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Differential mechanisms in the regulation of endogenous levels of
thrombopoietin and interleukin-11 during thrombocytopenia: insight into the
regulation of platelet production
M Chang, Y Suen, G Meng, JS Buzby, J Bussel, V Shen, C van de Ven and MS Cairo
Division of Hematology/Oncology and Blood and Marrow Transplantation,
Children's Hospital of Orange Country, CA 92668, USA.
The regulation of megakaryocytopoiesis and thrombopoiesis appears to be
under the control of an array of hematopoietic growth factors. To determine
the relationship of endogenous thrombopoietic cytokine levels and
circulating platelet (PLT) counts, we measured the levels of
thrombo-poietin (TPO), interleukin-11 (IL-11), and interleukin-6 (IL-6) in
patients with significant thrombocytopenia secondary to both marrow
hypoplasia and increased PLT destruction. Increased endogenous levels of
TPO and IL-11, but not IL-6, were detected in bone marrow transplant
patients with thrombocytopenia following myeloablative therapy (BMT/MAT)
(TPO: 1,455.5 +/- 87.3 pg/mL, [PLT 39,600 +/- 7,800/microL], P < .001, n
= 12; IL-11: 227.9 +/- 35 pg/mL, [PLT 32,900 +/- 57,000/microL], P <
.05, n = 19; IL-6: 25.8 +/- 8.4 pg/mL, [PLT 32,800 +/- 5,057/microL], P
> .05, n = 4] v normal donors [TPO < 150 pg/mL, n = 8; IL-11 < 50
pg/mL, n = 9; IL-6 < 10 pg/mL, n = 5 [PLT 203,000 +/- 7,500/microL].
There was a significant inverse correlation between endogenous levels of
TPO and IL-11, but not IL-6, and PLT counts in the MAT/BMT patients (TPO: r
= -0.57, P < .0001, n = 188; IL-11: r = - 0.329, P < .0001, n = 249;
IL-6: r = -0.1147, P > .05, n = 62). In patients with immune
thrombocytopenia purpura (ITP), with decreased PLT survival, but intact
bone marrow megakaryocytopoiesis, endogenous IL-11 levels were
significantly increased (328.0 +/- 92.6 pg/mL, [PLT: 20,900 +/-
3,000/microL], P < .05, n = 25). However, endogenous TPO levels remained
undetectable (< 150 pg/mL, [PLT 30,500 +/- 5,500/microL], n = 15). These
results suggest that there may be differential mechanisms regulating
endogenous TPO, IL-11, and IL-6 levels during acute thrombocytopenia and
suggest that the absolute number of circulating PLTs may not always be the
sole regulator of endogenous TPO levels. Other mpl-expressing cells of the
megakaryocyte lineage may contribute to the regulation of circulating TPO
levels as well. Our results also suggest IL-11 levels may in part, be
regulated by a negative feedback loop based on circulating PLT counts, but
also may, in part, be regulated by a variety of inflammatory agonists. Both
TPO and IL-11, therefore, appear to be active thrombopoietic cytokines
regulating, in part, megakaryocytopoiesis during states of acute
thrombocytopenia.
Volume 88,
Issue 9,
pp. 3354-3362,
11/01/1996
Copyright © 1996 by The American Society of Hematology
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