Thrombophilia pathophysiology

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

Overview

Pathophysiology

  • The primary mechanism for thrombus formation in common inherited thrombophilic states involves thrombin dysregulation.
  • Anticoagulants that regulate thrombin include antithrombin, protein C, protein S.
  • Mutations in antithrombin, can lead to increased thrombus formation[1].
  • 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[2]. 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[2].
  • 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 activty 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 illustrating thrombus formation in inherited thrombophilias. Adapted from: N Engl J Med. 2001 Apr 19;344(16):1222-31[2].

References

  1. EGEBERG O (1965). "INHERITED ANTITHROMBIN DEFICIENCY CAUSING THROMBOPHILIA.". Thromb Diath Haemorrh 13: 516-30. PMID 14347873.
  2. 2.0 2.1 2.2 Seligsohn U, Lubetsky A (2001). "Genetic susceptibility to venous thrombosis.". N Engl J Med 344 (16): 1222-31. doi:10.1056/NEJM200104193441607. PMID 11309638.
  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. doi:<0499:LDOD>2.0.CO;2 10.1043/0003-9985(2002)126<0499:LDOD>2.0.CO;2. PMID 11900586.

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