The coagulation system and endothelial cells are believed to contribute to the vascular pathology of sickle cell disease (SCD). Elevated plasma homocysteine (Hcy) is associated with vascular disease and thrombosis in the general population and is believed to induce endothelial cell dysfunction and activate the coagulation system. Patients with SCD exhibit activation of coagulation and an increase in activated circulating endothelial cells (CEC). Preliminary data demonstrate that hyperhomocysteinemia (HHcy) is present in 38% of patients with SCD and that a majority (62%) of these individuals have pyridoxine deficiency, compared to race and age-matched controls. It is hypothesized that HHcy is associated with activation of coagulation and CEC in SCD and that a lowering of Hcy with pyridoxine supplementation will reduce this activation. Therefore, the aims of this study are to determine the following in patients with SCD: (1) prevalence of HHcy and its association with vitamin cofactor deficiencies (2) correlation of HHcy with activation of CEC and coagulation (3) responsiveness of HHcy to pyridoxine supplementation (4) correlation of a decrease in Hcy levels with reduction in the activation of CEC and coagulation. The following laboratory determinations will be made in patients with SCD and in race and age-matched controls: fasting and post-methionine load Hcy, levels of red cell folate, serum vitamin B12, pyridoxal 5'-phosphate, the C677T MTHFR genotype; markers of activation of coagulation (prothrombin fragment 1.2, thrombin:antithrombin complexes), and fibrinolysis (plasmin:antiplasmin complexes, D-dimer); enumeration of CECs and the presence of activation markers VCAM-1 and tissue factor on CECs. SCD patients with HHcy will be randomized to receive a 6-week trial of pyridoxine supplementation or placebo and levels of Hcy, pyridoxine, and determination of markers of activation of coagulation and CECs will be repeated. This study is a collaborative trial open to all the sickle cell centers and at least 248 SCD patients and 248 controls will be recruited. Hey levels will be regressed on age in the controls and 95% confidence intervals will be determined. The chi-square statistic will be used to test the difference. Linear regression will be used to determine the relationship between Hcy and the activation markers. Paired t-tests will be used to test the other hypotheses. Pyridoxine supplementation is a simple therapy with the potential to reduce thrombotic complications of sickle cell disease.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHL1)
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Cincinnati Children's Hospital Medical Center
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