Am J Perinatol
DOI: 10.1055/a-2211-5052
Original Article

Thrombotic Markers in Pregnant Patients with and without SARS-CoV-2 Infection

Ann M. Bruno
1   Department of Obstetrics & Gynecology, University of Utah Health, Salt Lake City, Utah
2   Department of Obstetrics & Gynecology, Intermountain Health, Salt Lake City, Utah
,
Amanda A. Allshouse
1   Department of Obstetrics & Gynecology, University of Utah Health, Salt Lake City, Utah
,
Ashley E. Benson
3   Department of Obstetrics & Gynecology, Oregon Health and Science University, Portland, Oregon
,
Christian Con Yost
1   Department of Obstetrics & Gynecology, University of Utah Health, Salt Lake City, Utah
4   Molecular Medicine Program, Molecular Medicine Program, University of Utah, Salt Lake City, Utah
,
Torri D. Metz
1   Department of Obstetrics & Gynecology, University of Utah Health, Salt Lake City, Utah
2   Department of Obstetrics & Gynecology, Intermountain Health, Salt Lake City, Utah
,
1   Department of Obstetrics & Gynecology, University of Utah Health, Salt Lake City, Utah
,
Robert M. Silver
1   Department of Obstetrics & Gynecology, University of Utah Health, Salt Lake City, Utah
,
D. Ware Branch
1   Department of Obstetrics & Gynecology, University of Utah Health, Salt Lake City, Utah
2   Department of Obstetrics & Gynecology, Intermountain Health, Salt Lake City, Utah
› Author Affiliations
Funding This work was supported by the James R. and Jo Scott Research Chair Endowment and the H.A. and Edna Benning Presidential Chair Endowment. C.C.Y. has received research support from Peel Therapeutics, Inc.

Abstract

Background Coronavirus disease 2019 (COVID-19) is associated with coagulation abnormalities and increased risk for venous and arterial thrombi. This study aimed to evaluate D-dimer levels and lupus anticoagulant (LAC) positivity in pregnant individuals with and without Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.

Study Design This was a prospective cohort study of pregnant individuals delivering at a single academic institution from April 2020 to March 2022. Individuals with a positive SARS-CoV-2 result during pregnancy were compared with a convenience sample of those without a positive SARS-CoV-2 result. For individuals with SARS-CoV-2 infection, severity was assessed based on the National Institutes of Health classification system. The primary outcome was D-dimer level measured during delivery admission. The secondary outcomes were LAC positivity and thromboembolic events. Outcomes were compared between individuals with and without a positive SARS-CoV-2 result, and further by disease severity.

Results Of 98 participants, 77 (78.6%) were SARS-CoV-2 positive during pregnancy. Among individuals with SARS-CoV-2 infection, severity was asymptomatic in 20 (26.0%), mild in 13 (16.9%), moderate in 4 (5.2%), severe in 38 (49.4%), and critical in 2 (2.6%). The D-dimer concentration at delivery did not significantly differ between those with a SARS-CoV-2 positive result compared with those without (mean 2.03 µg/mL [95% confidence interval {CI} 1.72–2.40] vs. 2.37 µg/mL [95% CI 1.65–3.40]; p = 0.43). Three individuals (4%) with SARS-CoV-2 infection and none (0%) without infection were LAC positive (p = 0.59). There were no clinically apparent thromboses in either group. D-dimer concentrations and LAC positive results did not differ by COVID-19 severity.

Conclusion Thrombotic markers did not differ in pregnant individuals by SARS-CoV-2 infection; however, high rates of LAC positivity were detected.

Key Points

  • Thrombotic markers did not differ in pregnant individuals by SARS-CoV-2 infection.

  • Higher than expected rates of LAC positivity were detected.

  • There were no clinically apparent thromboses.

Supplementary Material



Publication History

Received: 02 May 2023

Accepted: 13 November 2023

Accepted Manuscript online:
15 November 2023

Article published online:
07 December 2023

© 2023. Thieme. All rights reserved.

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  • References

  • 1 Guan WJ, Ni ZY, Hu Y. et al; China Medical Treatment Expert Group for Covid-19. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med 2020; 382 (18) 1708-1720
  • 2 Levi M, Thachil J, Iba T, Levy JH. Coagulation abnormalities and thrombosis in patients with COVID-19. Lancet Haematol 2020; 7 (06) e438-e440
  • 3 Cui S, Chen S, Li X, Liu S, Wang F. Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia. J Thromb Haemost 2020; 18 (06) 1421-1424
  • 4 Middeldorp S, Coppens M, van Haaps TF. et al. Incidence of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18 (08) 1995-2002
  • 5 Connors JM, Levy JH. COVID-19 and its implications for thrombosis and anticoagulation. Blood 2020; 135 (23) 2033-2040
  • 6 Panigada M, Bottino N, Tagliabue P. et al. Hypercoagulability of COVID-19 patients in intensive care unit: a report of thromboelastography findings and other parameters of hemostasis. J Thromb Haemost 2020; 18 (07) 1738-1742
  • 7 Middleton EA, He XY, Denorme F. et al. Neutrophil extracellular traps contribute to immunothrombosis in COVID-19 acute respiratory distress syndrome. Blood 2020; 136 (10) 1169-1179
  • 8 McBane II RD, Torres Roldan VD, Niven AS. et al. Anticoagulation in COVID-19: a systematic review, meta-analysis, and rapid guidance from Mayo Clinic. Mayo Clin Proc 2020; 95 (11) 2467-2486
  • 9 Bikdeli B, Madhavan MV, Jimenez D. et al; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC State-of-the-Art Review. J Am Coll Cardiol 2020; 75 (23) 2950-2973
  • 10 Sadeghipour P, Talasaz AH, Rashidi F. et al; INSPIRATION Investigators. Effect of intermediate-dose vs standard-dose prophylactic anticoagulation on thrombotic events, extracorporeal membrane oxygenation treatment, or mortality among patients with COVID-19 admitted to the intensive care unit: The INSPIRATION Randomized Clinical Trial. JAMA 2021; 325 (16) 1620-1630
  • 11 National Institutes of Health. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. Bethesda (MD): National Institutes of Health (U.S.); Accessed April 1, 2023 at: 2021. https://www.covid19treatmentguidelines.nih.gov/
  • 12 Zhang Y, Xiao M, Zhang S. et al. Coagulopathy and antiphospholipid antibodies in patients with Covid-19. N Engl J Med 2020; 382 (17) e38
  • 13 Ranucci M, Ballotta A, Di Dedda U. et al. The procoagulant pattern of patients with COVID-19 acute respiratory distress syndrome. J Thromb Haemost 2020; 18 (07) 1747-1751
  • 14 Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18 (04) 844-847
  • 15 Zhang L, Yan X, Fan Q. et al. D-dimer levels on admission to predict in-hospital mortality in patients with Covid-19. J Thromb Haemost 2020; 18 (06) 1324-1329
  • 16 Harzallah I, Debliquis A, Drénou B. Lupus anticoagulant is frequent in patients with Covid-19. J Thromb Haemost 2020; 18 (08) 2064-2065
  • 17 Gazzaruso C, Carlo Stella N, Mariani G. et al. High prevalence of antinuclear antibodies and lupus anticoagulant in patients hospitalized for SARS-CoV2 pneumonia. Clin Rheumatol 2020; 39 (07) 2095-2097
  • 18 Bowles L, Platton S, Yartey N. et al. Lupus anticoagulant and abnormal coagulation tests in patients with Covid-19. N Engl J Med 2020; 383 (03) 288-290
  • 19 Uthman IW, Gharavi AE. Viral infections and antiphospholipid antibodies. Semin Arthritis Rheum 2002; 31 (04) 256-263
  • 20 Caso F, Costa L, Ruscitti P. et al. Could Sars-coronavirus-2 trigger autoimmune and/or autoinflammatory mechanisms in genetically predisposed subjects?. Autoimmun Rev 2020; 19 (05) 102524
  • 21 Reyes Gil M, Barouqa M, Szymanski J, Gonzalez-Lugo JD, Rahman S, Billett HH. Assessment of lupus anticoagulant positivity in patients with coronavirus disease 2019 (COVID-19). JAMA Netw Open 2020; 3 (08) e2017539
  • 22 Ferrari E, Sartre B, Squara F. et al. High prevalence of acquired thrombophilia without prognosis value in patients with coronavirus disease 2019. J Am Heart Assoc 2020; 9 (21) e017773
  • 23 Di Renzo GC, Giardina I. Coronavirus disease 2019 in pregnancy: consider thromboembolic disorders and thromboprophylaxis. Am J Obstet Gynecol 2020; 223 (01) 135
  • 24 Ahmed I, Azhar A, Eltaweel N, Tan BK. First COVID-19 maternal mortality in the UK associated with thrombotic complications. Br J Haematol 2020; 190 (01) e37-e38
  • 25 Benhamou D, Keita H, Ducloy-Bouthors AS. Obstetric Anaesthesia and Critical Care Club Working Group. Coagulation changes and thromboembolic risk in COVID-19 obstetric patients. Anaesth Crit Care Pain Med 2020; 39 (03) 351-353
  • 26 Metz TD, Clifton RG, Hughes BL. et al; National Institute of Child Health and Human Development Maternal-Fetal Medicine Units (MFMU) Network. Association of SARS-CoV-2 infection with serious maternal morbidity and mortality from obstetric complications. JAMA 2022; 327 (08) 748-759
  • 27 Metz TD, Clifton RG, Hughes BL. et al; for the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) Maternal-Fetal Medicine Units (MFMU) Network. Disease Severity and perinatal outcomes of pregnant patients with coronavirus disease 2019 (COVID-19). Obstet Gynecol 2021; 137 (04) 571-580
  • 28 Silver RM, Draper ML, Scott JR, Lyon JL, Reading J, Branch DW. Clinical consequences of antiphospholipid antibodies: a historic cohort study. Obstet Gynecol 1994; 83 (03) 372-377
  • 29 Committee on Practice Bulletins—Obstetrics, American College of Obstetricians and Gynecologists. Practice Bulletin No. 132: Antiphospholipid syndrome. Obstet Gynecol 2012; 120 (06) 1514-1521
  • 30 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
  • 31 National Institutes of Health. Clinical Spectrum of SARS-CoV-2 Infection. Coronavirus Disease 2019 (COVID-19) Treatment Guidelines. 2020 . Accessed April 1, 2023 at: https://www.covid19treatmentguidelines.nih.gov/overview/clinical-spectrum/
  • 32 Devreese KMJ, de Groot PG, de Laat B. et al. Guidance from the Scientific and Standardization Committee for lupus anticoagulant/antiphospholipid antibodies of the International Society on Thrombosis and Haemostasis: Update of the guidelines for lupus anticoagulant detection and interpretation. J Thromb Haemost 2020; 18 (11) 2828-2839
  • 33 Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)–a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform 2009; 42 (02) 377-381
  • 34 von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP. STROBE Initiative. The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. Lancet 2007; 370 (9596) 1453-1457
  • 35 Paliogiannis P, Mangoni AA, Dettori P, Nasrallah GK, Pintus G, Zinellu A. D-dimer concentrations and COVID-19 severity: a systematic review and meta-analysis. Front Public Health 2020; 8: 432
  • 36 Huang C, Wang Y, Li X. et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395 (10223): 497-506
  • 37 Short SAP, Gupta S, Brenner SK. et al; STOP-COVID Investigators. D-dimer and death in critically ill patients with coronavirus disease 2019. Crit Care Med 2021; 49 (05) e500-e511
  • 38 Goligher EC, Bradbury CA, McVerry BJ. et al; REMAP-CAP Investigators, ACTIV-4a Investigators, ATTACC Investigators. Therapeutic anticoagulation with heparin in critically ill patients with Covid-19. N Engl J Med 2021; 385 (09) 777-789
  • 39 Sholzberg M, Tang GH, Rahhal H. et al; RAPID trial investigators. Effectiveness of therapeutic heparin versus prophylactic heparin on death, mechanical ventilation, or intensive care unit admission in moderately ill patients with covid-19 admitted to hospital: RAPID randomised clinical trial. BMJ 2021; 375 (2400) n2400
  • 40 Spyropoulos AC, Goldin M, Giannis D. et al; HEP-COVID Investigators. Efficacy and safety of therapeutic-dose heparin vs standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19: The HEP-COVID Randomized Clinical Trial. JAMA Intern Med 2021; 181 (12) 1612-1620
  • 41 Grgić G, Cerovac A, Hudić I. et al. Clinical manifestation and obstetric outcomes in pregnant women with SARS-CoV-2 infection at delivery: a retrospective cohort analysis. J Pers Med 2022; 12 (09) 12
  • 42 Kovac MK, Lalic-Cosic SZ, Dmitrovic JM, Djordjevic VJ, Radojkovic DP. Thrombin generation, D-dimer and protein S in uncomplicated pregnancy. Clin Chem Lab Med 2015; 53 (12) 1975-1979
  • 43 Kline JA, Williams GW, Hernandez-Nino J. D-dimer concentrations in normal pregnancy: new diagnostic thresholds are needed. Clin Chem 2005; 51 (05) 825-829
  • 44 Morse M. Establishing a normal range for D-dimer levels through pregnancy to aid in the diagnosis of pulmonary embolism and deep vein thrombosis. J Thromb Haemost 2004; 2 (07) 1202-1204
  • 45 Lombardi A, Duiella S, Li Piani L. et al. Inflammatory biomarkers in pregnant women with COVID-19: a retrospective cohort study. Sci Rep 2021; 11 (01) 13350
  • 46 Mantovani Cardoso E, Hundal J, Feterman D, Magaldi J. Concomitant new diagnosis of systemic lupus erythematosus and COVID-19 with possible antiphospholipid syndrome. Just a coincidence? A case report and review of intertwining pathophysiology. Clin Rheumatol 2020; 39 (09) 2811-2815
  • 47 Devreese KMJ, Linskens EA, Benoit D, Peperstraete H. Antiphospholipid antibodies in patients with COVID-19: a relevant observation?. J Thromb Haemost 2020; 18 (09) 2191-2201
  • 48 Gozzoli GI, Piovani E, Negri B. et al. Frequency of positive antiphospholipid antibodies in pregnant women with SARS-CoV-2 infection and impact on pregnancy outcome: a single-center prospective study on 151 pregnancies. Front Immunol 2022; 13: 953043
  • 49 Pattison NS, Chamley LW, McKay EJ, Liggins GC, Butler WS. Antiphospholipid antibodies in pregnancy: prevalence and clinical associations. Br J Obstet Gynaecol 1993; 100 (10) 909-913
  • 50 Gibbins KJ, Tebo AE, Nielsen SK, Branch DW. Antiphospholipid antibodies in women with severe preeclampsia and placental insufficiency: a case-control study. Lupus 2018; 27 (12) 1903-1910