Thrombocytopenia affects 20-30% of infants admitted to the neonatal intensive care unit. In 25% of affected neonates (25,000-30,000 per year in the US), the thrombocytopenia is severe, and 9% of them experience clinically significant bleeding (usually intracranial). Up to 10% of severely thrombocytopenic neonates have low platelet counts lasting >30 days, prompting multiple platelet transfusions, with all their associated risks. The causes underlying the predisposition of neonates to develop thrombocytopenia are not understood, but are clearly related to the unique biological characteristics of fetal/neonatal megakaryocytes (MKs). However, there is a fundamental gap in understanding the mechanisms underlying the differences between neonatal and adult MKs, and lack of such knowledge has impaired our ability to treat neonatal thrombocytopenia and other disorders that selectively affect fetal/neonatal MK progenitors. Over the last period of support, we discovered that fetal megakaryopoiesis is characterized by a unique uncoupling of proliferation, polyploidization, and cytoplasmic maturation, and that cell-intrinsic and micro-environmental factors contribute to this pattern. Specifically, our data suggest that a pathway involving the miRNA let-7b mediates their high proliferative rate. Furthermore, we found that neonatal MK progenitors respond differently to thrombopoietin (Tpo) compared to adults and exhibit differences in Tpo receptor expression and signaling pathways. This finding is of high clinical significance, given the recent FDA approval of 2 Tpo mimetics (Romiplostim and Eltrombopag) for the treatment of thrombocytopenic adults. While some thrombocytopenic neonates are appealing candidates for treatment with these mimetics, our data suggest that simply extrapolating observations from adults to neonates would represent a serious pitfall. The objectives of the current proposal are two-fold: 1) to advance our understanding of the mechanisms underlying the unique features of fetal/neonatal megakaryopoiesis;and 2) to characterize the responses of neonatal MK progenitors to these novel Tpo agonists, with the long term goal of improving the treatment of thrombocytopenic neonates. To achieve our objectives, we designed the following Specific Aims: 1) To dissect the contributions of cell intrinsic and microenvironmental factors (Tpo and others) on the phenotype of fetal/neonatal megakaryopoiesis;2) To characterize the effects of romiplostim and eltrombopag on fetal, neonatal, and adult human megakaryocytopoiesis;and 3) To establish the platelet production rate at baseline and in response to romiplostim in newborn mice with thrombocytopenia.
These aims will be accomplished through a blend of in vitro studies on primary human MKs and in vivo studies using knockout mice and murine models of thrombocytopenia. We expect our findings to have a substantial impact on both our fundamental understanding of fetal MK biology and on the clinical management of thrombocytopenic neonates.
Low platelet counts are common among sick newborn infants, particularly those born very prematurely, and are usually treated with platelet transfusions in an effort to decrease the incidence or severity of bleeding. Two factors that stimulate platelet production were recently approved by the FDA for the treatment of adults with low platelet counts, but studies from our laboratory suggest that the process of platelet production and the response to these factors are very different in neonates compared to adults. The studies in this proposal are of high clinical relevance, as they will determine whether and how these new medications work in neonates, with the ultimate goal of reducing the number of platelet transfusions they receive and improving outcomes.
|Patel, Ravi M; Josephson, Cassandra D; Shenvi, Neeta et al. (2018) Platelet transfusions and mortality in necrotizing enterocolitis. Transfusion :|
|Cakir, Bertan; Liegl, Raffael; Hellgren, Gunnel et al. (2018) Thrombocytopenia is associated with severe retinopathy of prematurity. JCI Insight 3:|
|Sparger, Katherine A; Ramsey, Haley; Lorenz, Viola et al. (2018) Developmental differences between newborn and adult mice in response to romiplostim. Platelets 29:365-372|
|Machlus, Kellie R; Wu, Stephen K; Vijey, Prakrith et al. (2017) Selinexor-induced thrombocytopenia results from inhibition of thrombopoietin signaling in early megakaryopoiesis. Blood 130:1132-1143|
|Lorenz, Viola; Ramsey, Haley; Liu, Zhi-Jian et al. (2017) Developmental Stage-Specific Manifestations of Absent TPO/c-MPL Signalling in Newborn Mice. Thromb Haemost 117:2322-2333|
|Liu, Zhi-Jian; Bussel, James B; Lakkaraja, Madhavi et al. (2015) Suppression of in vitro megakaryopoiesis by maternal sera containing anti-HPA-1a antibodies. Blood 126:1234-6|
|Bender, Markus; Thon, Jonathan N; Ehrlicher, Allen J et al. (2015) Microtubule sliding drives proplatelet elongation and is dependent on cytoplasmic dynein. Blood 125:860-8|
|Ferrer-Marin, F; Gutti, R; Liu, Z-J et al. (2014) MiR-9 contributes to the developmental differences in CXCR-4 expression in human megakaryocytes. J Thromb Haemost 12:282-285|
|Ferrer-Marin, F; Gutti, R; Liu, Z-J et al. (2014) MiR-9 contributes to the developmental differences in CXCR-4 expression in human megakaryocytes. J Thromb Haemost 12:282-5|
|Liu, Zhi-Jian; Hoffmeister, Karin M; Hu, Zhongbo et al. (2014) Expansion of the neonatal platelet mass is achieved via an extension of platelet lifespan. Blood 123:3381-9|
Showing the most recent 10 out of 35 publications