Long COVID Plasma Induces Endothelial Injury and Reduces Syndecan-1 and von Willebrand Factor Levels in Human Umbilical Vein Endothelial Cells

Endothelial dysfunction and persistent coagulopathy (thrombotic endothelialitis) are central drivers of Long COVID pathophysiology. However, the effects of insoluble circulating fibrinaloid microclot complexes (FMCs) on endothelial function remain unclear. This study investigated the impact of Long COVID platelet-poor plasma (PPP), containing FMCs, on endothelial activation, glycocalyx degradation, and endothelial injury. FMC burden was quantified in control (n = 5) and Long COVID (n = 10) PPP using Thioflavin T and imaging flow cytometry. Healthy (passage ≤8) and senescent (passage 10) human umbilical vein endothelial cells were exposed to control PPP, Long COVID PPP, fibrinogen with serum amyloid A and spike protein S1, or DMSO (to induce cell death). Water-soluble tetrazolium 1 assays were used for metabolic activity, confocal microscopy for VWF and syndecan-1, and scanning electron and light microscopes for morphological assessments. Long COVID PPP showed significantly increased FMCs (p < 0.001). Although metabolic activity was unchanged, Long COVID PPP significantly reduced VWF compared to untreated (p < 0.001) and control PPP-treated (p < 0.01), indicating endothelial activation. Syndecan-1 was also decreased (p < 0.05), suggesting glycocalyx degradation. Morphological assessments revealed endothelial injury. Long COVID PPP, containing increased FMCs,promotes endothelial dysfunction, highlighting the therapeutic potential of targeting vascular restoration and FMC reduction.