated as about 10% in the general population and 24-37% in patients with venous thrombosis. Inherited deficiency of natural anticoagulants, which play an important role in the downregulation of coagulation, result in an increased generation of thrombin and predisposition to thrombosis. The prevalence of the deficiency of natural anticoagulants in the general population is only 1% (and 7% in patients with venous thrombosis). The most common types of inherited thrombophilia, factor V Leiden and the prothrombin mutation G20210A, cause an overactivity of coagulation factors. Factor V Leiden is the result of a mutation in the factor V gene at position 1691 which causes a change in factor V protein, making it resistant to inactivation by activated protein C. The mutation G20210A in the 3΄ untraslated region of the prothrombin gene results in high levels of prothombin that predispose in excess thrombin generation and thrombosis. The prevalence of factor V Leiden and prothrombin mutation in the European populations is 5-8% and 0,7-4% respectively, accounting for 50% of cases of inherited thrombophilia in Caucasians. Elevated factor VIII levels (>150%) is a very frequent disorder (11% in the general population) that predispose to venous thrombosis via enhanced thrombin formation and/or through the induction of acquired activated protein C resistance. Mild hyperhomocysteinemia (5% in the general population) is caused mainly by a mutation in the methylenetetrahydrofolate reductase gene that results in a thermo- labile variant of the enzyme, usually with inadequate intake of folic acid. Hyperhomocysteinemia can cause both arterial and vein thrombosis by numerous different mechanisms. Furthermore, there are many acquired or transient conditions that result to a prothrombotic state, including cancer, surgery, strict immobilization, pregnancy, estrogen containing medications e.t.c. The concept is that patients with thrombophilia have an intrinsic prothrombotic state that is in itself insufficient to cause thrombosis, but may lead to an event when superimposed on (clinical) risk factors.