title: Romiplostim administration shows reduced megakaryocyte response-capacity and increased myelofibrosis in a mouse model of MYH9-RD.
abstract: Macrothrombocytopenia in MYH9-related disease (MYH9-RD) results from defects in nonmuscular myosin-IIA function. Thrombopoietin receptor agonists (eltrombopag; romiplostim) seem to improve hemostasis, but little is known about their biologic effects in MYH9-RD. We administered romiplostim to Myh9(-/-) mice (100 μg/kg, every 3 days, during 1 month). MKs increased to similar numbers in Myh9(-/-) and wild-type (WT) mice (with an increase in immature MKs), but Myh9(-/-) platelet count response was much less (2.5-fold vs 8-fold increase). A strong increase in MK nuclei emboli in the lung, in WT and Myh9(-/-) mice, indicates increased transmigration of MKs from the BM. Prolonged (but not acute) treatment with romiplostim decreased expression of GPIb-IX-V complex and GPVI, but not of GPIIbIIIa, and bleeding time increased in WT mice. Microcirculation was not altered by the increased number of large platelets in any of the assessed organs, but in Myh9(-/-) mice a much stronger increase in BM reticulin fibers was present after 4 weeks of romiplostim treatment vs WT mice. These data further encourage short-term use of thrombopoietic agents in patients with MYH9-RDs; however, myelofibrosis has to be considered as a potential severe adverse effect during longer treatment. Reduction of GPIbIX/GPVI expression by romiplostim requires further studies.
authors.affiliation: Unité Mixte de Recherche_S949 INSERM, Université de Strasbourg and Etablissement Français du Sang-Alsace, Strasbourg, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Léon
authors.forename: Katja
authors.initials: K
authors.lastname: Evert
authors.forename: Frank
authors.initials: F
authors.lastname: Dombrowski
authors.forename: Fabien
authors.initials: F
authors.lastname: Pertuy
authors.forename: Anita
authors.initials: A
authors.lastname: Eckly
authors.forename: Patricia
authors.initials: P
authors.lastname: Laeuffer
authors.forename: Christian
authors.initials: C
authors.lastname: Gachet
authors.forename: Andreas
authors.initials: A
authors.lastname: Greinacher
mesh_terms: D000818:Animals; D001760:Bleeding Time; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D004617:Embolism / Q000139:chemically induced; D005164:Factor IX / Q000378:metabolism; D005165:Factor V / Q000378:metabolism; D005260:Female; D007958:Leukocyte Count; D008168:Lung / Q000473:pathology; D008297:Male; D008533:Megakaryocytes / Q000187:drug effects* / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018995:Myosin Heavy Chains; D024507:Nonmuscle Myosin Type IIA / Q000235:genetics* / Q000378:metabolism; D019007:P-Selectin / Q000378:metabolism; D010976:Platelet Count; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000378:metabolism; D010980:Platelet Membrane Glycoproteins / Q000378:metabolism; D055728:Primary Myelofibrosis / Q000378:metabolism*; D011961:Receptors, Fc / Q000008:administration & dosage; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology*; D012155:Reticulin / Q000378:metabolism; D013154:Spleen / Q000166:cytology; D013921:Thrombocytopenia / Q000235:genetics* / Q000378:metabolism*; D013926:Thrombopoietin / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D008562:Membrane Glycoproteins; C525088:Myh9 protein, mouse; D019007:P-Selectin; D019039:Platelet Glycoprotein GPIIb-IIIa Complex; D010980:Platelet Membrane Glycoproteins; D011961:Receptors, Fc; D011993:Recombinant Fusion Proteins; D012155:Reticulin; C098341:platelet membrane glycoprotein VI; D005165:Factor V; D005164:Factor IX; D013926:Thrombopoietin; D024507:Nonmuscle Myosin Type IIA; D018995:Myosin Heavy Chains; C488777:romiplostim