Comment to: Gonzalez Ochoa AJ, Raffetto J, Hernandez Ibarra AG, Zavala N, Gutierrez O, Vargas A, Loustaunau J. Sulodexide in the treatment of patients with early stages of COVID-19: a randomized controlled trial. Thromb Haemost. 2021 Mar 7. doi: 10.1055/a-1414-5216. Epub ahead of print. PMID: 33677827.

The endothelial surface layer in the lungs plays a critical role in the immune response to SARS-CoV-2 infection and that viral inclusion in the endothelium and diffuse inflammation (endothelialitis) trigger a systemic release of inflammatory cytokines. The resulting proinflammatory and prothrombotic state can cause microvascular thrombosis, which might explain the impaired systemic function of various vascular beds and their clinical sequelae in some patients. Amplification of the rate of viral replication and its increasingly disruptive effects producing both local and systemic cytokine storms lead to a combination of uncontrolled inflammation and a widespread endotheliitis². COVID-19-induced endothelialitis may be a particularly relevant concern for vulnerable patients with pre-existing endothelial dysfunction, which is associated with males, old age and chronic comorbidities – all of which are linked with adverse disease outcomes¹.

Several studies are investigating the type and dose of anticoagulants to mitigate the risk of thromboembolic complications caused by COVID-19 however pulmonary endothelial cells have been largely overlooked as a therapeutic target. Sulodexide has several pleiotropic endothelial actions that can be beneficial in COVID-19 patients. As a precursor for the synthesis of glycosaminoglycans, sulodexide can help restore a shredded endothelial glycocalyx and prevent further degradation. This improvement restores endothelial barrier function and allows the endothelium to better modulate the generation of key inflammatory molecules, while downregulating its response to them. This can help prevent the aberrant immunothrombosis reaction seen in COVID-19 some patients. Sulodexide’s antithrombotic and profibrinolytic effects may still be significant against the procoagulant state caused by SARS-CoV-2. Finally, sulodexide is also associated with a lower bleeding risk than is seen with other oral anticoagulants².

A recent randomized controlled trial evaluated whether sulodexide’s, thanks to its pleiotropic properties, can improve the clinical outcome and reduce the need for hospital care. Indeed, Ochoa and co-authors hypothesized that Sulodexide due to its endothelial-protective properties can prevent the SARS-CoV-2-mediated endothelialitis therefore reducing the clinical outcomes¹. Patients, at a high risk of severe clinical progression due to chronic comorbidities were included in the trial within three days of COVID-19 clinical onset. Participants were randomly assigned to receive an oral dose of sulodexide (500 LRU twice a day) or placebo for 21 days.

Sulodexide was effective in decreasing the need for hospital admission – 17.7% patients required hospitalization in the sulodexide group compared to 29.4% in the placebo group, p=0.03 – and supplemental oxygen treatment – 29.8% required oxygen support in the sulodexide group vs 42% in the placebo group, p=0.05 and for fewer days [9 (7.2 SD) in the sulodexide group vs. 11.5 (9.6 SD) in the placebo group; p=0.02]. Sulodexide-treated patients also had lower serum levels of C-reactive protein and D-dimer as markers for inflammatory and prothrombotic states¹.

In many COVID-19 patients with severe clinical progression, the endothelial surface layer may already be dysfunctional, and sulodexide might serve as a precursor for the synthesis of the glycosaminoglycans needed for glycocalyx restoration. The protective effect of sulodexide on vascular glycocalyx is also achieved through reducing the degradation of GAGs. The clinical progression of COVID-19 is associated with a severe inflammatory response in which symptoms can rapidly progress to full acute respiratory distress syndrome (ARDS), which requires treatment with supplemental oxygen and/or hospital care. Sulodexide modulates and inhibits the generation of free radicals and critical inflammatory molecules, such as interleukin (IL)-1 beta (p), IL-6, IL-8 and tumor necrosis factor alfa (TNF-α). Although sulodexide’s effect in modulating the glycocalyx can take time, its impact on modulating the endothelial response to these molecules (particularly IL6, which is very relevant in COVID-19) can occur quickly. This effect could help explain the reduced need for hospital care and supplemental oxygen observed in the sulodexide group².

The clinical progression of COVID-19 is associated with a severe inflammatory response in which symptoms can rapidly progress to full acute respiratory distress syndrome (ARDS), which requires treatment with supplemental oxygen and/or hospital care. Sulodexide is already well known for its antithrombotic effect however in the setting of this study, where a mild disease was addressed, its endothelial protective properties may add a benefit of equal or greater importance. The reduction in D-dimer levels can be potentially an indirect marker representing the prevention benefit of sulodexide.

Sulodexide activity on COVID-19 severe progression represents an extreme model of thrombogenesis on an endothelial inflammatory basis. Also, the results of the paper have beneficial implications in the patient’s well-being, making sulodexide a favorable medication until an effective vaccine or an antiviral becomes available¹.

References

1. Gonzalez Ochoa AJ, Raffetto J, Hernandez Ibarra AG, et al. Sulodexide in the treatment of patients with early stages of COVID-19: a randomized controlled trial. Thromb Haemost. Published online March 7, 2021. doi:10.1055/a-1414-5216
2. Magnani HN. Rationale for the Role of Heparin and Related GAG Antithrombotics in COVID-19 Infection. Clin Appl Thromb Hemost. 2021;27:1076029620977702. doi:10.1177/1076029620977702