Markers of in vivo thrombus formation together with thrombin-generating a) phosphatidyl-serine-rich microparticles, and b) activated platelets appear transiently in the circulation of sickle cell disease (SCD) patients during episodes of pain, implicating thrombotic processes in the pathogenesis of sickle erythrocyte-dependent tissue infarction. It is hypothesized that sickle erythrocytes produce mechanical microvascular injury and induce the formation of prothrombotic microparticles, that lead to local generation of thrombin, which, in turn, activates platelets, forms fibrin, and ultimately causes thrombo- occlusive infarction. Moreover, thrombin-generating microparticles may also arise from activated platelets and tissue factor-expressing activated mononuclear blood leukocytes as well as from sickle erythrocytes. Recent research in non-human primates shows that dietary n-3 fatty acids (n-3FAs) abolish thrombus formation at sites of mechanical vascular injury without significantly impairing hemostatic function. Dietary n-3FAs produce this antithrombotic outcome by reducing the thrombotic responses of blood, and interrupting the thrombogenicity of exposed subendothelial extracellular matrix constituents. In this project we propose to test the thrombosis postulate of crisis development in SCD by administering dietary n-3FAs to prevent thrombus formation while sparing hemostasis. Initially in 20-25 SCD patients during and after recovery from episodes of pain, we will a) characterize the thrombus-promoting properties of sickle erythrocytes, b) define the origin and thrombin-generating characteristics of the microparticles, c) establish the frequency, extent and time course for activation of platelets, monocytes and coagulation pathways, d) evaluate endothelial cell-derived enzymes as blood markers of vascular injury, and e) determine in these patients the effects of dietary n-3FAs on the blood markers of vascular injury/thrombosis in vivo and the frequency of pain crises. Subsequently, 50-75 symptomatic patients with sickle cell disease will be randomly allocated to receive either dietary n-3FAs or olive oil placebo in a double blind study while receiving conventional management; the frequency of hospital treatments with parenteral analgesia for acute pain crises and changes in the blood measurements of in vivo vascular injury/thrombosis will be compared.
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