Harker L A, Marzec U M, Novembre F, Sundell I B, Waller E K, Karpatkin S, McClure H M, Kelly A B, Stead R B
Division of Hematology and Oncology, Yerkes Primate Research Center, Emory University School of Medicine, Atlanta, GA 30322, USA.
Blood. 1998 Jun 15;91(12):4427-33.
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 x 10(3)/microL (P = .004 compared with 228 +/- 92 x 10(3)/microL in 44 normal control animals), mean platelet volumes of 11.2 +/- 1.8 fL (P > .5 compared with 10.9 +/- 0. 7 fL in normal controls), endogenous thrombopoietin (TPO) levels of 926 +/- 364 pg/mL (P < .001 compared with 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 x 10(3) RNA viral copies/mL. Pegylated recombinant human megakaryocyte growth and development factor (PEG-rHuMGDF) was administered subcutaneously (25 microg/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 platelet counts 10-fold (from 64 +/- 19 to 599 +/- 260 x 10(3) platelets/microL; P = .02); (2) marrow megakaryocyte numbers 30-fold (from 11.7 +/- 6.5 x 10(6)/kg to 353 +/- 255 x 10(6)/kg; P = .04); (3) marrow megakaryocyte progenitor cells fourfold (from a mean of 3.6 +/- 0.6 to 14.1 x 10(3) CFU-Meg/1, 000 CD34(+) marrow cells); and (4) serum levels of Mpl ligand from 926 +/- 364 pg/mL (endogenous TPO) to predosing trough levels of 1, 840 +/- 353 pg/mL PEG-rHuMGDF (P = .02). The peripheral neutrophil counts were also transiently increased from 5.2 +/- 2.6 x 10(3)/microL to 9.9 +/- 5.0 x 10(3)/microL (P = .01), but neither the erythrocyte counts nor the reticulocyte counts were altered significantly (P > .1). The serum levels of antiplatelet GPIIIa49-66 antibodies exhibited reciprocal reductions during periods of thrombocytosis (P < .07). PEG-rHuMGDF therapy did not increase viral loads significantly (395, 189, and 53 x 10(3) RNA viral copies/mL; P > .5 compared with 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 in thrombocytopenic HIV-infected patients.
三只感染人类免疫缺陷病毒（HIV）的黑猩猩在5年、4年和2年后出现了显著的慢性血小板减少症，外周血小板计数平均为64±19×10³/μL（与44只正常对照动物的228±92×10³/μL相比，P = 0.004），平均血小板体积为11.2±1.8 fL（与正常对照的10.9±0.7 fL相比，P＞0.5），内源性血小板生成素（TPO）水平为926±364 pg/mL（与正常对照的324±256 pg/mL相比，P＜0.001），血小板抗糖蛋白（GP）IIIa49 - 66抗体均升高，相应的病毒载量分别为534、260和15×10³RNA病毒拷贝/mL。对这组血小板减少的HIV感染黑猩猩皮下注射聚乙二醇化重组人巨核细胞生长和发育因子（PEG - rHuMGDF）（25μg/kg，每周两次，共3剂），以确定刺激血小板生成对其外周血小板浓度的影响。PEG - rHuMGDF治疗使（1）外周血小板计数增加了10倍（从64±19增至599±260×10³血小板/μL；P = 0.02）；（2）骨髓巨核细胞数量增加了30倍（从11.7±6.5×10⁶/kg增至353±255×10⁶/kg；P = 0.04）；（3）骨髓巨核细胞祖细胞增加了4倍（从平均3.6±0.6增至14.1×10³CFU - Meg/1000 CD34⁺骨髓细胞）；以及（4）Mpl配体的血清水平从926±364 pg/mL（内源性TPO）增至给药前谷值水平1840±353 pg/mL PEG - rHuMGDF（P = 0.02）。外周中性粒细胞计数也从5.2±2.6×10³/μL短暂增加至9.9±5.0×10³/μL（P = 0.01），但红细胞计数和网织红细胞计数均无显著改变（P＞0.1）。在血小板增多期间，抗血小板GPIIIa49 - 66抗体的血清水平呈反向降低（P＜0.07）。PEG - rHuMGDF治疗未显著增加病毒载量（395、189和53×10³RNA病毒拷贝/mL；与基线值相比，P＞0.5）。PEG - rHuMGDF治疗使外周血小板计数显著增加，这表明HIV感染黑猩猩的血小板减少症归因于尽管巨核细胞生成受到刺激，但HIV损害血小板释放导致血小板生成的代偿性扩张不足。这些数据表明，PEG - rHuMGDF治疗可能同样能纠正HIV感染血小板减少患者的外周血小板计数。
