Premorbid Hemostasis in Women with a History of Pregnancy LossFunding This work was supported by NIH grants HL135254, U01HL116330, NSF grant DMR1505662, the Program for Competitive Growth at Kazan Federal University, grants 19–015–00075, 18–415–160004, and 19–51–15004 from the Russian Foundation for Basic Research, a grant of the Ministry of Science and Higher Education of the Russian Federation (project АААА-А18–118012390250–0), and a grant of the Presidium of the Russian Academy of Sciences (the Program for fundamental research “Fundamentals of the technology of physiological adaptations”).
23 May 2019
19 July 2019
06 October 2019 (online)
Background Congenital and acquired hemostatic disorders are among the pathogenic factors of pregnancy loss. Studying mechanistic relations between impaired hemostasis and fetal losses is important for the prognosis and prophylaxis of obstetric complications.
Objective This article aims to establish latent hemostatic disorders in nonpregnant women as an important premorbid risk factor of pregnancy loss.
Methods and Results Hemostasis was characterized using two relatively new in vitro assays, namely thrombodynamics (spatial clot growth) and kinetics of blood clot contraction, which together reflect the hemostatic or thrombotic potential. In addition, platelet functionality was assessed using flow cytometry. Our study included 50 women with a history of pregnancy loss and 30 parous women without previous obstetric complications. In patients with pregnancy loss, hypercoagulability was observed along with significant impairment of blood clot contraction associated with chronic platelet activation and dysfunction. Both hypercoagulability and defective clot contraction were significantly more pronounced in patients with a history of three or more miscarriages compared with patients with a history of one or two miscarriages. In addition, a significant inhibition of clot contraction was found in patients with miscarriage occurring after 10 weeks of gestation compared with those who lost a fetus earlier in pregnancy.
Conclusion These results indicate that chronic hypercoagulability and impaired clot contraction constitute a premorbid status in patients with pregnancy loss. The data confirm a significant pathogenic role of hemostatic disorders in pregnancy loss and suggest the predictive value of thrombodynamics and blood clot contraction assays in evaluating the risk of pregnancy loss.
R.I.L., S.I.S., F.I.A., and J.W.W designed the research; A.D.P. and N.G.E. performed experiments; A.D.P., S.I.S., Y.S.B., F.I.A., J.W.W., and R.I.L. analyzed the data; A.D.P., J.W.W., and R.I.L. wrote the paper.
- 1 Kolte AM, Bernardi LA, Christiansen OB. , et al; ESHRE Special Interest Group, Early Pregnancy. Terminology for pregnancy loss prior to viability: a consensus statement from the ESHRE early pregnancy special interest group. Hum Reprod 2015; 30 (03) 495-498
- 2 Ford HB, Schust DJ. Recurrent pregnancy loss: etiology, diagnosis, and therapy. Rev Obstet Gynecol 2009; 2 (02) 76-83
- 3 Practice Committee of the American Society for Reproductive Medicine. Evaluation and treatment of recurrent pregnancy loss: a committee opinion. Fertil Steril 2012; 98 (05) 1103-1111
- 4 de Jong PG, Goddijn M, Middeldorp S. Testing for inherited thrombophilia in recurrent miscarriage. Semin Reprod Med 2011; 29 (06) 540-547
- 5 Shahine L, Lathi R. Recurrent pregnancy loss: evaluation and treatment. Obstet Gynecol Clin North Am 2015; 42 (01) 117-134
- 6 Bennett SA, Bagot CN, Appiah A. , et al. Women with unexplained recurrent pregnancy loss do not have evidence of an underlying prothrombotic state: experience with calibrated automated thrombography and rotational thromboelastometry. Thromb Res 2014; 133 (05) 892-899
- 7 Soshitova NP, Karamzin SS, Balandina AN. , et al. Predicting prothrombotic tendencies in sepsis using spatial clot growth dynamics. Blood Coagul Fibrinolysis 2012; 23 (06) 498-507
- 8 Sinauridze EI, Gorbatenko AS, Seregina EA, Lipets EN, Ataullakhanov FI. Moderate plasma dilution using artificial plasma expanders shifts the haemostatic balance to hypercoagulation. Sci Rep 2017; 7 (01) 843
- 9 Tutwiler V, Litvinov RI, Lozhkin AP. , et al. Kinetics and mechanics of clot contraction are governed by the molecular and cellular composition of the blood. Blood 2016; 127 (01) 149-159
- 10 utwiler V, Peshkova AD, Andrianova IA, Khasanova DR, Weisel JW, Litvinov RI. Contraction of blood clots is impaired in acute ischemic stroke. Arterioscler Thromb Vasc Biol 2017; 37 (02) 271-279
- 11 Peshkova AD, Malyasev DV, Bredikhin RA. , et al. Contraction of blood clots is impaired in deep vein thrombosis. Bionanoscience 2016; 6: 457-459
- 12 Le Minh G, Peshkova AD, Andrianova IA. , et al. Impaired contraction of blood clots as a novel prothrombotic mechanism in systemic lupus erythematosus. Clin Sci (Lond) 2018; 132 (02) 243-254
- 13 Peshkova AD, Malyasyov DV, Bredikhin RA. , et al. Reduced contraction of blood clots in patients with venous thromboembolism is a possible thrombogenic and embologenic mechanism. TH Open 2018; 2 (01) e104-e115
- 14 Dundar O, Pektas MK, Bodur S, Bakır LV, Cetin A. Recurrent pregnancy loss is associated with increased red cell distribution width and platelet distribution width. J Obstet Gynaecol Res 2015; 41 (04) 551-558
- 15 Budzianowski J, Pieszko K, Burchardt P, Rzeźniczak J, Hiczkiewicz J. The role of hematological indices in patients with acute coronary syndrome. Dis Markers 2017; 2017: 3041565
- 16 Rai R, Tuddenham E, Backos M. , et al. Thromboelastography, whole-blood haemostasis and recurrent miscarriage. Hum Reprod 2003; 18 (12) 2540-2543
- 17 Bick RL, Hoppensteadt D. Recurrent miscarriage syndrome and infertility due to blood coagulation protein/platelet defects: a review and update. Clin Appl Thromb Hemost 2005; 11 (01) 1-13
- 18 Réger B, Péterfalvi A, Litter I. , et al. Challenges in the evaluation of D-dimer and fibrinogen levels in pregnant women. Thromb Res 2013; 131 (04) e183-e187
- 19 Szecsi PB, Jørgensen M, Klajnbard A, Andersen MR, Colov NP, Stender S. Haemostatic reference intervals in pregnancy. Thromb Haemost 2010; 103 (04) 718-727
- 20 Pasquier E, De Saint Martin L, Bohec C, Collet M, Dignat George F, Mottier D. Unexplained pregnancy loss: a marker of basal endothelial dysfunction?. Fertil Steril 2013; 100 (04) 1013-1017
- 21 Lukanov TH, Veleva GL, Konova EI, Ivanov PD, Kovacheva KS, Stoykov DJ. Levels of platelet-leukocyte aggregates in women with both thrombophilia and recurrent pregnancy loss. Clin Appl Thromb Hemost 2011; 17 (02) 181-187
- 22 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
- 23 Ke RW. Endocrine basis for recurrent pregnancy loss. Obstet Gynecol Clin North Am 2014; 41 (01) 103-112
- 24 Kitaya K, Matsubayashi H, Takaya Y. , et al. Live birth rate following oral antibiotic treatment for chronic endometritis in infertile women with repeated implantation failure. Am J Reprod Immunol 2017; 78 (05) e12719
- 25 Naser HA, Ibrahem AF, Hashim HA. Basophil count as predictor to the deep vein thrombosis and the thrombo-embolization. Muthanna Med. J. 2018; 5: 95-106
- 26 Glueck CJ, Kupferminc MJ, Fontaine RN, Wang P, Weksler BB, Eldor A. Genetic hypofibrinolysis in complicated pregnancies. Obstet Gynecol 2001; 97 (01) 44-48
- 27 Bigdeli R, Younesi MR, Panahnejad E. , et al. Association between thrombophilia gene polymorphisms and recurrent pregnancy loss risk in the Iranian population. Syst Biol Reprod Med 2018; 64 (04) 274-282
- 28 Adler G, Mahmutbegovic E, Valjevac A. , et al. Association between – 675 ID, 4G/5G PAI-1 gene polymorphism and pregnancy loss: f systematic review. Acta Inform Med 2018; 26 (03) 156-159
- 29 Magdoud K, Herbepin VG, Touraine R, Almawi WY, Mahjoub T. Plasminogen activator inhibitor 1 4G/5G and -844G/A variants in idiopathic recurrent pregnancy loss. Am J Reprod Immunol 2013; 70 (03) 246-252
- 30 Goodman CS, Coulam CB, Jeyendran RS, Acosta VA, Roussev R. Which thrombophilic gene mutations are risk factors for recurrent pregnancy loss?. Am J Reprod Immunol 2006; 56 (04) 230-236
- 31 Subrt I, Ulcova-Gallova Z, Cerna M. , et al. Recurrent pregnancy loss, plasminogen activator inhibitor-1 (-675) 4G/5G polymorphism and antiphospholipid antibodies in Czech women. Am J Reprod Immunol 2013; 70 (01) 54-58