The p53 gene is well known as a key tumor suppressor gene; it is vital for hematopoietic stem cell differentiation and growth. In the present study, the change of platelets (PLTs) in p53 knockout mice (p53-/- mice) was investigated. The peripheral blood cell subsets and PLT parameters in p53-/-mice were compared with those in age-matched p53+/+ mice. Bleeding time as well as the alteration of PLT levels, were analyzed with the PLT marker CD41 antibody using flow cytometry. The results revealed that the number of PLTs in p53-/- mice was significantly lower than that in p53+/+ mice. Bleeding time was prolonged in the peripheral blood of p53-/- mice compared with that of p53+/+ mice. Furthermore, the related gene expression of the PI3K signaling pathway in the bone marrow of p53-/- mice was shown to be associated with plateletogenesis. PI3K inhibitor (LY294002) was also used to treat p53-/- mice, and the results demonstrated that LY294002 revert the change of PLTs in these mice. In summary, PLTs were altered in p53-/- mice, and the PI3K signaling pathway was involved in that process, suggesting that the p53-dependent PI3K signaling pathway is involved in thrombocytopenia or PLT diseases. PLT number is reduced in p53 deficiency; however, this reduction could be reverted by inhibiting the PI3K pathway. Copyright: © Yang et al.