Associate Research Scientist Yale School of Medicine New Haven, Connecticut, United States
Disclosure(s):
Rafael Bayarri-Olmos, PhD: No financial relationships to disclose
Introduction/Rationale: Long COVID (LC) is a multisystem condition following SARS-CoV-2 infection, characterized by persistent symptoms including fatigue, myalgia, and cognitive dysfunction. While estimated to affect more than 400 million individuals worldwide, the mechanisms underlying its development and persistence remain poorly understood. Recent studies suggest that a subset of LC patients exhibits sustained systemic complement activation, potentially contributing to vascular and end-organ damage that may explain some LC symptoms. Here, we performed multiparametric complement and thrombo-inflammatory profiling in LC patients to identify mechanistic drivers and define biochemical endotypes that could justify the use of complement therapeutics.
Methods: We analyzed a cohort of LC patients (n = 82), COVID-19 convalescent controls (CVC, n = 22), and healthy controls (HC, n = 31) using LC-MS-based proteomics; specific ELISAs for complement function (CH50), activity (C1s-C1INH), and circulating levels of selected components; and multiplexed endothelial injury panels.
Results: Plasma proteomics revealed a systemic reduction in components across all three activation pathways. Validation by ELISA confirmed significantly decreased total hemolytic activity (CH50, HC vs LC) and marked depletion of pathway-specific markers (e.g., C1s/C1-INH, CL-11, MASP-2, MASP-3, Factor P, Factor I, HC vs LC for all). This profile was accompanied by a concurrent reduction in coagulation factors of the intrinsic (Factor XII), extrinsic (Factor VII), common (Factor X, Factor II, Factor 13B), and anticoagulant pathways (Protein C, Protein S, and Protein C receptor), contrasting with significant elevations in fibrinogen (HC vs LC) and von Willebrand factor (vWF) (HC vs LC).
Conclusion: Our data suggest a state of chronic, low-grade thrombo-inflammation at the vascular interface, characterized by ongoing consumption of complement and coagulation proteins and endothelial distress.
