COVID-19-Associated Hyper-Fibrinolysis: Mechanism and Implementations

Abstract

The emerging novel coronavirus disease (COVID-19), which is caused by the SARS-CoV-2 presents with high infectivity, morbidity and mortality. It presenting a need for immediate understanding of its pathogenicity. Inflammation and coagulation systems are over-activated in COVID-19. SARS-CoV-2 damages endothelial cell and pneumocyte, resulting in hemostatic disorder and ARDS. An influential biomarkers of poor outcome in COVID-19 are high circulating cytokines and D-dimer level. This latter is due to hyper-fibrinolysis and hyper-coagulation. Plasmin is a key player in fibrinolysis and is involved in the cleavage of many viruses envelop proteins, including SARS-CoV. This function is similar to that of TMPRSS2, which underpins the entry of viruses into the host cell. In addition, plasmin is involved in the pathophysiology of ARDS in SARS and promotes secretion of cytokine, such as IL-6 and TNF, from activated macrophages. Here, we suggest an out-of-the-box treatment for alleviating fibrinolysis and the ARDS of COVID-19 patients. This proposed treatment is concomitant administration of an anti-fibrinolytic drug and the anticoagulant.

Keywords: COVID-19; SARS-CoV-2; coagulation; fibrinolysis; tranexamic acid.

FIGURE 1

The figure displays the coagulation and fibrinolysis processes. Traditionally, the extrinsic pathway of the main coagulation cascade depends on the release of tissue factor (TF). Injured endothelial cells (EC) by any cause results in increased expression of TF in the cell membrane. This increased expression activates FVII, which then results in TF-FVIIa binding and activating FX. FX is also activated via the intrinsic pathway (collagen path). TF-FVII-FXa is the coagulation initiation complex which binds to EC and stimulates the generation of thrombin from prothrombin. Thrombin triggers many processes, which include fibrin generation, FXIII activation, and activation of protein C. FXIIIa polymerizes fibrin to form the final stable clot. Thrombin binds to the endothelial Protein C receptor (EPCR) and combines with thrombomodulin to activate protein C (aPC) and generate the EPCR-aPC complex. This complex has anti-coagulation activity by blocking the procoagulant factors, FVa and FVIIIa (accelerator factors) and a cytoprotective effect via the protease-activated receptor 1 (PAR1). Fibrinolysis (clot solubilization) is triggered in the presence of fibrin. The conversion of circulating zymogen plasminogen to plasmin is done by endothelial enzymes and the tissue and urokinase plasminogen activators (tPA and uPA, respectively). Plasmin, a key player in fibrinolysis, is a serine protease which cleaves fibrin to generate fibrin degradation products (FDP). Plasminogen activator-inhibitor (PAI) blocks both tPA and uPA. The main plasmin inhibitor is α2-antiplasmin, which is a potent free plasmin (not bounded to fibrin) scavenger. In addition, TAFI (thrombin-activatable fibrinolysis inhibitor) attenuates plasmin generation.

FIGURE 2

This figure displays a suggested relationship between coagulation and inflammation in patients with a SARS-CoV-2-infection. Spike proteins in the coronavirus’ envelope first bind to angiotensin-converting enzyme 2 (ACE2) receptors on the surface of epithelial cells (e.g., EC, endothelial cell). Type II transmembrane serine protease (TMPRSS2) then cleaves the spike protein in order to facilitate viral entry. The SARS-CoV-2 virus damages EC and promotes activation of the coagulation cascade (see Figure 1) via the TF-FVIIa (tissue factor pathway) and boosts fibrin generation (hyper-coagulation state). This hyper-activation of the fibrinolytic system results in increased plasmin production. Plasmin binds to the EC-plasmin receptor and degrades fibrin that leads to high plasma DDI levels. Membranous plasmin, which is a potent serine protease, could cleave the virus’ protein S hereby aiding its entry into host cells. This shared viral cleavage function with TMPRSS2 contributes to the increased infectivity of the virus and facilitates its spread (this function has been established in many viral infections, see text). In addition, over-production of plasmin (increased plasmin-receptor occupancy) activates the protease-activated receptor 1 and 2 (PAR 1, 2) signaling pathways which are involved in inflammation and immune responses. The EPCR-protein C complex is probably overwhelmed by hypercoagulability, thereby losing its cytoprotective activity. This virus-related pro-coagulation-inflammatory state also involves macrophages. This pathophysiologic paradigm explains the increased infectivity (and replication?) of the virus and the association between high D-dimer production and the cytokine storm (mainly IL-6, IL-10, and TNF) in COVID-19.