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Licensed Unlicensed Requires Authentication Published by De Gruyter January 20, 2022

Venous thrombosis risk factors in pregnant women

  • Victoria Bitsadze EMAIL logo , Jamilya Khizroeva , Makatsariya Alexander and Ismail Elalamy


Venous thromboembolism (VTE) is the third most common cause of death on Earth after myocardial infarctions and strokes, according to the World Health Organization (WHO). Pregnancy is a unique condition of woman, when enormous changes occur in functioning of the most important systems of homeostasis in a relatively short time. These are physiological hypercoagulation, slowing of blood flow, increase in circulating blood volume, etc. However, while being physiological, these changes increase the risks of venous thromboembolism by almost 6 times. In some cases, there appears an imbalance or dissociation between the functioning of natural antithrombotic systems and the activation of coagulation as a consequence of genetically or acquired determined causes (genetic thrombophilia, antiphospholipid syndrome, comorbidities, obstetric complications and other exogenous and endogenous factors). Accordingly, identification of risk factors, their systematization, and determination of VTE risks in pregnancy and puerperium is one of the most important tasks of clinical medicine. Various recommendations have appeared for practitioners during the last 10–15 years on the basis of the risk factors analysis in order to prevent VTE in pregnant women more effectively. Nevertheless, none of these recommendations can yet take into account all risk factors, although convenient scoring systems have emerged for risk assessment and clear recommendations on anti-thrombotic prophylaxis regimens in risk groups in recent years. This article will review historical understanding of thrombosis in pregnant women, progress in understanding VTE risk factors in pregnant women, and available reserves in identifying new risk factors during pregnancy and puerperium in order to stratify risks more efficiently.

Corresponding author: Victoria Bitsadze, Professor, MD, PhD, Department of Obstetrics and Gynecology, Russian Academy of, Sciences, I.M.Sechenov First Moscow State Medical University, (Sechenov University), Trubetskaya st. 8, bl. 2, 119048, Moscow, Russia, Phone: +7 (495) 788 58 40, Mobile: +7 926 231 3829, E-mail:

  1. Research funding: None declared.

  2. Author contributions: All authors have accepted responsibility for the entire content of this manuscript and approved its submission.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Not applicable.

  5. Ethical approval: Not applicable.


1. Blanco-Molina, A, Trujillo-Santos, J, Criado, J, Lopez, L, Lecumberri, R, Gutierrez, R, et al.. RIETE Investigators. Venous thromboembolism during pregnancy or postpartum: findings from the RIETE Registry. Thromb Haemostasis 2007;97:186–90. in Google Scholar

2. Say, L, Chou, D, Gemmill, A, Tuncalp, O, Moller, AB, Daniels, J, et al.. Global causes of maternal death: a WHO systematic analysis. Lancet Global Health 2014;2:e323–33. in Google Scholar

3. James, AH. Thrombosis in pregnancy and maternal outcomes. Birth Defects Res C Embrio Today 2015;105:159–66. in Google Scholar PubMed

4. Kourlaba, G, Relakis, J, Kontodimas, S, Holm, MV, Manjadakis, N. A systematic review and meta-analysis of the epidemiology and burden of venous thromboembolism among pregnant women. Int J Gynecol Obstet 2015;132:4–10. in Google Scholar PubMed

5. Heit, JA, Kobbervig, CE, James, AH, Petterson, TM, Bailey, KR, Melton, LJ3rd. Trends in the incidence of venous thromboembolism during pregnancy or postpartum: a 30-year population-based study. Ann Intern Med 2005;143:697–706. in Google Scholar PubMed

6. Goodacre, S, Hunt, B, Nelson-Piercy, C. Diagnosis of pulmonary embolism during pregnancy. Ann Intern Med 2019;171:146–7. in Google Scholar

7. Gherman, RB, Goodwin, TM, Leung, B, Byme, JD, Hethumumi, R, Montoro, M. Incidence, clinical characteristics and timing of objectively diagnosed venous thromboembolism during pregnancy. Obstet Gynecol 1999;94:730–4. in Google Scholar

8. James, A, Jamison, MG, Brancazio, LR, Miers, ER. Venous Thromboembolism during pregnancy and the postpartum period: incidence, risk factors and mortality. Am J Obstet Gynecol 2006;194:1311–5. in Google Scholar PubMed

9. Marik, PE, Plante, LA. Venous thromboembolic disease and pregnancy. N Engl J Med 2008;359:2025–33. in Google Scholar PubMed

10. Meignan, M, Rosso, J, Gauthier, H, Brunengo, F, Claudel, S, Sagnard, L, et al.. Systematic lung scan reveal a high frequency of silent pulmonary embolism in patients with proximal deep venous thrombosis. Arch Intern Med 2000;160:159–64. in Google Scholar PubMed

11. Jacobsen, AF, Skjeldestad, FE, Sandset, PM. Incidence and risk patterns of venous thromboembolism in pregnancy and puerperium: a register-based case-control study. Am J Obstet Gynecol 2008;198:232–7. in Google Scholar

12. James, AH. Venous thromboembolism in pregnancy. Arterioscler Thromb Vasc Biol 2009;29:326–31. in Google Scholar

13. Bourjelly, G, Paidas, M, Khalil, H, Rosene-Montella, K, Roger, M. Pulmonaty embolism in pregnancy. Lancet 2010;375:500–12. in Google Scholar

14. Greer, IA. Venous thrombosis in women: pregnancy, the contraceptive pill and hormone replacement therapy, 1st ed. London: Taylor & Francis e-Library; 2005:108 p.10.3109/9780203486122-30Search in Google Scholar

15. Gzihal, M, Hoffmann, U. Upper extremity deep venous thrombosis. Vasc Med 2011;16:191–202.10.1177/1358863X10395657Search in Google Scholar PubMed

16. Hansen, AT, Kesmodel, US, Juul, S, Hvas, AM. Increased venous thrombosis incidence in pregnancies after in vitro fertilization. Hum Reprod 2014;29:611–7. in Google Scholar PubMed

17. Tepper, NK, Boulet, SL, Whiteman, MK, Monsour, ID, Marchbanks, PA, Hooper, WC, et al.. Postpartum venous thromboembolism: incidence and risk factors. Obstet Gynecol 2014;123:987–96. in Google Scholar PubMed

18. McColl, MD, Ramsay, JE, Tait, RC, Walker, ID, McCall, F, Conkie, JA, et al.. Risk factors for pregnancy associated venous thromboembolism. Thromb Haemostasis 1997;78:1183–8. in Google Scholar

19. Eroğlu, A. The distribution of Factor V Leiden mutation. J Thromb Thrombolysis 2013;36:341–2. in Google Scholar PubMed

20. Manucci, PM. Venous thrombosis: history of knowledge. Pathophysiol Haemostasis Thrombosis 2002;32:209–12.10.1159/000073567Search in Google Scholar PubMed

21. Galanaud, J-P, Laroche, J-P, Righini, M. The history and historical treatments of deep vein thrombosis. J Thromb Haemostasis 2013;11:402–11. in Google Scholar

22. Clark, P. Changes of hemostasis variables during pregnancy. Semin Vasc Med 2003;3:13–24. in Google Scholar

23. Tsikouras, P, von Tempelhoff, GF, Rath, W. Epidemiology, risk factors and risk stratification of venous thromboembolism in pregnancy and the puerperium. Z Geburtshilfe Neonatol 2017;221:161–74. in Google Scholar

24. Holmes, VA, Wallace, JM. Haemostasis in normal pregnancy: a balancing act? Biochem Soc Trans 2005;33:428–32. in Google Scholar

25. O’Riordan, MN, Higgins, JR. Haemostasis in normal and abnormal pregnancy. Best Pract Res Clin Obstet Gynaecol 2003;17:385–96. in Google Scholar

26. Brenner, B. Hemostatic changes in pregnancy. Thromb Res 2004;114:409–14. in Google Scholar PubMed

27. 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;82:591–4. in Google Scholar

28. Hellgren, M. Hemostasis during normal pregnancy and puerperium. Semin Thromb Hemost 2003;29:125–30. in Google Scholar PubMed

29. Moiz, B. A review of haemostasis in normal pregnancy and puerperium. Natl J Health Sci 2017;2:123–7. in Google Scholar

30. Ghosh, A, Cockrell, E, Silverstein, R. Platelet CD36 mediates interactions with endothelial cell-derived microparticles and contributes to thrombosis in mice. J Clin Invest 2008;118:1934–43. in Google Scholar PubMed PubMed Central

31. Alijotas-Reig, J, Palacio-Garcia, C, Llubra, E, Villardell-Tarres, M. Cell-derived microparticles and vascular pregnancy complications: a systematic and comprehensive review. Fertil Steril 2013;99:441–9. in Google Scholar PubMed

32. Cines, DB, Levine, LD. Thrombocytopenia in pregnancy. Blood 2017;130:2271–7. in Google Scholar PubMed PubMed Central

33. Yan, M, Malinowski, AK, Shehata, N. Thrombocytopenic syndromes in pregnancy. Obstet Med 2016;9:15–20. in Google Scholar PubMed PubMed Central

34. Sheu, JR, Hsiao, G, Shen, MY, Lin, WY, Tzeng, CR. The hyperaggregability of platelets from normal pregnancy is mediated through thromboxane A2 and cyclic AMP pathways. Clin Lab Haemotol 2002;24:121–9. in Google Scholar

35. Taylor, J, Hicks, CW, Heller, JA. The hemodynamic effects of pregnancy on the lower extremity venous system. J Vasc Surg Venous Lymphat Disord 2018;6:246–55. in Google Scholar PubMed

36. Krabbendam, I, Spaanderman, ME. Venous adjustments in healthy and hypertensive pregnancy. Expet Rev Obstet Gynecol 2007;2:671–9. in Google Scholar

37. Soma-Pillay, P, Nelson-Piercy, C, Tolppanen, H, Mebazaa, A. Physiological changes in pregnancy. Cardiovasc J Afr 2016;27:89–94. in Google Scholar

38. Burwen, DR, Wu, C, Cirillo, D, Rossouw, JE, Margolis, KL, Limacher, M, et al.. Venous thromboembolism incidence, recurrence and mortality based on Women’s Health Initiative Data and Medicare claims. Thromb Res 2017;T.150:S78–85. in Google Scholar PubMed

39. De Stefano, V, Chiusolo, P, Paciaroni, K, Leone, G. Epidemiology of Factor V Leiden: clinical implications. Semin Thromb Hemost 1998;24:367–79. in Google Scholar PubMed

40. Limdi, NA, Beasley, TM, Allison, DB, Rivers, CA, Acton, RT. Racial differences in the prevalence of Factor V Leiden mutation among patients on chronic warfarin therapy. Blood Cells Mol Dis 2006;37:100–6. in Google Scholar PubMed PubMed Central

41. Nelson-Piercy, C. Thromoembolic disease. Handbook of obstetric medicine, 5th ed. New York: CRC Press Taylor&Francis Group; 2015:47–9 pp. Chapter 3.10.1201/b18316Search in Google Scholar

42. Iorio, A, Kearon, C, Filippucci, E, Marcucci, M, Macura, A, Pengo, V, 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;170:1710–6. in Google Scholar PubMed

43. Bates, SM. Pregnancy-associated venous thromboembolism: prevention and treatment. Semin Hematol 2011;48:271–84. in Google Scholar PubMed

44. Villani, M, Favuzzi, G, Totaro, P, Chinni, E, Vecchione, G, Vergura, P, et al.. Venous thromboembolism in assisted reproductive technologies: comparison between unsuccessful versus successful cycles in an Italian cohort. J Thromb Thrombolysis 2018;45:234–9. in Google Scholar PubMed

45. Czihal, M, Hoffmann, U. Upper extremity deep venous thrombosis. Vasc Med 2011;16:191–202. in Google Scholar PubMed

46. Grandone, E, Di Micco, PP, Villani, M, Colaizzo, D, Fernandez-Capitan, C, Del Toro, J, et al.. RIETE investigators. Venous thromboembolism in women undergoing assisted reproductive technologies: data from the RIETE registry. Thromb Haemostasis 2018;118:1962–1968. in Google Scholar PubMed

47. Bates, SM, Rajasekhar, A, Middeldorp, S, McLintock, C, Rodger, MA, James, AH, et al.. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv 2018;2:3317–59. in Google Scholar PubMed PubMed Central

48. Prusova, K, Churcher, L, Tyler, A, Lokugamage, AU. Royal College of Obstetricians and Gynaecologists Guidelines: how evidence-based are they? J Obstet Gynaecol 2014;34:706–11. in Google Scholar PubMed PubMed Central

49. Michikawa, T, Nitta, H, Nakayama, SF, Yamazaki, S, Isobe, T, Tamura, K, et al.. Japan Environment and Children’s Study Group. Baseline profile of participants in the Japan Environment and Children’s Study (JECS). J Epidemiol 2018;28:99–104. in Google Scholar

50. Sugiura-Ogasawara, M, Ebara, T, Matsuki, T, Yamada, Y, Omori, T, Yosuke Matsumoto, Y, et al.. Japan Environment & Children’s Study (JECS). Endometriosis and recurrent pregnancy loss as new risk factors for venous thromboembolism during pregnancy and post-partum: the JECS birth cohort. Thromb Haemostasis 2019;119:606–17. in Google Scholar PubMed

51. Kimura, R, Honda, S, Kawasaki, T, Tsuji, H, Madoiwa, S, Sakata, Y, et al.. Protein S-K196E mutation as a genetic risk factor for deep vein thrombosis in Japanese patients. Blood 2006;107:1737–8. in Google Scholar PubMed

52. Giudice, LC. Clinical practice. Endometriosis. N Engl J Med 2010;362:2389–98. in Google Scholar PubMed PubMed Central

53. Miyakis, S, Lockshin, MD, Atsumi, T, Branch, DW, Brey, RL, Cervera, R, et al.. International concensus statement on an update of the classification criteria for definite antiphospholipide syndrome (APS). J Thromb Haemostasis 2006;4:295–306. in Google Scholar PubMed

54. Pereza, N, Ostojić, S, Kapović, M, Peterlin, B. Systematic review and meta-analysis of genetic association studies in idiopathic recurrent spontaneous abortion. Fertil Steril 2017;107:150–9. in Google Scholar PubMed

55. Okoroh, EM, Hooper, WC, Atrash, HK, Yusuf, HR, Boulet, SL. Is polycystic ovary syndrome another risk factor for venous thromboembolism? United States, 2003–2008. Am J Obstet Gynecol 2012;207:377.e1–e8. in Google Scholar PubMed PubMed Central

56. Van Cott, EM, Khor, B, Zehnder, JL. Factor V Leiden. Am J Hematol 2016;91:46–9. in Google Scholar PubMed

57. Dahlbaeck, B. Early days of APC resistance and FV Leiden. Haemostaseologie 2008;28:103–9.10.1055/s-0037-1617167Search in Google Scholar

58. Mannucci, PM, Franchini, M. Classic thrombophilic gene variants. Thromb Haemostasis 2015;114:885–9. in Google Scholar PubMed

59. Louis-Jacques, AF, Maggio, L, Romero, ST. Prenatal screening for thrombophilias: indications and controversies, an update. Clin Lab Med 2016;36:421–34. in Google Scholar PubMed

60. Jenkins, PV, Rawley, O, Smith, OP, O’Donnell, JS. Elevated Factor VIII levels and risk of venous thrombosis. Br J Haematol 2012;157:653–63. in Google Scholar PubMed

61. Franchini, M, Mannucci, PM. ABO blood group and thrombotic vascular disease. Thromb Haemostasis 2014;112:1103–9. in Google Scholar PubMed

62. Timp, JF, Lijfering, WM, Flinterman, LE, van Hylckama Vlieg, A, le Cessie, S, Rosendaal, FR, et al.. Predictive value of factor VIII levels for recurrent venous thrombosis: results from the MEGA follow-up study. J Thromb Haemostasis 2015;13:1823–32. in Google Scholar PubMed

63. Parunov, LA, Soshitova, NP, Ovanesov, MA, Panteleev, MA, SerebrivskyII. Epidemiology of venous thromboembolism (VTE) associated with pregnancy. Birth Defects Res C Embryo Today 2015;105:167–84. in Google Scholar PubMed

64. Pomp, ER, Lenselink, AM, Rosendaal, FR, Doggen, CJM. Pregnancy, the postpartum period and prothrombotic defects: risk of venous thrombosis in the MEGA study. J Thromb Haemostasis 2008;6:632–7. in Google Scholar PubMed

65. Stefano, VD, Grandone, E, Martinelli, I. Recommendations for prophylaxis of pregnancy-related venous thromboembolism in carriers of inherited thrombophilia. Comment on the 2012 ACCP Guidelines. J Thromb Haemostasis 2013;11:1779–81. in Google Scholar PubMed

66. 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. in Google Scholar PubMed PubMed Central

67. Cuker, A. Clinical scoring system in thrombosis and hemostasis. Semin Thromb Hemost 2017;43:447–8. in Google Scholar PubMed

68. Calhaz-Jorge, C, de Geyter, C, Kupka, MS, de Mouzon, J, Erb, K, Mocanu, E, et al.. European IVF Monitoring Consortium (EIM) for the European Society of Human Reproduction and Embryology (ESHRE). Assisted reproductive technology in Europe, 2012: results generated from European registers by ESHRE. Hum Reprod 2016;31:1638–52. in Google Scholar PubMed

69. Delvigne, A, Rozenberg, S. Epidemiology and prevention of ovarian hyperstimulation syndrome (OHSS): a review. Hum Reprod Update 2002;8:559–77. in Google Scholar PubMed

70. Szpera-Gozdzievich, A, Majcherek, M, Boruczkowski, M, Gozdziewicz, T, Dworacki, G, Wicherek, L, et al.. Circulating endothelial cells, circulating endothelial progenitor cells and von Willebrand factor in pregnancies complicated by hypertensive disorders. Am J Reprod Immunol 2017;77:е12625.10.1111/aji.12625Search in Google Scholar PubMed

71. Lattuada, A, Rossi, E, Calzarossa, C, Candolfi, R, Mannucci, PM. Mild to moderate reduction of a von Willebrand factor cleaving protease (ADAMTS-13) in pregnant women with HELLP microangiopatic syndrome. Hematologica 2003;88:1029–34.Search in Google Scholar

72. Aref, S, Goda, H. Increased VWF antigen levels and decreased ADAMTS13 activity in preeclampsia. Hematology 2013;18:237–24. in Google Scholar PubMed

73. Trigg, DE, Wood, MG, Kouides, PA, Kadir, RA. Hormonal influence on hemostasis in women. Semin Thromb Hemost 2011;37:77–86. in Google Scholar PubMed

74. Lenting, PJ, Casari, C, Christophe, OD, Denis, CV. von Willebrand factor: the old, the new and the unknown. J Thromb Haemostasis 2012;10:2428–37. in Google Scholar PubMed

75. Calabro, P, Gragnano, F, Golia, E, Grove, EL. Von Willebrand factor and venous thromboembolism: pathogenic link and therapeutic implications. Semin Thromb Hemost 2018;44:249–60. in Google Scholar PubMed

76. Hoxa, A, Mattia, E, Tonello, M, Grava, C, Pengo, V, Ruffatti, A. Antiphosphatidylserine/antiprothrombin antibodies as biomarkers to identify severe primary antiphospholipid syndrome. Clin Chem Lab Med 2017;55. in Google Scholar PubMed

77. Franchini, M, Martinelli, I, Mannucci, PM. Uncertain thrombophilia markers. Thromb Haemostasis 2016;115:25–30. in Google Scholar PubMed

78. Anthony, W, Austin, A, Wissmann, T, von Kanel, R. Stress and haemostasis: an update. Semin Thromb 2013;39:902–12. in Google Scholar PubMed

79. Tang, L, Wang, QY, Cheng, ZP, Hu, B, Liu, JD, Hu, Y. Air pollution and venous thrombosis: a meta-analysis. Sci Rep 2016;6:32794. in Google Scholar PubMed PubMed Central

80. Giaglis, S, Stoikou, M, Sur Chowdhury, C, Schaefer, G, Grimolizzi, F, Rossi, SW, et al.. Multimodal regulation of NET formation in pregnancy: progesterone antagonizes the pro-NETotic effect of estrogen and G-CSF. Front Immunol 2016;7:565. in Google Scholar PubMed PubMed Central

81. Scheres, LJJ, Lijfering, WM, Cannegieter, SC. Current and future burden of venous thrombosis: not simply predictable. Res Pract Thromb Haemost 2018;2:199–208. in Google Scholar PubMed PubMed Central

Received: 2022-01-07
Accepted: 2022-01-07
Published Online: 2022-01-20
Published in Print: 2022-06-27

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