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Increased Levels of Inflammatory and Endothelial Biomarkers in Blood of Long COVID Patients Point to Thrombotic Endothelialitis
The prevailing hypotheses for the persistent symptoms of Long COVID have been narrowed down to immune dysregulation and autoantibodies, widespread organ damage, viral persistence, and fibrinaloid microclots (entrapping numerous inflammatory molecules) together with platelet hyperactivation. Here we demonstrate significantly increased concentrations of von Willebrand factor (VWF), platelet factor 4 (PF4), serum amyloid A (SAA), α-2 antiplasmin (α-2AP), endothelial-leukocyte adhesion molecule 1 (E-selectin), and platelet endothelial cell adhesion molecule (PECAM-1) in the soluble part of the blood. It was noteworthy that the mean level of α-2 antiplasmin exceeded the upper limit of the laboratory reference range in Long COVID patients, and the other 5 were significantly elevated in Long COVID patients as compared to the controls. This is alarming if we take into consideration that a significant amount of the total burden of these inflammatory molecules has previously been shown to be entrapped inside fibrinolysis-resistant microclots (thus decreasing the apparent level of the soluble molecules). We conclude that presence of microclotting, together with relatively high levels of six biomarkers known to be key drivers of endothelial and clotting pathology, points to thrombotic endothelialitis as a key pathological process in Long COVID.
Keywordslong COVID - von Willebrand factor - platelet factor 4 - serum amyloid A - α2-antiplasmin - E-selectin - PECAM-1 - thrombotic endothelialitis
Institutional Review Board Statement
The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board of Stellenbosch University (B21/03/001_ COVID-19, project ID: 21911 [Long COVID Registry] and N19/03/043, project ID 9521 with yearly re-approval). Participants were either recruited via the Long COVID registry or identified from our clinical collaborator's practice. The experimental objectives, risks, and details were explained to volunteers and informed consent was obtained prior to blood collection. Strict compliance to ethical guidelines and principles of the Declaration of Helsinki, South African Guidelines for Good Clinical Practice, and Medical Research Council Ethical Guidelines for Research were kept for the duration of the study and for all research protocols.
Informed Consent Statement
Informed consent was obtained from all individuals involved in the study.
Conceptualization: E.P. and D.B.K.
Methodologies: S.T., E.P., C.A.N., T.J.U.
Sample curation: C.V.
Clinician input: G.J.L., A.K., and M.A.K.
Writing of the manuscript: E.P. and S.T.
All authors reviewed and edited the manuscript.
Article published online:
19 May 2023
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