1. ¹Stem Cell Biology Program, James Graham Brown Cancer Center, University of Louisville, Louisville, KY, USA
2. ²Department of Physiopathology, Pomeranian Medical University, Szczecin, Poland

Correspondence: Dr MZ Ratajczak, Stem Cell Biology Program, James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA. E-mail: mzrata01@louisville.edu

Received 4 December 2006; Revised 16 January 2007; Accepted 25 January 2007; Published online 1 March 2007.

Abstract

We hypothesized that the third complement component (C3) cleavage fragments (C3a and _des-ArgC3a) are involved in stress/inflammation-related thrombocytosis, and investigated their potential role in reactive thrombocytosis induced by bleeding. We found that platelet counts are lower in C3-deficient mice in response to excessive bleeding as compared to normal littermates and that C3a and _des-ArgC3a enhance stromal-derived factor-1 (SDF-1)-dependent megakaryocyte (Megs) migration, adhesion and platelet shedding. At the molecular level, C3a stimulates in Megs MAPKp42/44 phosphorylation, and enhances incorporation of CXCR4 into membrane lipid rafts increasing the responsiveness of Megs to SDF-1. We found that perturbation of lipid raft formation by statins decreases SDF-1/C3a-dependent platelet production in vitro and in an in vivo model statins ameliorated post-bleeding thrombocytosis. Thus, inhibition of lipid raft formation could find potential clinical application as a means of ameliorating some forms of thrombocytosis.