Schematic drawing of pro- and antisurvival proteins in thrombopoiesis. (A) In mature megakaryocytes platelet production is coordinately regulated by the balanced expression of the prosurvival members Bcl-x_L and Mcl-1. (B) Loss of Mcl-1 does not affect platelet production and platelet lifetime. However, when challenged by the proapoptotic ABT-737 substance, Mcl-1 deficient megakaryocytes are more “sensitive” to cell death. (C) Megakaryocyte-specific loss of Bcl-x_L leads to severely reduced platelet life span, low platelet counts, and increased platelet volume. In addition, mice with megakaryocyte-specific loss of Bcl-x_L have higher megakaryocyte numbers in the bone marrow as a compensatory mechanism to boost platelet production. (D) Megakaryocyte-specific loss of Bcl-x_L and 1 allele of Mcl-1 results in low platelet counts and enlarged platelets, similar to the phenotype observed in Bcl-x_L^Pf4Δ/Pf4Δ mice. However, Bcl-x_L^Pf4Δ/Pf4Δ Mcl-1^+/Pf4Δ megakaryocytes are prone to premature cell death leading to megakaryocyte numbers lower than those found in Bcl-x_L^Pf4Δ/Pf4Δ mice. Megakaryocyte-specific loss of Bcl-x_L and Mcl-1 leads to hemorrhage and mortality (not shown).