Treatment of Thrombocytopenia in Chimpanzees Infected With Human
Immunodeficiency Virus by Pegylated Recombinant Human Megakaryocyte
Growth and Development Factor
Laurence A. Harker,
Ulla M. Marzec,
Francis Novembre,
I. Birgitta Sundell,
Edmund K. Waller,
Simon Karpatkin,
Harold M. McClure,
Andrew B. Kelly, and
Richard B. Stead
From the Division of Hematology and Oncology, Yerkes Primate Research
Center, Emory University School of Medicine, Atlanta, GA; the New York
University Medical Center, New York, NY; and Amgen Inc, Thousand Oaks,
CA.
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 × 103/µL (P = .004 compared with 228 ± 92 × 103/µL 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 × 103 RNA
viral copies/mL. Pegylated recombinant human megakaryocyte growth and
development factor (PEG-rHuMGDF) was administered subcutaneously (25 µg/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 × 103 platelets/µL;
P = .02); (2) marrow megakaryocyte numbers 30-fold (from 11.7 ± 6.5 × 106/kg to 353 ± 255 × 106/kg;
P = .04); (3) marrow megakaryocyte progenitor cells fourfold (from a mean of 3.6 ± 0.6 to 14.1 × 103 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 × 103/µL to 9.9 ± 5.0 × 103/µL (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 × 103 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.
Blood, Vol. 91 No. 12 (June 15), 1998:
pp. 4427-4433
© 1998 by The American Society of Hematology.
