The Bcl-2 Protein Family Is Essential for Platelet Survival In Vivo.

Platelets are small, anuclear cytoplasmic fragments that play an essential role in blood clotting and hemostasis. They are produced by megakaryocytes: large, polyploid cells that reside primarily in the bone marrow. Once shed into the blood stream, platelets are consumed either by their participation in hemostatic processes, or their eventual destruction by the reticulo-endothelial system. The latter occurs when platelets have reached the end of their lifespan, which is 9–10 days in human, 4–5 days in mice. Like the other lineages of blood cells, the steady state level of platelets reflects the balance between their production and destruction. Any imbalance can result in bleeding or clotting tendencies, both of which may be life threatening.

We have found that a pro-survival member of the Bcl-2 protein family is essential for the maintainence of platelet survival in vivo. Mutations in the gene encoding this protein dramatically reduce platelet lifespan in a dose-dependent manner, resulting in thrombocytopenia. Strikingly, no effect on platelet production was observed, allowing us to distinguish the molecular control of platelet survival from that of platelet production. In a complementary approach, we employed a specific small molecule antagonist of the pro-survival Bcl-2-like protein. Treatment with this BH3 mimetic agent triggers features of apoptosis in platelets, dramatically reducing their survival both in vivo and in vitro. Platelet death can be prevented if they are pre-treated with a broad-spectrum caspase inhibitor or if platelets are derived from mice lacking an essential downstream mediator of apoptosis. Furthermore, the heritable thrombocytopenia in mice lacking the specific Bcl-2-like protein is corrected when this downstream target is genetically ablated. Thus, the balance between a Bcl-2-like pro-survival protein and its direct downstream pro-apoptotic target critically determines platelet survival, and hence circulating platelet numbers, in vivo.

These findings have notable implications for our understanding of platelet biology, strategies to promote platelet survival, and approaches to remove excess platelets that contribute to pro-thrombotic states.