THROMBOPOIETIN PRIMES HUMAN PLATELET-AGGREGATION INDUCED BY SHEAR-STRESS AND BY MULTIPLE AGONISTS

Recombinant thrombopoietin has been reported to stimulate megakaryocyt opoiesis and thrombopoiesis and it may be quite useful to treat patien ts with low platelet counts after chemotherapy. As little is known reg arding the possible activation of platelets by thrombopoietin, we exam ined the effects of thrombopoietin on platelet aggregation induced by shear stress and various agonists in native plasma. Using hirudin as a n anticoagulant, thrombopoietin (1 to 100 ng/mL) enhanced platelet agg regation induced by 2 mu mol/L adenosine-diphosphate (ADP) in a dose d ependent fashion. The enhancement was not affected by treatment of pla telets with 1 mmol/L aspirin plus SQ-29548 (a thromboxane antagonist, 1 mu mol/L) but was inhibited by a soluble form of the thrombopoietin receptor, suggesting that the enhancement was mediated by the specific receptors and does not require thromboxane production. Epinephrine (1 mu mol/L), which does not induce platelet aggregation in hirudin plat elet rich plasma (PRP), did so in the presence of thrombopoietin (10 n g/mL). Thrombopoietin (10 ng/mL) also enhanced or primed platelet aggr egation induced by collagen (0.5 mu g/mt), thrombin, serotonin, and va sopressin. Thrombopoietin does not induce any rise in cytosolic ionize d calcium concentration nor activation of protein kinase C, as estimat ed by phosphorylation of preckstrin, indicating that the priming effec ts of thrombopoietin does not require those processes. The ADP- or thr ombin-induced rise in cytosolic ionized calcium concentration was not enhanced by thrombopoietin (100 ng/mL). Further, shear (ca. 90 dyn/cm( 2))-induced platelet aggregation was also potentiated by thrombopoieti n. The priming effect on epinephrine-induced platelet aggregation in h irudin PRP was unique to thrombopoietin, with no effects seen using in terleukin-6 (IL-6), IL-ll, IL-3, erythropoietin, granulocyte-colony st imulating factor, granulocyte macrophage-colony stimulating factor, or c-kit ligand. These data indicate that monitoring of platelet functio ns may be necessary in the clinical trials of thrombopoietin. (C) 1996 by The American Society of Hematology.