Unraveling the biomechanical regulation of platelet adhesiveness by membrane cholesterol in arterial thrombosis

Arterial thrombosis is a lethal pathological condition characterized by large “platelet clumps” on the artery, known as thrombi. Despite primary and secondary preventive measures, arterial thrombotic events still claim ~900,000 American lives per year1-3. Hypercholesterolemia, a well- established risk factor for cardiovascular diseases (CVDs) (e.g., stroke and heart attack) known to induce atherosclerosis, also has a significant correlation with platelet hyperactivity in arterial thrombosis. However, current understandings cannot adequately elucidate the mechanistic link between hypercholesterolemia and platelet hyperactivity. As an essential but understudied mechanism of arterial thrombosis, platelets can be driven by high shear forces in stenotic arteries to form large aggregates—a phenomenon we termed “biomechanical platelet aggregation. Distinct from the classic biochemical platelet aggregation, biomechanical platelet aggregation does not require soluble agonists (e.g., ADP, thrombin) to induce platelet activation. Instead, it is primarily driven by force-strengthened platelet crosslinking via the binding of platelet receptor glycoprotein Iba (GPIba) to the multimeric plasma protein von Willebrand factor (VWF)9,10. No antithrombotic agent is currently available to target biomechanical platelet aggregation. Whether hypercholesterolemia affects biomechanical platelet aggregation was also never studied. Our preliminary study discovered that blood from patients with hypercholesterolemia can achieve stronger biomechanical platelet aggregation, and are also physically more elastic. Furthermore, we found that a higher membrane cholesterol content increases platelet elasticity, and a more elastic environment reinforces GPIba–VWF molecular binding under force. We thus hypothesize that: higher membrane cholesterol content promotes platelet elasticity to intensify GPIba binding and exacerbate biomechanical platelet aggregation and arterial thrombosis, and weakening GPIba binding under force can effectively and safely prevent hypercholesterolemia-associated arterial thrombosis.