N3 FATTY ACIDS EFFECT ON SICKLE CELL PAIN EPISODES

Emory University, Atlanta GA

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Abstract

Our studies show that sickle cell disease (SCD) patients have platelet activation, increased thrombin formation and fibrinolysis, in vivo, and that activation of thrombosis increases significantly during pain episodes. Moreover, in a small controlled pilot trial evaluating dietary n-3 fatty acids (n-3 Fas) in SCD patients with frequent pain episodes, the frequency of pain episodes was significantly decreased in dietary n-3 FA-treated patients compared to olive oil treated controls. Moreover, markers of thrombosis decreased to near those observed in the control subjects. In addition, the Multicenter Study of Hydroxyurea in Sickle Cell Anemia reports that reduction in pain frequency with hydroxyurea was directly correlated to reduction in neutrophil and monocyte counts. We hypothesize that pain episodes in SCD patients are caused by local microcirculatory occlusion mediated by sickle cells that cause microvascular damage inducing expression of adhesion molecules and counter-receptors by monocytes and endothelial cells. This stimulates TF expression by vascular cells and blood monocytes causing TF induced thrombin production and thrombosis. TF expression provides feed-back amplification via thrombin-mediated monocyte activation, accumulation, expression of TF that increases thrombosis enhancing microvascular occlusion and ischemic damage. Because preliminary findings indicate that dietary n-3 FAs are safe and down-regulate multiple membrane-activation pathways of circulating blood and vascular wall cells, we propose to test the therapeutic efficacy of dietary n-3 FAs by conducting a double-blind, olive oil- controlled clinical trial of dietary n-3 FAs in 60 SCD patients with frequent pain episodes, randomly allocated to dietary n-3 FAs or control olive oil. The primary outcome is the frequency of pain episodes. Based on the pilot study, this trial has a 90 percent probability of demonstrating a 50 percent decrease in frequency of pain episodes. Our hypothesis will be tested in secondary analysis of the effects of dietary n-3 FAs on blood markers of thrombosis and inflammation. Blood tests of thrombosis will include flow cytometric assessment of platelet activation and microparticle formation, thrombin:antithrombin complex (TAT) levels, activation fragment of prothrombin (F1.2), thrombin's fibrinogen cleavage product (FPA), platelet-specific secretion proteins platelet factor 4 (PF4) and beta-thromboglobulin (betaTG), and products of fibrinolysis including plasmin-antiplasmin complex (PAP) and D-dimer. Blood tests of inflammation to be measured include flow cytometric assessment of monocyte activation and expression of tissue factor and plasma levels of soluble vascular cell adhesion molecules (sVCAM) and monocyte chemotactic protein-1 (MCP-1).