An elevated platelet count is frequently observed in several clinical conditions (e.g., chronic inflammation, acute hemorrhage) that may lead to reactive thrombocytosis (RT). Recently we found that i) complement is activated/cleaved in the bone marrow with release of C3a and des-Arg C3a fragments that sensitize responses of hematopoietic cells to SDF-1 (

Blood 2003;101:3784
), an alpha-chemokine that plays an important role in Meg maturation/proplatelet formation, and ii) C3 deficient mice display delayed recovery of platelet counts after sublethal irradiation (Leukemia 2004, in press). Thus, since levels of C3 cleavage products (C3a and des-Arg C3a) and SDF-1 are elevated in bone marrow during inflammation and acute hemorrhage, we hypothesized that they may play a role in the pathogenesis of RT by enhancing Meg maturation/platelet production. In support of this notion we found that i) the receptor for C3a (C3aR) is highly expressed and functional on CFU-Meg progenitors and maturating Megs, ii) C3a induces a calcium flux and actin polymerization in Megs and enhances chemotactic response of human CFU-Meg and maturing Megs to an SDF-1 gradient, and iii) in the presence of C3a + SDF-1, Megs secrete more VEGF and MMP-9, which play a role in proplatelet formation. These effects were not inhibited by the small molecular antagonist of C3aR, SB290157, suggesting the involvement of the C3a derivative, des-Arg-C3a, that binds another C3a receptor called C5L2. At the molecular level we observed that C3a and des-ArgC3 promote the incorporation of CXCR4 into membrane lipid rafts in hematopoietic cells, allowing for its better interaction with small GTP-ases (Rac/Rho). We conclude that C3a and des-Arg C3a modulate the responsiveness of Megs to SDF-1 and postulate that the novel crosstalk between C3aR, C5L2 and CXCR4-G-protein coupled receptors we identified here plays an important and previously unrecognized role in the final maturation of Megs and pro-platelet formation during stress. Thus our results shed more light on the pathogenesis of RT and suggest that inhibitors of both CXCR4 and C3 could find a potential novel clinical application as drugs controlling elevated platelet counts.

Topics:
complement system proteins, reactive thrombocytosis, megakaryocytopoiesis, stromal cell-derived factor 1, cxcr4 receptors, acute hemorrhage, antagonists, calcium, chronic inflammation, cxc chemokines

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2005, The American Society of Hematology
2004
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