Evolving Knowledge on Primary and Secondary Prevention of Venous Thromboembolism in Carriers of Hereditary Thrombophilia: A Narrative Review

Abstract

The association between heritability of venous thromboembolism (VTE) and thrombophilia was first reported clinically in 1956, later followed by the first description of a congenital cause of hypercoagulability—antithrombin deficiency—in 1965. Since then, our knowledge of hereditary causes of hypercoagulability, which may predispose carriers to VTE has improved greatly. Novel genetic defects responsible for severe thrombophilia have been recently identified and we have learned that a wide range of interactions between thrombophilia and other genetic and acquired risk factors are important determinants of the overall individual risk of developing VTE. Furthermore, therapeutic strategies in thrombophilic patients have benefited significantly from the introduction of direct oral anticoagulants. The present review is an overview of the current knowledge on the mechanisms underlying inherited thrombophilia, with a particular focus on the latest achievements in anticoagulation protocols and prevention strategies for thrombosis in carriers of this prothrombotic condition.

Keywords

thrombophilia - hypercoagulability - venous thrombosis - heparin - direct oral anticoagulants

Publication History

Article published online:
02 September 2022

• References

• 1 Bagot CN, Arya R. Virchow and his triad: a question of attribution. Br J Haematol 2008; 143 (02) 180-190
• 2 Simioni P, Tormene D, Spiezia L. et al. Inherited thrombophilia and venous thromboembolism. Semin Thromb Hemost 2006; 32 (07) 700-708
• 3 Martinelli I, De Stefano V, Mannucci PM. Inherited risk factors for venous thromboembolism. Nat Rev Cardiol 2014; 11 (03) 140-156
• 4 Campello E, Spiezia L, Adamo A, Simioni P. Thrombophilia, risk factors and prevention. Expert Rev Hematol 2019; 12 (03) 147-158
• 5 Jordan FL, Nandorff A. The familial tendency in thrombo-embolic disease. Acta Med Scand 1956; 156 (04) 267-275
• 6 Egeberg O. Inherited antithrombin deficiency causing thrombophilia. Thromb Diath Haemorrh 1965; 13: 516-530
• 7 Griffin JH, Evatt B, Zimmerman TS, Kleiss AJ, Wideman C. Deficiency of protein C in congenital thrombotic disease. J Clin Invest 1981; 68 (05) 1370-1373
• 8 Comp PC, Esmon CT. Recurrent venous thromboembolism in patients with a partial deficiency of protein S. N Engl J Med 1984; 311 (24) 1525-1528
• 9 Schwarz HP, Fischer M, Hopmeier P, Batard MA, Griffin JH. Plasma protein S deficiency in familial thrombotic disease. Blood 1984; 64 (06) 1297-1300
• 10 Dahlbäck B, Carlsson M, Svensson PJ. Familial thrombophilia due to a previously unrecognized mechanism characterized by poor anticoagulant response to activated protein C: prediction of a cofactor to activated protein C. Proc Natl Acad Sci U S A 1993; 90 (03) 1004-1008
• 11 Bertina RM, Koeleman BP, Koster T. et al. Mutation in blood coagulation factor V associated with resistance to activated protein C. Nature 1994; 369 (6475): 64-67
• 12 Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. 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 1996; 88 (10) 3698-3703
• 13 Simioni P, Tormene D, Tognin G. et al. X-linked thrombophilia with a mutant factor IX (factor IX Padua). N Engl J Med 2009; 361 (17) 1671-1675
• 14 Takagi Y, Murata M, Kozuka T. et al. Missense mutations in the gene encoding prothrombin corresponding to Arg596 cause antithrombin resistance and thrombomodulin resistance. Thromb Haemost 2016; 116 (06) 1022-1031
• 15 Simioni P, Cagnin S, Sartorello F. et al. Partial F8 gene duplication (factor VIII Padua) associated with high factor VIII levels and familial thrombophilia. Blood 2021; 137 (17) 2383-2393
• 16 Campello E, Spiezia L, Simion C. et al. Direct oral anticoagulants in patients with inherited thrombophilia and venous thromboembolism: a prospective cohort study. J Am Heart Assoc 2020; 9 (23) e018917
• 17 Tait RC, Walker ID, Perry DJ. et al. Prevalence of antithrombin deficiency in the healthy population. Br J Haematol 1994; 87 (01) 106-112
• 18 MacCallum P, Bowles L, Keeling D. Diagnosis and management of heritable thrombophilias. BMJ 2014; 349: g4387
• 19 Bauer KA, Nguyen-Cao TM, Spears JB. Issues in the diagnosis and management of hereditary antithrombin deficiency. Ann Pharmacother 2016; 50 (09) 758-767
• 20 Middeldorp S. Evidence-based approach to thrombophilia testing. J Thromb Thrombolysis 2011; 31 (03) 275-281
• 21 Di Minno MN, Ambrosino P, Ageno W, Rosendaal F, Di Minno G, Dentali F. Natural anticoagulants deficiency and the risk of venous thromboembolism: a meta-analysis of observational studies. Thromb Res 2015; 135 (05) 923-932
• 22 Walker ID. Congenital thrombophilia. Baillieres Clin Obstet Gynaecol 1997; 11 (03) 431-445
• 23 Rhéaume M, Weber F, Durand M, Mahone M. Pregnancy-related venous thromboembolism risk in asymptomatic women with antithrombin deficiency: a systematic review. Obstet Gynecol 2016; 127 (04) 649-656
• 24 Miletich J, Sherman L, Broze Jr G. Absence of thrombosis in subjects with heterozygous protein C deficiency. N Engl J Med 1987; 317 (16) 991-996
• 25 De Stefano V, Finazzi G, Mannucci PM. Inherited thrombophilia: pathogenesis, clinical syndromes, and management. Blood 1996; 87 (09) 3531-3544
• 26 Tait RC, Walker ID, Reitsma PH. et al. Prevalence of protein C deficiency in the healthy population. Thromb Haemost 1995; 73 (01) 87-93
• 27 Martinelli I, Mannucci PM, De Stefano V. et al. Different risks of thrombosis in four coagulation defects associated with inherited thrombophilia: a study of 150 families. Blood 1998; 92 (07) 2353-2358
• 28 Koster T, Rosendaal FR, Briët E. et al. Protein C deficiency in a controlled series of unselected outpatients: an infrequent but clear risk factor for venous thrombosis (Leiden Thrombophilia Study). Blood 1995; 85 (10) 2756-2761
• 29 Mannucci PM, Franchini M. The real value of thrombophilia markers in identifying patients at high risk of venous thromboembolism. Expert Rev Hematol 2014; 7 (06) 757-765
• 30 Sanson BJ, Simioni P, Tormene D. et al. The incidence of venous thromboembolism in asymptomatic carriers of a deficiency of antithrombin, protein C, or protein S: a prospective cohort study. Blood 1999; 94 (11) 3702-3706
• 31 Simioni P, Sanson BJ, Prandoni P. et al. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost 1999; 81 (02) 198-202
• 32 Zöller B, García de Frutos P, Dahlbäck B. Evaluation of the relationship between protein S and C4b-binding protein isoforms in hereditary protein S deficiency demonstrating type I and type III deficiencies to be phenotypic variants of the same genetic disease. Blood 1995; 85 (12) 3524-3531
• 33 Simioni P, Tormene D, Manfrin D. et al. Prothrombin antigen levels in symptomatic and asymptomatic carriers of the 20210A prothrombin variant. Br J Haematol 1998; 103 (04) 1045-1050
• 34 Campello E, Spiezia L, Simioni P. Diagnosis and management of factor V Leiden. Expert Rev Hematol 2016; 9 (12) 1139-1149
• 35 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346 (8983): 1133-1134
• 36 Awidi A, Shannak M, Bseiso A. et al. High prevalence of factor V Leiden in healthy Jordanian Arabs. Thromb Haemost 1999; 81 (04) 582-584
• 37 Van Cott EM, Khor B, Zehnder JL. Factor V Leiden. Am J Hematol 2016; 91 (01) 46-49
• 38 Simone B, De Stefano V, Leoncini E. et al. Risk of venous thromboembolism associated with single and combined effects of Factor V Leiden, Prothrombin 20210A and Methylenetethraydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls. Eur J Epidemiol 2013; 28 (08) 621-647
• 39 Rosendaal FR, Koster T, Vandenbroucke JP, Reitsma PH. High risk of thrombosis in patients homozygous for factor V Leiden (activated protein C resistance). Blood 1995; 85 (06) 1504-1508
• 40 Rosendaal FR, Doggen CJ, Zivelin A. et al. Geographic distribution of the 20210 G to A prothrombin variant. Thromb Haemost 1998; 79 (04) 706-708
• 41 Margaglione M, Brancaccio V, Giuliani N. et al. Increased risk for venous thrombosis in carriers of the prothrombin G–>A20210 gene variant. Ann Intern Med 1998; 129 (02) 89-93
• 42 Leroyer C, Mercier B, Oger E. et al. Prevalence of 20210 A allele of the prothrombin gene in venous thromboembolism patients. Thromb Haemost 1998; 80 (01) 49-51
• 43 Shemesh A, Hoffman R, Nadir Y. et al. Clinical significance of prothrombin G20210A mutation in homozygous patients. Am J Hematol 2017; 92 (10) E618-E620
• 44 Martinelli I, Bucciarelli P, Margaglione M, De Stefano V, Castaman G, Mannucci PM. The risk of venous thromboembolism in family members with mutations in the genes of factor V or prothrombin or both. Br J Haematol 2000; 111 (04) 1223-1229
• 45 Emmerich J, Rosendaal FR, Cattaneo M. et al; Study Group for Pooled-Analysis in Venous Thromboembolism. Combined effect of factor V Leiden and prothrombin 20210A on the risk of venous thromboembolism—pooled analysis of 8 case-control studies including 2310 cases and 3204 controls. Thromb Haemost 2001; 86 (03) 809-816
• 46 Manderstedt E, Lind-Halldén C, Halldén C. et al; Regeneron Genetics Center 4 [Link]. Classic thrombophilias and thrombotic risk among middle-aged and older adults: a population-based cohort study. J Am Heart Assoc 2022; 11 (04) e023018
• 47 Wu W, Xiao L, Wu X. et al. Factor IX alteration p.Arg338Gln (FIX Shanghai) potentiates FIX clotting activity and causes thrombosis. Haematologica 2021; 106 (01) 264-268
• 48 Djordjevic V, Kovac M, Miljic P. et al. A novel prothrombin mutation in two families with prominent thrombophilia—the first cases of antithrombin resistance in a Caucasian population. J Thromb Haemost 2013; 11 (10) 1936-1939
• 49 Sivasundar S, Oommen AT, Prakash O. et al. Molecular defect of ‘Prothrombin Amrita’: substitution of arginine by glutamine (Arg553 to Gln) near the Na(+) binding loop of prothrombin. Blood Cells Mol Dis 2013; 50 (03) 182-183
• 50 Bulato C, Radu CM, Campello E. et al. New prothrombin mutation (Arg596Trp, Prothrombin Padua 2) associated with venous thromboembolism. Arterioscler Thromb Vasc Biol 2016; 36 (05) 1022-1029
• 51 Rosendaal FR. Venous thrombosis: a multicausal disease. Lancet 1999; 353 (9159): 1167-1173
• 52 Koeleman BP, Reitsma PH, Bertina RM. Familial thrombophilia: a complex genetic disorder. Semin Hematol 1997; 34 (03) 256-264
• 53 Tormene D, Campello E, Simion C. et al. Incidence of VTE in asymptomatic children with deficiencies of antithrombin, protein C, and protein S: a prospective cohort study. Blood Adv 2020; 4 (21) 5442-5448
• 54 Tormene D, Noventa F, Campello E. et al. The risk of arterial thrombosis in carriers of natural coagulation inhibitors: a prospective family cohort study. Intern Emerg Med 2021; 16 (04) 997-1003
• 55 Visseren FLJ, Mach F, Smulders YM. et al; ESC Scientific Document Group. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur J Prev Cardiol 2022; 29 (01) 5-115
• 56 Caprini JA. Thrombosis risk assessment as a guide to quality patient care. Dis Mon 2005; 51 (2-3): 70-78
• 57 Gould MK, Garcia DA, Wren SM. et al. Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl. 02) e227S-e277S
• 58 Patnaik MM, Moll S. Inherited antithrombin deficiency: a review. Haemophilia 2008; 14 (06) 1229-1239
• 59 Anderson DR, Morgano GP, Bennett C. et al. American Society of Hematology 2019 guidelines for management of venous thromboembolism: prevention of venous thromboembolism in surgical hospitalized patients. Blood Adv 2019; 3 (23) 3898-3944
• 60 Heit JA. Venous thromboembolism epidemiology: implications for prevention and management. Semin Thromb Hemost 2002; 28 (Suppl. 02) 3-13
• 61 Schünemann HJ, Cushman M, Burnett AE. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients. Blood Adv 2018; 2 (22) 3198-3225
• 62 Stuck AK, Spirk D, Schaudt J, Kucher N. Risk assessment models for venous thromboembolism in acutely ill medical patients. A systematic review. Thromb Haemost 2017; 117 (04) 801-808
• 63 Barbar S, Noventa F, Rossetto V. et al. A risk assessment model for the identification of hospitalized medical patients at risk for venous thromboembolism: the Padua Prediction Score. J Thromb Haemost 2010; 8 (11) 2450-2457
• 64 Spyropoulos AC, Anderson Jr FA, FitzGerald G. et al; IMPROVE Investigators. Predictive and associative models to identify hospitalized medical patients at risk for VTE. Chest 2011; 140 (03) 706-714
• 65 Kahn SR, Lim W, Dunn AS. et al. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl. 02) e195S-e226S
• 66 Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008; 111 (10) 4902-4907
• 67 Mosaad M, Elnaem MH, Cheema E. et al. Cancer-associated thrombosis: a clinical scoping review of the risk assessment models across solid tumours and haematological malignancies. Int J Gen Med 2021; 14: 3881-3897
• 68 Carrier M, Abou-Nassar K, Mallick R. et al; AVERT Investigators. Apixaban to prevent venous thromboembolism in patients with cancer. N Engl J Med 2019; 380 (08) 711-719
• 69 Khorana AA, Soff GA, Kakkar AK. et al. CASSINI Investigators. Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer. N Engl J Med 2019; 380 (08) 720-728
• 70 Prandoni P, Campello E. Venous thromboembolism in cancer patients undergoing chemotherapy: risk factors and prevention. Semin Thromb Hemost 2021; 47 (08) 914-919
• 71 Robertson L, Wu O, Langhorne P. et al; Thrombosis: Risk and Economic Assessment of Thrombophilia Screening (TREATS) Study. Thrombophilia in pregnancy: a systematic review. Br J Haematol 2006; 132 (02) 171-196
• 72 Bates SM, Middeldorp S, Rodger M, James AH, Greer I. Guidance for the treatment and prevention of obstetric-associated venous thromboembolism. J Thromb Thrombolysis 2016; 41 (01) 92-128
• 73 Greer IA, Nelson-Piercy C. Low-molecular-weight heparins for thromboprophylaxis and treatment of venous thromboembolism in pregnancy: a systematic review of safety and efficacy. Blood 2005; 106 (02) 401-407
• 74 Bates SM, Greer IA, Middeldorp S, Veenstra DL, Prabulos AM, Vandvik PO. VTE, thrombophilia, antithrombotic therapy, and pregnancy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl. 02) e691S-e736S
• 75 Royal College of Obstetricians and Gynaecologists. Green-top Guideline No. 37a. Reducing the risk of thrombosis and embolism during pregnancy and the puerperium. . Accessed at: https://wwwrcogorguk/en/guidelines-researchservices/guidelines/gtg37a 2015
• 76 Bates SM, Rajasekhar A, Middeldorp S. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv 2018; 2 (22) 3317-3359
• 77 Pacheco LD, Saade G, Metz TD. Society for Maternal-Fetal Medicine (SMFM). Electronic address: [e-mail]. Society for Maternal-Fetal Medicine Consult Series #51: Thromboembolism prophylaxis for cesarean delivery. Am J Obstet Gynecol 2020; 223 (02) B11-B17
• 78 Kotaska A. Postpartum venous thromboembolism prophylaxis may cause more harm than benefit: a critical analysis of international guidelines through an evidence-based lens. BJOG 2018; 125 (09) 1109-1116
• 79 Kearon C, Akl EA, Ornelas J. et al. Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 2016; 149 (02) 315-352
• 80 Schulman S, Tengborn L. Treatment of venous thromboembolism in patients with congenital deficiency of antithrombin III. Thromb Haemost 1992; 68 (06) 634-636
• 81 Liumbruno G, Bennardello F, Lattanzio A, Piccoli P, Rossetti G. Italian Society of Transfusion Medicine and Immunohaematology (SIMTI) Working Party. Recommendations for the use of antithrombin concentrates and prothrombin complex concentrates. Blood Transfus 2009; 7 (04) 325-334
• 82 Marlar RA, Montgomery RR, Broekmans AW. Diagnosis and treatment of homozygous protein C deficiency. Report of the working party on homozygous protein C deficiency of the subcommittee on protein C and protein S, International Committee on Thrombosis and Haemostasis. J Pediatr 1989; 114 (4 Pt 1): 528-534
• 83 De Stefano V, Mastrangelo S, Schwarz HP. et al. Replacement therapy with a purified protein C concentrate during initiation of oral anticoagulation in severe protein C congenital deficiency. Thromb Haemost 1993; 70 (02) 247-249
• 84 Skelley JW, White CW, Thomason AR. The use of direct oral anticoagulants in inherited thrombophilia. J Thromb Thrombolysis 2017; 43 (01) 24-30
• 85 Goldhaber SZ, Eriksson H, Kakkar A. et al. Efficacy of dabigatran versus warfarin in patients with acute venous thromboembolism in the presence of thrombophilia: findings from RE-COVER®, RE-COVER™ II, and RE-MEDY™. Vasc Med 2016; 21 (06) 506-514
• 86 Bertoletti L, Benhamou Y, Béjot Y. et al. Direct oral anticoagulant use in patients with thrombophilia, antiphospholipid syndrome or venous thrombosis of unusual sites: a narrative review. Blood Rev 2018; 32 (04) 272-279
• 87 Boey JP, Jolley A, Nicholls C. et al. Novel protein C gene mutation in a compound heterozygote resulting in catastrophic thrombosis in early adulthood: diagnosis and long-term treatment with subcutaneous protein C concentrate. Br J Haematol 2016; 172 (05) 811-813
• 88 Undas A, Goralczyk T. Non-vitamin K antagonist oral anticoagulants in patients with severe inherited thrombophilia: a series of 33 patients. Blood Coagul Fibrinolysis 2017; 28 (06) 438-442
• 89 Wypasek E, Potaczek DP, Alhenc-Gelas M, Undas A. PROS1 mutations associated with protein S deficiency in Polish patients with residual vein obstruction on rivaroxaban therapy. Thromb Res 2014; 134 (01) 199-201
• 90 Elsebaie MAT, van Es N, Langston A, Büller HR, Gaddh M. Direct oral anticoagulants in patients with venous thromboembolism and thrombophilia: a systematic review and meta-analysis. J Thromb Haemost 2019; 17 (04) 645-656
• 91 Martinelli I, Lensing AW, Middeldorp S. et al. Recurrent venous thromboembolism and abnormal uterine bleeding with anticoagulant and hormone therapy use. Blood 2016; 127 (11) 1417-1425
• 92 Brekelmans MP, Scheres LJ, Bleker SM. et al. Abnormal vaginal bleeding in women with venous thromboembolism treated with apixaban or warfarin. Thromb Haemost 2017; 117 (04) 809-815
• 93 Beyer-Westendorf J, Michalski F, Tittl L, Hauswald-Dorschel S, Marten S. Management and outcomes of vaginal bleeding and heavy menstrual bleeding in women of reproductive age on direct oral anti-factor Xa inhibitor therapy: a case series. Lancet Haematol 2016; 3 (10) e480-e488
• 94 Ferreira M, Barsam S, Patel JP. et al. Heavy menstrual bleeding on rivaroxaban. Br J Haematol 2016; 173 (02) 314-315
• 95 Huisman MV, Ferreira M, Feuring M, Fraessdorf M, Klok FA. Less abnormal uterine bleeding with dabigatran than warfarin in women treated for acute venous thromboembolism. J Thromb Haemost 2018; 16 (09) 1775-1778
• 96 DeCamillo D, Ellsworth S, Kaatz S, Barnes GD. Use of apixaban and rivaroxaban in young adults with acute venous thromboembolism: a multi-center retrospective case series. J Thromb Thrombolysis 2020; 50 (04) 844-848
• 97 Kearon C, Julian JA, Kovacs MJ. et al; ELATE Investigators. Influence of thrombophilia on risk of recurrent venous thromboembolism while on warfarin: results from a randomized trial. Blood 2008; 112 (12) 4432-4436
• 98 Prandoni P, Barbar S, Milan M. et al. Optimal duration of anticoagulation. Provoked versus unprovoked VTE and role of adjunctive thrombophilia and imaging tests. Thromb Haemost 2015; 113 (06) 1210-1215
• 99 Segal JB, Brotman DJ, Necochea AJ. et al. Predictive value of factor V Leiden and prothrombin G20210A in adults with venous thromboembolism and in family members of those with a mutation: a systematic review. JAMA 2009; 301 (23) 2472-2485
• 100 Marchiori A, Mosena L, Prins MH, Prandoni P. The risk of recurrent venous thromboembolism among heterozygous carriers of factor V Leiden or prothrombin G20210A mutation. A systematic review of prospective studies. Haematologica 2007; 92 (08) 1107-1114
• 101 Prandoni P, Noventa F, Ghirarduzzi A. et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica 2007; 92 (02) 199-205
• 102 De Stefano V, Simioni P, Rossi E. et al. The risk of recurrent venous thromboembolism in patients with inherited deficiency of natural anticoagulants antithrombin, protein C and protein S. Haematologica 2006; 91 (05) 695-698
• 103 Brouwer JL, Lijfering WM, Ten Kate MK, Kluin-Nelemans HC, Veeger NJ, van der Meer J. High long-term absolute risk of recurrent venous thromboembolism in patients with hereditary deficiencies of protein S, protein C or antithrombin. Thromb Haemost 2009; 101 (01) 93-99
• 104 Vossen CY, Walker ID, Svensson P. et al. Recurrence rate after a first venous thrombosis in patients with familial thrombophilia. Arterioscler Thromb Vasc Biol 2005; 25 (09) 1992-1997
• 105 Zöller B, Ohlsson H, Sundquist J, Sundquist K. Familial risk of venous thromboembolism in first-, second- and third-degree relatives: a nationwide family study in Sweden. Thromb Haemost 2013; 109 (03) 458-463
• 106 Hron G, Eichinger S, Weltermann A. et al. Family history for venous thromboembolism and the risk for recurrence. Am J Med 2006; 119 (01) 50-53
• 107 Gauthier K, Kovacs MJ, Wells PS, Le Gal G, Rodger M. REVERSE investigators. Family history of venous thromboembolism (VTE) as a predictor for recurrent VTE in unprovoked VTE patients. J Thromb Haemost 2013; 11 (01) 200-203
• 108 Kearon C, Akl EA, Comerota AJ. et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl. 02) e419S-e496S
• 109 Stevens SM, Woller SC, Kreuziger LB. et al. Antithrombotic therapy for VTE disease: second update of the CHEST guideline and expert panel report. Chest 2021; 160 (06) e545-e608
• 110 Ortel TL, Neumann I, Ageno W. et al. American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism. Blood Adv 2020; 4 (19) 4693-4738
• 111 Konstantinides SV, Meyer G, Becattini C. et al; The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS): The Task Force for the diagnosis and management of acute pulmonary embolism of the European Society of Cardiology (ESC). Eur Respir J 2019; 54 (03) 1901647
• 112 Weitz JI, Prandoni P, Verhamme P. Anticoagulation for patients with venous thromboembolism: when is extended treatment required?. TH Open 2020; 4 (04) e446-e456