COVID-19 and immunothrombosis: Pathophysiology and therapeutic implications

Abstract

The coagulopathy of COVID-19 is characterised by significantly elevated D Dimer and fibrinogen, mild thrombocytopenia and a mildly prolonged PT/APTT. A high incidence of thrombotic complications occurs despite standard thromboprophylaxis. The evidence to date supports immunothrombosis as the underlying mechanism for this coagulopathy which is triggered by a hyperinflammatory response and endotheliopathy. A hypercoagulable state results from endothelial damage/activation, complement activation, platelet hyperactivity, release of Extracellular Neutrophil Traps, activation of the coagulation system and a "hypofibrinolytic" state. Significant cross-talk occurs between the innate/adaptive immune system, endothelium and the coagulation system. D dimer has been shown to be the most reliable predictor of disease severity, thrombosis, and overall survival. In this context, targeting pathways upstream of coagulation using novel or repurposed drugs alone or in combination with other anti-thrombotic agents may be a rational approach to prevent the mortality/morbidity due to COVID-19 associated coagulopathy.

Keywords: COVID-19; Coagulopathy; Immunothrombosis; Pathophysiology; Venous thromboembolism.

Graphical abstract

Fig. 1

Pathophysiology of COVID-19 associated coagulopathy. SARS-CoV2 triggers the release of cytokines from monocytes, macrophages and neutrophils leading to a cytokine storm. This results in activation of monocytes, macrophages and neutrophils with upregulation of tissue factor and release of NETs. The endothelium is damaged/activated due to pyroptosis induced by direct viral invasion, release of cytokines, complement activation and downregulation of ACE2. This leads to exposure of the thrombogenic basement membrane, upregulation of tissue factor and release of factor VIII, VWF and P-Selectin from WPB resulting in activation of platelets and coagulation factors. Fibrinolysis is also suppressed due to inhibition of PAI-I further contributing to the procoagulant state. In addition, there is significant cross talk between the immune, complement, and coagulation systems leading to a positive feedback loop, thus amplifying this response. ACE-2, angiotensin converting enzyme 2; C, complement; COVID-19, coronavirus disease 2019; IL, interleukin; NET, neutrophil extracellular trap; MASP2, Mannan-binding lectin serine protease 2; MAC; membrane attack complex; NLP3, NLR pyrin domain containing 3; PAI-1, plasminogen activator inhibitor 1; SARS-CoV2, severe acute respiratory syndrome coronavirus 2; TF, tissue factor; TNF, tumour necrosis factor; WPB, Weibel Palade body.