Response to Maccio et al, “Multifactorial pathogenesis of COVID‐19‐related coagulopathy: Can defibrotide have a role in the early phases of coagulation disorders?”

Richardson, Edward; Carlo‐Stella, Carmelo; Jara, Rubén; Vlodavsky, Israël; Iacobelli, Massimo; Fareed, Jawed; Mo, Clifton C.; O’Gorman, Peter; Yanik, Gregory A.; Palomo, Marta; Díaz‐Ricart, Maribel; Moraleda, José Marı́a

doi:10.1111/jth.15088

Cited by 11 publications

(12 citation statements)

References 11 publications

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“…Lastly and most importantly, DF has also been shown to decrease the activity of p38 MAPK and its pathway, 93 the importance of which is increasingly recognised in the pathogenesis of the COVID-19 hyperinflammation syndrome and this may be a key therapeutic target in this process. 58,108 In summary, the multitargeted endothelial-based therapeutic properties of DF and its relative safety, as well as its regulatory approval, make it an ideal potential therapeutic candidate for the treatment of COVID-19 vascular complications. 28 In contrast to heparin, DF also exhibits broader anticytokine, anti-inflammatory and endothelial-stabilising properties.…”

Section: Defibrotidementioning

confidence: 99%

“…By reducing P‐selectin and other adhesion molecules expression, DF may inhibit monocyte‐derived inflammatory and pro‐coagulant signals. Lastly and most importantly, DF has also been shown to decrease the activity of p38 MAPK and its pathway, 93 the importance of which is increasingly recognised in the pathogenesis of the COVID‐19 hyperinflammation syndrome and this may be a key therapeutic target in this process 58,108 …”

Section: Agents Targeting Ec‐related Disordersmentioning

confidence: 99%

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COVID‐19‐induced endotheliitis: emerging evidence and possible therapeutic strategies

et al. 2021

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Section: Defibrotidementioning

confidence: 99%

Section: Agents Targeting Ec‐related Disordersmentioning

confidence: 99%

COVID‐19‐induced endotheliitis: emerging evidence and possible therapeutic strategies

et al. 2021

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“…[54][55][56][57] Therefore, endothelial protection should be considered as an important new strategy to prevent complications also in COVID-19. 58 In this regard, there is currently a phase IIb randomized, double blind, placebo-controlled clinical trial to evaluate the effect of defibrotide to treat the respiratory distress and cytokine release syndrome in COVID-19 patients, as well as other single-arm studies underway. 59 The present study presents some limitations.…”

Section: Discussionmentioning

confidence: 99%

Progressive endothelial cell damage in correlation with sepsis severity. Defibrotide as a contender

Fernández

Palomo

Molina

et al. 2021

Journal of Thrombosis and Haemostasis

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Background:The vascular endothelium plays a key role in sepsis pathophysiology and the associated organ dysfunction. Methods:We evaluated endothelial function in an experimental in vitro model of sepsis, using endothelial cells grown in the presence of serum from patients with septic syndromes (sepsis, severe sepsis, and septic shock), noninfectious systemic inflammatory response syndrome (NI-SIRS) and healthy volunteers. Experiments were performed in the absence and presence of defibrotide (DF) (100 µg/ml) to evaluate its potential protective effect.Results: After exposure to patients' sera, there was a progressive endothelial cell activation in correlation with sepsis severity, with a proinflammatory and prothrombotic phenotype, exhibiting significantly increased expression of adhesion receptors at the surface (intercellular adhesion molecule-1, p < .05 and vascular cell adhesion molecule-1, p < .05); higher production and release to the extracellular matrix (ECM) of von Willebrand factor (p < .001); augmented thrombogenicity of the ECM toward platelets (p < .001); and increased phosphorylation of intracellular p38MAPK. DF prevented these changes in all groups. Conclusions: Markers of endothelial damage increased progressively in association with the severity of septic syndromes. The endothelium is therefore an important | 1949 FERNÁNDEZ Et al.

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“…For these reasons, and for its demonstrated long-term safety even in high-risk pediatric populations [ 155 ], DF stands as a promising candidate for the treatment of COVID-19, based on the complex pathophysiology of COVID-19 and DF’s pleiotropic mechanisms of action [ 156 ].…”

Section: Therapeutic Strategies To Protect the Endotheliummentioning

confidence: 99%

Is the Endothelium the Missing Link in the Pathophysiology and Treatment of COVID-19 Complications?

Castro

Palomo

Moreno-Castaño

et al. 2021

Cardiovasc Drugs Ther

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Patients with COVID-19 present a wide spectrum of disease severity, from asymptomatic cases in the majority to serious disease leading to critical care and even death. Clinically, four different scenarios occur within the typical disease timeline: first, an incubation and asymptomatic period; second, a stage with mild symptoms due mainly to the virus itself; third, in up to 20% of the patients, a stage with severe symptoms where a hyperinflammatory response with a cytokine storm driven by host immunity induces acute respiratory distress syndrome; and finally, a post-acute sequelae (PASC) phase, which present symptoms that can range from mild or annoying to actually quite incapacitating. Although the most common manifestation is acute respiratory failure of the lungs, other organs are also frequently involved. The clinical manifestations of the COVID-19 infection support a key role for endothelial dysfunction in the pathobiology of this condition. The virus enters into the organism via its interaction with angiotensin-converting enzyme 2-receptor that is present prominently in the alveoli, but also in endothelial cells, which can be directly infected by the virus. Cytokine release syndrome can also drive endothelial damage independently. Consequently, a distinctive feature of SARS-CoV-2 infection is vascular harm, with severe endothelial injury, widespread thrombosis, microangiopathy, and neo-angiogenesis in response to endothelial damage. Therefore, endothelial dysfunction seems to be the pathophysiological substrate for severe COVID-19 complications. Biomarkers of endothelial injury could constitute strong indicators of disease progression and severity. In addition, the endothelium could represent a very attractive target to both prevent and treat these complications. To establish an adequate therapy, the underlying pathophysiology and corresponding clinical stage should be clearly identified. In this review, the clinical features of COVID-19, the central role of the endothelium in COVID-19 and in other pathologies, and the potential of specific therapies aimed at protecting the endothelium in COVID-19 patients are addressed.

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Response to Maccio et al, “Multifactorial pathogenesis of COVID‐19‐related coagulopathy: Can defibrotide have a role in the early phases of coagulation disorders?”

Cited by 11 publications

References 11 publications

COVID‐19‐induced endotheliitis: emerging evidence and possible therapeutic strategies

COVID‐19‐induced endotheliitis: emerging evidence and possible therapeutic strategies

Progressive endothelial cell damage in correlation with sepsis severity. Defibrotide as a contender

Is the Endothelium the Missing Link in the Pathophysiology and Treatment of COVID-19 Complications?

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