SUMMARY Platelet dysregulation is drastically increased with advanced age and contributes to making cardiovascular disorders the leading cause of death of elderly humans. Hematopoietic stem and progenitor cells continuously give rise to platelets, but their contributions to variable platelet production and activity throughout life remain unclear. Here we reveal a direct differentiation pathway from hematopoietic stem cells into platelets that is unique to aging. An unequivocal genetic lineage tracing mouse model demonstrated that this age-specific pathway is progressively propagated over time. Remarkably, the age-specific platelet path is decoupled from all other hematopoietic lineages, including erythropoiesis, and operates as an additional layer in parallel with canonical platelet production. This results in two molecularly and functionally distinct populations of megakaryocyte progenitor cells that that operate in parallel. The age-specific megakaryocyte progenitor population has profoundly enhanced capacity to engraft, expand, and reconstitute platelets, and produces an additional platelet population that exists only in old mice. Consistent with increased thrombotic incidence upon aging, the two pools of co-existing platelets contribute to age-related thrombocytosis and dramatically increased thrombosis in vivo . Upon acute, platelet-specific stress, the age-specific MkPs endowed old mice with superior capacity to rapidly restore platelet counts. These findings reveal stem cell-based aging as a mechanism for platelet dysregulation and identify an aging-induced population of functionally enhanced MkPs as a unique source of age-specific platelets. &gt;HIGHLIGHTS Aging leads to two parallel platelet specification paths from HSCs The shortcut platelet pathway is perpetuated by highly expansive MkPs unique to aging The age-specific differentiation path contributes to thrombosis and platelet hyperreactivity Age-specific MkPs serve as potent first responders to acute platelet loss

An age-specific platelet differentiation path from hematopoietic stem cells contributes to exacerbated thrombosis