Thrombophilia pathophysiology: Difference between revisions
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{{Thrombophilia}} | {{Thrombophilia}} | ||
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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 thrombus formation due to abnormalities in the [[coagulation]] cascade. | |||
==Pathophysiology== | ==Pathophysiology== | ||
The | * The primary mechanism for thrombus formation in most inherited thrombophilic states involves [[thrombin]] dysregulation. | ||
* [[ | * Anticoagulants that regulate thrombin include [[antithrombin]], [[Protein_C|protein C]], [[Protein_S|protein S]] | ||
* [[ | * Mutations in [https://en.wikipedia.org/wiki/Antithrombin antithrombin], can lead to increased thrombus formation<ref name="pmid14347873">{{cite journal| author=EGEBERG O| title=INHERITED ANTITHROMBIN DEFICIENCY CAUSING THROMBOPHILIA. | journal=Thromb Diath Haemorrh | year= 1965 | volume= 13 | issue= | pages= 516-30 | pmid=14347873 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14347873 }} </ref>. | ||
* [[ | * 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<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>. '''APC resistance''' occurs when APC fails to inactivate downstream coagulation factors, specifically [[Factor_V|Factor V]] and [[Factor_VIII|Factor VIII]]. | ||
* The most common inherited thrombophilia is [[Factor V Leiden]], which is a polymorphism of Factor V that is resistant to APC inactivation<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 second most common inherited thrombophilia involves a gain of function mutation of the prothrombin gene ([https://en.wikipedia.org/wiki/Prothrombin_G20210A Prothrombin G20210A]) resulting in increased protein activity and thrombus formation<ref name="pmid8916933">{{cite journal| author=Poort SR, Rosendaal FR, Reitsma PH, Bertina RM| title=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. | journal=Blood | year= 1996 | volume= 88 | issue= 10 | pages= 3698-703 | pmid=8916933 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8916933 }} </ref> | |||
* [[Familial_dysfibrinogenemia|Dysfibrinogenemia]] is a disorder of fibrinogen formation or activty resulting in predisposition for bleeding, thrombosis or both<ref name="pmid11900586">{{cite journal| author=Cunningham MT, Brandt JT, Laposata M, Olson JD| title=Laboratory diagnosis of dysfibrinogenemia. | journal=Arch Pathol Lab Med | year= 2002 | volume= 126 | issue= 4 | pages= 499-505 | pmid=11900586 | doi=10.1043/0003-9985(2002)126<0499:LDOD>2.0.CO;2 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11900586 }} </ref> | |||
'''Figure''' illustrating thrombus formation in inherited thrombophilias: | |||
[[Image: | [[Image: Thrombophilia_Path.jpg|thumb|center|700px|Thrombus formation in inherited thrombophilia. In thrombophilia, procoagulant and anticoagulant factors are dysregulated, leading to thrombus formation]] | ||
Adapted from: N Engl J Med. 2001 Apr 19;344(16):1222-31. | Adapted from: N Engl J Med. 2001 Apr 19;344(16):1222-31<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>. | ||
==References== | ==References== | ||
Revision as of 21:52, 23 June 2016
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] 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 thrombus formation due to abnormalities in the coagulation cascade.
Pathophysiology
- The primary mechanism for thrombus formation in most 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]
Figure illustrating thrombus formation in inherited thrombophilias:
Adapted from: N Engl J Med. 2001 Apr 19;344(16):1222-31[2].
References
- ↑ EGEBERG O (1965). "INHERITED ANTITHROMBIN DEFICIENCY CAUSING THROMBOPHILIA". Thromb Diath Haemorrh. 13: 516–30. PMID 14347873.
- ↑ 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.
- ↑ 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.