REGULATION OF TPO DEPENDENT PLATELET PRODUCTION

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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.