Oral Sulodexide Downregulates Biomarkers of Endothelial Dysfunction Among Convalescent COVID-19 Patients

Introduction

Endothelial dysfunction is central to the pathophysiology of COVID-19, and with the emergence of Long COVID-19 as a serious health issue, there is growing interest in its role in post-COVID-19 complications. Persistent elevation of biomarkers associated with endothelial dysfunction, such as Thrombomodulin (TM), von Willebrand Factor (vWF), and Interleukin 6 (IL-6), in convalescent COVID-19 patients may indicate ongoing endothelial activation. This activation potentially increases the risk of long-term cardiovascular complications, including long COVID-19 syndrome, for which therapeutic option remain limited. Ongoing research is focused on developing targeted therapies to preserve or restore endothelial health and improve long-term outcomes for these patients.

This study aims to evaluate whether the pleiotropic effects of sulodexide influence serum levels of endothelial dysfunction biomarkers in convalescent patients from moderate to severe COVID-19.

Method

We conducted a single-center, prospective, randomized, placebo-controlled trial with a parallel-group design (registry number 223300410A0037/2022). Key inclusion criteria included confirmed SARS-CoV-2 infection, convalescent status (defined as at least 10 days post-symptom onset, no fever for at least 24 hours without antipyretics, and improved respiratory symptoms), and chronic comorbidities associated with high risk for endothelial dysfunction (e.g., hypertension, diabetes, obesity). Exclusion criteria included more than 40 days since the onset of COVID-19 symptoms and current anticoagulation therapy.

Patients were allocated to receive either sulodexide (250 LRU orally twice daily) or a masked placebo for 8 weeks. Outcomes were assessed at weeks 4 and 8 post-randomization. The primary endpoint was the between group comparison of TM serum levels. Secondary endpoints included comparison of serum levels of vWF, IL-6, CRP, D-dimer, ICAM-1, VCAM-1, and P-selectin. Commercially available sandwich ELISA methods were used from the same vendor for the biomarkers analyzed. Physicians, patients, and laboratory personnel were blinded to treatment allocation.

For statistical analysis, continuous variables were expressed as mean and standard deviation and compared using the student's t-test or the Wilcoxon rank sum test (depending on data distribution and assumptions), and categorical variables were compared with the Chi-square test or the Fisher exact test. Proportions were compared between the two intervention arms within each group using the Fisher exact test and presented as relative risk ratio (RR). The Huber method was used for covariates analysis.

Trial populations were analyzed by intention-to-treat (ITT) for all endpoints and per protocol for the primary endpoint only.

Results

A total of 206 patients were included in the final analysis (103 in each group), with a mean age of 61 years and an average of 22 days from symptom onset. The cohort was 63.1% female and 95% Hispanic, with 80.3% having received at least one dose of COVID-19 vaccine.

At week 8, the sulodexide group exhibited significantly lower mean serum levels of TM (25.2 ± 7.9 ng/mL vs. 29.9 ± 14.7 ng/mL, p = 0.005), vWF (232 ± 131 U/dL vs. 266 ± 122 U/dL, p = 0.028), IL-6 (12.5 ± 13.2 pg/mL vs. 16.2 ± 16.5 pg/mL, p < 0.01), D-dimer (511 ± 407 ng FEU/mL vs. 781 ± 998 ng FEU/mL, p < 0.01), and CRP (8.2 ± 8.8 mg/L vs. 15.8 ± 19.7 mg/L, p < 0.01) compared to the placebo group. No significant differences were observed between groups for P-selectin, fibrinogen, VCAM-1, or ICAM-1 levels.

Conclusions

In this study, patients with cardiometabolic risk factors who were in a convalescent phase from moderate or severe COVID-19 within 40 days of clinical presentation exhibit elevated serum levels of biomarkers indicative of ongoing endothelial cell activation and dysfunction. Patients receiving sulodexide for eight weeks showed a reduction in TM, vWF, D-dimer, CRP, and IL-6 serum levels compared to placebo, suggesting a potential protective effect against thromboinflammation and endothelial damage.

These findings may translate into improved clinical outcomes, though further studies are needed to confirm these results and explore their long-term implications.

No relevant conflicts of interest to declare.

Sulodexide is a mixture of two glycosaminoglycans (GAGs), one a fast-moving heparin fraction (80%), the other dermatan sulfate (20%). As a precursor for the synthesis of GAGs, sulodexide can help restore a shredded endothelial glycocalyx and prevent further degradation.approved for the treatment of Chronic venous disease, venous ulcers, thromboprophylaxis, post thrombotic syndrome.