Sickle cell disease (SCD) is characterized by acute clinical manifestations, including painful crisis, acute chest syndrome, priapism, and stroke, as well as chronic irreversible damage to the heart, lungs, kidneys, eyes, spleen and femoral heads. Vascular injury and occlusion, primarily affecting the microvasculature, underlie most of these complications. Another characteristic of sickle cell patients, both adult and pediatric, is a high prevalence of low vitamin B6 status (exceeding 50%), as indicated by low plasma pyridoxal-5'- phosphate levels (<20 nmol/L). B6 deficiency is a risk factor for cardiovascular disease, peripheral vascular disease, and stroke in the general population, but it is unknown if low B6 status affects vascular morbidity in SCD patients. Preliminary data from our laboratory indicate that low B6 status is associated with increased circulating levels of adhesion molecules that mediate erythrocyte and leukocyte adhesion to the vascular endothelium, key events in the pathogenesis of vascular occlusion in SCD patients. Accordingly, the long- term objective of this proposal is to test the hypothesis that B6 supplements in SCD patients will reduce levels of adhesion molecules and improve vascular function.
The specific aims are 1) to assess the cross- sectional relationships between B6 status, vascular adhesion molecules, and microvascular morphology and function in SCD patients, and 2) to assess the effect of B6 supplements on these parameters in the same patients. Adult and pediatric SCD patients, characterized using standard hematological measurements, will be assessed at baseline for blood levels of pyridoxal-5'-phosphate, soluble adhesion molecules known to be related to vascular injury (by real-time multiplex assay), and blood flow velocity and microvessel morphometry (by direct real-time computer-assisted intravital microscopy). To test the hypothesis that B6 supplements will result in improved microvascular morphometry and blood flow associated with a decrease in levels of circulating adhesion molecules, these patients will be treated for one year with vitamin B6 supplements using a double-blind, placebo-controlled study design. Repeat measurements of B6 status, levels of adhesion molecules and microvascular characteristics will be carried out at three-month intervals during the period of intervention. The vascular complications of SCD have a major negative impact on morbidity, mortality, and quality of life for these patients. The positive health impact of vitamin supplementation that could ameliorate the high morbidity and mortality associated with this disorder has the potential for high benefit with minimal cost and risk.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Integrative Nutrition and Metabolic Processes Study Section (INMP)
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Werner, Ellen
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University of California Davis
Schools of Medicine
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Krishnan, V V; Ravindran, Resmi; Wun, Ted et al. (2014) Multiplexed measurements of immunomodulator levels in peripheral blood of healthy subjects: Effects of analytical variables based on anticoagulants, age, and gender. Cytometry B Clin Cytom 86:426-35
Cheung, Anthony T W; Miller, Joshua W; Miguelino, Maricel G et al. (2012) Exchange transfusion therapy and its effects on real-time microcirculation in pediatric sickle cell anemia patients: an intravital microscopy study. J Pediatr Hematol Oncol 34:169-74
Carmichael, Owen; Mungas, Dan; Beckett, Laurel et al. (2012) MRI predictors of cognitive change in a diverse and carefully characterized elderly population. Neurobiol Aging 33:83-95
Miller, Joshua W (2010) Vitamin D and cognitive function in older adults: are we concerned about vitamin D-mentia? Neurology 74:13-5
Cheung, Anthony T W; Miller, Joshua W; Craig, Sarah M et al. (2010) Comparison of real-time microvascular abnormalities in pediatric and adult sickle cell anemia patients. Am J Hematol 85:899-901
Green, Ralph (2009) Is it time for vitamin B-12 fortification? What are the questions? Am J Clin Nutr 89:712S-6S
Green, Ralph (2008) Indicators for assessing folate and vitamin B12 status and for monitoring the efficacy of intervention strategies. Food Nutr Bull 29:S52-63;discussion S64-6