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BACKGROUND: Superficial plaque erosion causes many acute coronary syndromes. However, mechanisms of plaque erosion remain poorly understood, and we lack directed therapeutics for thrombotic complication. Human eroded plaques can harbor neutrophil extracellular traps (NETs) that propagate endothelial damage at experimental arterial lesions that recapitulate superficial erosion. Clonal Hematopoiesis of Indeterminate Potential (CHIP) denotes age-related clonal expansion of bone marrow-derived cells harboring somatic mutations in the absence of overt hematological disease. CHIP heightens the risk of cardiovascular disease, with the greatest increase seen in individuals with JAK2. Neutrophils from mice and humans with JAK2 undergo NETosis more readily than Jak2 (wild-type) cells. We hypothesized that JAK2, by increasing propensity to NETosis, exacerbates aspects of superficial erosion.METHODS AND RESULTS: We generated Jak2 and Jak2 mice with heterozygous Jak2 in myeloid cells. We induced areas of denuded endothelium that recapitulate features of superficial erosion and assessed endothelial integrity, cellular composition of the erosion, thrombosis rates, and response to ruxolitinib, a clinically available JAK1/2 inhibitor, in relation to genotype. Following experimental erosion, Jak2 mice have greater impairment of endothelial barrier function and increased rates of arterial thrombosis. Neointimas in Jak2 mice exhibit increased apoptosis, NETosis, and platelet recruitment. Jak2 mice treated with ruxolitinib show increased endothelial continuity and reduced apoptosis in the neointima comparable to levels in Jak2.CONCLUSIONS: These observations provide new mechanistic insight into the pathophysiology of superficial erosion, the heightened risk for myocardial infarction in JAK2 CHIP, and point the way to personalized therapeutics based on CHIP status.