DIFFERENTIAL MECHANISMS IN THE REGULATION OF ENDOGENOUS LEVELS OF THROMBOPOIETIN AND INTERLEUKIN-11 DURING THROMBOCYTOPENIA - INSIGHT INTO THE REGULATION OF PLATELET PRODUCTION

The regulation of megakaryocytopoiesis and thrombopoiesis appears to b e under the control of an array of hematopoietic growth factors. To de termine the relationship of endogenous thrombopoietic cytokine levels and circulating platelet (PLT) counts, we measured the levels of throm bopoietin (TPO), interleukin-ll (IL-11), and interleukin-6 (IL-6) in p atients with significant thrombocytopenia secondary to both marrow hyp oplasia and increased PLT destruction. increased endogenous levels of TPO and IL-11, but not IL-6, were detected in bone marrow transplant p atients with thrombocytopenia following myeloablative therapy (BMT/MAT ) (TPO: 1,455.5 +/- 87.3 pg/mL, [PLT 39,600 +/- 7,800/mu L]. P<.001, n = 12; IL-11: 227.9 +/- 35 pg/mL, [PLT 32,900 +/- 5,7000/mu L], P<.05, n = 19; IL-6: 25.8 +/- 8.4 pg/mL, [PLT 32,800 +/- 5,057/mu L], 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/mu L]. There was a sig nificant inverse correlation between endogenous levels of TPO and IL-1 1, 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 megakaryocytopo iesis, endogenous IL-11 levels were significantly increased (328.0 +/- 92.6 pg/ml, [PLT: 20,900 +/- 3.000/mu L], P<.05, n = 25). However, en dogenous TPO levels remained undetectable (<150 pg/mL, [PLT 30,500 +/- 5,500/mu L], n = 15). These results suggest that there may be differe ntial mechanisms regulating endogenous TPO, IL-11, and IL-6 levels dur ing acute thrombocytopenia and suggest that the absolute number of cir culating PLTs may not always be the sole regulator of endogenous TPO l evels. Other mpl-expressing cells of the megakaryocyte lineage may con tribute to the regulation of circulating TPO levels as well. Our resul ts also suggest IL-11 levels may in part, be regulated by a negative f eedback loop based on circulating PLT counts, but also may, in part, b e regulated by a variety of inflammatory agonists. Both TPO and IL-11, therefore, appear to be active thrombopoietic cytokines regulating, i n part, megakaryocytopoiesis during states of acute thrombocytopenia. (C) 1996 by The American Society of Hematology.