Thrombophilia pathophysiology: Difference between revisions
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==Overview== | ==Overview== | ||
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|Virchow's Triad]]) can predispose to [[thrombus|clot formation]]. Multiple [[Thrombophilia_classification|genetic mutations and predisposing conditions]] have been associated with the increased risk of [[thrombosis]] due to abnormalities in the [[coagulation]] cascade.<ref name="pmid11309638">{{cite journal| author=Seligsohn U, Lubetsky A| title=Genetic susceptibility to venous thrombosis. | journal=N Engl J Med | year= 2001 | volume= 344 | issue= 16 | pages= 1222-31 | pmid=11309638 | doi=10.1056/NEJM200104193441607 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11309638 }} </ref> The most common genes involved in the pathogenesis of acquired thrombophilias are [[Factor V Leiden]] and '''[[prothrombin]] gene mutations'''. | 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|Virchow's Triad]]) can predispose to [[thrombus|clot formation]]. Multiple [[Thrombophilia_classification|genetic mutations and predisposing conditions]] have been associated with the increased risk of [[thrombosis]] due to abnormalities in the [[coagulation]] cascade.<ref name="pmid11309638">{{cite journal| author=Seligsohn U, Lubetsky A| title=Genetic susceptibility to venous thrombosis. | journal=N Engl J Med | year= 2001 | volume= 344 | issue= 16 | pages= 1222-31 | pmid=11309638 | doi=10.1056/NEJM200104193441607 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11309638 }} </ref> The most common genes involved in the pathogenesis of acquired thrombophilias are [[Factor V Leiden]] and '''[[prothrombin]] gene mutations'''. | ||
*Coagulation is an inherent property of the hematologic system and under healthy conditions, normal blood flow is maintained by the balance between the pro-coagulant and anti-thrombotic factors. A hypercoagulable state and subsequent thromboembolism is a result of overactivity of pro-coagulant factors or a deficiency in anti-coagulants. The interplay of factors is complicated - coagulation activators and inhibitors and their production and degradation (quantitative) and functional properties (qualitative) all influence thrombosis. The triad of hypercoagulability, vascular stasis and vascular trauma as described by Virchow in 1856 still holds and remains the harbinger of vascular thrombosis. Arterial thrombosis results from atherosclerotic plaque rupture around which a platelet-rich white thrombus forms. Stasis behind venous valves contributes to venous thrombosis and red thrombus. Mutations influence coagulation depending on whether they are present in heterozygous or homozygous genotype. | |||
==Pathophysiology== | ==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]
Overview
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.
- Coagulation is an inherent property of the hematologic system and under healthy conditions, normal blood flow is maintained by the balance between the pro-coagulant and anti-thrombotic factors. A hypercoagulable state and subsequent thromboembolism is a result of overactivity of pro-coagulant factors or a deficiency in anti-coagulants. The interplay of factors is complicated - coagulation activators and inhibitors and their production and degradation (quantitative) and functional properties (qualitative) all influence thrombosis. The triad of hypercoagulability, vascular stasis and vascular trauma as described by Virchow in 1856 still holds and remains the harbinger of vascular thrombosis. Arterial thrombosis results from atherosclerotic plaque rupture around which a platelet-rich white thrombus forms. Stasis behind venous valves contributes to venous thrombosis and red thrombus. Mutations influence coagulation depending on whether they are present in heterozygous or homozygous genotype.
Pathophysiology
- 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]
Figure: Thrombus formation in inherited thrombophilias. Adapted from: N Engl J Med. 2001 Apr 19;344(16):1222-31.[1]
References
- ↑ 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. doi:10.1056/NEJM200104193441607. PMID 11309638.
- ↑ EGEBERG O (1965). "INHERITED ANTITHROMBIN DEFICIENCY CAUSING THROMBOPHILIA". Thromb Diath Haemorrh. 13: 516–30. PMID 14347873.
- ↑ 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.
- ↑ Cunningham MT, Brandt JT, Laposata M, Olson JD (2002). "Laboratory diagnosis of dysfibrinogenemia". Arch Pathol Lab Med. 126 (4): 499–505. doi:10.1043/0003-9985(2002)126<0499:LDOD>2.0.CO;2. PMID 11900586.