Download PDF
Semin Respir Crit Care Med 2021; 42(02): 271-283
DOI: 10.1055/s-0041-1723937
Review Article

Venous Thromboembolism: Genetics and Thrombophilias

Manila Gaddh
1   Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia
,
Rachel P. Rosovsky
2   Division of Hematology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts
› Author Affiliations
› Further Information
    Permissions and Reprints

Abstract

Venous thromboembolism (VTE) is a major cause of morbidity and mortality throughout the world. Up to one half of patients who present with VTE will have an underlying thrombophilic defect. This knowledge has led to a widespread practice of testing for such defects in patients who develop VTE. However, identifying a hereditary thrombophilia by itself does not necessarily change outcomes or dictate therapy. Furthermore, family history of VTE by itself can increase an asymptomatic person's VTE risk several-fold, independent of detecting a known inherited thrombophilia. In this article, we will describe the current validated hereditary thrombophilias including their history, prevalence, and association with VTE. With a focus on evaluating both risks and benefits of testing, we will also explore the controversies of why, who, and when to test as well as discuss contemporary societal guidelines. Lastly, we will share how these tests have been integrated into clinical practice and how to best utilize them in the future.

Keywords

thrombophilia - venous thromboembolism - pulmonary embolism - deep vein thrombosis - hereditary


Publication History

Article published online:
10 March 2021

© 2021. Thieme. All rights reserved.

Thieme Medical Publishers, Inc.
333 Seventh Avenue, 18th Floor, New York, NY 10001, USA

 

  • References

  • 1 Deitelzweig SB, Johnson BH, Lin J, Schulman KL. Prevalence of clinical venous thromboembolism in the USA: current trends and future projections. Am J Hematol 2011; 86 (02) 217-220
    CrossrefPubMedGoogle Scholar
  • 2 Heit JA. Venous thromboembolism: disease burden, outcomes and risk factors. J Thromb Haemost 2005; 3 (08) 1611-1617
    CrossrefPubMedGoogle Scholar
  • 3 Heit JA, Spencer FA, White RH. The epidemiology of venous thromboembolism. J Thromb Thrombolysis 2016; 41 (01) 3-14
    CrossrefPubMedGoogle Scholar
  • 4 Lijfering WM, Rosendaal FR, Cannegieter SC. Risk factors for venous thrombosis - current understanding from an epidemiological point of view. Br J Haematol 2010; 149 (06) 824-833
    CrossrefPubMedGoogle Scholar
  • 5 Nygaard KK, Brown GE. Essential thrombophilia: report of five cases. Arch Intern Med (Chic) 1937; 59 (01) 82-106
    CrossrefPubMedGoogle Scholar
  • 6 Egeberg O. Thrombophilia caused by inheritable deficiency of blood antithrombin. Scand J Clin Lab Invest 1965; 17: 92
    CrossrefPubMedGoogle Scholar
  • 7 Lee EJ, Dykas DJ, Leavitt AD. et al. Whole-exome sequencing in evaluation of patients with venous thromboembolism. Blood Adv 2017; 1 (16) 1224-1237
    CrossrefPubMedGoogle Scholar
  • 8 de Haan HG, van Hylckama Vlieg A, Lotta LA. et al; INVENT Consortium. Targeted sequencing to identify novel genetic risk factors for deep vein thrombosis: a study of 734 genes. J Thromb Haemost 2018; 16 (12) 2432-2441
    CrossrefPubMedGoogle Scholar
  • 9 Morange PE, Trégouët DA. Current knowledge on the genetics of incident venous thrombosis. J Thromb Haemost 2013; 11 (Suppl. 01) 111-121
    CrossrefPubMedGoogle Scholar
  • 10 Bauer KA. The thrombophilias: well-defined risk factors with uncertain therapeutic implications. Ann Intern Med 2001; 135 (05) 367-373
    CrossrefPubMedGoogle Scholar
  • 11 Rabinovich A, Cohen JM, Prandoni P, Kahn SR. Association between thrombophilia and the post-thrombotic syndrome: a systematic review and meta-analysis. J Thromb Haemost 2014; 12 (01) 14-23
    CrossrefPubMedGoogle Scholar
  • 12 Coppens M, van de Poel MH, Bank I. et al. A prospective cohort study on the absolute incidence of venous thromboembolism and arterial cardiovascular disease in asymptomatic carriers of the prothrombin 20210A mutation. Blood 2006; 108 (08) 2604-2607
    CrossrefPubMedGoogle Scholar
  • 13 Middeldorp S, Meinardi JR, Koopman MM. et al. A prospective study of asymptomatic carriers of the factor V Leiden mutation to determine the incidence of venous thromboembolism. Ann Intern Med 2001; 135 (05) 322-327
    CrossrefPubMedGoogle Scholar
  • 14 Mahmoodi BK, Brouwer JL, Ten Kate MK. et al. A prospective cohort study on the absolute risks of venous thromboembolism and predictive value of screening asymptomatic relatives of patients with hereditary deficiencies of protein S, protein C or antithrombin. J Thromb Haemost 2010; 8 (06) 1193-1200
    CrossrefPubMedGoogle Scholar
  • 15 Rodger MA, Kahn SR, Wells PS. et al. Identifying unprovoked thromboembolism patients at low risk for recurrence who can discontinue anticoagulant therapy. CMAJ 2008; 179 (05) 417-426
    CrossrefPubMedGoogle Scholar
  • 16 Tosetto A, Iorio A, Marcucci M. et al. Predicting disease recurrence in patients with previous unprovoked venous thromboembolism: a proposed prediction score (DASH). J Thromb Haemost 2012; 10 (06) 1019-1025
    CrossrefPubMedGoogle Scholar
  • 17 Eichinger S, Heinze G, Jandeck LM, Kyrle PA. Risk assessment of recurrence in patients with unprovoked deep vein thrombosis or pulmonary embolism: the Vienna prediction model. Circulation 2010; 121 (14) 1630-1636
    CrossrefPubMedGoogle Scholar
  • 18 Cohn DM, Vansenne F, de Borgie CA, Middeldorp S. Thrombophilia testing for prevention of recurrent venous thromboembolism. Cochrane Database Syst Rev 2012; 12: CD007069
    PubMedGoogle Scholar
  • 19 Bank I, Scavenius MP, Büller HR, Middeldorp S. Social aspects of genetic testing for factor V Leiden mutation in healthy individuals and their importance for daily practice. Thromb Res 2004; 113 (01) 7-12
    CrossrefPubMedGoogle Scholar
  • 20 Cohn DM, Vansenne F, Kaptein AA, De Borgie CA, Middeldorp S. The psychological impact of testing for thrombophilia: a systematic review. J Thromb Haemost 2008; 6 (07) 1099-1104
    CrossrefPubMedGoogle Scholar
  • 21 Noboa S, Le Gal G, Lacut K. et al; EDITH Collaborative Study Group. Family history as a risk factor for venous thromboembolism. Thromb Res 2008; 122 (05) 624-629
    CrossrefPubMedGoogle Scholar
  • 22 Dexter L. The chair and venous thrombosis. Trans Am Clin Climatol Assoc 1973; 84: 1-15
    PubMedGoogle Scholar
  • 23 Galanaud JP, Laroche JP, Righini M. The history and historical treatments of deep vein thrombosis. J Thromb Haemost 2013; 11 (03) 402-411
    CrossrefPubMedGoogle Scholar
  • 24 Anning ST. The historical aspects of venous thrombosis. Med Hist 1957; 1 (01) 28-37
    CrossrefPubMedGoogle Scholar
  • 25 Mannucci PM. Venous thrombosis: the history of knowledge. Pathophysiol Haemost Thromb 2002; 32 (5-6): 209-212
    CrossrefPubMedGoogle Scholar
  • 26 Parapia LA. History of bloodletting by phlebotomy. Br J Haematol 2008; 143 (04) 490-495
    PubMedGoogle Scholar
  • 27 Bagot CN, Arya R. Virchow and his triad: a question of attribution. Br J Haematol 2008; 143 (02) 180-190
    CrossrefPubMedGoogle Scholar
  • 28 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
    CrossrefPubMedGoogle Scholar
  • 29 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
    CrossrefPubMedGoogle Scholar
  • 30 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
    CrossrefPubMedGoogle Scholar
  • 31 Dahlbäck B, Hildebrand B. Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V. Proc Natl Acad Sci U S A 1994; 91 (04) 1396-1400
    CrossrefPubMedGoogle Scholar
  • 32 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
    CrossrefPubMedGoogle Scholar
  • 33 Rees DC, Cox M, Clegg JB. World distribution of factor V Leiden. Lancet 1995; 346 (8983): 1133-1134
    CrossrefPubMedGoogle Scholar
  • 34 de Visser MC, Rosendaal FR, Bertina RM. A reduced sensitivity for activated protein C in the absence of factor V Leiden increases the risk of venous thrombosis. Blood 1999; 93 (04) 1271-1276
    CrossrefPubMedGoogle Scholar
  • 35 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 methylenetetrahydrofolate reductase C677T: a meta-analysis involving over 11,000 cases and 21,000 controls. Eur J Epidemiol 2013; 28 (08) 621-647
    CrossrefPubMedGoogle Scholar
  • 36 Vossen CY, Conard J, Fontcuberta J. et al. Familial thrombophilia and lifetime risk of venous thrombosis. J Thromb Haemost 2004; 2 (09) 1526-1532
    CrossrefPubMedGoogle Scholar
  • 37 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 39 De Stefano V, Martinelli I, Mannucci PM. et al. The risk of recurrent venous thromboembolism among heterozygous carriers of the G20210A prothrombin gene mutation. Br J Haematol 2001; 113 (03) 630-635
    CrossrefPubMedGoogle Scholar
  • 40 Lindmarker P, Schulman S, Sten-Linder M, Wiman B, Egberg N, Johnsson H. The risk of recurrent venous thromboembolism in carriers and non-carriers of the G1691A allele in the coagulation factor V gene and the G20210A allele in the prothrombin gene. DURAC Trial Study Group. Duration of anticoagulation. Thromb Haemost 1999; 81 (05) 684-689
    Article in Thieme ConnectPubMedGoogle Scholar
  • 41 Simioni P, Prandoni P, Lensing AW. et al. Risk for subsequent venous thromboembolic complications in carriers of the prothrombin or the factor V gene mutation with a first episode of deep-vein thrombosis. Blood 2000; 96 (10) 3329-3333
    CrossrefPubMedGoogle Scholar
  • 42 Tait RC, Walker ID, Perry DJ. et al. Prevalence of antithrombin deficiency in the healthy population. Br J Haematol 1994; 87 (01) 106-112
    CrossrefPubMedGoogle Scholar
  • 43 Lijfering WM, Veeger NJ, Middeldorp S. et al. A lower risk of recurrent venous thrombosis in women compared with men is explained by sex-specific risk factors at time of first venous thrombosis in thrombophilic families. Blood 2009; 114 (10) 2031-2036
    CrossrefPubMedGoogle Scholar
  • 44 Rossi E, Ciminello A, Za T, Betti S, Leone G, De Stefano V. In families with inherited thrombophilia the risk of venous thromboembolism is dependent on the clinical phenotype of the proband. Thromb Haemost 2011; 106 (04) 646-654
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Abildgaard U. Highly purified antithrombin 3 with heparin cofactor activity prepared by disc electrophoresis. Scand J Clin Lab Invest 1968; 21 (01) 89-91
    CrossrefPubMedGoogle Scholar
  • 46 Huber R, Carrell RW. Implications of the three-dimensional structure of alpha 1-antitrypsin for structure and function of serpins. Biochemistry 1989; 28 (23) 8951-8966
    CrossrefPubMedGoogle Scholar
  • 47 Olds RJ, Lane DA, Chowdhury V, De Stefano V, Leone G, Thein SL. Complete nucleotide sequence of the antithrombin gene: evidence for homologous recombination causing thrombophilia. Biochemistry 1993; 32 (16) 4216-4224
    CrossrefPubMedGoogle Scholar
  • 48 Lane DA, Bayston T, Olds RJ. et al; For the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Antithrombin mutation database: 2nd (1997) update. Thromb Haemost 1997; 77 (01) 197-211
    Article in Thieme ConnectPubMedGoogle Scholar
  • 49 Lane DA, Olds RJ, Boisclair M. et al. Antithrombin III mutation database: first update. For the Thrombin and its Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Thromb Haemost 1993; 70 (02) 361-369
    Article in Thieme ConnectPubMedGoogle Scholar
  • 50 Pabinger I, Schneider B. Gesellschaft fur Thrombose- und Hamostaseforschung (GTH) Study Group on Natural Inhibitors. Thrombotic risk in hereditary antithrombin III, protein C, or protein S deficiency. A cooperative, retrospective study. Arterioscler Thromb Vasc Biol 1996; 16 (06) 742-748
    CrossrefPubMedGoogle Scholar
  • 51 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
    Google Scholar
  • 52 Margaglione M, Grandone E. Population genetics of venous thromboembolism. A narrative review. Thromb Haemost 2011; 105 (02) 221-231
    Article in Thieme ConnectPubMedGoogle Scholar
  • 53 Esmon CT. Regulation of blood coagulation. Biochim Biophys Acta 2000; 1477 (1-2): 349-360
    CrossrefPubMedGoogle Scholar
  • 54 Foster DC, Yoshitake S, Davie EW. The nucleotide sequence of the gene for human protein C. Proc Natl Acad Sci U S A 1985; 82 (14) 4673-4677
    CrossrefPubMedGoogle Scholar
  • 55 Reitsma PH, Bernardi F, Doig RG. et al. Protein C deficiency: a database of mutations, 1995 update. On behalf of the Subcommittee on Plasma Coagulation Inhibitors of the Scientific and Standardization Committee of the ISTH. Thromb Haemost 1995; 73 (05) 876-889
    Article in Thieme ConnectPubMedGoogle Scholar
  • 56 Broekmans AW. Hereditary protein C deficiency. Haemostasis 1985; 15 (04) 233-240
    PubMedGoogle Scholar
  • 57 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
    CrossrefPubMedGoogle Scholar
  • 58 Dykes AC, Walker ID, McMahon AD, Islam SI, Tait RC. A study of Protein S antigen levels in 3788 healthy volunteers: influence of age, sex and hormone use, and estimate for prevalence of deficiency state. Br J Haematol 2001; 113 (03) 636-641
    CrossrefPubMedGoogle Scholar
  • 59 Dahlbäck B. Inhibition of protein Ca cofactor function of human and bovine protein S by C4b-binding protein. J Biol Chem 1986; 261 (26) 12022-12027
    CrossrefPubMedGoogle Scholar
  • 60 Hackeng TM, van't Veer C, Meijers JC, Bouma BN. Human protein S inhibits prothrombinase complex activity on endothelial cells and platelets via direct interactions with factors Va and Xa. J Biol Chem 1994; 269 (33) 21051-21058
    CrossrefPubMedGoogle Scholar
  • 61 Gandrille S, Borgel D, Ireland H. et al; For the Plasma Coagulation Inhibitors Subcommittee of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Protein S deficiency: a database of mutations. Thromb Haemost 1997; 77 (06) 1201-1214
    Article in Thieme ConnectPubMedGoogle Scholar
  • 62 Anderson DR, Brill-Edwards P, Walker I. Warfarin-induced skin necrosis in 2 patients with protein S deficiency: successful reinstatement of warfarin therapy. Haemostasis 1992; 22 (03) 124-128
    PubMedGoogle Scholar
  • 63 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
    CrossrefPubMedGoogle Scholar
  • 64 Mazzolai L, Duchosal MA. Hereditary thrombophilia and venous thromboembolism: critical evaluation of the clinical implications of screening. Eur J Vasc Endovasc Surg 2007; 34 (04) 483-488
    CrossrefPubMedGoogle Scholar
  • 65 Christiansen SC, Cannegieter SC, Koster T, Vandenbroucke JP, Rosendaal FR. Thrombophilia, clinical factors, and recurrent venous thrombotic events. JAMA 2005; 293 (19) 2352-2361
    CrossrefPubMedGoogle Scholar
  • 66 Baglin T, Luddington R, Brown K, Baglin C. Incidence of recurrent venous thromboembolism in relation to clinical and thrombophilic risk factors: prospective cohort study. Lancet 2003; 362 (9383): 523-526
    CrossrefPubMedGoogle Scholar
  • 67 Coppens M, Reijnders JH, Middeldorp S, Doggen CJ, Rosendaal FR. Testing for inherited thrombophilia does not reduce the recurrence of venous thrombosis. J Thromb Haemost 2008; 6 (09) 1474-1477
    CrossrefPubMedGoogle Scholar
  • 68 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
    CrossrefPubMedGoogle Scholar
  • 69 Bezemer ID, van der Meer FJ, Eikenboom JC, Rosendaal FR, Doggen CJ. The value of family history as a risk indicator for venous thrombosis. Arch Intern Med 2009; 169 (06) 610-615
    CrossrefPubMedGoogle Scholar
  • 70 Couturaud F, Leroyer C, Tromeur C. et al. Factors that predict thrombosis in relatives of patients with venous thromboembolism. Blood 2014; 124 (13) 2124-2130
    CrossrefPubMedGoogle Scholar
  • 71 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 72 Stevens SM, Woller SC, Bauer KA. et al. Guidance for the evaluation and treatment of hereditary and acquired thrombophilia. J Thromb Thrombolysis 2016; 41 (01) 154-164
    CrossrefPubMedGoogle Scholar
  • 73 Hicks LK, Bering H, Carson KR. et al. The ASH Choosing Wisely® campaign: five hematologic tests and treatments to question. Blood 2013; 122 (24) 3879-3883
    CrossrefPubMedGoogle Scholar
  • 74 Baglin T, Gray E, Greaves M. et al; British Committee for Standards in Haematology. Clinical guidelines for testing for heritable thrombophilia. Br J Haematol 2010; 149 (02) 209-220
    CrossrefPubMedGoogle Scholar
  • 75 National Institute for Health and Care Excellence. Venous Thromboembolic Diseases: Diagnosis, Management and Thrombophilia Testing NICE Guideline [NG158]. 2020
    Google Scholar
  • 76 The Royal Australian College of General Practitioners. Genomics in General Practice: Hereditary Thrombophilias. 2018
    Google Scholar
  • 77 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 (2, Suppl): e419S-e496S
    CrossrefPubMedGoogle Scholar
  • 78 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
    CrossrefPubMedGoogle Scholar
  • 79 van Sluis GL, Söhne M, El Kheir DY, Tanck MW, Gerdes VE, Büller HR. Family history and inherited thrombophilia. J Thromb Haemost 2006; 4 (10) 2182-2187
    CrossrefPubMedGoogle Scholar
  • 80 Warwick R, Hutton RA, Goff L, Letsky E, Heard M. Changes in protein C and free protein S during pregnancy and following hysterectomy. J R Soc Med 1989; 82 (10) 591-594
    CrossrefPubMedGoogle Scholar
  • 81 Favaloro EJ, Mohammed S, Pati N, Ho MY, McDonald D. A clinical audit of congenital thrombophilia investigation in tertiary practice. Pathology 2011; 43 (03) 266-272
    CrossrefPubMedGoogle Scholar
  • 82 Gaddh M, Cheng E, Elsebaie MAT, Bodó I. Clinical utilization and cost of thrombophilia testing in patients with venous thromboembolism. TH Open 2020; 4 (03) e153-e162
    Article in Thieme ConnectPubMedGoogle Scholar
  • 83 Meyer MR, Witt DM, Delate T. et al. Thrombophilia testing patterns amongst patients with acute venous thromboembolism. Thromb Res 2015; 136 (06) 1160-1164
    CrossrefPubMedGoogle Scholar
  • 84 Mou E, Kwang H, Hom J. et al. Magnitude of potentially inappropriate thrombophilia testing in the inpatient hospital setting. J Hosp Med 2017; 12 (09) 735-738
    CrossrefPubMedGoogle Scholar
  • 85 Shen Y-MTJ, Tsai J, Taiwo E. et al. Analysis of thrombophilia test ordering practices at an academic center: a proposal for appropriate testing to reduce harm and cost. PLoS One 2016; 11 (05) e0155326
    CrossrefPubMedGoogle Scholar
  • 86 Somma J, Sussman II, Rand JH. An evaluation of thrombophilia screening in an urban tertiary care medical center: a “real world” experience. Am J Clin Pathol 2006; 126 (01) 120-127
    CrossrefPubMedGoogle Scholar
  • 87 Germain M, Chasman DI, de Haan H. et al; Cardiogenics Consortium. Meta-analysis of 65,734 individuals identifies TSPAN15 and SLC44A2 as two susceptibility loci for venous thromboembolism. Am J Hum Genet 2015; 96 (04) 532-542
    CrossrefPubMedGoogle Scholar
  • 88 Trégouët DA, Delluc A, Roche A. et al. Is there still room for additional common susceptibility alleles for venous thromboembolism?. J Thromb Haemost 2016; 14 (09) 1798-1802
    CrossrefPubMedGoogle Scholar
  • 89 Trégouët DA, Morange PE. What is currently known about the genetics of venous thromboembolism at the dawn of next generation sequencing technologies. Br J Haematol 2018; 180 (03) 335-345
    CrossrefPubMedGoogle Scholar
  • 90 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
    CrossrefPubMedGoogle Scholar
  • 91 Juul K, Tybjaerg-Hansen A, Schnohr P, Nordestgaard BG. Factor V Leiden and the risk for venous thromboembolism in the adult Danish population. Ann Intern Med 2004; 140 (05) 330-337
    CrossrefPubMedGoogle Scholar
  • 92 Lijfering WM, Brouwer JL, Veeger NJ. et al. Selective testing for thrombophilia in patients with first venous thrombosis: results from a retrospective family cohort study on absolute thrombotic risk for currently known thrombophilic defects in 2479 relatives. Blood 2009; 113 (21) 5314-5322
    CrossrefPubMedGoogle Scholar
  • 93 Lijfering WM, Middeldorp S, Veeger NJ. et al. Risk of recurrent venous thrombosis in homozygous carriers and double heterozygous carriers of factor V Leiden and prothrombin G20210A. Circulation 2010; 121 (15) 1706-1712
    CrossrefPubMedGoogle Scholar
  • 94 Middeldorp S, Henkens CM, Koopman MM. et al. The incidence of venous thromboembolism in family members of patients with factor V Leiden mutation and venous thrombosis. Ann Intern Med 1998; 128 (01) 15-20
    CrossrefPubMedGoogle Scholar
  • 95 De Stefano V, Leone G, Mastrangelo S. et al. Clinical manifestations and management of inherited thrombophilia: retrospective analysis and follow-up after diagnosis of 238 patients with congenital deficiency of antithrombin III, protein C, protein S. Thromb Haemost 1994; 72 (03) 352-358
    Article in Thieme ConnectPubMedGoogle Scholar
  • 96 Ho WK, Hankey GJ, Quinlan DJ, Eikelboom JW. Risk of recurrent venous thromboembolism in patients with common thrombophilia: a systematic review. Arch Intern Med 2006; 166 (07) 729-736
    CrossrefPubMedGoogle Scholar
  • 97 Margaglione M, D'Andrea G, Colaizzo D. et al. Coexistence of factor V Leiden and Factor II A20210 mutations and recurrent venous thromboembolism. Thromb Haemost 1999; 82 (06) 1583-1587
    Article in Thieme ConnectPubMedGoogle Scholar
  • 98 van den Belt AG, Sanson BJ, Simioni P. et al. Recurrence of venous thromboembolism in patients with familial thrombophilia. Arch Intern Med 1997; 157 (19) 2227-2232
    CrossrefPubMedGoogle Scholar
  • 99 Brown K, Luddington R, Williamson D, Baker P, Baglin T. Risk of venous thromboembolism associated with a G to A transition at position 20210 in the 3′-untranslated region of the prothrombin gene. Br J Haematol 1997; 98 (04) 907-909
    CrossrefPubMedGoogle Scholar
  • 100 Miles JS, Miletich JP, Goldhaber SZ, Hennekens CH, Ridker PM. G20210A mutation in the prothrombin gene and the risk of recurrent venous thromboembolism. J Am Coll Cardiol 2001; 37 (01) 215-218
    CrossrefPubMedGoogle Scholar
  • 101 Pabinger I, Brücker S, Kyrle PA. et al. Hereditary deficiency of antithrombin III, protein C and protein S: prevalence in patients with a history of venous thrombosis and criteria for rational patient screening. Blood Coagul Fibrinolysis 1992; 3 (05) 547-553
    CrossrefPubMedGoogle Scholar
  • 102 Simioni P, Sanson BJ, Prandoni P. et al. Incidence of venous thromboembolism in families with inherited thrombophilia. Thromb Haemost 1999; 81 (02) 198-202
    Article in Thieme ConnectPubMedGoogle Scholar
  • 103 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
    CrossrefPubMedGoogle Scholar
  • 104 Koster T, Rosendaal FR, de Ronde H, Briët E, Vandenbroucke JP, Bertina RM. Venous thrombosis due to poor anticoagulant response to activated protein C: Leiden Thrombophilia Study. Lancet 1993; 342 (8886-8887): 1503-1506
    CrossrefPubMedGoogle Scholar
  • 105 Ridker PM, Hennekens CH, Lindpaintner K, Stampfer MJ, Eisenberg PR, Miletich JP. 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 1995; 332 (14) 912-917
    CrossrefPubMedGoogle Scholar
  • 106 Eichinger S, Weltermann A, Mannhalter C. et al. The risk of recurrent venous thromboembolism in heterozygous carriers of factor V Leiden and a first spontaneous venous thromboembolism. Arch Intern Med 2002; 162 (20) 2357-2360
    CrossrefPubMedGoogle Scholar
  • 107 De Stefano V, Martinelli I, Mannucci PM. et al. The risk of recurrent deep venous thrombosis among heterozygous carriers of both factor V Leiden and the G20210A prothrombin mutation. N Engl J Med 1999; 341 (11) 801-806
    CrossrefPubMedGoogle Scholar
  • 108 Nicolaides AN, Fareed J, Kakkar AK. et al. Prevention and treatment of venous thromboembolism—international consensus statement. Int Angiol 2013; 32 (02) 111-260
    Google Scholar
  • 109 Moll S. Thrombophilia: clinical-practical aspects. J Thromb Thrombolysis 2015; 39 (03) 367-378
    CrossrefPubMedGoogle Scholar