Douglas B. Kell *
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 highlights their potential as
both diagnostic markers and therapeutic targets.
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