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

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.

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

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

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.