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The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications

The Emerging Threat of (Micro)Thrombosis in COVID-19 and Its Therapeutic Implications
  • 1 From the Atherothrombosis and Vascular Biology Program, Baker Heart and Diabetes Institute, Melbourne, Victoria, Australia (J.D.M., H.S., K.P.).
  • 2 Clinical Hematology Department (J.D.M., H.S.), Alfred Hospital, Melbourne, Victoria, Australia.
  • 3 Department of Medicine, Monash University, Melbourne, Victoria, Australia (J.D.M., H.S., K.P.).
  • 4 Department of Cardiology (K.P.), Alfred Hospital, Melbourne, Victoria, Australia.
The recent emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the ensuing global pandemic has presented a health emergency of unprecedented magnitude. Recent clinical data has highlighted that coronavirus disease 2019 (COVID-19) is associated with a significant risk of thrombotic complications ranging from microvascular thrombosis, venous thromboembolic disease, and stroke. Importantly, thrombotic complications are markers of severe COVID-19 and are associated with multiorgan failure and increased mortality. The evidence to date supports the concept that the thrombotic manifestations of severe COVID-19 are due to the ability of SARS-CoV-2 to invade endothelial cells via ACE-2 (angiotensin-converting enzyme 2), which is expressed on the endothelial cell surface. However, in patients with COVID-19 the subsequent endothelial inflammation, complement activation, thrombin generation, platelet, and leukocyte recruitment, and the initiation of innate and adaptive immune responses culminate in immunothrombosis, ultimately causing (micro)thrombotic complications, such as deep vein thrombosis, pulmonary embolism, and stroke. Accordingly, the activation of coagulation (eg, as measured with plasma D-dimer) and thrombocytopenia have emerged as prognostic markers in COVID-19. Given thrombotic complications are central determinants of the high mortality rate in COVID-19, strategies to prevent thrombosis are of critical importance. Several antithrombotic drugs have been proposed as potential therapies to prevent COVID-19-associated thrombosis, including heparin, FXII inhibitors, fibrinolytic drugs, nafamostat, and dipyridamole, many of which also possess pleiotropic anti-inflammatory or antiviral effects. The growing awareness and mechanistic understanding of the prothrombotic state of COVID-19 patients are driving efforts to more stringent diagnostic screening for thrombotic complications and to the early institution of antithrombotic drugs, for both the prevention and therapy of thrombotic complications. The shifting paradigm of diagnostic and treatment strategies holds significant promise to reduce the burden of thrombotic complications and ultimately improve the prognosis for patients with COVID-19.
Keywords: coronavirus; mortality; stroke; thrombosis; viruses.
Figure 4.
Treatments for targeting coronavirus disease 2019 (COVID-19)-associated thrombosis. Heparins, including unfractionated heparin (UFH) and low molecular weight heparin (LMWH), bind antithrombin (AT), and potentiate the inhibitory effect of AT on coagulation factors Xa and thrombin. Furthermore, UFH may have antiviral effects by having the ability to bind the receptor-binding domain of the S protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in addition to potentially acting as a decoy for naturally expressed heparan sulfate thus reducing the ability of the virus to bind to and invade cells. The putative anti-inflammatory effects of UFH is related to its ability to bind danger-associated molecular pattern (DAMPs). Inhibitors of FXII block the contact factor pathway of coagulation, initiated by NETs, and also appear to have pleiotropic anti-inflammatory effects. Antiplatelet agents, such as dipyridamole, nafamostat, and aspirin inhibit platelet activation, which can inhibit NETosis and the release of platelet-derived DAMPs such as HMGB (high mobility group box)-1. Nafamostat may inhibit the TMPRSS-2 (transmembrane protease serine 2) and therefore impede viral entry. Fibrinolytics, such as tPA (tissue-type plasminogen activator), degrade cross-linked fibrin.
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