Thrombophilia pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Asiri Ediriwickrema, M.D., M.H.S. [2]


The pathogenesis of thrombophilia is multi-factorial. It is characterized by hypercoagulability, which by itself or in synergy with endothelial injury or stasis (Virchow's Triad) can predispose to clot formation. Multiple genetic mutations and predisposing conditions have been associated with the increased risk of thrombosis due to abnormalities in the coagulation cascade.[1] The most common genes involved in the pathogenesis of acquired thrombophilias are Factor V Leiden and prothrombin gene mutations.


  • The primary mechanism for thrombus formation in common inherited thrombophilic states involves thrombin dysregulation.
  • Anticoagulants that regulate thrombin include antithrombin, protein C, and protein S.
  • Mutations in antithrombin can lead to increased thrombus formation.[2]
  • Protein C and S are natural anticoagulants which inhbit thrombin formation. Dysregulation in activated protein C (APC) can occur as either defects in the protein C or S molecule (Protein C and S deficiency) or as resistance to APC activity.[1] APC resistance occurs when APC fails to inactivate downstream coagulation factors, specifically Factor V and Factor VIII.
  • The most common inherited thrombophilia is Factor V Leiden, which is a polymorphism of Factor V that is resistant to APC inactivation.[1]
  • The second most common inherited thrombophilia involves a gain of function mutation of the prothrombin gene (Prothrombin G20210A) resulting in increased protein activity and thrombus formation.[3]
  • Dysfibrinogenemia is a disorder of fibrinogen formation or activity resulting in predisposition for bleeding, thrombosis or both.[4]

Thrombus formation in inherited thrombophilia. In thrombophilia, procoagulant and anticoagulant factors are dysregulated, leading to thrombus formation

Figure: Thrombus formation in inherited thrombophilias. Adapted from: N Engl J Med. 2001 Apr 19;344(16):1222-31.[1]


  1. 1.0 1.1 1.2 1.3 Seligsohn U, Lubetsky A (2001). "Genetic susceptibility to venous thrombosis.". N Engl J Med. 344 (16): 1222–31. PMID 11309638. doi:10.1056/NEJM200104193441607. 
  2. EGEBERG O (1965). "INHERITED ANTITHROMBIN DEFICIENCY CAUSING THROMBOPHILIA.". Thromb Diath Haemorrh. 13: 516–30. PMID 14347873. 
  3. Poort SR, Rosendaal FR, Reitsma PH, Bertina RM (1996). "A common genetic variation in the 3'-untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis.". Blood. 88 (10): 3698–703. PMID 8916933. 
  4. Cunningham MT, Brandt JT, Laposata M, Olson JD (2002). "Laboratory diagnosis of dysfibrinogenemia.". Arch Pathol Lab Med. 126 (4): 499–505. PMID 11900586. doi:10.1043/0003-9985(2002)126<0499:LDOD>2.0.CO;2.