Hamostaseologie 2022; 42(05): 320-329
DOI: 10.1055/a-1841-0399
Review Article

Management of Antithrombin Deficiency in Pregnancy

Christina Hart
1   Department of Haematology and Oncology, University Hospital Regensburg, Regensburg, Germany
Hannelore Rott
2   Gerinnungszentrum Rhein/Ruhr, Duisburg, Germany
Susanne Heimerl
3   Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Regensburg, Regensburg, Germany
Birgit Linnemann
4   Division of Angiology, University Hospital Regensburg - University Center of Vascular Medicine, Regensburg, Bavaria, Germany
› Author Affiliations


Antithrombin (AT) deficiency is a high-risk thrombophilia and a rare condition. The risk of venous thromboembolism (VTE) is increased in AT-deficient women during pregnancy and the postpartum period and is especially high in women with a prior history of VTE. A thorough assessment of VTE risk is recommended in pregnant AT-deficient women, comprising the degree and type of AT deficiency, genetic mutations, personal and family history, and additional preexisting or pregnancy-specific risk factors. Due to a lack of adequate study data, there is limited guidance on the management of AT deficiency in pregnancy, including the need for prophylactic anticoagulation, the appropriate dose of low-molecular-weight heparin (LMWH), and the role of AT substitution. LMWH is the medication of choice for the pharmacological prophylaxis and treatment of VTE in pregnancy. Patients with a history of VTE should receive full-dose LMWH during pregnancy and the postpartum period. AT concentrates are a treatment option when anticoagulation is withheld in potentially high-risk events such as childbirth, bleeding, or surgery and in cases of acute VTE despite the use of therapeutic dose anticoagulation. Women with AT deficiency should be counseled at specialized centers for coagulation disorders or vascular medicine, and close cooperation between obstetricians and anesthesiologists is warranted before delivery and during the peripartum period.

Publication History

Received: 11 February 2022

Accepted: 02 May 2022

Article published online:
02 November 2022

© 2022. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

  • References

  • 1 Kottke-Marchant K, Duncan A. Antithrombin deficiency: issues in laboratory diagnosis. Arch Pathol Lab Med 2002; 126 (11) 1326-1336
  • 2 Olson ST, Richard B, Izaguirre G, Schedin-Weiss S, Gettins PG. Molecular mechanisms of antithrombin-heparin regulation of blood clotting proteinases. A paradigm for understanding proteinase regulation by serpin family protein proteinase inhibitors. Biochimie 2010; 92 (11) 1587-1596
  • 3 Egeberg O. Thrombophilia caused by inheritable deficiency of blood antithrombin. Scand J Clin Lab Invest 1965; 17: 92
  • 4 Melissari E, Monte G, Lindo VS. et al. Congenital thrombophilia among patients with venous thromboembolism. Blood Coagul Fibrinolysis 1992; 3 (06) 749-758
  • 5 Tait RC, Walker ID, Perry DJ. et al. Prevalence of antithrombin deficiency in the healthy population. Br J Haematol 1994; 87 (01) 106-112
  • 6 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
  • 7 Croles FN, Borjas-Howard J, Nasserinejad K, Leebeek FWG, Meijer K. Risk of venous thrombosis in antithrombin deficiency: a systematic review and bayesian meta-analysis. Semin Thromb Hemost 2018; 44 (04) 315-326
  • 8 Shang F, Ding Q, Qi M, Wang N, Qu X. Successful treatment of a massive sinus thrombosis in a Chinese woman with antithrombin III deficiency: a case report and review of the literature. Blood Coagul Fibrinolysis 2020; 31 (06) 410-415
  • 9 Findakly D, Komro J. Not just another headache: cerebral venous sinus thrombosis in a patient with isolated antithrombin III deficiency. Cureus 2020; 12 (05) e8383
  • 10 Yokota H, Miyazaki M, Kinjo C, Kogaki S, Iida JI. Cerebral venous sinus thrombosis in child with antithrombin deficiency and novel SERPINC1 variant. Acta Neurol Belg 2021; 121 (03) 811-814
  • 11 Qi X, De Stefano V, Wang J. et al. Prevalence of inherited antithrombin, protein C, and protein S deficiencies in portal vein system thrombosis and Budd-Chiari syndrome: a systematic review and meta-analysis of observational studies. J Gastroenterol Hepatol 2013; 28 (03) 432-442
  • 12 Olivieri M, Bidlingmaier C, Schetzeck S, Borggräfe I, Geisen C, Kurnik K. Arterial thrombosis in homozygous antithrombin deficiency. Hamostaseologie 2012; 32 (Suppl. 01) S79-S82
  • 13 Roldán V, Ordoñez A, Marín F. et al. Antithrombin Cambridge II (A384S) supports a role for antithrombin deficiency in arterial thrombosis. Thromb Haemost 2009; 101 (03) 483-486
  • 14 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
  • 15 Bravo-Pérez C, Vicente V, Corral J. Management of antithrombin deficiency: an update for clinicians. Expert Rev Hematol 2019; 12 (06) 397-405
  • 16 Stenson PD, Ball EV, Mort M. et al. Human Gene Mutation Database (HGMD): 2003 update. Hum Mutat 2003; 21 (06) 577-581
  • 17 Bauer KA, Nguyen-Cao TM, Spears JB. Issues in the diagnosis and management of hereditary antithrombin deficiency. Ann Pharmacother 2016; 50 (09) 758-767
  • 18 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
  • 19 Mannucci PM, Franchini M. Classic thrombophilic gene variants. Thromb Haemost 2015; 114 (05) 885-889
  • 20 Gindele R, Oláh Z, Ilonczai P. et al. Founder effect is responsible for the p.Leu131Phe heparin-binding-site antithrombin mutation common in Hungary: phenotype analysis in a large cohort. J Thromb Haemost 2016; 14 (04) 704-715
  • 21 Van Cott EM, Orlando C, Moore GW, Cooper PC, Meijer P, Marlar R. Subcommittee on Plasma Coagulation Inhibitors. Recommendations for clinical laboratory testing for antithrombin deficiency; Communication from the SSC of the ISTH. J Thromb Haemost 2020; 18 (01) 17-22
  • 22 Rao AK, Niewiarowski S, Guzzo J, Day HJ. Antithrombin III levels during heparin therapy. Thromb Res 1981; 24 (1-2): 181-186
  • 23 Gosselin R, Grant RP, Adcock DM. Comparison of the effect of the anti-Xa direct oral anticoagulants apixaban, edoxaban, and rivaroxaban on coagulation assays. Int J Lab Hematol 2016; 38 (05) 505-513
  • 24 Kim YA, Gosselin R, Van Cott EM. The effects of dabigatran on lupus anticoagulant, diluted plasma thrombin time, and other specialized coagulation assays. Int J Lab Hematol 2015; 37 (04) e81-e84
  • 25 Exner T, Rigano J, Favaloro EJ. The effect of DOACs on laboratory tests and their removal by activated carbon to limit interference in functional assays. Int J Lab Hematol 2020; 42 (Suppl. 01) 41-48
  • 26 Linnemann B, Hart C. Laboratory diagnostics in thrombophilia. Hamostaseologie 2019; 39 (01) 49-61
  • 27 Maclean PS, Tait RC. Hereditary and acquired antithrombin deficiency: epidemiology, pathogenesis and treatment options. Drugs 2007; 67 (10) 1429-1440
  • 28 Pomp ER, Lenselink AM, Rosendaal FR, Doggen CJ. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemost 2008; 6 (04) 632-637
  • 29 Jackson E, Curtis KM, Gaffield ME. Risk of venous thromboembolism during the postpartum period: a systematic review. Obstet Gynecol 2011; 117 (03) 691-703
  • 30 Kamel H, Navi BB, Sriram N, Hovsepian DA, Devereux RB, Elkind MS. Risk of a thrombotic event after the 6-week postpartum period. N Engl J Med 2014; 370 (14) 1307-1315
  • 31 Hart C, Bauersachs R, Scholz U. et al. Prevention of venous thromboembolism during pregnancy and the puerperium with a special focus on women with hereditary thrombophilia or prior VTE-Position Paper of the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH). Hamostaseologie 2020; 40 (05) 572-590
  • 32 Rogenhofer N, Bohlmann MK, Beuter-Winkler P. et al. Prevention, management and extent of adverse pregnancy outcomes in women with hereditary antithrombin deficiency. Ann Hematol 2014; 93 (03) 385-392
  • 33 Abbattista M, Gianniello F, Novembrino C. et al. Risk of pregnancy-related venous thromboembolism and obstetrical complications in women with inherited type I antithrombin deficiency: a retrospective, single-centre, cohort study. Lancet Haematol 2020; 7 (04) e320-e328
  • 34 Conard J, Horellou MH, Van Dreden P, Lecompte T, Samama M. Thrombosis and pregnancy in congenital deficiencies in AT III, protein C or protein S: study of 78 women. Thromb Haemost 1990; 63 (02) 319-320
  • 35 De Stefano V, Leone G, Mastrangelo S. et al. Thrombosis during pregnancy and surgery in patients with congenital deficiency of antithrombin III, protein C, protein S. Thromb Haemost 1994; 71 (06) 799-800
  • 36 Middeldorp S. Thrombosis in women: what are the knowledge gaps in 2013?. J Thromb Haemost 2013; 11 (Suppl. 01) 180-191
  • 37 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
  • 38 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 (2, Suppl): e691S-e736S
  • 39 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
  • 40 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
  • 41 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
  • 42 Gerhardt A, Scharf RE, Greer IA, Zotz RB. Hereditary risk factors for thrombophilia and probability of venous thromboembolism during pregnancy and the puerperium. Blood 2016; 128 (19) 2343-2349
  • 43 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
  • 44 Bramham K, Retter A, Robinson SE, Mitchell M, Moore GW, Hunt BJ. How I treat heterozygous hereditary antithrombin deficiency in pregnancy. Thromb Haemost 2013; 110 (03) 550-559
  • 45 Pearson-Stuttard B, Bagot C, Ciantar E. et al. Severe antithrombin deficiency in pregnancy: achieving adequate anticoagulation. Obstet Med 2019; 12 (01) 45-51
  • 46 Croles FN, Lukens MV, Mulder R, de Maat MPM, Mulder AB, Meijer K. Monitoring of heparins in antithrombin-deficient patients. Thromb Res 2019; 175: 8-12
  • 47 Ignjatovic V, Summerhayes R, Gan A. et al. Monitoring unfractionated heparin (UFH) therapy: which anti-factor Xa assay is appropriate?. Thromb Res 2007; 120 (03) 347-351
  • 48 James AH, Konkle BA, Bauer KA. Prevention and treatment of venous thromboembolism in pregnancy in patients with hereditary antithrombin deficiency. Int J Womens Health 2013; 5: 233-241
  • 49 Paidas MJ, Triche EW, James AH. et al. Recombinant human antithrombin in pregnant patients with hereditary antithrombin deficiency: integrated analysis of clinical data. Am J Perinatol 2016; 33 (04) 343-349
  • 50 Refaei M, Xing L, Lim W, Crowther M, Boonyawat K. Management of venous thromboembolism in patients with hereditary antithrombin deficiency and pregnancy: case report and review of the literature. Case Rep Hematol 2017; 2017: 9261351
  • 51 Chan WS, Rey E, Kent NE. et al; VTE in Pregnancy Guideline Working Group; Society of Obstetricians and Gynecologists of Canada. Venous thromboembolism and antithrombotic therapy in pregnancy. J Obstet Gynaecol Can 2014; 36 (06) 527-553
  • 52 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
  • 53 Nelson-Piercy C, MacCallum P, Mackillop L. for the Royal College of Obstetricians and Gynaecologists. Reducing the risk of venous thromboembolism in pregnancy and the puerperium. Green-Top Guideline No 37a. London: RCOG; 2015
  • 54 American College of Obstetricians and Gynecologists' Committee on Practice Bulletins—Obstetrics. ACOG Practice Bulletin No. 196: Thromboembolism in pregnancy. Obstet Gynecol 2018; 132 (01) e1-e17
  • 55 Linnemann B, Scholz U, Rott H. et al; Working Group in Women's Health of the Society of Thrombosis and Hemostasis. Treatment of pregnancy-associated venous thromboembolism - position paper from the Working Group in Women's Health of the Society of Thrombosis and Haemostasis (GTH). Vasa 2016; 45 (02) 103-118
  • 56 Haas S, Encke A, Kopp I. German S3 guideline for the prevention of venous thromboembolism updated Comment on Vasa Supplement 92. Vasa 2016; 45 (05) 347-348
  • 57 James AH, Bates SM, Bauer KA. et al. Management of hereditary antithrombin deficiency in pregnancy. Thromb Res 2017; 157: 41-45
  • 58 Pabinger I, Thaler J. How I treat patients with hereditary antithrombin deficiency. Blood 2019; 134 (26) 2346-2353