Inflammation and thrombosis in COVID-19 pathophysiology: proteinase-activated and purinergic receptors as drivers and candidate therapeutic targets

Abstract

Evolving information has identified disease mechanisms and dysregulation of host biology that might be targeted therapeutically in coronavirus disease 2019 (COVID-19). Thrombosis and coagulopathy, associated with pulmonary injury and inflammation, are emerging clinical features of COVID-19. We present a framework for mechanisms of thrombosis in COVID-19 that initially derive from interaction of SARS-CoV-2 with ACE2, resulting in dysregulation of angiotensin signaling and subsequent inflammation and tissue injury. These responses result in increased signaling by thrombin (proteinase-activated) and purinergic receptors, which promote platelet activation and exert pathological effects on other cell types (e.g., endothelial cells, epithelial cells, and fibroblasts), further enhancing inflammation and injury. Inhibitors of thrombin and purinergic receptors may, thus, have therapeutic effects by blunting platelet-mediated thromboinflammation and dysfunction in other cell types. Such inhibitors include agents (e.g., anti-platelet drugs) approved for other indications, and that could be repurposed to treat, and potentially improve the outcome of, COVID-19 patients. COVID-19, caused by the SARS-CoV-2 virus, drives dysregulation of angiotensin signaling, which, in turn, increases thrombin-mediated and purinergic-mediated activation of platelets and increase in inflammation. This thromboinflammation impacts the lungs and can also have systemic effects. Inhibitors of receptors that drive platelet activation or inhibitors of the coagulation cascade provide opportunities to treat COVID-19 thromboinflammation.

Keywords: GPCR; angiotensin; endothelium; platelets; thrombin.

Graphical abstract

FIGURE 1.

An overview of COVID-19 pathobiology: thromboinflammation in coronavirus disease 2019 (COVID-19) results from cell injury, platelet activation, and the coagulation cascade. Enhanced ANG II-mediated signaling via imbalance of angiotensin-converting enzyme (ACE) 1/ACE 2 by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection with resultant alteration in function of alveolar and neighboring cells, which leads to thrombosis through multiple mechanisms. The contribution of von Willebrand Factor (vWF) and other extracellular matrix (ECM) proteins (discussed in the text) is not shown. MGKS, megakaryocytes; NET, neutrophil extracellular trap; TPO, thrombopoietin.

FIGURE 2.

A proposed sequence of events in coronavirus disease 2019 (COVID-19) thromboinflammation A: alveolar injury drives thrombin (PAR) signaling and platelet activation, followed by purinergic signaling (B). As cell death increases, ADP is released from platelets and activates purinergic receptors. C: activated platelets produce entities that can further inflammation. Platelet-neutrophil interactions can also act in the opposite direction, with NETosis activating platelets. D: as inflammation increases (and perhaps via increased thrombin and purinergic signaling) megakaryocytopoiesis is enhanced. ADP/ATP: adenosine diphosphate/triphosphate; ANG II/ANG 1–7, ANG II/ANG 1–7; ACE1/ACE2, angiotensin-converting enzyme 1/2; CXCL5, C-X-C motif chemokine 5; FVa, factor Va; IL-1β, interleukin 1β; MGKs, megakaryocytes; PAF, platelet activating factor; PAR1/PAR4, proteinase-activated receptor 1/4; TPO, thrombopoietin; TXA2, thromboxane A2.

FIGURE 2.

A proposed sequence of events in coronavirus disease 2019 (COVID-19) thromboinflammation A: alveolar injury drives thrombin (PAR) signaling and platelet activation, followed by purinergic signaling (B). As cell death increases, ADP is released from platelets and activates purinergic receptors. C: activated platelets produce entities that can further inflammation. Platelet-neutrophil interactions can also act in the opposite direction, with NETosis activating platelets. D: as inflammation increases (and perhaps via increased thrombin and purinergic signaling) megakaryocytopoiesis is enhanced. ADP/ATP: adenosine diphosphate/triphosphate; ANG II/ANG 1–7, ANG II/ANG 1–7; ACE1/ACE2, angiotensin-converting enzyme 1/2; CXCL5, C-X-C motif chemokine 5; FVa, factor Va; IL-1β, interleukin 1β; MGKs, megakaryocytes; PAF, platelet activating factor; PAR1/PAR4, proteinase-activated receptor 1/4; TPO, thrombopoietin; TXA2, thromboxane A2.

FIGURE 3.

Interactions between the components of the complement and coagulation cascades in driving thromboinflammation.

FIGURE 4.

A schematic of the interaction between ANG II-mediated injury in coronavirus disease 2019 (COVID-19), with actions of the complement cascade and activation of the coagulation cascade. ACE2, angiotensin-converting enzyme; SARS-CoV-2, severe acute respiratory syndrome coronavirus-2.

FIGURE 5.

Mild-moderate and severe COVID-19: The balance between immune response, inflammation, and thrombosis (thromboinflammation). Disease course of COVID-19 as a function of time, with putative progression of inflammation, adaptive immune response, and viral clearance in parallel with coagulopathy and thrombosis for (top) more mild/moderate disease and (bottom) severe disease. This general framework is adapted from that presented by Romagnoli et al. (17) and highlights specific aspects of disease pathophysiology discussed in the text.

FIGURE 6.

Approaches for targeting thromboinflammation in coronavirus disease 2019 (COVID-19), via the repurposing of drugs discussed in TABLE 1. The approaches shown target various steps in the coagulation cascade, inhibiting the formation of thrombin and subsequent platelet activation, or antagonize receptors for thrombin or ADP, which promote platelet activation and induce pathological effects on other cell types implicated in COVID-19 pathobiology.