Comprhensive Sickle Cell Center Program Project

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DESCRIPTION (provided by applicant): The fundamental challenge of sickle cell disease (SCD) is how a point mutation, which changes a single amino acid in a single protein, in a single circulating cell, causes a disease with protean manifestations, and complex and unpredictable clinical symptoms. The Marian Anderson Comprehensive Sickle Cell Center has been using the first few years of life, a physiologically crucial period when infants with SCD manifest high levels of HbF, to longitudinally evaluate whether potentially important relationships exist between HbF and other biologic parameters related to SCD pathophysiology, and has demonstrated important relationships between HbF, fluid phase coagulation and adhesion markers. The proposed continuation of this prospective, longitudinal study of infants and children (3 months to 4 yrs) will provide critical new information on the importance of specific biologic markers as they relate to the pathophysiology of the microvessel occlusive phenomenon. In addition, these longitudinal studies will create a "biologic footprint" as the infant grows, providing a unique look at the temporal sequence of changes in adherence, endothelial, platelet, white cell and hemostatic activation in the infant and young child as the protective effects of HbF decline, and the subject begins to experience the unfolding systemic effects of HbS polymerization including anemia and pain. An additional clinical project not only provides the fundamental information on the pain experienced by these infants and young children needed to make the biologic and physiologic correlates, it also proposes using innovative new technologies to facilitate clinical and research communication between families, investigators, and clinical staff. The utility of these technologies will be further demonstrated in the development and evaluation of a parent-mediated pain management protocol for young children with SCD. An examination of endothelial cell receptors for PS-positive sickle erythrocytes will serve as the Center's basic science study and combines new information obtained by current Center investigators with innovative molecular biology studies assisted by investigators new to the Center. This unique blend of meticulous clinical care and research is highlighted in the collaborative network protocol which proposes a clinical trial comparing hydroxyurea to hydroxyurea and phlebotomy in SC disease using statistical techniques and preliminary data developed from the Center's previous pain studies, and detailed laboratory studies to help understand the pathophysiology of this poorly understood sickle syndrome. Supporting these studies is a clinical core of dedicated staff that also supports the Center's growing patient population, which now includes adult and pediatric patients in Philadelphia, and a virtual Center at the University of Louisville in Kentucky. Rounding out the Center is a patient services core with a focus on translating our state-of-the-art research and patient care into practice through education and community outreach in Pennsylvania and Kentucky.