Complex evaluation of coagulation, fibrinolysis, and inflammatory cytokines in SARS-CoV-2 infected pregnant women: a prospective, case-control study

Zsuzsa Bagoly ^1* Eszter Lilla Tóth ^2,3 Rita Orbán-Kálmãndi ⁴ Linda Lóczi ⁵ Tamás Deli ² Olga Torok ² Bence Kozma ² Sándor Baráth ⁶ Parvind Singh ⁶ Zsuzsanna Hevessy ⁶ Judit Tóth ⁶ Éva Katona ¹ Szabolcs Molnár ² Zoard Krasznai ²

• ¹ Division of Clinical Laboratory Sciences, Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary, Debrecen, Hungary
• ² Department of Obstetrics and Gynecology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary
• ³ Doctoral School of Molecular Medicine, University of Debrecen, Debrecen, Hungary
• ⁴ Healthcare Industry Institute, University of Debrecen, Faculty of Pharmacy, Debrecen, Hungary
• ⁵ Division of Clinical Laboratory Sciences, Department of Laboratory Medicine, Faculty of Medicine, Kálmán Laki Doctoral School University of Debrecen, Debrecen, Hungary, Debrecen, Hungary
• ⁶ Department of Laboratory Medicine, Faculty of Medicine, University of Debrecen, Debrecen, Hungary

Background. Given the physiological hemostasis changes during pregnancy, limited data exists on COVID-19-induced inflammatory response and hemostasis alterations in pregnant women. Objectives. To test a comprehensive set of hemostasis and inflammatory cytokines in pregnancies with/without COVID-19 and correlate results with maternal and perinatal outcomes. Patients/Methods. In this observational case-control study, 100 women with acute COVID-19 at 24-40 gestational weeks (COVID-19+ group), and 100 healthy, age-and gestational week-matched, SARS-CoV-2 negative pregnant women (32 with proven recovery of COVID-19) were enrolled. All women were outpatients with mild/no symptoms at admission. Detailed hemostasis (fibrinogen, FVIII, FXIII, VWF, plasminogen, α2-plasmin inhibitor, PAI-1, thrombin generation, clot lysis, D-dimer) and inflammatory cytokine/chemokine panels were performed. Clinical parameters of pregnancy, labour and postpartum period were registered. Results. COVID-19+ women exhibited significantly lower FVIII, FXIII, plasminogen, higher VWF levels, decreased peak thrombin and enhanced clot lysis vs. controls. Despite mild/no symptoms, significantly elevated cytokine levels, including IL-6, INF-γ, MCP-1, and IL-18 were observed in COVID-19+ pregnancies, associated with distinct hemostasis alterations. Admission IL-1β and IL-33 were significantly lower, while IL-18 was significantly higher in cases when COVID-19 became more severe, along with significantly decreased FVIII, FXIII and plasminogen. In the COVID-19+ group, postpartum hemorrhage (PPH) developed in 4 cases, associated with significantly reduced plasminogen, α2-plasmin inhibitor, and increased IL-8, IL-17A, IL-23 levels. Conclusion. In third trimester mild/asymptomatic COVID-19+ pregnancies, marked inflammatory cytokine changes, hemostasis alterations and enhanced fibrinolysis were found. A potential link between inflammation and PPH in the context of COVID-19 warrants further research.