Longitudinal Assessment of Plasma Syndecan-1 Predicts 60-Day Mortality in Patients with COVID-19

Abstract

Background: Endotheliopathy is a common pathologic finding in patients with acute and long COVID-19. It may be associated with disease severity and predispose patients to long-term complications. Plasma levels of a proteoglycan, syndecan-1, are found to be significantly elevated in patients with COVID-19, but its roles in assessing disease severity and predicting long-term outcome are not fully understood. Methods: A total of 124 consecutive hospitalized patients with SARS-CoV-2 infection were prospectively enrolled and blood samples were collected on admission (T1), 3–4 days following treatment (T2), and 1–2 days prior to discharge or death (T3). Plasma levels of syndecan-1 were determined using an immunosorbent assay; various statistical analyses were performed to determine the association between plasma syndecan-1 levels and disease severity or the 60-day mortality rate. Results: Compared with those in the healthy controls, plasma levels of syndecan-1 in patients with critical COVID-19 were significantly higher (p < 0.0001). However, there was no statistically significant difference among patients with different disease severity (p > 0.05), resulting from large individual variability. Longitudinal analysis demonstrated that while the levels fluctuated during hospitalization in all patients, plasma syndecan-1 levels were persistently elevated from baseline in critical COVID-19 patients. Cox proportional hazard regression analyses revealed that elevated plasma levels of syndecan-1 (>260 ng/mL at T1, >1018 ng/mL at T2, and >461 ng/mL at T3) were significantly associated with the 60-day mortality rate. Conclusions: Endotheliopathy, marked by glycocalyx degradation and elevated plasma syndecan-1, occurs in nearly all hospitalized patients with SARS-CoV-2 infection; elevated plasma syndecan-1 is associated with increased mortality in COVID-19 patients.

Dynamic Measurement of Plasma von Willebrand Factor and ADAMTS13 Predicts Mortality in Hospitalized Patients with SARS-CoV2 Infection

“…Endotheliopathy, marked by the increased levels of plasma VWF (32,33) and syndecan-1 (4) , has been previously shown to be associated with the disease severity. It may predispose to a long-term cardiovascular complication.…”

“…These patients were divided into 4 groups: asymptomatic, moderate, severe, and critical groups based on an updated WHO guideline. The demographic, clinical, and laboratory characteristics of this cohort of patient were previously described (4) .…”

“…Vascular endothelium lining on the inner surface of blood vessel wall plays significant role in controlling vasomotor tone, cells and nutrient trafficking, maintaining blood fluidity, and angiogenesis (1) . When disrupted, caused by infection, toxin, trauma, irradiation, and ischemia, etc., endotheliopathy develops, resulting in the release of several adhesion molecular such as von Willebrand factor (VWF) (2) , proteoglycan syndecan-1 (3,4) , and soluble thrombomodulin (5) , etc. 2 VWF, a multimeric glycoprotein, is stored in the Weibel-Palade bodies of endothelial cells and alpha granules of megakaryocytes.…”

Therapeutic strategies targeting the endothelial glycocalyx

“…The level of glycocalyx damage may be dependent on COVID-19 severity, as in vitro findings indicate that blood derived from patients with mild symptoms reduced the glycocalyx by approximately 49%, whereas sera from patients with severe symptoms reduced the height of the glycocalyx by >60% [40]. COVID-19 severity is also related to the magnitude of elevation in blood concentrations of syndecan-1, heparinase, heparin sulfate, and hyaluronan [37,40,41 ▪▪ ,42,43,44 ▪ ,45]. The loss of syndecan-1 from the endothelial glycocalyx leads to increased adhesion of leukocytes to endothelial cells, enhanced vascular permeability, and intravascular coagulation [39,40,46], which is a major concern as glycocalyx damage could increase the severity of inflammatory response to COVID-19, as well as the length of recovery.…”

Dynamic Assessment of Plasma von Willebrand Factor and ADAMTS13 Predicts Mortality in Hospitalized Patients with SARS-CoV-2 Infection

“…Many studies have demonstrated that endothelial injury and microvascular thrombosis are associated with the pathogenic processes of severe and critical COVID-19 disease [5][6][7][8][9][10][11][12]. The vascular endothelium is a single and flat cell layer that maintains the entire balance of blood fluid hemostasis and prevents thrombosis [13,14].…”