The prothrombotic and proadhesive blood milieu in the MPNs. (A) Under normal conditions, the monolayer of quiescent ECs that line the intimal surface of the circulatory tree displays a thromboresistant, anticoagulant, antiadhesive, anti-inflammatory phenotype that promotes blood fluidity. (B) Activation or dysfunction of ECs in the MPNs changes this milieu to cause activation and adhesion of platelets, leukocytes, and red cells to endothelium, formation of circulating platelet-leukocyte aggregates, NETs and microparticles, generation of thrombin, and release of proinflammatory cytokines. The main triggers for this “thromboinflammatory” state are most likely (i) cell-intrinsic abnormalities of platelets, leukocytes, red cells, and ECs as a function of their origin in a mutant hematopoietic clone and (ii) the establishment of a proinflammatory state, both serving as mutually amplifying factors. Professional illustration by Patrick Lane, ScEYEnce Studios.