Thrombocytopenia is a significant clinical problem post-chemotherapy and in patients with immune thrombocytopenia purpura and myelodysplastic syndrome, all of which are associated with intramedullary megakaryocyte apoptosis. Using murine models, I have demonstrated that platelet factor 4 (PF4), which is synthesized in developing megakaryocytes, is released from these cells and behaves as a negative paracrine, especially in clinical settings associate with intramedullary lysis of megakaryocytes. Further, in a murine model of chemotherapy-induced thrombocytopenia (CIT), strategies that block PF4 can ameliorate the thrombocytopenia. This application is to support a mentored research experience as I translate my murine studies to clinical application. These observations will be expanded in three specific aims.
Specific Aim 1 : Define the role of PF4 in megakaryopoiesis in human primary hematopoietic cells. I have found that PF4 may target a megakaryocyte precursor cell through the scavenger receptor LRP-1 in mice. I propose to define the specific megakaryocyte progenitor cell targeted in humans and demonstrate that these cells express LRP-1 and that PF4 affects human megakaryopoiesis through these receptors. These studies will provide important insight into the molecular biology of megakaryopoiesis and may in lead to novel therapeutic strategies to prevent thrombocytopenia in CIT and related clinical settings.
Specific Aim 2 : Define the distribution of PF4 in a normal pediatric population. Preliminary data using adult samples suggest that -10% of the human population has high platelet PF4 levels. I plan to confirm this result in a healthy population in whom platelet PF4 levels should reflect megakaryocyte PF4 levels as a prelude to studies in the following specific aim that will examine whether patients with high PF4 levels are at greater risk of significant CIT.
Specific Aim 3 : Clinical studies of the in vivo inhibition of megakaryopoiesis by PF4. I will analyze the relationship between platelet PF4 content and the duration and severity of thrombocytopenia in a common form of cancer where patients have a fairly uniform clinical course and in which a significant number of patients undergo remission. The broader impact of this research is a better understanding of megakaryopoiesis leading to novel therapies for thrombocytopenia in multiple clinical settings. Combined with my didactic training and structured mentoring in this application, I believe that the proposed research will provide novel new insights into the management of thrombocytopenia in a number of important settings and should enable me to establish myself as an independently funded pediatric hematologist with expertise in the care and management of the thrombocytopenias.
