Early prognostic markers of adverse outcomes associated with hemostasis and fibrinolysis in severe COVID‐19 infection

Abstract

Summary. Introduction. The mechanisms underlying coagulopathy associated with severe COVID‐19, focusing on outcomes of this infectious disease during the first week after emergency admission to an infectious disease hospital. Aim: to identify prognostic markers related to the inflammatory response, hemocoagulation, and fibrinolysis that are associated with an adverse outcome in SARS‐CoV‐2 infection. Materials and Methods. A two‐center observational study was conducted in 2021–2022 and included 96 patients aged 22–80 years with a verified diagnosis of severe or critical COVID‐19. Examinations were performed within the first 24 hours after admission to the intensive care unit (ICU) of a COVID hospital. A set of 32 laboratory methods was used to assess parameters reflecting markers of the inflammatory response and endotheliopathy, as well as changes in the vascular–platelet, coagulation, and anticoagulant components of the haemostatic system and fibrinolytic reactions. Results. Mortality within the first week after hospitalization was 53%. When analysing laboratory parameters during the initiation of intensive therapy, including active oxygen therapy, eight parameters were identified as prognostically unfavourable. These included markers of endotheliopathy (von Willebrand factor and thrombomodulin), prothrombin, physiological anticoagulants (antithrombin and protein C), and, within the fibrinolytic system, levels of D‐dimer, plasminogen, and t‐PA/PAI‐1 complex (tissue plasminogen activator/plasminogen activator inhibitor‐1). Conclusion. The presented data may be useful for clinical decision‐making, including intensification of therapy, in the context of disease caused by new genetic variants of SARS‐CoV‐2.

For citation: Momot D.A., Mamaev A.N., Momot A.P., Fedorov D.V., Shakhmatov I.I., Belozerskaya G.G., Tsyvkina L.P. Early prognostic markers of adverse outcomes associated with hemostasis and fibrinolysis in severe COVID‐19 infection. Tromboz, gemostaz i reologiya. 2026;(2):27–36. (In Russ.).

References 

1.      Connors J.M., Levy J.H. COVID‐19 and its implications for thrombosis and anticoagulation. Blood. 2020;135(23):2033–40. DOI: 10.1182/ blood.2020006000.

2.      Li Y., Deng Y., Ye L., et al. Clinical significance of plasma D‐dimer in COVID‐19 mortality. Front Med (Lausanne). 2021;8:638097. DOI: 10.3389/fmed.2021.638097.

3.      Hanafi F.D., Esa T., Nurulita A., Mumang A.A. D‐Dimer, ferritin, and lactate dehydrogenase (LDH) as predictors of mortality in hospitalized COVID‐19 patients. J Infect Dev Ctries. 2024;18(9.1): S27–S32. DOI: 10.3855/jidc.18833.

4.      Yan L., Zhang H‐T., Goncalves J. et al. An interpretable mortality prediction model for COVID‐19 patients. Nat Mach Intell. 2020;2:283–8.

5.      Diniz S.M., Mauad V.A.Q., Fernandes C.C.F., Bacci M.R. Evaluation of d‐dimer as outcome biomarker in COVID‐19 acute respiratory distress patients. Rev Inst Med Trop Sao Paulo. 2024;23(66):e57. DOI: 10.1590/S1678‐9946202466057.

6.      Dumache R., Muresan C.O., Laitin S.M.D. et al. COVID‐19 organ injury pathology and D‐dimer expression patterns: a retrospective analysis. Diagnostics (Basel). 2025;15(15):1860. DOI: 10.3390/ diagnostics15151860.

7.      Matvienko O.U., Smirnova O.A., Korsakova N.E. et al. The prognostic value of some hemostasis parameters predicting the course of a new coronavirus infection. Vestnik gematologii. 2023;19(3):18– 21. (In Russ.).

8.      Matvienko O.Yu., Smirnova O.A., Golovina O.G. Determination of predictors of adverse disease outcome in patients with COVID‐19 based on hemostasis system analysis. Medicina ekstremal’nyh situ- acij. 2025;27(4):587–93. DOI 10.47183/mes.2025–306. (In Russ.).

9.      Clinical laboratory diagnostics. National guidelines. Eds. V.V. Dolgov, V.V. Menshikov. Vol. 1. Moscow: GEOTAR-Media, 2012. 928 pр. (In Russ.).

1. Barkagan Z.S., Momot A.P. Diagnostics and controlled therapy of hemostasis disorders: monograph. 3‐e izd. Moscow: N’yudiamed, 2008. 292 pр. (In Russ.).
2. Mamaev A.N., Gilmanov A.Zh., Vavilova T.V., Momot A.P. The preanalytical stage of studying the hemostatic system. Klinicheskaya laboratornaya diagnostika. 2011;(4):35–8. (In Russ.).
3. Mehta D.F., Mc Auley M., Brown E. et al. COVID‐19: consider cytokine storm syndromes and immunosuppression. Lancet. 2020;395(10229):1033–4. DOI: 10.1016/S0140‐6736(20)30628‐0.
4. Sinkovits G., Réti M., Müller V. et al. Associations between the von Willebrand factor‐ADAMTS13 axis, complement activation, and COVID‐19 severity and mortality. Thromb Haemost. 2022;122(2):240–56. DOI: 10.1055/s‐0041‐1740182.
5. Goshua G., Pine A.B., Meizlish M.L. et al. Endotheliopathy in COVID‐19‐associated coagulopathy: evidence from a single‐centre, cross‐sectional study. Lancet Haematol. 2020;7(8):e575‐е582. DOI: 10.1016/S2352‐3026(20)30216‐7.
6. Bazzan M., Montaruli B., Sciascia S. et al. Low ADAMTS 13 plasma levels are predictors of mortality in COVID‐19 patients. Intern Emerg Med. 2020;15(5):861–3. DOI: 10.1007/s11739‐020‐02394‐0.
7. Al‐Samkari H., Karp Leaf R.S., Dzik W.H. et al. COVID‐19 and coagulation: bleeding and thrombotic manifestations of SARSCoV‐2 infection. Blood. 2020;136(4):489–500. DOI: 10.1182/blood. 2020006520.
8. Wool G. D., Miller J. L. The impact of COVID‐19 disease on platelets and coagulation. Pathobiology. 2021;88(1):15–27. DOI: 10.1159/000512007.
9. Lippi G., Plebani M., Henry B.M. Thrombocytopenia is associated with severe coronavirus disease 2019 (COVID‐19) infections: a meta‐analysis. Clin Chim Acta. 2020;506:145–8. DOI: 10.1016/j.cca.2020.03.022.
10. Gong J., Ou J., Qiu X. et al. A tool for early prediction of severe coronavirus disease 2019 (COVID‐19): a multicenter study using the risk nomogram in Wuhan and Guangdong, China. Clin Infect Dis. 2020;71(15):833–40. DOI: 10.1093/cid/ciaa443.
11. Wang D., Hu B., Hu C. et al. Clinical characteristics of 138 hospitalized patients with 2019 novel Coronavirus–Infected pneumonia in Wuhan, China. JAMA. 2020;323(11):1061–9. DOI: 10.1001/ jama.2021.1585.
12. Bashash D., Abolghasemi H., Salari S. Elevation of D‐dimer, but not Pt and aPTT, reflects the progression of covid‐19 toward an unfavorable outcome: a meta‐analysis. Iran J Blood Cancer. 2020;12:47–53.
13. Asakura H., Ogawa H. COVID‐19‐associated coagulopathy and disseminated intravascular coagulation. Int J Hematol. 2021;113(1):45– 57. DOI: 10.1007/s12185‐020‐03029‐y.
14. Parks A.L., Auerbach A.D., Schnipper J.L. et al. COVID‐19 coagulopathy and thrombosis: analysis of hospital protocols in response to the rapidly evolving pandemic. Thromb Res. 2020;196:355–8. DOI: 10.1016/j.thromres.2020.09.018.
15. 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(4):844–7. DOI: 10.1111/jth.14768.
16. Stefely J.A., Christensen B.B., Gogakos T. et al. Marked factor V activity elevation in severe COVID‐19 is associated with venous thromboembolism. Am J Hematol. 2020;95(12):1522–30. DOI: 10.1002/ajh.25979.
17. Helms J., Tacquard C., Severac F. et al. High risk of thrombosis in patients with severe SARSCoV‐2 infection: a multicenter prospective cohort study. Intensive Care Med. 2020;46(6):1089–98. DOI: 10.1007/s00134‐020‐06062‐x.
18. Nougier C., Benoit R., Simon M. et al. Hypofibrinolytic state and high thrombin Generation may play a major role in SARS‐COV2 associated thrombosis. J Thromb Haemost. 2020;18(9):2215–9. DOI: 10.1111/jth.15016.
19. Levi M., Toh C.H., Thachil J., Watson H.G. Guidelines for the diagnosis and management of disseminated intravascular coagulation. British Committee for Standards in Haematology. Br J Hae- matol. 2009;145(1):24–33. DOI: 10.1111/j.1365‐2141.2009.07600.x.
20. Lee R.H., Wang S., Akerman M., D’Andrea J. Role of peak Ddimer in predicting mortality and venous thromboembolism in COVID‐19 patients. Sci Prog. 2025;108(1):368504241247982. DOI: 10.1177/00368504241247982.
21. Hvas C.L, Larsen J.B., Adelborg K. et al. Dynamic hemostasis and fibrinolysis assays in Intensive care COVID‐19 patients and association with thrombosis and bleeding — a systematic review and a cohort study. Semin Thromb Hemost. 2022;48(1):31–54. DOI: 10.1055/s‐0041‐1735454.
22. Whyte C.S., Simpson M., Morrow G.B. et al. The suboptimal fibrinolytic response in COVID‐19 is dictated by high PAI‐1. J Thromb Haemost. 2022;20(10):2394–406. DOI: 10.1111/jth.15806.
23. Wright F.L., Vogler T.O., Moore E.E. et al. Fibrinolysis shutdown correlates to thromboembolic events in severe COVID‐19 infection. J Am Coll Surg. 2020;231(2):193–203.e1. DOI: 10.1016/j.jamcollsurg.2020.05.007.
24. Liao D., Zhou F., Luo L. et al. Haematological characteristics and risk factors in the classification and prognosis evaluation of COVID‐19: a retrospective cohort study. Lancet Haematol. 2020;7(9):e671‐e678. DOI: 10.1016/S2352‐3026(20)30217‐9.
25. Zhou F., Yu T., Du R. et al. Clinical course and risk factors for mortality of adult inpatients with COVID‐19 in Wuhan, China: a retrospective cohort study. Lancet. 2020;395(10229):1054–62. DOI: 10.1016/S0140‐6736(20)30566‐3.
26. Wu Y.P., Wei R., Liu Z.H. et al. Analysis of thrombotic factors in severe acute respiratory syndrome (SARS) patients. Thromb Hae- most. 2006;96(1):100–1. DOI: 10.1160/TH05‐12‐0827.
27. Grimmer B., Kuebler W.M. The endothelium in hypoxic pulmonary vasoconstriction. J Appl Physiol (1985). 2017;123(6):1635–46. DOI: 10.1152/japplphysiol.00120.2017.
28. Barkagan Z.S. Hemostasis. In: Guidelines for Hematology. Ed. A.I. Vorobyov. Moscow: Newdiamed, 2005. Vol. 3. 9–147. (In Russ.).
29. Hoffman M., Monroe D.M. A cell‐based model of hemostasis. Thromb.Haemost. 2001;85(6):958–65.
30. Rijken D.C., Lijnen H.R. New insights into the molecular mechanisms of the fibrinolytic system. J Thromb Haemost. 2009;7(1):4– 13. DOI: 10.1111/j.1538‐7836.2008.03220.x.
31. Zuo Y., Warnock M., Harbaugh A. et al. Plasma tissue plasminogen activator and plasminogen activator inhibitor‐1 in hospitalized COVID‐19 patients. Sci Rep. 2021;11(1):1580. DOI: 10.1038/s41598‐020‐80010‐z.
32. Bach‐Gansmo E.T., Strand O., Godal H.C. et al. Discrepancy between latex and ELISA D‐dimer values in sepsis may be caused by human neutrophil elastase. Thromb Res. 1997;86(2):141–52. DOI: 10.1016/ s0049‐3848(97)00057‐1.
33. Plow E.F., Gramse M., Havemann K. Immunochemical discrimination of leukocyte elastase from plasmic degradation products of fibrinogen. J Lab Clin Med. 1983;102(6):858–69.