Thrombophilia overview: Difference between revisions
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__NOTOC__ | __NOTOC__ | ||
{{Thrombophilia}} | {{Thrombophilia}} | ||
{{CMG}} | {{CMG}}; {{AE}} {{asiri}}, {{MKA}}, {{S.G.}} | ||
==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 | '''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. | ||
==Historical Perspective== | ==Historical Perspective== | ||
Rudolf Virchow described hypercoagulability in the mid 1800s<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> | 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> | ||
==Classification== | ==Classification== | ||
Thrombophilias | 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. | ||
==Pathophysiology== | ==Pathophysiology== | ||
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'''. | |||
==Causes== | ==Causes== | ||
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> | |||
==Differentiating Thrombophilia from other Diseases== | |||
==Differentiating | Thrombophilias must be differentiated from other diseases that cause the following clinical presentations: family history of [[thrombosis]], especially at an early age (< 45 years), unprovoked [[thrombosis]] at an early age (<40-55 for [[Venous thromboembolism|venous thrombosis]] and <50-55 for [[arterial thrombosis]]), recurrent [[thrombosis]] including [[deep venous thrombosis]], [[pulmonary embolism]], or [[superficial venous thrombosis]]. | ||
==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> | |||
===Age=== | ===Age=== | ||
Patients of all age groups may develop thrombophilias. Acquired thrombophilias are more commonly observed among elderly patients (age > 60) as age is a risk factor for thrombosis. Inherited thrombophilias can be seen among young patients aged <40-55 years old. | |||
===Gender=== | ===Gender=== | ||
Epidemiologic studies have provided mixed results regarding the effect of gender on venous thrombosis. Certain groups observed increased risk of thrombosis in younger females and older males, whereas other groups found similar frequencies in both genders.<ref name="pmid12814979">{{cite journal| author=White RH| title=The epidemiology of venous thromboembolism. | journal=Circulation | year= 2003 | volume= 107 | issue= 23 Suppl 1 | pages= I4-8 | pmid=12814979 | doi=10.1161/01.CIR.0000078468.11849.66 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=12814979 }} </ref> A prospective follow up study performed by Christiansen et al, revealed an age corrected hazard ratio of 2.7 of recurrent thrombosis in male patients with inherited thrombophilias compared to women.<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> In patients with inherited thrombophilias, a prospective follow up study performed by Christiansen et al revealed an age corrected hazard ratio of 2.7 for recurrent thrombosis in male patients compared to women.<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> | |||
===Race=== | ===Race=== | ||
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> | |||
==Risk Factors== | ==Risk Factors== | ||
The most common risk factors in the development of acquired thrombophlias are [[trauma]], [[surgery]], [[immobility]], pregnancy, [[oral contraceptives]], [[hormone replacement therapy]], and age. Common risk factors for the development of inherited thrombophilias are a family history of [[thrombosis]] at an early age or a family history of inherited thrombophilia. Common genetic risk factors in the development of inherited thrombophilias are mutations in [[Factor_V_Leiden|Factor V Leiden]] and [[prothrombin]] G20210A. | |||
== Natural History, Complications and Prognosis== | == Natural History, Complications and Prognosis== | ||
The 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> 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]) is low (<0.06%) .<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> 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> 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> 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> Certain high risk thrombophilias require indefinate [[anticoagulant|anticoagulation]]. | |||
== Diagnosis == | == Diagnosis == | ||
===Diagnostic Criteria=== | ===Diagnostic Criteria=== | ||
The diagnosis of an inherited thrombophilia is made with specific [[Thrombophilia_laboratory_findings|laboratory tests]] for each inherited condition. | |||
=== Symptoms === | === Symptoms === | ||
Common symptoms of thrombophilias may include symptoms of [[Deep venous thrombosis]], [[Pulmonary embolus]], and superficial venous thrombosis. | |||
=== Physical Examination === | === Physical Examination === | ||
Physical examination of patients with thrombophilia is usually remarkable for 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]], arterial thrombosis, [[Portal_hypertension_physical_examination|portal hypertension]] which can be sign of [https://en.wikipedia.org/wiki/Portal_vein_thrombosis| portal vein thrombosis], [[Warfarin_necrosis|warfarin skin necrosis]], or [https://en.wikipedia.org/wiki/Livedo_reticularis livedo reticularis].<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> | |||
=== Screening === | |||
According to the American Society of Hematology, screening for inherited thrombophilias in adult patients with venous [[thrombosis]] in the setting of major transient risk factors which include surgery, trauma, or prolonged immobility is not recommended.<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. | |||
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=== Laboratory Findings === | === Laboratory Findings === | ||
Laboratory findings consistent with the diagnosis of inherited thrombophilias include specific [[Thrombophilia_laboratory_findings|laboratory findings]] associated with each inherited thrombophilia.<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> | |||
===Imaging Findings=== | ===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]] may be diagnostic of acute thrombosis, which is associated with the diagnosis of thrombophilia. | |||
== Treatment == | == Treatment == | ||
=== Medical Therapy === | === 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> 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> 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. All patients on anticoagulation should be monitored for bleeding. | |||
=== Surgery === | === Surgery === | ||
Surgery is not required for treatment for thrombophilia. [[IVC_filter|IVC filter]] placement may be indicated if the patient has contraindications to or complications from [[anticoagulation]], recurrent thrombosis on anticoagulation, or failure to acheive therapeutic anticoagulation levels.<ref>Inferior Vena Cava Filters. Medscape (2015). URL Accessed on July 17, 2016</ref> | |||
=== Prevention === | === Prevention === | ||
[[Thrombophilia_medical_therapy|Prophylaxis]] with [[anticoagulation]] may be recommended for primary prevention of acute thrombosis in [[Thrombophilia_medical_therapy|certain scenarios]]. Once diagnosed and successfully treated, patients with thrombophilia are followed-up routinely to monitor anticoagulation and clinically if thrombosis recurrs | |||
==References== | ==References== | ||
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[[Category:Disease]] | [[Category:Disease]] | ||
[[Category:Hematology]] | [[Category:Hematology]] | ||
Latest revision as of 08:28, 7 March 2021
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Thrombophilia Microchapters |
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Diagnosis |
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Treatment |
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Case Studies |
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Thrombophilia overview On the Web |
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American Roentgen Ray Society Images of Thrombophilia overview |
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Risk calculators and risk factors for Thrombophilia overview |
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Asiri Ediriwickrema, M.D., M.H.S. [2], M. Khurram Afzal, MD [3], Sogand Goudarzi, MD [4]
Overview
Thrombophilia is a complex condition which increases the risk of thrombosis or thromboembolic disease. The predisposition to 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, 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.[1] Thrombophilia screening is controversial, but may aid in managing the initiation and duration of anticoagulation in affected patients and primary prevention in relatives.
Historical Perspective
Rudolf Virchow described hypercoagulability in the mid 1800s, however, it was not until 1965 that the first descriptions of inherited thrombophilia were published.[2][3][4] Later, in the 1990s, the more common mutations associated with primary hypercoagulable states were identified.[5][6]
Classification
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.
Pathophysiology
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.[7] The most common genes involved in the pathogenesis of acquired thrombophilias are Factor V Leiden and prothrombin gene mutations.
Causes
Thrombophilia may be caused by either 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).[7][8]
Differentiating Thrombophilia from other Diseases
Thrombophilias must be differentiated from other diseases that cause the following clinical presentations: family history of thrombosis, especially at an early age (< 45 years), unprovoked thrombosis at an early age (<40-55 for venous thrombosis and <50-55 for arterial thrombosis), recurrent thrombosis including deep venous thrombosis, pulmonary embolism, or superficial venous thrombosis.
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.[9][7] 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.[10][11][12] The incidence of inherited thrombophilia in incident venous thrombosis is approximately 150-840 per 100,000 person years.[8] The incidence of inherited thrombophilia in recurrent venous thrombosis is approximately 3,500-10,500 per 100,000 person-years.[8]
Age
Patients of all age groups may develop thrombophilias. Acquired thrombophilias are more commonly observed among elderly patients (age > 60) as age is a risk factor for thrombosis. Inherited thrombophilias can be seen among young patients aged <40-55 years old.
Gender
Epidemiologic studies have provided mixed results regarding the effect of gender on venous thrombosis. Certain groups observed increased risk of thrombosis in younger females and older males, whereas other groups found similar frequencies in both genders.[13] A prospective follow up study performed by Christiansen et al, revealed an age corrected hazard ratio of 2.7 of recurrent thrombosis in male patients with inherited thrombophilias compared to women.[14] In patients with inherited thrombophilias, a prospective follow up study performed by Christiansen et al revealed an age corrected hazard ratio of 2.7 for recurrent thrombosis in male patients compared to women.[14]
Race
The factor V leiden G1691A and prothrombin G20210A mutations are exceedingly rare in non-white populations.[7]
Risk Factors
The most common risk factors in the development of acquired thrombophlias are trauma, surgery, immobility, pregnancy, oral contraceptives, hormone replacement therapy, and age. Common risk factors for the development of inherited thrombophilias are a family history of thrombosis at an early age or a family history of inherited thrombophilia. Common genetic risk factors in the development of inherited thrombophilias are mutations in Factor V Leiden and prothrombin G20210A.
Natural History, Complications and Prognosis
The annual thrombotic risks are variable and depend on the underlying thrombophilia.[15] If left untreated, the annual incidence of incident thrombosis in asymptomatic patients with Factor V Leiden and (Prothrombin G20210A) is low (<0.06%) .[16] The risk is approximately equivalent to treatment with oral contraceptives (OCPs). Whereas the annual incidence of significant bleeds is approximately 2-3%.[17] 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.[14][18] Christiansen et al and De Stefano et al observed a mild increased risk for recurrent thrombosis in patients with protein C, protein S, and antithrombin deficiency.[14][19] OCPs, hormone replacement therapy, and pregnancy can significantly increase thrombotic risk in patients with thrombophilia.[20] Certain high risk thrombophilias require indefinate anticoagulation.
Diagnosis
Diagnostic Criteria
The diagnosis of an inherited thrombophilia is made with specific laboratory tests for each inherited condition.
Symptoms
Common symptoms of thrombophilias may include symptoms of Deep venous thrombosis, Pulmonary embolus, and superficial venous thrombosis.
Physical Examination
Physical examination of patients with thrombophilia is usually remarkable for signs of deep venous thrombosis, pulmonary thrombosis, renal vein thrombosis, cerebral vein thrombosis, superficial vein thrombosis, arterial thrombosis, portal hypertension which can be sign of portal vein thrombosis, warfarin skin necrosis, or livedo reticularis.[1][8][7]
Screening
According to the American Society of Hematology, screening for inherited thrombophilias in adult patients with venous thrombosis in the setting of major transient risk factors which include surgery, trauma, or prolonged immobility is not recommended.[21] However, given the 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.
Laboratory Findings
Laboratory findings consistent with the diagnosis of inherited thrombophilias include specific laboratory findings associated with each inherited thrombophilia.[7]
Imaging Findings
Ultrasongraphy, computed tomography angiography (CTA or CT Angiography), magnetic resonance angiography (MRA or MR Angiography) and projectional angiography may be diagnostic of acute thrombosis, which is associated with the diagnosis of thrombophilia.
Treatment
Medical Therapy
The treatment for thrombophilia depends on the underlying hypercoagulable state and the clinical presentation.[1][8][7] The mainstay of therapy for thrombophilia is anticoagulation with either warfarin, low molecular weight heparin, direct Xa inhibitors, or direct thrombin inhibitors.[22][23][24] 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. All patients on anticoagulation should be monitored for bleeding.
Surgery
Surgery is not required for treatment for thrombophilia. IVC filter placement may be indicated if the patient has contraindications to or complications from anticoagulation, recurrent thrombosis on anticoagulation, or failure to acheive therapeutic anticoagulation levels.[25]
Prevention
Prophylaxis with anticoagulation may be recommended for primary prevention of acute thrombosis in certain scenarios. Once diagnosed and successfully treated, patients with thrombophilia are followed-up routinely to monitor anticoagulation and clinically if thrombosis recurrs
References
- ↑ 1.0 1.1 1.2 DeLoughery TG. Hemostasis and Thrombosis. Springer; 2014.
- ↑ Schafer AI (1994). "Hypercoagulable states: molecular genetics to clinical practice". Lancet. 344 (8939–8940): 1739–42. PMID 7997003.
- ↑ EGEBERG O (1965). "INHERITED ANTITHROMBIN DEFICIENCY CAUSING THROMBOPHILIA". Thromb Diath Haemorrh. 13: 516–30. PMID 14347873.
- ↑ Beck EA, Charache P, Jackson DP (1965). "A new inherited coagulation disorder caused by an abnormal fibrinogen ('fibrinogen Baltimore')". Nature. 208 (5006): 143–5. PMID 4956920.
- ↑ Bertina RM, Koeleman BP, Koster T, Rosendaal FR, Dirven RJ, de Ronde H; et al. (1994). "Mutation in blood coagulation factor V associated with resistance to activated protein C." Nature. 369 (6475): 64–7. doi:10.1038/369064a0. PMID 8164741.
- ↑ 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.
- ↑ 7.0 7.1 7.2 7.3 7.4 7.5 7.6 Seligsohn U, Lubetsky A (2001). "Genetic susceptibility to venous thrombosis". N Engl J Med. 344 (16): 1222–31. doi:10.1056/NEJM200104193441607. PMID 11309638.
- ↑ 8.0 8.1 8.2 8.3 8.4 Cohoon KP, Heit JA (2014). "Inherited and secondary thrombophilia". Circulation. 129 (2): 254–7. doi:10.1161/CIRCULATIONAHA.113.001943. PMC 3979345. PMID 24421360.
- ↑ Stevens SM, Woller SC, Bauer KA, Kasthuri R, Cushman M, Streiff M; et al. (2016). "Guidance for the evaluation and treatment of hereditary and acquired thrombophilia". J Thromb Thrombolysis. 41 (1): 154–64. doi:10.1007/s11239-015-1316-1. PMC 4715840. PMID 26780744.
- ↑ Margaglione M, Brancaccio V, Giuliani N, D'Andrea G, Cappucci G, Iannaccone L; et al. (1998). "Increased risk for venous thrombosis in carriers of the prothrombin G-->A20210 gene variant". Ann Intern Med. 129 (2): 89–93. PMID 9669991.
- ↑ Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP (1995). "Mutation in the gene coding for coagulation factor V and the risk of myocardial infarction, stroke, and venous thrombosis in apparently healthy men". N Engl J Med. 332 (14): 912–7. doi:10.1056/NEJM199504063321403. PMID 7877648.
- ↑ Koster T, Rosendaal FR, de Ronde H, Briët E, Vandenbroucke JP, Bertina RM (1993). "Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study". Lancet. 342 (8886–8887): 1503–6. PMID 7902898.
- ↑ White RH (2003). "The epidemiology of venous thromboembolism". Circulation. 107 (23 Suppl 1): I4–8. doi:10.1161/01.CIR.0000078468.11849.66. PMID 12814979.
- ↑ 14.0 14.1 14.2 14.3 Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR (2005). "Thrombophilia, clinical factors, and recurrent venous thrombotic events". JAMA. 293 (19): 2352–61. doi:10.1001/jama.293.19.2352. PMID 15900005. Review in: Evid Based Med. 2006 Apr;11(2):59
- ↑ Bauer KA (2001). "The thrombophilias: well-defined risk factors with uncertain therapeutic implications". Ann Intern Med. 135 (5): 367–73. PMID 11529700.
- ↑ Bates SM, Ginsberg JS (2004). "Clinical practice. Treatment of deep-vein thrombosis". N Engl J Med. 351 (3): 268–77. doi:10.1056/NEJMcp031676. PMID 15254285.
- ↑ Linkins LA, Choi PT, Douketis JD (2003). "Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis". Ann Intern Med. 139 (11): 893–900. PMID 14644891.
- ↑ Baglin T, Luddington R, Brown K, Baglin C (2003). "Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study". Lancet. 362 (9383): 523–6. doi:10.1016/S0140-6736(03)14111-6. PMID 12932383.
- ↑ De Stefano V, Simioni P, Rossi E, Tormene D, Za T, Pagnan A; et al. (2006). "The risk of recurrent venous thromboembolism in patients with inherited deficiency of natural anticoagulants antithrombin, protein C and protein S." Haematologica. 91 (5): 695–8. PMID 16670075.
- ↑ Dalen JE (2008). "Should patients with venous thromboembolism be screened for thrombophilia?". Am J Med. 121 (6): 458–63. doi:10.1016/j.amjmed.2007.10.042. PMID 18501222.
- ↑ Hicks LK, Bering H, Carson KR, Kleinerman J, Kukreti V, Ma A; et al. (2013). "The ASH Choosing Wisely®campaign: five hematologic tests and treatments to question". Hematology Am Soc Hematol Educ Program. 2013: 9–14. doi:10.1182/asheducation-2013.1.9. PMID 24319155.
- ↑ Streiff MB, Agnelli G, Connors JM, Crowther M, Eichinger S, Lopes R; et al. (2016). "Guidance for the treatment of deep vein thrombosis and pulmonary embolism". J Thromb Thrombolysis. 41 (1): 32–67. doi:10.1007/s11239-015-1317-0. PMC 4715858. PMID 26780738.
- ↑ Martinelli I, Franchini M, Mannucci PM (2008). "How I treat rare venous thromboses". Blood. 112 (13): 4818–23. doi:10.1182/blood-2008-07-165969. PMID 18805965.
- ↑ De Stefano V, Grandone E, Martinelli I (2013). "Recommendations for prophylaxis of pregnancy-related venous thromboembolism in carriers of inherited thrombophilia. Comment on the 2012 ACCP guidelines". J Thromb Haemost. 11 (9): 1779–81. doi:10.1111/jth.12330. PMID 23789890.
- ↑ Inferior Vena Cava Filters. Medscape (2015). URL Accessed on July 17, 2016