Role of microthrombosis in coronary microvascular dysfunction

Coronary microvascular dysfunction is a common and prognostically important event of ischemic heart disease, yet effective therapeutic strategies remain limited. Microthrombosis is a pivotal driver of microvascular obstruction and no-reflow. This review focuses on the self-amplifying loop between inflammation and platelet activation that sustains microvascular occlusion. Within this loop, myocardial inflammatory signaling suppresses protective autophagy, predominantly in cardiomyocytes, and promotes endothelial dysfunction. The resulting prothrombotic endothelial surface supports activated platelet adhesion, inflammatory mediator release, and platelet-leukocyte aggregation. Neutrophil-derived web-like structures, known as neutrophil extracellular traps (NETs), further enhance platelet aggregation and fibrin deposition. These thromboinflammatory processes lead to microinfarcts, contractile dysfunction, and elevated cardiac troponin, and extend to multiple organs, particularly in patients with common cardiometabolic risk factors such as hypertension, diabetes, dyslipidemia, and hyperhomocysteinemia. Platelet-derived microparticles, platelet-monocyte aggregates, and soluble activation markers show promise as diagnostic biomarkers, but further clinical validation is required. Current antiplatelet, anti-inflammatory strategies, or ischemic conditioning are limited by bleeding risk, narrow therapeutic windows, or inconsistent efficacy. We outline future directions, including developing validated biomarker panels, multi-target therapies that block key inflammatory pathways or NET formation, and human-relevant microphysiological models. Understanding the positive feedback cycle between inflammation and platelets is essential for developing novel diagnostic and therapeutic approaches to mitigate microvascular damage in coronary artery disease as well as other thromboinflammatory disorders.