Fibrinogen, Fibrin, and Fibrin Degradation Products in COVID-19

Abstract

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) is the highly pathogenic and highly transmissible human coronavirus that is the causative agent for the worldwide COVID-19 pandemic. COVID-19 manifests predominantly as a respiratory illness with symptoms consistent with viral pneumonia, but other organ systems (e.g., kidney, heart, brain) can also become perturbed in COVID-19 patients. Accumulating data suggest that significant activation of the hemostatic system is a common pathological manifestation of SARS-CoV-2 infection. The clotting protein fibrinogen is one of the most abundant plasma proteins. Following activation of coagulation, the central coagulation protease thrombin converts fibrinogen to fibrin monomers, which selfassemble to form a matrix, the primary structural component of the blood clot. Severe COVID-19 is associated with a profound perturbation of circulating fibrinogen, intra- and extravascular fibrin deposition and persistence, and fibrin degradation. Current findings suggest high levels of fibrinogen and the fibrin degradation product D-dimer are biomarkers of poor prognosis in COVID-19. Moreover, emerging studies with in vitro and animal models indicate fibrin(ogen) as an active player in COVID-19 pathogenesis. Here, we review the current literature regarding fibrin(ogen) and COVID-19, including possible pathogenic mechanisms and treatment strategies centered on clotting and fibrin(ogen) function.

Keywords: COVID-19; D-dimer; Fibrinogen; coagulation; fibrin; fibrinolysis.

Fig. (1).

Summary of fibrinogen conversion to fibrin matrix and subsequent plasmin-mediated breakdown of fibrin polymer into fibrin degradation products (FDPs), including D-dimer. Figure produced with the assistance of Biorender.

Fig. (2).

Molecular basis of the COVID-19 fibrin(ogen) paradox. Severe COVID-19 is marked by the accumulation of persistent intravascular and extravascular fibrin in tissues (e.g., lung) and significantly elevated D-dimer in circulation. Current data indicate that patients suffering from COVID-19 have exuberant fibrinogen production, thrombin generation, and fibrin formation, but an insufficient counterbalance of plasmin generation necessary for fibrin clearance. Figure produced with the assistance of Biorender.

Fig. (3).

Possible mechanism of extravascular fibrin deposition and disease progression in mild and severe COVID-19. In patients who develop a mild or asymptomatic disease, fibrin is readily cleared by plasmin. In patients who develop severe COVID-19, persistent fibrin deposits lead to the activation of proinflammatory immune cells (e.g., macrophages and neutrophils) that promote local tissue damage and destruction. Figure produced with the assistance of Biorender.