Host Defense Antimicrobial Peptides (HDPs) as Regulators of Hemostasis and Vascular Biology

Host defense peptides (HDPs), ancestral effectors of innate immunity, have emerged as pleiotropic regulators transcending their antimicrobial origins. This review critically examines the complex interplay among HDPs, hemostasis, and tissue repair. We analyze molecular mechanisms governing interactions with platelets and endothelial cells, highlighting a fundamental paradigm shift: platelets and megakaryocytes are active synthesizers of a specific peptide repertoire rather than passive carriers. Functional dualities are elucidated, contrasting LL-37-driven platelet agonism via glycoprotein VI (GPVI) against the amyloid-like stabilization of fibrin by defensins. Based on these mechanisms, we propose a framework wherein HDPs function as concentration-dependent molecular switches between physiological repair and pathological thromboinflammation. Furthermore, the review addresses the hypothesis of “adaptive thrombopoiesis,” where systemic peptide surges act as danger signals to reprogram the function of newly formed platelets. Finally, therapeutic implications are evaluated, emphasizing the design of protease-resistant peptidomimetics to harness protective effects while mitigating vascular toxicity.