Biomakers in Sickle Cell Anemia: Response to Hydroxyurea

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In a landmark clinical trial, oral hydroxyurea (HU) decreased the frequency of vaso-occlusive crises and acute chest syndrome, and reduced the need for transfusions and hospitalizations in adult patients with homozygous SS disease (HbSS). While the consensus from this study, and others is that HU has pleotropic modes of action in HbSS with effects on HbF, dense cells, reticulocytes, white cells and red cell-endothelial interactions, the relative merits of these individual modes of action on disease amelioration are not known. The NHLBI will be conducting a pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) in which HU will be tested in a randomized double-blinded, placebo-controlled trial for the prevention of chronic organ damage in 200 infants with HbSS. As a prelude to the major study, in 2003, a pilot Baby HUG randomized placebo-controlled, two-year trial of 40 infants (ages 12 to 17 months at study entry) will be conducted to ascertain the feasibility of the larger proposal. The validity of primary and secondary end points, i.e. splenic and renal function, and CNS involvement will be ascertained, and the effects of HU on growth, physical and cognitive development in this young cohort will be assessed. Organ evaluations will include splenic scintigraphy and pitted red cell counts; glomerular filtration rate, and evaluation for microalbuminuria and urine concentrating ability; brain MRI/MRA and transcranial doppler (TCD) measurements. This study provides us the unique opportunity for an evaluation of various biomarkers to assess whether HU modulates activation of the circulating cellular elements of blood, and cell-cell interactions, with resulting ameliorative effects on the HbSS infant's vascular pathology and clinical course. Biomarkers to be evaluated will include functional assessment of erythrocyte adhesion to endothelium and to immobilized extra-cellular matrix proteins, F cell numbers, erythrocyte markers including CD71 (stress reticulocyte), various red cell adhesion molecules and phosphatidylserine (PS) positivity. Markers of coagulation activation will include whole blood tissue factor activity (WBTF) and prothrombin fragment F1.2 levels. Endothelial activation will be assessed by plasma sol VCAM-1 and a quantitative and qualitative assessment of circulating endothelial microparticles. Platelet and white cell activation will be evaluated by sol P-selectin and L-selectin levels respectively. We predict that HU therapy, when compared to placebo will result in a pattern of biomarker changes suggestive of a treatment effect. Our evaluations will also provide information delineating the mechanisms by which HU modulates these cell-cell interactions. The two-year follow-up evaluations of clinical course and organ dysfunction in the BABY HUG pilot protocol will also provide us the unique opportunity to assess whether abnormal values of a specific biomarker(s) will predate or occur in conjunction with specific organ dysfunction, or vascular pathology. Large differences will be detectable in these comparisons, while smaller differences will provide the basis for further specimen collection and analysis in the additional 160 children to be later entered in the Phase III Clinical trial. Since our Center possesses significant past experience in biomarker evaluations in infants with HbSS, the incorporation of these appropriately chosen biologic markers to assess disease progression will complement this pilot protocol. Our ancillary proposal should enhance the long-term benefits and scientific productivity of this important multiinstitutional NHLBI-sponsored research. In addition, findings from this study could have significant implications for other disease states associated with vasculopathy.

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