Low LDL-Cholesterol and Hemorrhagic Risk: Mechanistic Insights and Clinical Perspectives

Abstract

Low-density lipoprotein cholesterol (LDL-C) plays a central role in lipid metabolism and is a well-established therapeutic target for the prevention of atherosclerotic cardiovascular diseases (CVDs). In recent years, increasingly aggressive lipid-lowering strategies have been adopted to achieve ultra-low LDL-C concentrations (<55 mg/dL or even <30 mg/dL) in high-risk patients. While the benefits of LDL-C reduction in lowering the incidence of myocardial infarction and ischemic stroke are well documented, emerging clinical evidence has raised concerns about a potential association between very low LDL-C levels and an increased risk of bleeding, particularly hemorrhagic stroke and gastrointestinal hemorrhage. This review critically examines the molecular mechanisms by which reduced LDL-C levels may influence the hemostatic system and vascular integrity. It explores the complex interplay between cholesterol availability and platelet function, endothelial barrier stability, and coagulation pathways. In addition, we assess experimental and clinical studies supporting this association and discuss how these findings may inform risk stratification and personalized lipid-lowering strategies. A deeper understanding of the biological basis of this paradoxical risk is essential for achieving a safe, balanced, and effective approach to cardiovascular prevention.

Keywords: atherosclerosis; cholesterol; hemostasis; personalized medicine; vascular integrity.

Figure 1

Schematic representation of the proposed mechanisms linking very low LDL-C levels to increased bleeding risk. Disruption of platelet lipid rafts impairs activation and aggregation. Endothelial cholesterol depletion weakens tight junctions and reduces NO production, promoting vascular fragility. Hepatic and cellular cholesterol deficiency alters coagulation factor synthesis and tissue factor expression, shifting the balance toward hypocoagulability.