Prolonged and Severe Thrombocytopenia in Neonates

新生儿长期和严重的血小板减少症

• 批准号: 6464531
• 负责人: Martha C. Sola-Visner
• 金额: $ 28.82万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6464531
• 关键词: blood disorder chemotherapy; clinical trial phase I; drug screening /evaluation; human subject; human therapy evaluation; megakaryocytes; neonatal intensive care; newborn human (0-6 weeks); patient oriented research; recombinant proteins; thrombocytopenia; thrombopoiesis; thrombopoietic factor

DESCRIPTION (provided by applicant): Thrormbocytopenia is one of the most common hematologic problems among patients in Neonatal Intensive Case Units (NICU), affecting 20-35 percent of NICU patients. In 20-25 percent of these patients the thrombocytopenia is severe and requires treatment with platelet transfusions. In adults, the administration of recombinant thrombopoietin (rTpo) is being investigated as an alternative to platelet transfusions. Our previous in vitro and in vivo studies have shown that megakaryocyte progenitors of neonates are more sensitive to rTpo than are megakaryocyte progenitors of adults, suggesting that rTpo administration could be an effective therapy for thrombocytopenic neonates. Since rTpo does not increase the platelet count until 4 to 6 days after starting therapy, the only appropriate candidates would be neonates whose thrombocytopenia is severe and prolonged. However, the application of new therapies to thrombocytopenic neonates has been significantly hampered by our lack of understanding of even the basic kinetic mechanisms responsible for their thrombocytopenias (platelet destruction versus decreased platelet production). With the development of rTpo, there is now a pressing need to clarify these mechanisms in neonates with severe and prolonged thrombocytopenia. With this in mind, we propose to; (1) identify the kinetic mechanisms responsible for severe and prolonged thrombocytopenia in NICU patients, (2) establish the correlation between peripheral blood and bone marrow indicators of thrombopoiesis in thrombocytopenic neonates, and (3) conduct a multicenter, open-label, phase I/Il, dose-escalation trial of rTpo administration to neonates with severe and prolonged thrombocytopenia. The first two studies will use techniques specifically developed for the study of megakaryocyte number, size, and ploidy in the bone marrow of neonates, and will correlate these with newly developed indirect measures of thrombopoiesis (i.e. reticulated platelet counts, serum Tpo concentrations, and circulating megakaryocyte progenitors). The last study will test the biological effects, pharmacokinetics, and safety of rTpo administration to neonates with prolonged and severe thrombocytopenia.

描述（由申请人提供）：Thrombococytopenia是最多的 新生儿密集型病例单位中患者的常见血液学问题 （NICU），影响20-35％的NICU患者。其中20-25％ 患者血小板减少症很严重，需要血小板治疗 输血。在成年人中，重组血栓蛋白的给药 （RTPO）正在研究作为血小板输血的替代方法。我们的 以前的体外和体内研究表明，巨核细胞祖细胞 新生儿对RTPO更敏感 成人，表明RTPO给药可能是有效的疗法 血小板减少新生儿。由于RTPO不会增加血小板计数 直到开始治疗后4至6天，唯一合适的候选人将 是血小板减少症严重且延长的新生儿。但是， 将新疗法应用于血小板减少新生儿已有 由于我们对基本动力学的了解，我们对我们缺乏理解的影响很大。 负责其血小板减少症的机制（血小板破坏与 血小板产生降低）。随着RTPO的发展，现在有一个 紧迫需要阐明严重且延长的新生儿的这些机制 血小板减少症。考虑到这一点，我们建议； （1）识别动力学 NICU的严重和长时间血小板减少症的机制 患者，（2）建立外周血和骨骼之间的相关性 血小板减少新生儿中血小板的骨髓指标，（3） 进行多中心，开放标签，I/IL期，RTPO的剂量升级试验 给药严重且长时间的血小板减少症。这 前两项研究将使用专门开发的技术 新生儿的骨髓中的巨核细胞数，大小和倍状，并将 将这些与新开发的血小板措施相关联（即 网状血小板计数，血清TPO浓度和循环 巨核细胞祖细胞）。最后一项研究将测试生物学效应， RTPO给药的药代动力学和延长的新生儿的安全性 和严重的血小板减少症。