Eptifibatide as Treatment for Acute Pain Episodes in Sickle Cell Disease

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) has been referred to both as a hypercoagulable and chronic inflammatory state. Despite the abundant laboratory evidence of hypercoagulability and chronic inflammation, the contribution of these changes to the pathogenesis of SCD remains uncertain. Patients with SCD exhibit increased platelet and coagulation activation in the non-crisis, steady state. In addition, there is evidence that platelet and coagulation activation increase even further when SCD patients experience an acute pain episode compared to the non- crisis, steady state. The potent inflammatory mediator, CD40 ligand (CD40L), is known to increase leukocyte proliferation, endothelial adhesiveness and procoagulant activity, once it is exposed on the platelet surface and released into plasma following platelet activation. We recently showed that levels of CD40L are markedly higher in the plasma of SCD patients and significantly reduced in the platelets of these patients relative to unaffected, healthy individuals. In addition, plasma levels of CD40L are increased further in SCD patients with acute pain episodes compared to patients in their non-crisis, steady states. Acute pain episodes represent the most common clinical manifestation of SCD, and are largely responsible for making the lives of these patients so unpredictable. Despite an improved understanding of the pathophysiology of SCD, the treatment of acute pain episodes remains inadequate, consisting mainly of opioid analgesics. The UNC Sickle Cell Program offers a large and closely followed patient population in whom we will be able to study in detail, the contribution of platelet activation and chronic inflammation to the pathogenesis of SCD. The overall hypothesis that we seek to test is that increased platelet activation and the resultant inflammatory responses are important contributors to the pathophysiology of SCD. We believe that by decreasing platelet aggregation, and the release of mediators of inflammation and thrombosis, we will affect the clinical course of SCD-related complications. We propose to test this hypothesis by carrying out the following specific aims: a) We will evaluate the safety of the 1IIb23 antagonist, eptifibatide in SCD patients during an acute pain episode. Furthermore, we will perform an exploratory study to evaluate the effect of eptifibatide on acute pain episodes in these patients. b) We will evaluate the effect of eptifibatide on in vivo platelet function, platelet-leukocyte aggregates, coagulation activation, endothelial activation and inflammatory markers during an acute pain episode. At the conclusion of our proposed work, we will have an improved understanding of the contribution of platelet activation and inflammation to the pathogenesis of SCD. If the data support the hypothesis that eptifibatide is safe and effective, we plan on carrying out adequately powered studies to more definitively evaluate the safety and efficacy of antiplatelet agents for the treatment and/or prevention of acute pain episodes in SCD. Accomplishment of these goals should allow more treatment options for patients with this chronic disease. PUBLIC HEALTH RELEVANCE: The treatment of acute pain episodes (or vaso-occlusive pain crises) in patients with sickle cell disease is limited to analgesics, gentle hydration and occasionally, supplemental oxygen. As these patients manifest evidence of chronic inflammation and activated blood coagulation, we have proposed a study of the glycoprotein IIb/IIIa inhibitor, eptifibatide, to determine its safety and effectiveness in acute pain episodes. If this agent is found to be safe and effective, it will lead to the development of new treatment options for sickle cell disease patients during acute pain episodes.