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| __NOTOC__ | | __NOTOC__ |
| {{Thrombophilia}} | | {{Thrombophilia}} |
| {{CMG}} {{AE}} {{asiri}} | | {{CMG}} {{AE}} {{asiri}} |
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| ==Overview== | | ==Overview== |
| '''Thrombophilia''' is a complex condition which increases the risk of [[thrombosis]] or thromboembolic disease. The predisposition to [[thrombus|clotting]], or '''thrombotic risk''', can be multi-factorial, and is due to an abnormality in [[coagulation]] described as '''hypercoagulability'''. Hypercoagulability is a component of [[Virchow's_triad|Virchow's Triad]], which by itself or in synergy with '''stasis''' or '''trauma''' can predispose to clot formation. The thrombotic risk associated with thrombophilic states is variable and depends on the underlying coagulopathy. Thrombophilias are classified as either inherited or a primary hypercoagulable state, acquired or a secondary hypercoagulable state, or mixed/unknown. [[Factor V Leiden]] and '''[[prothrombin]] gene mutations''' are the most common forms of inherited hypercoagulable states. Patients with thrombophilia can have a family history of [[thrombosis]], or present with frequent or unprovoked blood clots (primarily as [[deep vein thrombosis]] or [[pulmonary embolism]]), thrombosis at a young age, or blood clots in multiple or unusual sites.<ref name=?>DeLoughery TG. Hemostasis and Thrombosis. Springer; 2014.</ref> [[Thrombophilia screening|Thrombophilia screening]] is controversial, but may aid in managing the initiation and duration of [[anticoagulation]] in affected patients and primary prevention in relatives.
| | Due to the multitude and complexity of inherited thrombophilias, the true [[prevalence]] is unknown, and current data may be providing an underestimate. Comparison among different epidemiologic studies becomes difficult due to variation in study design and inclusion criteria. Prevalence of common inherited thrombophilias is variable among both healthy patients and patients with recurrent [[thrombosis]]. According to epidemiologic and modeling studies obtained from certain sources, the prevalence of inherited thrombophilias was estimated to be between 0.01-7% in caucasians.<ref name="pmid26780744">{{cite journal| author=Stevens SM, Woller SC, Bauer KA, Kasthuri R, Cushman M, Streiff M et al.| title=Guidance for the evaluation and treatment of hereditary and acquired thrombophilia. | journal=J Thromb Thrombolysis | year= 2016 | volume= 41 | issue= 1 | pages= 154-64 | pmid=26780744 | doi=10.1007/s11239-015-1316-1 | pmc=4715840 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26780744 }} </ref><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> In certain studies, the prevalence of inherited thrombophilias, specifically, '''activated protein C resistance''' and '''prothrombin G20210A''', rises to approximately 10-60% in patients with documented venous thrombosis compared to less than 10% among controls.<ref name="pmid9669991">{{cite journal| author=Margaglione M, Brancaccio V, Giuliani N, D'Andrea G, Cappucci G, Iannaccone L et al.| title=Increased risk for venous thrombosis in carriers of the prothrombin G-->A20210 gene variant. | journal=Ann Intern Med | year= 1998 | volume= 129 | issue= 2 | pages= 89-93 | pmid=9669991 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9669991 }} </ref><ref name="pmid7877648">{{cite journal| author=Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP| title=Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. | journal=N Engl J Med | year= 1995 | volume= 332 | issue= 14 | pages= 912-7 | pmid=7877648 | doi=10.1056/NEJM199504063321403 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7877648 }} </ref><ref name="pmid7902898">{{cite journal| author=Koster T, Rosendaal FR, de Ronde H, Briët E, Vandenbroucke JP, Bertina RM| title=Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. | journal=Lancet | year= 1993 | volume= 342 | issue= 8886-8887 | pages= 1503-6 | pmid=7902898 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7902898 }} </ref> The incidence of inherited thrombophilia in incident venous thrombosis is approximately 150-840 per 100,000 person years.<ref name="pmid24421360">{{cite journal| author=Cohoon KP, Heit JA| title=Inherited and secondary thrombophilia. | journal=Circulation | year= 2014 | volume= 129 | issue= 2 | pages= 254-7 | pmid=24421360 | doi=10.1161/CIRCULATIONAHA.113.001943 | pmc=3979345 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24421360 }} </ref> The incidence of inherited thrombophilia in recurrent venous thrombosis is approximately 3,500-10,500 per 100,000 person-years.<ref name="pmid24421360">{{cite journal| author=Cohoon KP, Heit JA| title=Inherited and secondary thrombophilia. | journal=Circulation | year= 2014 | volume= 129 | issue= 2 | pages= 254-7 | pmid=24421360 | doi=10.1161/CIRCULATIONAHA.113.001943 | pmc=3979345 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24421360 }} </ref> |
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| ==Historical Perspective==
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| Rudolf Virchow described hypercoagulability in the mid 1800s, however, it was not until 1965 that the first descriptions of inherited thrombophilia were published.<ref name="pmid7997003">{{cite journal| author=Schafer AI| title=Hypercoagulable states: molecular genetics to clinical practice. | journal=Lancet | year= 1994 | volume= 344 | issue= 8939-8940 | pages= 1739-42 | pmid=7997003 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7997003 }} </ref><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><ref name="pmid4956920">{{cite journal| author=Beck EA, Charache P, Jackson DP| title=A new inherited coagulation disorder caused by an abnormal fibrinogen ('fibrinogen Baltimore'). | journal=Nature | year= 1965 | volume= 208 | issue= 5006 | pages= 143-5 | pmid=4956920 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=4956920 }} </ref> Later, in the 1990s, the more common mutations associated with primary hypercoagulable states were identified.<ref name="pmid8164741">{{cite journal| author=Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H et al.| title=Mutation in blood coagulation factor V associated with resistance to activated protein C. | journal=Nature | year= 1994 | volume= 369 | issue= 6475 | pages= 64-7 | pmid=8164741 | doi=10.1038/369064a0 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=8164741 }} </ref><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>
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| ==Classification==
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| Thrombophilias may be classified into three groups: '''inherited or primary hypercoagulable states''', '''acquired or secondary hypercoagulable states''', or '''mixed/unknown'''. Certain conditions are associated with greater thrombotic risks and both venous and arterial clots.
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| ==Pathophysiology==
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| 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'''.
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| ==Causes==
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| Thrombophilia may be caused by either [[Thrombophilia_classification|acquired, inherited, or, more commonly, a combination of both conditions]]. The most frequent forms of inherited thrombophilia are Factor V Leiden (20-50% prevalence in patients with recurrent venous thrombosis) and prothrombon G20210A (5-20% prevalence in patients with recurrent venous thrombosis).<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><ref name="pmid24421360">{{cite journal| author=Cohoon KP, Heit JA| title=Inherited and secondary thrombophilia. | journal=Circulation | year= 2014 | volume= 129 | issue= 2 | pages= 254-7 | pmid=24421360 | doi=10.1161/CIRCULATIONAHA.113.001943 | pmc=3979345 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24421360 }} </ref>
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| ==Differentiating Inherited Thrombophilia from other Diseases==
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| Inherited thrombophilia must be differentiated from acquired thrombophilia, as it may influence the selection and duration of [[Anticoagulant|anticoagulation]]. Inherited thrombophilias should be suspected in patients with the certain [[Thrombophilia_history_and_symptoms|clinical presentations]].<ref name="pmid24421360">{{cite journal| author=Cohoon KP, Heit JA| title=Inherited and secondary thrombophilia. | journal=Circulation | year= 2014 | volume= 129 | issue= 2 | pages= 254-7 | pmid=24421360 | doi=10.1161/CIRCULATIONAHA.113.001943 | pmc=3979345 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24421360 }} </ref><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> [[Thrombophilia screening|Screening]] for inherited thrombophilias is controversial and should be performed in the appropriate clinical context.<ref name="pmid21340752">{{cite journal| author=Middeldorp S| title=Evidence-based approach to thrombophilia testing. | journal=J Thromb Thrombolysis | year= 2011 | volume= 31 | issue= 3 | pages= 275-81 | pmid=21340752 | doi=10.1007/s11239-011-0572-y | pmc=3056012 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21340752 }} </ref>
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| ==Epidemiology and Demographics== | | ==Epidemiology and Demographics== |
| Due to the multitude and complexity of inherited thrombophilias, the true [[prevalence]] is unknown, and current data may be providing an underestimate. Comparison among different epidemiologic studies becomes difficult due to variation in study design and inclusion criteria. Prevalence of common inherited thrombophilias is variable among both healthy patients and patients with recurrent [[thrombosis]]. According to epidemiologic and modeling studies obtained from certain sources, the prevalence of inherited thrombophilias was estimated to be between 0.01-7% in caucasians.<ref name="pmid26780744">{{cite journal| author=Stevens SM, Woller SC, Bauer KA, Kasthuri R, Cushman M, Streiff M et al.| title=Guidance for the evaluation and treatment of hereditary and acquired thrombophilia. | journal=J Thromb Thrombolysis | year= 2016 | volume= 41 | issue= 1 | pages= 154-64 | pmid=26780744 | doi=10.1007/s11239-015-1316-1 | pmc=4715840 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26780744 }} </ref><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> In certain studies, the prevalence of inherited thrombophilias, specifically, '''activated protein C resistance''' and '''prothrombin G20210A''', rises to approximately 10-60% in patients with documented venous thrombosis compared to less than 10% among controls.<ref name="pmid9669991">{{cite journal| author=Margaglione M, Brancaccio V, Giuliani N, D'Andrea G, Cappucci G, Iannaccone L et al.| title=Increased risk for venous thrombosis in carriers of the prothrombin G-->A20210 gene variant. | journal=Ann Intern Med | year= 1998 | volume= 129 | issue= 2 | pages= 89-93 | pmid=9669991 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=9669991 }} </ref><ref name="pmid7877648">{{cite journal| author=Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP| title=Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men. | journal=N Engl J Med | year= 1995 | volume= 332 | issue= 14 | pages= 912-7 | pmid=7877648 | doi=10.1056/NEJM199504063321403 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7877648 }} </ref><ref name="pmid7902898">{{cite journal| author=Koster T, Rosendaal FR, de Ronde H, Briët E, Vandenbroucke JP, Bertina RM| title=Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. | journal=Lancet | year= 1993 | volume= 342 | issue= 8886-8887 | pages= 1503-6 | pmid=7902898 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=7902898 }} </ref> The incidence of inherited thrombophilia in incident venous thrombosis is approximately 150-840 per 100,000 person years.<ref name="pmid24421360">{{cite journal| author=Cohoon KP, Heit JA| title=Inherited and secondary thrombophilia. | journal=Circulation | year= 2014 | volume= 129 | issue= 2 | pages= 254-7 | pmid=24421360 | doi=10.1161/CIRCULATIONAHA.113.001943 | pmc=3979345 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24421360 }} </ref> The incidence of inherited thrombophilia in recurrent venous thrombosis is approximately 3,500-10,500 per 100,000 person-years.<ref name="pmid24421360">{{cite journal| author=Cohoon KP, Heit JA| title=Inherited and secondary thrombophilia. | journal=Circulation | year= 2014 | volume= 129 | issue= 2 | pages= 254-7 | pmid=24421360 | doi=10.1161/CIRCULATIONAHA.113.001943 | pmc=3979345 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24421360 }} </ref>
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| ===Age=== | | ===Age=== |
| *Patients of all age groups may develop thrombophilias. | | *Patients of all age groups may develop thrombophilias. |
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| * The factor V leiden G1691A and prothrombin G20210A mutations are exceedingly rare in non-white populations.<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 factor V leiden G1691A and prothrombin G20210A mutations are exceedingly rare in non-white populations.<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> |
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| ==Risk Factors== | | ===Prevalence of select inherited thrombophilias among whites=== |
| * Inherited thrombophilias should be suspected in certain [[Thrombophilia_history_and_symptoms|clinical presentations]].
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| * Refer to the [[Thrombophilia_classification|thrombophilia classification]] page for a list conditions associated with acquired thrombophilias, and to the page on [[Thrombophilia_causes|causes of thrombophilia by organ system]].
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| == Natural History, Complications and Prognosis==
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| * Refer to the [[Thrombophilia_history_and_symptoms|clinical symptoms]] section regarding early clinical features of patients with thrombophilia.
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| * Annual thrombotic risks are variable and depend on the underlying thrombophilia.<ref name="pmid11529700">{{cite journal| author=Bauer KA| title=The thrombophilias: well-defined risk factors with uncertain therapeutic implications. | journal=Ann Intern Med | year= 2001 | volume= 135 | issue= 5 | pages= 367-73 | pmid=11529700 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11529700 }} </ref>
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| * If left untreated, the annual incidence of incident thrombosis in asymptomatic patients with [[Factor V Leiden]] and ([https://en.wikipedia.org/wiki/Prothrombin_G20210A Prothrombin G20210A]) (<0.06%) is low.<ref name="pmid15254285">{{cite journal| author=Bates SM, Ginsberg JS| title=Clinical practice. Treatment of deep-vein thrombosis. | journal=N Engl J Med | year= 2004 | volume= 351 | issue= 3 | pages= 268-77 | pmid=15254285 | doi=10.1056/NEJMcp031676 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15254285 }} </ref> The risk is approximately equivalent to treatment with [[Oral_contraceptive|oral contraceptives (OCPs)]]. Whereas the annual incidence of significant bleeds is approximately 2-3%.<ref name="pmid14644891">{{cite journal| author=Linkins LA, Choi PT, Douketis JD| title=Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. | journal=Ann Intern Med | year= 2003 | volume= 139 | issue= 11 | pages= 893-900 | pmid=14644891 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=14644891 }} </ref>
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| * Studies performed by Christiansen et al and Baglin et al revealed that inherited thrombophilia from factor V leiden and prothrombin G20210A did not predict for recurrent thrombosis.<ref name="pmid15900005">{{cite journal| author=Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR| title=Thrombophilia, clinical factors, and recurrent venous thrombotic events. | journal=JAMA | year= 2005 | volume= 293 | issue= 19 | pages= 2352-61 | pmid=15900005 | doi=10.1001/jama.293.19.2352 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15900005 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17213089 Review in: Evid Based Med. 2006 Apr;11(2):59] </ref><ref name="pmid12932383">{{cite journal| author=Baglin T, Luddington R, Brown K, Baglin C| title=Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. | journal=Lancet | year= 2003 | volume= 362 | issue= 9383 | pages= 523-6 | pmid=12932383 | doi=10.1016/S0140-6736(03)14111-6 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12932383 }} </ref>
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| * Christiansen et al and De Stefano et al observed a mild increased risk for recurrent thrombosis in patients with [[Protein_C|protein C]], [[Protein_S|protein S]], and [[antithrombin]] deficiency.<ref name="pmid15900005">{{cite journal| author=Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR| title=Thrombophilia, clinical factors, and recurrent venous thrombotic events. | journal=JAMA | year= 2005 | volume= 293 | issue= 19 | pages= 2352-61 | pmid=15900005 | doi=10.1001/jama.293.19.2352 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=15900005 }} [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=17213089 Review in: Evid Based Med. 2006 Apr;11(2):59] </ref><ref name="pmid16670075">{{cite journal| author=De Stefano V, Simioni P, Rossi E, Tormene D, Za T, Pagnan A et al.| title=The risk of recurrent venous thromboembolism in patients with inherited deficiency of natural anticoagulants antithrombin, protein C and protein S. | journal=Haematologica | year= 2006 | volume= 91 | issue= 5 | pages= 695-8 | pmid=16670075 | doi= | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16670075 }} </ref>
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| * OCPs, hormone replacement therapy, and pregnancy can significantly increase thrombotic risk in patients with thrombophilia.<ref name="pmid18501222">{{cite journal| author=Dalen JE| title=Should patients with venous thromboembolism be screened for thrombophilia? | journal=Am J Med | year= 2008 | volume= 121 | issue= 6 | pages= 458-63 | pmid=18501222 | doi=10.1016/j.amjmed.2007.10.042 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18501222 }} </ref>
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| * Certain high risk thrombophilias require indefinate [[anticoagulant|anticoagulation]].
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| == Diagnosis == | | {| border="1" cellpadding="5" cellspacing="0" align="center" class="sortable" |
| ===Diagnostic Criteria===
| | |- |
| *The diagnosis of an inherited thrombophilia is made with specific [[Thrombophilia_laboratory_findings|laboratory tests]] for each inherited condition.
| | ! Inherited thrombophilia |
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| | ! Healthy subjects/General population (%) |
| === Symptoms ===
| | ! Patients with recurrent thrombosis (%) |
| *Common symptoms of thrombophilias may include the following:
| | |- |
| :*[[Deep venous thrombosis]]
| | | [[Factor V Leiden]] |
| :*[[Pulmonary embolus]]
| | | 1 - 20 |
| :*Superficial venous thrombosis
| | | 18 - 50 |
|
| | |- |
| === Physical Examination ===
| | | [[Prothrombin]] G20210A |
| *Physical examination may be remarkable for:<ref name=?>DeLoughery TG. Hemostasis and Thrombosis: Springer International Publishing; 2014.</ref><ref name="pmid24421360">{{cite journal| author=Cohoon KP, Heit JA| title=Inherited and secondary thrombophilia. | journal=Circulation | year= 2014 | volume= 129 | issue= 2 | pages= 254-7 | pmid=24421360 | doi=10.1161/CIRCULATIONAHA.113.001943 | pmc=3979345 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24421360 }} </ref><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>
| | | 2 - 8 |
| :*Signs of [[Deep_vein_thrombosis_physical_examination|deep venous thrombosis]], [[Pulmonary_embolism_physical_examination|pulmonary thrombosis]], [[Renal_vein_thrombosis|renal vein thrombosis]], [[Cerebral_venous_sinus_thrombosis_physical_examination|cerebral vein thrombosis]], [[Superficial_vein_thrombosis|superficial vein thrombosis]], or arterial thrombosis
| | | 7 - 20 |
| :*[[Portal_hypertension_physical_examination|Portal hypertension]] can be sign of [https://en.wikipedia.org/wiki/Portal_vein_thrombosis| portal vein thrombosis].
| | |- |
| :*[[Warfarin_necrosis|Warfarin skin necrosis]]
| | | [[Antithrombin deficiency]] |
| :*[https://en.wikipedia.org/wiki/Livedo_reticularis Livedo reticularis]
| | | 0.02-2 |
| | | 1 - 5 |
| | |- |
| | | [[Dysfibrinogenemia]] |
| | | <1 |
| | | <1 |
| | |- |
| | | [[Protein C deficiency]] |
| | | 0.2 - 5 |
| | | 3 - 10 |
| | |- |
| | | [[Protein S deficiency]] |
| | | 0.3 - 3 |
| | | 2 - 10 |
| | |- |
| | | [[Hyperhomocystenemia]] |
| | | <5 |
| | | <10 |
| | |- |
| | | Elevated [[factor VIII]] levels |
| | | 11 |
| | | 25 |
| | |- |
| | |} |
|
| |
|
| === Screening ===
| | * In African and Asian patients, the prevalence of factor V leiden was approximately 0.05% and the prevalence of prothrombin G20210A was approximately 0.06%. |
| * The American Society of Hematology recommends against thrombophilia screening in adult patients with venous [[thrombosis]] in the setting of major transient risk factors which include surgery, trauma, or prolonged immobility.<ref name="pmid24319155">{{cite journal| author=Hicks LK, Bering H, Carson KR, Kleinerman J, Kukreti V, Ma A et al.| title=The ASH Choosing Wisely®campaign: five hematologic tests and treatments to question. | journal=Hematology Am Soc Hematol Educ Program | year= 2013 | volume= 2013 | issue= | pages= 9-14 | pmid=24319155 | doi=10.1182/asheducation-2013.1.9 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24319155 }} </ref> | |
| * However, given the [[Thrombophilia_natural_history,_complications_and_prognosis|associated risks]] for recurrent thrombosis, patients who have significant risk factors including a positive family history or concurrent treatment with hormonal therapies should seek expert consultation.
| |
| * Therefore, screening may be useful in the following situations.<ref name="pmid21340752">{{cite journal| author=Middeldorp S| title=Evidence-based approach to thrombophilia testing. | journal=J Thromb Thrombolysis | year= 2011 | volume= 31 | issue= 3 | pages= 275-81 | pmid=21340752 | doi=10.1007/s11239-011-0572-y | pmc=3056012 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=21340752 }} </ref>
| |
| ** '''Asymptomatic screening''': First degree relatives of patients with homozygosity for factor V leiden, antithrombin deficiency, protein C or S deficiency and anticipated hormone therapy or pregnancy.
| |
| ** '''Syptomatic screening''' (patients with acute thrombus) may be useful in patients with certain [[Thrombophilia_history_and_symptoms|clinical presentations]].
| |
| *Screening can be expensive, and are often performed at inappropriate times.
| |
| * Refer to [[Thrombophilia_laboratory_findings|thrombophilia laboratory findings]] for more information on specific screening tests.
| |
|
| |
|
| === Laboratory Findings ===
| | This data were consolidated from multiple sources.<ref name="pmid11309638">{{cite journal |author=Seligsohn U, Lubetsky A|title=Genetic susceptibility to venous thrombosis |journal=N. Engl. J. Med. |volume=344 |issue=16 |pages=1222–31 |year=2001 |month=April |pmid=11309638|doi=10.1056/NEJM200104193441607 |url=}}</ref><ref name="pmid24421360">{{cite journal| author=Cohoon KP, Heit JA| title=Inherited and secondary thrombophilia. | journal=Circulation | year= 2014 | volume= 129 | issue= 2 | pages= 254-7 | pmid=24421360 | doi=10.1161/CIRCULATIONAHA.113.001943 | pmc=3979345 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24421360 }} </ref><ref name="pmid12787534">{{cite journal |author=Buchanan GS, Rodgers GM, Ware Branch D |title=The inherited thrombophilias: genetics, epidemiology, and laboratory evaluation |journal=Best Pract Res Clin Obstet Gynaecol |volume=17 |issue=3 |pages=397–411 |year=2003 |month=June |pmid=12787534 |doi= |url=}}</ref><ref name="pmid11702218">{{cite journal |author=Franco RF, Reitsma PH |title=Genetic risk factors of venous thrombosis |journal=Hum. Genet. |volume=109 |issue=4 |pages=369–84 |year=2001 |month=October |pmid=11702218 |doi=10.1007/s004390100593 |url=}}</ref><ref name="pmid7740487">{{cite journal |author=Haverkate F, Samama M |title=Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC Subcommittee on Fibrinogen |journal=Thromb. Haemost. |volume=73 |issue=1 |pages=151–61 |year=1995 |month=January |pmid=7740487 |doi= |url=}}</ref> |
| * There are specific [[Thrombophilia_laboratory_findings|laboratory findings]] associated with each inherited thrombophilias.<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>
| |
| * Refer to page on [[Thrombophilia_screening|screening]] for recommendations regarding when to pursue thrombophilia testing.
| |
|
| |
| ===Imaging Findings===
| |
| *[[Ultrasound|Ultrasongraphy]], [https://en.wikipedia.org/wiki/Computed_tomography_angiography| computed tomography angiography (CTA or CT Angiography)], [https://en.wikipedia.org/wiki/Magnetic_resonance_angiography| magnetic resonance angiography (MRA or MR Angiography)] and [[Angiogram|projectional angiography]] are used to identify thrombosis, which is associated with the diagnosis of thrombophilia.
| |
|
| |
| == Treatment ==
| |
| === Medical Therapy ===
| |
| *The [[Thrombophilia_medical_therapy|treatment]] for thrombophilia depends on the underlying hypercoagulable state and the clinical presentation<ref name=?>DeLoughery TG. Hemostasis and Thrombosis: Springer International Publishing; 2014.</ref><ref name="pmid24421360">{{cite journal| author=Cohoon KP, Heit JA| title=Inherited and secondary thrombophilia. | journal=Circulation | year= 2014 | volume= 129 | issue= 2 | pages= 254-7 | pmid=24421360 | doi=10.1161/CIRCULATIONAHA.113.001943 | pmc=3979345 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=24421360 }} </ref><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>
| |
| *Treatment should be tailored to the individual patient
| |
| ** The risks and benefits, required monitoring, and costs associated with each form of anticoagulation should be discussed with the patient prior to initiation of therapy
| |
| *The mainstay of therapy for thrombophilia is [[anticoagulation]] with either [[warfarin]], [[Low_molecular_weight_heparin|low molecular weight heparin]], [[Direct_Xa_inhibitor|direct Xa inhibitors]], or [[Direct_thrombin_inhibitor|direct thrombin inhibitors]]<ref name="pmid26780738">{{cite journal| author=Streiff MB, Agnelli G, Connors JM, Crowther M, Eichinger S, Lopes R et al.| title=Guidance for the treatment of deep vein thrombosis and pulmonary embolism. | journal=J Thromb Thrombolysis | year= 2016 | volume= 41 | issue= 1 | pages= 32-67 | pmid=26780738 | doi=10.1007/s11239-015-1317-0 | pmc=4715858 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=26780738 }} </ref><ref name="pmid18805965">{{cite journal| author=Martinelli I, Franchini M, Mannucci PM| title=How I treat rare venous thromboses. | journal=Blood | year= 2008 | volume= 112 | issue= 13 | pages= 4818-23 | pmid=18805965 | doi=10.1182/blood-2008-07-165969 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18805965 }} </ref><ref name="pmid23789890">{{cite journal| author=De Stefano V, Grandone E, Martinelli I| title=Recommendations for prophylaxis of pregnancy-related venous thromboembolism in carriers of inherited thrombophilia. Comment on the 2012 ACCP guidelines. | journal=J Thromb Haemost | year= 2013 | volume= 11 | issue= 9 | pages= 1779-81 | pmid=23789890 | doi=10.1111/jth.12330 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=23789890 }} </ref>
| |
| *All patients on anticoagulation should be monitored for bleeding
| |
|
| |
| === Surgery ===
| |
| *Surgery is not required for treatment for thrombophilia
| |
| *[[IVC_filter|IVC filter]] placement may be indicated in certain scenarios:<ref> Inferior Vena Cava Filters. Medscape (2015). URL Accessed on July 17, 2016</ref>
| |
| **Contraindications to or complications from [[anticoagulation]]
| |
| **Recurrent thrombosis on anticoagulation, or failure to acheive therapeutic anticoagulation levels
| |
|
| |
| === Prevention ===
| |
| *[[Thrombophilia_medical_therapy|Prophylaxis]] may be indicated for thrombophilia in certain scenarios
| |
| *Once diagnosed and successfully treated, patients with thrombophilia are followed-up routinely to monitor anticoagulation and clinically if thrombosis recurrs
| |
|
| |
|
| ==References== | | ==References== |
| {{reflist|2}} | | {{reflist|2}} |
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| |
| {{WH}} | | {{WH}} |
| {{WS}} | | {{WS}} |
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| [[Category:Disease]] | | [[Category:Disease]] |
| [[Category:Hematology]] | | [[Category:Hematology]] |
| [[Category:Primary care]] | | |
| | |
| | [[Category:Needs content]] |