[Effects of heparin on megakaryocytopoiesis. From fundamental data to clinical applications]

Heparin, a glycosaminoglycan (GAG) derivative has been widely used as an anticoagulation agent for more than 50 years. This study was conducted to demonstrate that, due to their modulatory effect on cytokines, heparin and other GAGs can favor megakaryocytopoiesis both in vitro and in vivo in mice. In vitro addition of heparin and other GAGs (excepting keratane sulfate) into plasma clot cultures induces a significant increase in the number of megakaryocyte colonies. Optimal heparin and GAG concentrations for maximal effect are approximately 50-100 micrograms/ml. In agar culture without serum, all GAGs do not have this stimulating effect on megakaryocyte colonies. This would suggest that the GAG action depends on the presence of one or more plasma factors. Interactions between GAGs and cytokines such as IL3, IL6, G-SCF, GM-CSF, aFGF, TPO and EPO as well as PF4 and TGFB1 were also conducted. The results demonstrate that heparin and chondroitin sulfate significantly increases the action of TPO, IL6 and aFGF but not the action of IL3, G-SCF and EPO. Heparin and other GAGs can also neutralize PF4 and TGFB1 inhibitory action. In vivo, the effect of low-molecular-weight heparin (Fraxiparine) injected in normal mice treated with 5-fluorouracil increases megakaryocytopoiesis. The findings demonstrate that heparin and its derivatives have a potentializing effect on megakaryocytopoiesis and could be used as therapeutic agents in the treatment of thrombocytopenia.