Deletion of Crry and DAF on murine platelets stimulates thrombopoiesis and increases factor H-dependent resistance of peripheral platelets to complement attack.

Complement receptor 1–related gene/protein y (Crry) and decay-accelerating factor (DAF) are two murine membrane C3 complement regulators with overlapping functions. Crry deletion is embryonically lethal whereas DAF-deficient mice are generally healthy. Crry −/− DAF −/− mice were viable on a C3 −/− background, but platelets from such mice were rapidly destroyed when transfused into C3-sufficient mice. In this study, we used the cre-lox system to delete platelet Crry in DAF −/− mice and studied Crry/DAF-deficient platelet development in vivo. Rather than displaying thrombocytopenia, Pf4-Cre + -Crry flox/flox mice had normal platelet counts and their peripheral platelets were resistant to complement attack. However, chimera mice generated with Pf4-Cre + -Crry flox/flox bone marrows showed platelets from C3 −/− but not C3 +/+ recipients to be sensitive to complement activation, suggesting that circulating platelets in Pf4-Cre + -Crry flox/flox mice were naturally selected in a complement-sufficient environment. Notably, Pf4-Cre + -Crry flox/flox mouse platelets became complement susceptible when factor H function was blocked. Examination of Pf4-Cre + -Crry flox/flox mouse bone marrows revealed exceedingly active thrombopoiesis. Thus, under in vivo conditions, Crry/DAF deficiency on platelets led to abnormal platelet turnover, but peripheral platelet count was compensated for by increased thrombopoiesis. Selective survival of Crry/DAF-deficient platelets aided by factor H protection and compensatory thrombopoiesis demonstrates the cooperation between membrane and fluid phase complement inhibitors and the body’s ability to adaptively respond to complement regulator deficiencies.