REGULATION OF TPO DEPENDENT PLATELET PRODUCTION

三只黑猩猩实验性感染人类 免疫缺陷病毒（艾滋病毒）发展显著的慢性 外周血小板5年、4年和2年后的血小板减少症 计数平均值为64“19 x 103/：L（p=0.004，相比之下， 44只正常对照动物），平均血小板体积为11.2 - 1.8 /L （p>0.5，而正常对照组为10.9 ± 0.7 /L），内源性 血小板生成素（TPO）水平为926 - 364 pg/mL（p<0.001，与 正常对照组为324 - 256 pg/mL），血小板均匀升高 抗糖蛋白（GP）IIIa 49 -66抗体和相应的病毒 上样量为534、260和15 x103 RNA病毒拷贝/mL。 peg化 重组人巨核细胞生长发育因子 皮下施用（25：g/kg，每周两次）PEG-rHuMGDF 以确定刺激血小板的作用 在这个队列中， 艾滋病病毒感染的黑猩猩。 PEG-rHuMGDF治疗 1）外周血小板计数增加10倍; 2）骨髓 巨核细胞数量30倍; 3）骨髓巨核祖细胞 细胞4倍;和4）Mpl配体的血清水平从926 - 364 pg/mL （内源性TPO）至给药前的水平达到1840 - 353 pg/mL。 的 外周血中性粒细胞计数也一过性升高，但 红细胞计数和网织红细胞计数均未改变 显著 抗血小板GPIIIa 49 -66血清水平 抗体显示出相反的减少期间， 血小板增多症 PEG-rHuMGDF治疗未增加病毒载量 与基线值相比有显著性差异。 惊人的增长， PEG-rHuMGDF治疗产生的外周血小板计数表明 感染艾滋病病毒的黑猩猩的血小板减少症是由于 血小板生成代偿性扩张不足， 尽管受到刺激， 巨核细胞生成 这些数据表明PEG-rHuMGDF治疗可能 血小板减少症患者外周血小板计数同样正确 艾滋病毒感染者。

Three chimpanzees experimentally infected with human immunodeficiency virus (HIV) developed significant chronic thrombocytopenia after 5, 4 and 2 years with peripheral platelet counts averaging 64"19 x103/:L (p=0.004 compared to 228"92 x103/:L in 44 normal control animals), mean platelet volumes of 11.2"1.8 /L (p>0.5 compared to 10.9"0.7 /L in normal controls), endogenous thrombopoietin (TPO) levels of 926"364 pg/mL (p<0.001 compared to 324"256 pg/mL in normal controls), uniformly elevated platelet anti-glycoprotein (GP) IIIa49-66 antibodies, and corresponding viral loads of 534, 260 and 15 x103 RNA viral copies/mL. Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) was administered subcutaneously (25 :g/kg twice weekly for 3 doses) to determine the effects of stimulating platelet production on peripheral platelet concentrations in this cohort of thrombocytopenic HIV-infected chimpanzees. PEG-rHuMGDF therapy increased 1) peripheral platel et counts 10-fold; 2) marrow megakaryocyte numbers 30-fold; 3) marrow megakaryocyte progenitor cells 4-fold; and 4) serum levels of Mpl ligand from 926"364 pg/mL (endogenous TPO) to predosing through levels of 1840"353 pg/mL. The peripheral neutrophil counts were also transiently increased, but neither the erythrocyte counts nor reticulocyte counts were altered significantly. The serum levels of antiplatelet GPIIIa49-66 antibodies exhibited reciprocal reductions during periods of thrombocytosis. PEG-rHuMGDF therapy did not increase viral loads significantly compared to baseline values. The striking increase in peripheral platelet counts produced by PEG-rHuMGDF therapy implies that thrombocytopenia in HIV-infected chimpanzees is attributable to insufficient compensatory expansion in platelet production resulting from HIV-impaired delivery of platelets despite stimulated megakaryocytopoiesis. These data suggest that PEG-rHuMGDF therapy may similarly correct peripheral platelet counts i n thrombocytopenic HIV-infected patients.