Thrombocytopenia is common among patients in Neonatal Intensive Care Units (NICU). In fact, 20-35 percent of NICU patients, or 80,000-120,000 neonates in the USA annually, develop thrombocytopenia at some time during their hospital stay. Although many different varieties of thrombocytopenia can occur in NICU patients, the form receiving the greatest experimental attention has been maternal maternally-derived alloimmune thrombocytopenia. That condition, however, is relatively rare, occurring in about 1300 cases annually. Two of the most common varieties of thrombocytopenia among NICU patients, responsible for about 40,000 cases in the USA annually, have received relatively little experimental attention. These varieties occurs among prematurely delivered neonates who are either; (1) small for gestational age or are (2) born to women with pregnancy-induced hypertension. Little is known about the pathogenesis of these common forms of thrombocytopenia, and the only available treatment is platelet transfusions, administered repeatedly until the condition spontaneously remits, often after several weeks. Pressing needs exist to understand the pathogenesis of these thrombocytopenias and to provide better care for these neonates. Our preliminary studies suggest that both forms are the kinetic result of decreased platelet production, and that the megakaryocyte progenitors remain sensitive to recombinant Thrombopoietin (rTpo). We now propose to conclusively determine the kinetic mechanism responsible for these two common forms of thrombocytopenia and to determine the feasibility of rTpo as a treatment. The kinetic mechanism will be determined by; (1) a new marrow biopsy technique, we devised for preterm infants, which permits the direct assessment of megakaryocyte numbers by immunohistologic identification, (2) measurement of megakaryocyte ploidy, by FACS analysis of bone marrow megakaryocytes, (3) serial plasma Tpo quantification, and (4) rTpo dose-response relationships of megakaryocyte progenitors obtained from the marrow and the blood. These studies, along with results of rTpo (PEG-rHuMGDF) administration studies to newborn rhesus monkeys, which we have begun (funded outside this proposal) will permit the rational design of Phase I/II trials of rTpo administration to preterm neonates who have the common varieties of thrombocytopenia. This approach is essential to improve the care of the large number of NICU patients affected with these two common varieties of thrombocytopenia.
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