Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2020 Oct 28;9(11):3487.
doi: 10.3390/jcm9113487.

Covid-19-Associated Coagulopathy: Biomarkers of Thrombin Generation and Fibrinolysis Leading the Outcome

Marco Ranucci  1 , Clementina Sitzia  2 , Ekaterina Baryshnikova  1 , Umberto Di Dedda  1 , Rosanna Cardani  3 , Fabio Martelli  4 , Massimiliano Corsi Romanelli  2   3
Affiliations

Covid-19-Associated Coagulopathy: Biomarkers of Thrombin Generation and Fibrinolysis Leading the Outcome

Marco Ranucci et al. J Clin Med. .

Abstract

Background: Coronavirus Disease 2019 (COVID-19)-associated coagulopathy is characterized by a prothrombotic state not yet comprehensively studied. We investigated the coagulation pattern of patients with COVID-19 acute respiratory distress syndrome (ARDS), comparing patients who survived to those who did not. Methods: In this prospective cohort study on 20 COVID-19 ARDS patients, the following biomarkers were measured: thrombin generation (prothrombin fragment 1 + 2 (PF 1 + 2)), fibrinolysis activation (tissue plasminogen activator (tPA)) and inhibition (plasminogen activator inhibitor 2 (PAI-2)), fibrin synthesis (fibrinopeptide A) and fibrinolysis magnitude (plasmin-antiplasmin complex (PAP) and D-dimers). Measurements were done upon intensive care unit (ICU) admission and after 10-14 days. Results: There was increased thrombin generation; modest or null release of t-PA; and increased levels of PAI-2, fibrinopeptide A, PAP and D-dimers. At baseline, nonsurvivors had a significantly (p = 0.014) higher PAI-2/PAP ratio than survivors (109, interquartile range (IQR) 18.1-216, vs. 8.7, IQR 2.9-12.6). At follow-up, thrombin generation was significantly (p = 0.025) reduced in survivors (PF 1 + 2 from 396 pg/mL, IQR 185-585 to 237 pg/mL, IQR 120-393), whereas it increased in nonsurvivors. Fibrinolysis inhibition at follow-up remained stable in survivors and increased in nonsurvivors, leading to a significant (p = 0.026) difference in PAI-2 levels (161 pg/mL, IQR 50-334, vs. 1088 pg/mL, IQR 177-1565). Conclusion: Severe patterns of COVID-19 ARDS are characterized by a thrombin burst and the consequent coagulation activation. Mechanisms of fibrinolysis regulation appear unbalanced toward fibrinolysis inhibition. This pattern ameliorates in survivors, whereas it worsens in nonsurvivors.

Keywords: COVID-19; fibrinolysis; heparin; pulmonary thromboembolism; sepsis; thrombin generation.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Association between plasma levels of fibrinopeptide A and plasmin–antiplasmin (PAP) complexes (panel A) and D-dimers (panel B). Data in the text.
Figure 2
Figure 2
Dot plot distribution of PAI-2/PAP ratio (panel A) and D-dimers (panel B) in survivors and nonsurvivors. PAI2: plasminogen activator inhibitor 2; PAP: plasmin–antiplasmin complex. Data in the text.
Figure 3
Figure 3
The chain of inflammatory and hemostatic reactions in survivors (A) and nonsurvivors (B), from early to late phase. FP-A: fibrinopeptide A; IL-6: interleukin-6; PAI-2: plasminogen activator inhibitor 2; PAP: plasmin–antiplasmin complex; PF 1 + 2: prothrombin fragment 1 + 2; t-PA: tissue plasminogen activator. Red lines are prothrombotic; green lines are antithrombotic.
See this image and copyright information in PMC

References

    1. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y., Zhang L., Fan G., Xu J., Gu X., et al. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet. 2020;395:497–506. doi: 10.1016/S0140-6736(20)30183-5. - DOI - PMC - PubMed
    1. Chen N., Zhou M., Dong X., Qu J., Gong F., Han Y., Qiu Y., Wang J., Li Y., Wei Y., et al. Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: A descriptive study. Lancet. 2020;395:507–513. doi: 10.1016/S0140-6736(20)30211-7. - DOI - PMC - PubMed
    1. 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;18:1233–1234. doi: 10.1111/jth.14768. - DOI - PMC - PubMed
    1. Fogarty H., Townsend L., Cheallaigh C., Bergin C., Martin-Loeches I., Browne P., Bacon C.L., Gaule R., Gillett A., Byrne M., et al. COVID-19 Coagulopathy in Caucasian patients. Br. J. Haematol. 2020;189:1044–1049. doi: 10.1111/bjh.16749. - DOI - PMC - PubMed
    1. Kollias A., Kyriakoulis K.G., Dimakakos E., Poulakou G., Stergiou G.S., Syrigos K. Thromboembolic risk and anticoagulant therapy in COVID-19 patients: Emerging evidence and call for action. Br. J. Haematol. 2020;189:846–847. doi: 10.1111/bjh.16727. - DOI - PMC - PubMed