Endothelial dysfunction and its critical role in COVID‐19‐associated coagulopathy: Defibrotide as an endothelium‐protective, targeted therapy

Recent publications emphasize that patients with COVID-19 com-monly 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, α 2-antiplasmin and plasminogen activatorinhibitor-1(PAI-1)activities[2],suggestingthatweneednew 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, sug-gesting therapeutic strategies to normalize endothelial cell function and protect vascular integrity are indeed vital [2]. ThecrucialroleofendotheliitisinCOVID-19hasbeensubstantiated pathological findings autopsies We wish to also highlight the possible role of heparan sulfate and heparanase in the endothe-lialdysfunctionofCOVID-19,viatheheparansulfate-heparanasepath-


Endothelial dysfunction and its critical role in COVID-19-associated coagulopathy: Defibrotide as an endothelium-protective, targeted therapy
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.