Thrombin generation is associated with extracellular vesicle and leukocyte lipid membranes in acute coronary syndrome

Abstract

Background: Acute coronary syndrome (ACS) is caused by arterial thrombosis and is associated with sustained activation of coagulation. Clotting requires interactions of coagulation factors with aminophospholipids (aPL): phosphatidylserine (PS) and phosphatidylethanolamine (PE) on membrane surfaces. The aPL composition of circulating membranes in coronary disease has not been characterized. Furthermore, the contribution of external-facing aPL to elevated thrombotic risk in ACS is unknown. Methods and results: Thrombin generation was measured on platelet, leukocyte and extracellular vesicles (EV) from patients with ACS (n = 24), stable coronary artery disease (CAD, n = 18), risk factor positive (RF, n = 23) and healthy controls (HC, n = 24). The aPL composition on the surface of EV, platelets and leukocytes was determined using lipidomics. Leukocytes, platelets and EV externalized PE- and PS-containing fatty acids ranging from C16:0-20:4. These included both diacyl and plasmalogen forms, with significant increases stimulated by agonist activation. Thrombin generation on the surface of EV and leukocytes was higher in ACS than HC. Also, thrombin generation was higher for EV from CAD and RF, than HC. EV counts were higher in CAD and ACS compared with HC. Thrombin generation correlated positively with plasma EV counts and membrane surface area. Conclusion: The aPL membrane of EV and leukocytes may contribute to the activation of coagulation in CAD and ACS. Targeting EV formation/clearance and the aPL surface of EV and leukocyte membranes represents a novel anti-thrombotic target in CAD and ACS.