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Regulation of platelet production and function by megakaryocyte growth and
development factor in nonhuman primates
LA Harker, P Hunt, UM Marzec, AB Kelly, A Tomer, SR Hanson and RB Stead
Division of Hematology and Oncology, Yerkes Regional Primate Research
Center, Emory University School of Medicine, Atlanta, GA, USA.
The primary physiologic regulator of platelet production, Mpl ligand, has
recently been cloned and characterized. To define the regulatory role of
Mpl ligand on platelet production and function we measured the effects of a
recombinant truncated human Mpl ligand, megakaryocyte growth and
development factor (rHu-MGDF) on megakaryocytopoiesis, platelet function,
and thrombogenesis in nonhuman primates. rHu-MGDF was administered to 10
baboons for 28 days while performing pharmacokinetics and repeated
measurements of the following: (1) platelet count, volume, turnover, and
function ex vivo and in vitro; (2) marrow megakaryocyte number, volume, and
ploidy; and (3) platelet deposition and fibrin accumulation on segments of
vascular graft and endarterectomized aorta in vivo. Daily subcutaneous
injections of rHu- MGDF (5 microgram/kg/d) attained plasma concentrations
averaging 1,300 +/- 300 pg/mL 2 hours after injection with trough levels of
300 +/- 65 pg/mL before the next dose. These levels of rHu-MGDF
incrementally increased the peripheral platelet concentration threefold by
day 7 and fivefold by day 28 (P < 10(-4)) associated with a reciprocal
decrease of 25% in mean platelet volumes (P < 10(-3)). Platelet mass
turnover, a steady-state measure of platelet production, increased fivefold
(P < 10(-4)). Platelet morphology, life span, and recovery were normal.
No significant change occurred in peripheral leukocyte, neutrophil, or
erythrocyte counts (P > .1 in all cases). The platelet count gradually
returned to baseline within 2 weeks after discontinuing rHu-MGDF
infections. Marrow megakaryocyte volume doubled (P < 10(-3)) three days
after initiating rHu-MGDF therapy and the modal ploidy shifted from 16N to
64N (P < 10(-4)). Marrow megakaryocyte number increased twofold by day
7, and nearly fourfold by day 28 (P < 10(-4)), resulting in a 6.5- fold
increase in marrow megakaryocyte mass (P < 10(-3)). The effects of
rHu-MGDF on thrombosis were determined by comparing baseline, day 5, and
day 28 rHu-MGDF-treatment measurements of 111In-platelet deposition and
125I-fibrin accumulation on segments of homologous endarterectomized aorta
(EA) and vascular graft (VG) interposed in arteriovenous femoral shunts.
rHu-MGDF increased 111In-platelet deposition in direct proportion to the
circulating concentration of platelets for both EA and VG (r=.98 in both
cases), without significant changes in fibrin accumulation (P > .5 in
both cases). During the first week of rHu-MGDF treatment ex vivo platelet
aggregatory responsiveness was enhanced to physiologic agonists (adenosine
diphosphate, collagen, and thrombin receptor agonist peptide, TRAP1-6) (P
< .05 in all cases). Although in vitro platelet aggregation was not
induced by any concentration of rHu-MGDF tested (P > .5), rHu-MGDF
enhanced aggregatory responses to low doses of physiologic agonists,
effects that were maximal at 10 ng/mL for baboon platelets and 100 ng/mL
for human platelets, and were blocked by excess soluble c-Mpl receptor.
Flow cytometric expression of platelet activation epitopes was not
increased on resting platelets (ligand-induced binding sites, P- selectin,
or Annexin V binding sites; P > .1 in all cases). Megakaryocyte growth
and development factor regulates platelet production and function by
stimulating endoreduplication and megakaryocyte formation from marrow
progenitor cells, and transiently enhancing platelet functional responses
ex vivo. rHu-MGDF has the potential for achieving platelet hemostatic
protection with minimal thrombo-occlusive risk.
Volume 87,
Issue 5,
pp. 1833-1844,
03/01/1996
Copyright © 1996 by The American Society of Hematology
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