EFFECT OF HEPARIN ON MEGAKARYOCYTOPOIESIS - FROM FUNDAMENTAL-STUDIES TO CLINICAL-APPLICATIONS

Heparin, a glycosaminoglycan (GAG) derivative, has been widely used as an anticoagulation agent for more than 50 fears. This study was condu cted to demonstrate that, due to their modulatory effect on cytokines, heparin and other GAGs can favor megakaryocytopoiesis both in vitro a nd in vivo in mice, In vitro addition of heparin and other GAGs (excep ting keratane sulfate) into plasma clot cultures induces a significant increase in the number of megakaryoctyte colonies. Optimal heparin an d GAG concentrations for maximal effect are approximately 50-100 mu g/ ml. In agar culture without serum, all GAGs do not have this stimulati ng effect on megakaryocyte colonies, This would suggest that the GAG a ction depends on the presence of one or more plasma factors. Interacti ons between GAGs and cytokines such as IL3. IL6, G-SCF, GM-CSF, aFGF, TPO and EPO as well as PM and TGFB1 \rcre also conducted. The results demonstrate that heparin and chondroitin sulfate significantly increas es the action of TPO, IL6 and aFGF but not the action of IL3. G-SCF an d EPO. Heparin and other GAGs can also neutralize PF4 and TGFB1 inhibi tory action. bl vivo, the effect of low-molecular-weight heparin (Frax iparine(R)) injected in normal mice treated with 5-fluorouracil increa ses megakaryocytopoiesis. The findings demonstrate that heparin and it s derivatives have a potentializing effect on megakaryocytopoiesis and could be used as therapeutic agents in the treatment of thrombocytope nia.