Procoagulant platelets mediate cerebral arterial thrombosis in cancer

Cancer is associated with a systemic hypercoagulable state and an increased risk of acute ischemic stroke (AIS), yet the mechanisms underlying cancer-associated arterial thrombosis remain poorly defined. We conducted comprehensive analyses of blood and thrombi in patients with AIS and Cancer (AIS-Cancer), AIS without cancer, and cancer without AIS. AIS-Cancer showed the highest neutrophil activation, whereas biomarkers of systemic inflammation, endothelial dysfunction, and peripheral platelet phenotypes (proaggregant and procoagulant platelets and AV+ platelet-derived microvesicles) were similar across groups. In contrast, thrombi retrieved from large vessels in AIS-Cancer were predominantly platelet-rich and contained fibrin, neutrophils and neutrophil extracellular traps, whereas thrombi from non-cancer AIS were mainly red blood cell-rich. Platelets within AIS-Cancer thrombi exhibited a distinct procoagulant phenotype elicited in vitro with plasma from affected patients. Together, these findings suggest that cancer reprograms arterial thrombus formation toward a procoagulant and NET-rich phenotype, providing a rationale for therapies targeting procoagulant platelet activity in cancer-associated stroke.