key: cord-0718092-atgwiejs
authors: Lowenstein, Charles J.; Solomon, Scott D.
title: Severe COVID-19 Is a Microvascular Disease
date: 2020-09-02
journal: Circulation
DOI: 10.1161/circulationaha.120.050354
sha: 2a26bb23fcc7569ee19af8f9e49176b2571be94b
doc_id: 718092
cord_uid: atgwiejs

nan

Endothelial granules contain VWF, P-selectin, and other proinflammatory cytokines. During exocytosis, endothelial cells release VWF, which mediates platelet adherence and aggregation. Additionally during exocytosis, endothelial cells also externalize P-selectin where it mediates leukocyte adherence to the vessel wall (Figure) . P-selectin and VWF are not only stored together in the same granule but also interact to promote thrombosis. After exocytosis, P-selectin is displayed on the outer surface of the endothelial cells where it interacts with ultralong multimers of VWF, anchoring one end of the VWF multimer to the endothelial surface. Long strings of VWF unfurl from endothelial cells and platelets bind to these VWF strands, resembling pearls on a string. The synergistic relationship between P-selectin and VWF may lead to parallel activation of inflammatory and thrombotic pathways characteristic of severe COVID-19.

There are several mechanisms by which SARS-CoV-2 coronavirus might activate endothelial exocytosis. The first possibility is that SARS-CoV-2 directly activates exocytosis by binding to an endothelial surface receptor such as angiotensin-converting enzyme 2. The second possibility is that SARS-CoV-2 indirectly activates exocytosis by activating host responses and a plethora of cytokines which in turn activate exocytosis. A third possibility is that SARS-CoV-2 directly infects endothelial cells and viral polypeptides activate the exocytic machinery.

The cytokine storm in severe COVID-19 is likely caused by an auto-amplifying loop centered on injured endothelial cells. Endothelial exocytosis initiates leukocyte and platelet adherence to capillaries, which leads to microvascular obstruction, microthrombosis, and vascular inflammation. Extensive vascular inflammation can injure tissue which releases cytokines such as interleukin 6, interleukin 1β, and tumor necrosis factor α, which in turn can trigger endothelial exocytosis. In this construct, coronavirus serves as the initiator of vascular injury, with subsequent endothelial exocytosis that perpetuates a cycle of vascular injury and tissue inflammation contributing to the prolonged hyperinflammatory state in severe COVID-19.

This pathophysiologic construct might inform several potential novel host-directed therapies for COVID-19. Inhibitors of endothelial exocytosis may represent a novel therapeutic approach to the vasculopathy of COVID-19. Inhibition of P-selectin would block part of the pathway downstream of endothelial injury, including leukocyte rolling and platelet adherence to the vessel wall. Compounds that target the interaction of P-selectin with its

We propose that the coronavirus severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) injures endothelial cells. Endothelial cells respond to viral injury by exocytosis, mobilizing granules that release von Willebrand factor and P-selectin. P-selectin plays a dual role, accelerating thrombosis by binding to platelets, and mediating vascular inflammation by interacting with leukocytes. ligand PSGL-1 (P-selectin glycoprotein ligand 1) include small molecules, aptamers, ligand decoys, and antibodies. For example, small molecules like quinoline salicylate derivatives such as PSI-697 (2-[4-chlorobenzyl]-3-hydroxy-7,8,9,10-tetrahydrobenzo[h] quinoline-4-carboxylic acid) inhibit P-selectin and decrease leukocyte rolling in rodent models of inflammation. Oligonucleotide aptamers such as ARC5690 inhibit leukocyte binding to endothelial cells in vitro. Decoy ligands such as recombinant PSGL-1 decrease thrombosis in animals. Finally, monoclonal antibodies have been developed against P-selectin, including inclacumab and crizanlizumab. Crizanlizumab is currently approved for preventing vaso-occlusive crisis in sickle cell disease, which shares a number of pathophysiologic mechanisms with CO-VID-19 vasculopathy. The CRITICAL trial (Crizanlizumab in COVID-19 Vasculopathy; NCT04435184) is currently testing the hypothesis that crizanlizumab can reduce mediators of thrombosis and inflammation in patients with moderate COVID-19.

Inhibition of VWF would interfere with another part of the endothelial secretory pathway. Agents such as abciximab or eptifibatide block one of the cellular receptors of VWF, the glycoprotein IIb/IIIa receptor on platelets. Compounds targeting VWF or VWF receptors could decrease the risk of thrombosis in patients with COVID-19.

In summary, accumulating clinical, laboratory, and autopsy evidence suggests that endothelial exocytosis plays a central role in the pathogenesis of severe COVID-19. Endothelial release of P-selectin and VWF activate 2 parallel pathways, leukocyte adherence and platelet aggregation, that lead to the cytokine storm and massive thrombosis that are characteristic of severe COVID-19. Clinical trials are needed that test the efficacy of drugs that target the pathway of endothelial exocytosis in patients with COVID-19. 

This work was supported by National Institutes of Health/National Heart Lung and Blood Institute grants R01 HL134894 and R61 HL141791 and the Michel Mirowski, MD Professorship in Cardiology (C.J.L.).

Dr Lowenstein reports research grants from Novartis. In addition, Johns Hopkins University plans to file a use patent for crizanlizumab for COVID-19. Dr Lowenstein is the principal investigator of the CRITICAL trial which tests the safety and efficacy of a P-selectin inhibitor in patients with COVID-19. Dr Solomon reports grants and personal fees from Alnylam, grants and personal fees from Amgen, grants and personal fees from AstraZeneca, grants from Bellerophon, grants and personal fees from Bristol Myers Squibb, grants from Celladon, grants and personal fees from Gilead, grants and personal fees from GlaxoSmithKline, grants from Ionis, grants from Lone Star Heart, grants from Mesoblast, grants and personal fees from MyoKardia, grants from National Institutes of Health/National Heart, Lung, and Blood Institute, grants and personal fees from Novartis, grants from Sanofi Pasteur, grants and personal fees from Theracos, personal fees from Akros, grants and personal fees from Bayer, personal fees from Corvia, personal fees from Ironwood, personal fees from Merck, personal fees from Roche, personal fees from Takeda, personal fees from Quantum Genomics, personal fees from AoBiome, personal fees from Janssen, personal fees from Cardiac Dimensions, grants from Eidos, grants and personal fees from Cytokinetics, personal fees from Tenaya, personal fees from Daichi-Sankyo, personal fees from Arena, personal fees from Dinaqor, personal fees from Cardurion, personal fees from Tremeau, personal fees from Moderna, outside the submitted work; and Dr Solomon is a co-investigator of the CRITICAL trial which tests the safety and efficacy of a P-selectin inhibitor in patients with COVID-19.

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