key: cord-0890973-iwuk8fev
authors: García‐Bernal, David; Richardson, Edward; Vlodavsky, Israel; Carlo‐Stella, Carmelo; Iacobelli, Massimo; Jara, Rubén; Richardson, Paul G.; Moraleda, Jose M.
title: Endothelial dysfunction and its critical role in COVID‐19‐associated coagulopathy: Defibrotide as an endothelium‐protective, targeted therapy
date: 2021-06-22
journal: EJHaem
DOI: 10.1002/jha2.198
sha: baa29cd8e5eafb76d624a95ab064911383f96ae8
doc_id: 890973
cord_uid: iwuk8fev

nan

To the Editor:

Recent publications emphasize that patients with COVID-19 commonly present with lethal disseminated intravascular coagulopathy (DIC) characterized by increased levels of D-dimer, fibrinogen, and elevated prothrombin time and activated partial thromboplastin time [1] . These abnormalities are associated with increased rates of thromboembolism and a profound prothrombotic state. However, other authors have found that both severe and mild COVID-19 patients show similar levels of endogenous anticoagulants and similar anti-thrombin, protein C, protein S, α2-antiplasmin and plasminogen activator inhibitor-1 (PAI-1) activities [2] , suggesting that we need new diagnostic criteria since the COVID-19 coagulopathy is different to the usual forms of disseminated intravascular coagulopathy [3] . These authors conclude that preventive measures for thromboprophylaxis are key and diverse antithrombotic therapies may be especially helpful in COVID-19 patients. It has been also reported that other markers of endothelial stress, including von Willebrand factor (VWF) and thrombomodulin, may predict mortality in COVID-19 patients, suggesting therapeutic strategies to normalize endothelial cell function and protect vascular integrity are indeed vital [2] .

The crucial role of endotheliitis in COVID-19 has been substantiated by pathological findings from autopsies [4] . We wish to also highlight the possible role of heparan sulfate and heparanase in the endothelial dysfunction of COVID-19, via the heparan sulfate-heparanase pathway that triggers increased serum levels of inflammatory cytokines as part of disease pathobiology and additional targeted therapies derived thereon.

Specifically, SARS-CoV-2 damage to endothelial cells (EC), and subsequent endotheliitis [4] leads to upregulation of heparanase, an endo-β-glucuronidase that degrades the heparan sulfate scaffold of the glycocalyx and subendothelial basement membrane, increasing endothelial dysfunction and allowing extravasation of activated immune cells into the extravascular compartment [5, 6] . Heparan sulfate is an extracellular matrix sulfated glycosaminoglycan that pro- is upregulated by pro-inflammatory molecules and promotes expression of TNF-α, IL-6, MIP-2, and IL-1 in a pro-inflammatory loop, which contributes further to inflammatory cytokines elevations [5] .

Defibrotide is a complex mixture of poly-deoxyribonucleotides extracted from porcine gut mucosa with pleiotropic properties, including anti-thrombotic, pro-fibrinolytic, anti-inflammatory, and protective effects on small vessel endothelia [7] . Defibrotide increases tissue plasminogen activator and thrombomodulin expression, enhancing the activity of plasmin to hydrolyze fibrin clots, decreasing VWF, and PAI-1. Platelet adhesion is inhibited via increased nitric oxide and prostaglandin E 2 and I 2 release. Conversely, defibrotide decreases inflammatory mediators including IL-6, TNF-α, VEGF, thromboxane A2, leukotriene B4, and reactive oxygen species. Defibrotide downregulates endothelial adhesion molecules such as P-selectin, E-selectin, ICAM-1, VCAM-1, and has been shown to inhibit leukocyte-endothelial interactions [8] . Most importantly, defibrotide potently inhibits heparanase activity and its cell surface expression in variety of settings [7, 9] . Moreover, it blocks the heparanase-heparan sulfate axis, by competing with heparan sulfate, and so may in turn inhibit both heparanase-mediated viral release and spread, as well as heparanasemediated activation of immune cells and elevated inflammatory cytokines [5] .

Defibrotide is approved for the treatment of severe veno-occlusive disease/sinusoidal obstruction syndrome and has efficacy in patients with endothelial dysfunction and multiorgan failure, with activity in clinical studies and animal models of graft-versus-host disease incorporating lung injury [7, 8] . Its multitargeted endothelial-based therapeutic properties make it a potentially ideal candidate to treat vascular complications of COVID-19. Clinical studies are either planned or already underway in various countries, including Spain, Italy, and the United States, with the leading Spanish phase 2 study (ClinicalTrials.gov Identifier: NCT04348383) showing promising early results.

Hematological findings and complications of COVID-19

Endotheliopathy in COVID-19-associated coagulopathy: evidence from a single-centre, cross-sectional study

COVID-19 coagulopathy: is it disseminated intravascular coagulation?

Endothelial cell infection and endotheliitis in COVID-19

Heparanase, cell signaling, and viral infections

Beneficial nonanticoagulant mechanisms underlying heparin treatment of COVID-19 patients

The use of defibrotide in blood and marrow transplantation

Defibrotide inhibits donor leucocyte-endothelial interactions and protects against acute graft-versus-host disease

Preclinical studies in support of defibrotide for the treatment of multiple myeloma and other neoplasias

This study has been financed in part by the Instituto de Salud Carlos III (ISCIII) project COV20/00399. eJHaem. 2021;1-2.wileyonlinelibrary.com/journal/jha2