Abstract
The novel coronavirus disease (COVID-19) has many characteristics common to those in two other coronavirus acute respiratory diseases, severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS). They are all highly contagious and have severe pulmonary complications. Clinically, patients with COVID-19 run a rapidly progressive course of an acute respiratory tract infection with fever, sore throat, cough, headache and fatigue, complicated by severe pneumonia often leading to acute respiratory distress syndrome (ARDS). The infection also involves other organs throughout the body. In all three viral illnesses, the fibrinolytic system plays an active role in each phase of the pathogenesis. During transmission, the renin-aldosterone-angiotensin-system (RAAS) is involved with the spike protein of SARS-CoV-2, attaching to its natural receptor angiotensin-converting enzyme 2 (ACE 2) in host cells. Both tissue plasminogen activator (tPA) and plasminogen activator inhibitor 1 (PAI-1) are closely linked to the RAAS. In lesions in the lung, kidney and other organs, the two plasminogen activators urokinase-type plasminogen activator (uPA) and tissue plasminogen activator (tPA), along with their inhibitor, plasminogen activator 1 (PAI-1), are involved. The altered fibrinolytic balance enables the development of a hypercoagulable state. In this article, evidence for the central role of fibrinolysis is reviewed, and the possible drug targets at multiple sites in the fibrinolytic pathways are discussed.
Highlights
Infection by the highly contagious coronavirus severe acute respiratory syndrome (SARS)-CoV-2 has resulted in a global pandemic of coronavirus disease 2019 (COVID-19) [1,2,3]
plasminogen activator inhibitor 1 (PAI-1) is well recognized to play an important role in the pathogenesis of a wide variety of conditions, including aging, cellular senescence, obesity, cardiovascular disease, hypertension, diabetes, fibrosis and thrombosis [20,56,61,62,63,64,65], It is notable that people with many of these conditions are more susceptible to COVID-19 and have worse outcomes [66]
The absence of fibrinolysis characterizes a pathologic hypercoagulable condition often associated with thrombosis, showing decreased viscoelastic fibrinolysis associated with elevated D-dimer and plasmin-antiplasmin (PAP) complexes [87]
Summary
Infection by the highly contagious coronavirus SARS-CoV-2 has resulted in a global pandemic of coronavirus disease 2019 (COVID-19) [1,2,3]. In the lungs, this manifests as edema, macrophage infiltration and intra-alveolar fibrin deposition, leading to acute respiratory distress syndrome (ARDS) and acute respiratory failure. The two activators are tissue type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA) They bind to their respective receptors on cell surfaces. To maintain a physiologic balance, the fibrinolytic system is regulated by serine protease inhibitors (serpins) at various activation sites. Those inhibiting the conversion of plasminogen to plasmin are plasminogen activator inhibitor 1 (PAI-1), plasminogen activator inhibitor 2 (PAI-2), activated protein C inhibitor (APC) inhibitor (PAI-3), protease nexin 1 and defensin (for tPA only). Plasmin is inhibited by α2-antiplasmin, α2-macroglobulin, TAFI and several serine protease inhibitors (AT, α2-antitrypsin, protease nexin 1)
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