Why is Thrombosis an Age-Related Condition?

Thrombosis is the inappropriate clumping of platelets to form blood clots in blood vessels, leading to potential blockage and serious injury as tissues are deprived of blood flow. This undesirable situation occurs more readily with age. Platelets are produced by megakaryocyte cells, and the count of platelets in the blood tends to increase in older people. Why does this happen? Researchers here dig in to some of the details, and find that age-related changes in hematopoiesis in the bone marrow produce a distinct population of megakaryocytes that manufacture a greater number of platelets. Further, those platelets are more easily triggered into clot formation. Restoration of youthful hematopoiesis is already an important goal in the treatment of aging, and this adds one more reason for that to be the case.

Platelet dysregulation is drastically increased with advanced age and contributes to making cardiovascular disorders the leading cause of death of elderly humans. Here, we reveal a direct differentiation pathway from hematopoietic stem cells into platelets that is progressively propagated upon aging. Remarkably, the aging-enriched 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 progenitors.

The age-induced megakaryocyte progenitors have a profoundly enhanced capacity to engraft, expand, restore, and reconstitute platelets in situ and upon transplantation and produce an additional platelet population in old mice. The two pools of co-existing platelets cause age-related thrombocytosis and dramatically increased thrombosis in vivo. Strikingly, aging-enriched platelets are functionally hyper-reactive compared with the canonical platelet populations. These findings reveal stem cell-based aging as a mechanism for platelet dysregulation and age-induced thrombosis.

Link: https://doi.org/10.1016/j.cell.2024.04.018

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