Nature, Published online: 02 April 2025; doi:10.1038/s41586-025-08804-7In thromboinflammation, early tissue plasminogen activator administration directly improves endothelial barrier function, prophylactic defibrotide and enoxaparin suppress microvascular thromboinflammation through endothelium-mediated mechanisms and combining enoxaparin with crizanlizumab reduces microvascular occlusion and protects endothelial function in sickle cell disease.