RGD Reference Report - Decreased prothrombotic effects of pegylated recombinant human megakaryocyte growth and development factor in thrombocytopenic state in a rat thrombosis model.

General

Decreased prothrombotic effects of pegylated recombinant human megakaryocyte growth and development factor in thrombocytopenic state in a rat thrombosis model.
Authors:	Nishiyama, U Kuwaki, T Akahori, H Kato, T Ikeda, Y Miyazaki, H
Citation:	Nishiyama U, etal., J Thromb Haemost. 2005 Feb;3(2):355-60.
RGD ID:	10448997
Pubmed:	PMID:15670044 (View Abstract at PubMed)
DOI:	DOI:10.1111/j.1538-7836.2005.01113.x (Journal Full-text)
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 (PEG-rHuMGDF), 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 microg 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 microg kg(-1)). In rats rendered thrombocytopenic by total body irradiation, however, PEG-rHuMGDF, even at 300 microg 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.

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Term	Qualifier	Evidence	With	Reference	Notes	Source	Original Reference(s)
thrombocytopenia		ISO	Mpl (Rattus norvegicus)	10448997; 10448997	protein:decreased expression:blood and platelet (rat)	RGD
thrombocytopenia		IEP		10448997	protein:decreased expression:blood and platelet (rat)	RGD

Objects Annotated

Genes (Rattus norvegicus)

Mpl (MPL proto-oncogene, thrombopoietin receptor)

Genes (Mus musculus)

Mpl (myeloproliferative leukemia virus oncogene)

Genes (Homo sapiens)

MPL (MPL proto-oncogene, thrombopoietin receptor)

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