Decreased prothrombotic effects of pegylated recombinant human megakaryocyte growth and development factor in thrombocytopenic state in a rat thrombosis model

Abstract

Summary.Previous in vitro studies demonstrated that thrombopoietin (TPO) acts on platelets to activate a variety of intracellular signaling pathways and to enhance platelet sensitivity to multiple agonists. Little is known, however, about whether TPO exerts prothrombotic effects in vivo. The aim of this study was to examine the effects of pegylated recombinant human megakaryocyte growth and development factor (PEGrHuMGDF), a pegylated N-terminal domain of human TPO, in a rat model of venous thrombosis. A microthrombus was photochemically induced on the vessel wall of a mesenteric venule, but the vessel was not occluded by it. A single intravenous injection of PEG-rHuMGDF (3 lg kg )1 ) after the thrombus generation into normal rats enhanced the thrombus size, resulting in transient thrombotic occlusion in the majority of rats. Stimulatory effects on thrombus growth were also observed following administration of glycosylated recombinant human full-length TPO (6 lg kg )1). In rats rendered thrombocytopenic by total body irradiation, however, PEG-rHuMGDF, even at 300 lg kg )1, did not induce a significant increase in thrombus size or thrombotic occlusion. Platelets from thrombocytopenic rats had decreased surface levels of c-Mpl and decreased sensitivity to PEG-rHuMGDF in an in vitro aggregation response. Thus, decreased prothrombotic effects of PEG-rHuMGDF in thrombocytopenic rats might be the result not only of low platelet counts but also of decreased platelet reactivity to PEG-rHuMGDF. These results indicate that PEG-rHuMGDF has little effect on venous thrombus formation in thrombocytopenic states associated with high endogenous TPO levels.

Thrombopoietin as Biomarker and Mediator of Cardiovascular Damage in Critical Diseases

“…Decreased surface levels of c-Mpl together with decreased platelet sensitivity to exogenous stimulation in vitro with a pegylated N-terminal domain of human TPO (PEG-rHuMGDF) have also been evoked as a “protective” mechanism against the prothrombotic effects of in vivo treatment with PEG-rHuMGDF in a rat model of mesenteric microthrombosis [46]; however, the conclusions of this study refer only to thrombocytopenic states, in which endogenous TPO levels are elevated [44–46], whereas this and our subsequent studies were addressed to specific pathologic conditions in which TPO levels rise in presence of normal platelet counts. The precise origin of the rise in plasma TPO level in UA patients remains unclear.…”

Recombinant Human Thrombopoietin Accelerates the Recovery of Platelet in Patients With Lower-Risk Myelodysplastic Syndrome: A Proof-of-Concept Study

“…Furthermore, unilineage and bilineage responses were observed in 46% (5/11) and 55% (6/11) of patients with low-intermediate risk-1 MDS at 16 weeks after the start of EPAG treatment (32). This may be explained by the fact that c-MPL exists on the surface of various hematopoietic cells, including hematopoietic stem cells and hematopoietic progenitor cells of various lines (25,(33)(34)(35). Unlike other TPO-RAs, rhTPO mainly induces megakaryocyte development and platelet production and has less effect on erythroid and granulocyte differentiation (26,27), which illustrated our findings for platelet response only.…”