This is a chronological listing of grants held by this department, with the most recent listed first. New grants appear in this list weekly and contribute related to the department's Research Profile. The source of grants for this application comes directly from your institution.
COAGULATION ACTIVATION IN SICKLE CELL DISEASE ARRA
Kenneth Ataga; Alan Hinderliter; Nigel Key; Betsy Shilliday; Susan Jones9/15/2009 - 8/31/2012
|Sponsoring Organization:||NIH National Heart, Lung, and Blood Institute (NHLBI)|
|Awarding Organization Is:||University of North Carolina at Chapel Hill|
Alan L Hinderliter (Investigator)
Kenneth I Ataga (Lead Principal Investigator)
Nigel S Key (Investigator)
As a result of the presence of macrovascular thrombotic complications, as well as the biochemical evidence of ongoing hemostatic activation, sickle cell disease (SCD) is often referred to as a hypercoagulable state. However, the contribution of coagulation activation to the pathogenesis of SCD remains uncertain. While the majority of clinical studies using anticoagulants have shown no convincing benefit in the prevention or treatment of pain crises, most of these studies were small and poorly controlled. Furthermore, pain crisis may not be an ideal clinical endpoint for assessing the effect of anticoagulation. Pulmonary hypertension, a common complication associated with significant morbidity and mortality, represents a clinical endpoint that is likely due, at least in part to increased thrombin generation, and may therefore be used to evaluate the contribution of coagulation activation to the pathophysiology of SCD. The UNC Comprehensive Sickle Cell Program offers a large and closely followed patient population in whom we will be able to study in detail the contribution of hypercoagulability to the pathophysiology of SCD-associated pulmonary hypertension. Our expertise in the care of patients with SCD, as well as ongoing research interests in hemostasis and thrombosis makes our center an ideal one to answer this fundamental question. We hypothesize that increased thrombin generation, as well as platelet activation are central to the pathophysiology of SCD and contribute to the occurrence of several SCD-related complications, including pulmonary hypertension (PHT). As a consequence, treatment modalities that down-regulate thrombin generation would be expected to delay the progression of PHT and result in improved survival in patients with SCD. The long-term goals of our proposed work are to: 1) evaluate the safety and efficacy of anticoagulation in SCD-associated PHT; and 2) evaluate whether endogenous whole blood thrombin generation profiles are suitable biomarkers of PHT in patients with SCD. Primary Aims: 1) A. We will perform an exploratory study to evaluate the efficacy of anticoagulation in SCD-associated pulmonary hypertension. B. Furthermore, we will evaluate the effect of anticoagulation on thrombin generation, thrombin-mediated platelet activation, endothelial activation, mortality, and safety. 2) A. We will evaluate the endogenous whole blood thrombin generation profiles in patients with SCD compared to healthy control individuals. B. We will also explore whether the endogenous whole blood thrombin generation profiles, as well as whole blood and microparticle-associated tissue factor procoagulant activity are suitable biomarkers for SCD-associated pulmonary hypertension.