Abstract Hypercoagulability, immunothrombosis, and protein misfolding are deeply interconnected processes that converge on cell membranes as central orchestrators of thrombo-inflammation. In health, membrane lipid asymmetry, intact glycocalyx, and regulated receptor activity maintain vascular homeostasis. During inflammation or cell death, however, phosphatidylserine (PS) externalization, protein unfolding, and damage to glycosaminoglycans expose negatively charged, amyloidogenic surfaces that attract coagulation factors, inflammatory mediators, and adhesion proteins. These events generate catalytic sites for prothrombinase assembly. We review how cellular debris, microparticles, immune complexes such as neutrophil extracellular traps, and amyloidogenic plasma proteins, including serum amyloid A, interact with fibrinogen to form circulating (heterogeneous) procoagulant complexes, we term fibrinaloid microclot complexes (FMCs). Distinct from canonical fibrin clots, these FMCs display β-sheet–rich features, ThT-binding, and resistance to fibrinolysis, implicating them as key drivers of vascular pathology in inflammatory (and post-viral) syndromes. Recognizing different FMC phenotypes, mechanisms, and biochemical composition of these circulating complexes provides new insights into the pathogenesis of systemic inflammatory diseases and clarifies how membrane damage, protein misfolding, and coagulation converge to drive thrombo-inflammation. These insights position FMCs as a conceptual framework for understanding pathological clotting across inflammatory and post-infectious vascular syndromes.
Pretorius et al. (Tue,) studied this question.