Thrombophilic Disorders
Antithrombin (AT) deficiency, Protein C deficiency, and Prothrombin G20210A mutation are thrombophilic disorders that increase the risk of venous thromboembolism. 1
Confirmed Thrombophilic Disorders
Antithrombin (AT) deficiency is a hereditary thrombophilia characterized by decreased antithrombin levels, which significantly increases the risk of venous thromboembolism. One retrospective study found that relatives of patients with antithrombin III deficiency had an 18.4-fold increased risk of thromboembolism compared to the general population. 1
Protein C deficiency is an inherited hypercoagulable state that predisposes to venous thrombosis. Protein C is a natural anticoagulant, and its deficiency leads to increased thrombotic risk. Studies have shown that relatives of patients with protein C deficiency have a 16.2-fold increased risk of thromboembolism. 1
Prothrombin G20210A mutation is one of the most common genetic causes of thrombophilia. This mutation in the 3' untranslated region of the prothrombin gene results in elevated circulating prothrombin levels, increasing the risk of venous thromboembolism 2-10 times. 1, 2
Non-Thrombophilic Disorders
Hemophilia is not a thrombophilic disorder but rather a bleeding disorder. It is characterized by deficiency of clotting factors (factor VIII in hemophilia A or factor IX in hemophilia B), which leads to impaired clot formation and increased bleeding tendency. 1
Von Willebrand disease is also a bleeding disorder, not a thrombophilic condition. It is caused by deficiency or dysfunction of von Willebrand factor, which is necessary for platelet adhesion and factor VIII stabilization. This results in prolonged bleeding rather than thrombosis. 1
Clinical Implications of Thrombophilic Disorders
Thrombophilic disorders significantly increase the risk of venous thromboembolism, including deep vein thrombosis and pulmonary embolism. 1, 2
The risk of thrombosis is particularly high when multiple thrombophilic factors are present simultaneously. Studies have shown that the presence of two or more prothrombotic polymorphisms was found in 16.7% of patients with idiopathic venous thromboembolism compared to only 0.9% of controls. 3
Environmental factors such as oral contraceptive use, pregnancy, surgery, and immobilization can significantly increase thrombotic risk in individuals with inherited thrombophilias. For example, combined oral contraceptives produce a 30-fold increase in thrombotic risk when the Factor V Leiden mutation is also present. 2, 4
Testing Recommendations
Testing for thrombophilia is recommended in individuals with a first episode of venous thrombosis under age 50, venous thrombosis in unusual sites (such as cerebral venous thrombosis), recurrent venous thrombosis, or a strong family history of thrombotic disease. 2
When testing for one thrombophilic disorder, it is often recommended to test for others as well, as combined defects significantly increase thrombotic risk. For example, physicians ordering factor V Leiden testing should also consider screening for other heritable thrombophilic factors, especially prothrombin G20210A mutation. 1, 3
Selective screening based on prior history of venous thromboembolism is more cost-effective than universal screening for thrombophilia. 1
Management Considerations
Patients with severe inherited thrombophilia (including antithrombin deficiency, protein C deficiency, and homozygous prothrombin G20210A mutation) may require longer duration of anticoagulation therapy after a venous thromboembolism event due to their high risk of recurrence. 5
Women with thrombophilia and a personal history of venous thromboembolism should avoid hormonal contraceptives and consider alternative contraceptive methods. 2
Recent evidence suggests that carriers of factor V Leiden or prothrombin G20210A mutation may have a lower rate of major/clinically relevant bleeding while on anticoagulants for extended treatment of venous thromboembolism, which could influence anticoagulation management decisions. 6