Download PDF
Semin Thromb Hemost 2018; 44(04): 315-326
DOI: 10.1055/s-0038-1625983
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Risk of Venous Thrombosis in Antithrombin Deficiency: A Systematic Review and Bayesian Meta-analysis

F. Nanne Croles
1   Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
2   Department of Hematology, University of Groningen, UMC Groningen, Groningen, The Netherlands
,
Jaime Borjas-Howard
2   Department of Hematology, University of Groningen, UMC Groningen, Groningen, The Netherlands
,
Kazem Nasserinejad
3   Department of Hematology, Erasmus MC Cancer Institute-Clinical Trial Center, Rotterdam, The Netherlands
,
Frank W. G. Leebeek
1   Department of Hematology, Erasmus University Medical Center, Rotterdam, The Netherlands
,
Karina Meijer
2   Department of Hematology, University of Groningen, UMC Groningen, Groningen, The Netherlands
› Author Affiliations
Further Information

Publication History

Publication Date:
16 February 2018 (online)

    Permissions and Reprints

Abstract

Antithrombin deficiency is a strong risk factor for venous thromboembolism (VTE), but the absolute risk of the first and recurrent VTE is unclear. The objective of this paper is to establish the absolute risks of the first and recurrent VTE and mortality in individuals with antithrombin deficiency. The databases Embase, Medline Ovid, Web of Science, the Cochrane Library, and Google Scholar were systematically searched for case–control and cohort studies. Bayesian random-effects meta-analysis was used to calculate odds ratios (ORs), absolute risks, and probabilities of ORs being above thresholds. Thirty-five publications were included in the systematic review and meta-analysis. Based on 19 studies, OR estimates for the first VTE showed a strongly increased risk for antithrombin deficient individuals, OR 14.0; 95% credible interval (CrI), 5.5 to 29.0. Based on 10 studies, meta-analysis showed that the annual VTE risk was significantly higher in antithrombin-deficient than in non-antithrombin-deficient individuals: 1.2% (95% CrI, 0.8–1.7) versus 0.07% (95% CrI, 0.01–0.14). In prospective studies, the annual VTE risk in antithrombin deficient individuals was as high as 2.3%; 95% CrI, 0.2–6.5%. Data on antithrombin deficiency subtypes are very limited for reliable risk-differentiation. The OR for recurrent VTE based on 10 studies was 2.1; 95% CrI, 0.2 to 4.0. The annual recurrence risk without long-term anticoagulant therapy based on 4 studies was 8.8% (95% CrI, 4.6–14.1) for antithrombin-deficient and 4.3% (95% CrI, 1.5–7.9) for non-antithrombin-deficient VTE patients. The probability of the recurrence risk being higher in antithrombin-deficient patients was 95%. The authors conclude that antithrombin deficient individuals have a high annual VTE risk, and a high annual recurrence risk. Antithrombin deficient patients with VTE require long-term anticoagulant therapy.

Keywords

anticoagulants - antithrombin deficiency - venous thromboembolism - meta-analysis - Bayes theorem

Authors' Contribution

F. Nanne Croles designed the study protocol, performed the search, performed the data abstraction and statistics, and wrote the manuscript. Jaime Borjas-Howard performed the search, performed the data abstraction, and critically revised the manuscript. Kazem Nasserinejad designed and performed the statistics. Frank W. G. Leebeek and Karina Meijer designed the study protocol and critically revised the manuscript.


Supplementary Material

 

  • References

  • 1 Egeberg O. Thrombophilia caused by inheritable deficiency of blood antithrombin. Scand J Clin Lab Invest 1965; 17: 92
    CrossrefPubMedGoogle Scholar
  • 2 Lane DA, Kunz G, Olds RJ, Thein SL. Molecular genetics of antithrombin deficiency. Blood Rev 1996; 10 (02) 59-74
    CrossrefPubMedGoogle Scholar
  • 3 Mitsuguro M, Sakata T, Okamoto A. , et al. Usefulness of antithrombin deficiency phenotypes for risk assessment of venous thromboembolism: type I deficiency as a strong risk factor for venous thromboembolism. Int J Hematol 2010; 92 (03) 468-473
    CrossrefPubMedGoogle Scholar
  • 4 Luxembourg B, Pavlova A, Geisen C. , et al. Impact of the type of SERPINC1 mutation and subtype of antithrombin deficiency on the thrombotic phenotype in hereditary antithrombin deficiency. Thromb Haemost 2014; 111 (02) 249-257
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Croles FN, Nasserinejad K, Duvekot JJ, Kruip MJ, Meijer K, Leebeek FW. Pregnancy, thrombophilia, and the risk of a first venous thrombosis: systematic review and bayesian meta-analysis. BMJ 2017; 359: j4452
    CrossrefPubMedGoogle Scholar
  • 6 Konstantinides SV, Torbicki A, Agnelli G. , et al; Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). 2014 ESC guidelines on the diagnosis and management of acute pulmonary embolism. Eur Heart J 2014; 35 (43) 3033-3069 , 3069a–3069k
    CrossrefPubMedGoogle Scholar
  • 7 Guyatt GH, Akl EA, Crowther M. , et al. Executive summary: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2 Suppl): 7S-47S
    CrossrefPubMedGoogle Scholar
  • 8 Di Minno MND, 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
    CrossrefPubMedGoogle Scholar
  • 9 Wells GASB, O'Connell D, Peterson J. , et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomized studies in meta-analyses. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp . Accessed October 5, 2015
    PubMedGoogle Scholar
  • 10 Smith TC, Spiegelhalter DJ, Thomas A. Bayesian approaches to random-effects meta-analysis: a comparative study. Stat Med 1995; 14 (24) 2685-2699
    CrossrefPubMedGoogle Scholar
  • 11 R_Core_Team. R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. http://www.R-project.org/ . Accessed July 1, 2016
    PubMedGoogle Scholar
  • 12 Plummer M. JAGS: A program for analysis of Bayesian graphical models using Gibbs sampling. Proceedings of the 3rd International Workshop on Distributed Statistical Computing 2003;124
    PubMedGoogle Scholar
  • 13 Alhenc-Gelas M, Plu-Bureau G, Hugon-Rodin J, Picard V, Horellou MH. ; GFHT study group on Genetic Thrombophilia. Thrombotic risk according to SERPINC1 genotype in a large cohort of subjects with antithrombin inherited deficiency. Thromb Haemost 2017; 117 (06) 1040-1051
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 Brouwer JL, Veeger NJ, Kluin-Nelemans HC, van der Meer J. The pathogenesis of venous thromboembolism: evidence for multiple interrelated causes. Ann Intern Med 2006; 145 (11) 807-815
    CrossrefPubMedGoogle Scholar
  • 15 Bucciarelli P, Passamonti SM, Biguzzi E. , et al. Low borderline plasma levels of antithrombin, protein C and protein S are risk factors for venous thromboembolism. J Thromb Haemost 2012; 10 (09) 1783-1791
    CrossrefPubMedGoogle Scholar
  • 16 Bucciarelli P, Rosendaal FR, Tripodi A. , et al. Risk of venous thromboembolism and clinical manifestations in carriers of antithrombin, protein C, protein S deficiency, or activated protein C resistance: a multicenter collaborative family study. Arterioscler Thromb Vasc Biol 1999; 19 (04) 1026-1033
    CrossrefPubMedGoogle Scholar
  • 17 Chougule A, Rajpal S, Ahluwalia J. , et al. Coagulation factor VIII, IX and XI levels in north Indian patients with venous thromboembolism: first study from India. Blood Coagul Fibrinolysis 2016; 27 (01) 58-63
    CrossrefPubMedGoogle Scholar
  • 18 Cogo A, Lensing AWA, Prandoni P. , et al. Relevance of inherited risk factors in young patients with deep-vein thrombosis. Clin Appl Thromb Hemost 1996; 2 (01) 55-59
    CrossrefPubMedGoogle Scholar
  • 19 Cohen W, Castelli C, Alessi MC. , et al. ABO blood group and von ospholipid factor levels partially explained the incomplete penetrance of congenital thrombophilia. Arterioscler Thromb Vasc Biol 2012; 32 (08) 2021-2028
    CrossrefPubMedGoogle Scholar
  • 20 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
  • 21 Di Minno MN, Dentali F, Veglia F, Russolillo A, Tremoli E, Ageno W. Antithrombin levels and the risk of a first episode of venous thromboembolism: a case-control study. Thromb Haemost 2013; 109 (01) 167-169
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Folsom AR, Aleksic N, Wang L, Cushman M, Wu KK, White RH. Protein C, antithrombin, and venous thromboembolism incidence: a prospective population-based study. Arterioscler Thromb Vasc Biol 2002; 22 (06) 1018-1022
    CrossrefPubMedGoogle Scholar
  • 23 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
    PubMedGoogle Scholar
  • 24 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
  • 25 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
    CrossrefPubMedGoogle Scholar
  • 26 Mateo J, Oliver A, Borrell M, Sala N, Fontcuberta J. Increased risk of venous thrombosis in carriers of natural anticoagulant deficiencies. Results of the family studies of the Spanish Multicenter Study on Thrombophilia (EMET study). Blood Coagul Fibrinolysis 1998; 9 (01) 71-78
    CrossrefPubMedGoogle Scholar
  • 27 Okumus G, Kiyan E, Arseven O. , et al. Hereditary thrombophilic risk factors and venous thromboembolism in Istanbul, Turkey: the role in different clinical manifestations of venous thromboembolism. Clin Appl Thromb Hemost 2008; 14 (02) 168-173
    CrossrefPubMedGoogle Scholar
  • 28 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
  • 29 Sakata T, Okamoto A, Mannami T, Matsuo H, Miyata T. Protein C and antithrombin deficiency are important risk factors for deep vein thrombosis in Japanese. J Thromb Haemost 2004; 2 (03) 528-530
    CrossrefPubMedGoogle Scholar
  • 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
    PubMedGoogle Scholar
  • 31 Shen MC, Lin JS, Tsay W. Protein C and protein S deficiencies are the most important risk factors associated with thrombosis in Chinese venous thrombophilic patients in Taiwan. Thromb Res 2000; 99 (05) 447-452
    CrossrefPubMedGoogle Scholar
  • 32 Suchon P, Al Frouh F, Henneuse A. , et al. Risk factors for venous thromboembolism in women under combined oral contraceptive. The PILl Genetic RIsk Monitoring (PILGRIM) Study. Thromb Haemost 2016; 115 (01) 135-142
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Tormene D, Fortuna S, Tognin G. , et al. The incidence of venous thromboembolism in carriers of antithrombin, protein C or protein S deficiency associated with the HR2 haplotype of factor V: a family cohort study. J Thromb Haemost 2005; 3 (07) 1414-1420
    CrossrefPubMedGoogle Scholar
  • 34 Vossen CY, Conard J, Fontcuberta J. , et al. Risk of a first venous thrombotic event in carriers of a familial thrombophilic defect. The European Prospective Cohort on Thrombophilia (EPCOT). J Thromb Haemost 2005; 3 (03) 459-464
    CrossrefPubMedGoogle Scholar
  • 35 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
  • 36 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
  • 37 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 38 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
    PubMedGoogle Scholar
  • 39 Di Minno MN, Dentali F, Lupoli R, Ageno W. Mild antithrombin deficiency and risk of recurrent venous thromboembolism: a prospective cohort study. Circulation 2014; 129 (04) 497-503
    CrossrefPubMedGoogle Scholar
  • 40 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
    CrossrefPubMedGoogle Scholar
  • 41 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
    CrossrefPubMedGoogle Scholar
  • 42 Weingarz L, Schindewolf M, Schwonberg J. , et al. Thrombophilia and risk of VTE recurrence according to the age at the time of first VTE manifestation. Vasa 2015; 44 (04) 313-323
    CrossrefPubMedGoogle Scholar
  • 43 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
  • 44 Taliani MR, Becattini C, Agnelli G. , et al; Warfarin Optimal Duration Italian Trial (WODIT) Investigators. Duration of anticoagulant treatment and recurrence of venous thromboembolism in patients with and without thrombophilic abnormalities. Thromb Haemost 2009; 101 (03) 596-598
    Article in Thieme ConnectPubMedGoogle Scholar
  • 45 Santamaria MG, Agnelli G, Taliani MR. , et al; Warfarin Optimal Duration Italian Trial (WODIT) Investigators. Thrombophilic abnormalities and recurrence of venous thromboembolism in patients treated with standardized anticoagulant treatment. Thromb Res 2005; 116 (04) 301-306
    CrossrefPubMedGoogle Scholar
  • 46 Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrøm J. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 2007; 5 (04) 692-699
    CrossrefPubMedGoogle Scholar
  • 47 Mishra MN, Bedi VS. Prevalence of common thrombophilia markers and risk factors in Indian patients with primary venous thrombosis. Sao Paulo Med J 2010; 128 (05) 263-267
    CrossrefPubMedGoogle Scholar
  • 48 Heijboer H, Brandjes DP, Büller HR, Sturk A, ten Cate JW. Deficiencies of coagulation-inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. N Engl J Med 1990; 323 (22) 1512-1516
    CrossrefPubMedGoogle Scholar
  • 49 Bombeli T, Basic A, Fehr J. Prevalence of hereditary thrombophilia in patients with thrombosis in different venous systems. Am J Hematol 2002; 70 (02) 126-132
    CrossrefPubMedGoogle Scholar
  • 50 Higgins JPT, Green S. , eds. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 [updated March 2011]. The Cochrane Collaboration; 2011. . Available from http://handbook.cochrane.org
    Google Scholar
  • 51 Rossi E, Za T, Ciminello A, Leone G, De Stefano V. The risk of symptomatic pulmonary embolism due to proximal deep venous thrombosis differs in patients with different types of inherited thrombophilia. Thromb Haemost 2008; 99 (06) 1030-1034
    Article in Thieme ConnectPubMedGoogle Scholar
  • 52 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
  • 53 Howard LS, Hughes RJ. NICE guideline: management of venous thromboembolic diseases and role of thrombophilia testing. Thorax 2013; 68 (04) 391-393
    CrossrefPubMedGoogle Scholar
  • 54 Iorio A, Kearon C, Filippucci E. , et al. Risk of recurrence after a first episode of symptomatic venous thromboembolism provoked by a transient risk factor: a systematic review. Arch Intern Med 2010; 170 (19) 1710-1716
    CrossrefPubMedGoogle Scholar