Sickle cell disease (SCO) is an inherited disorder of hemoglobin that causes normally flexible red blood cellsto become very rigid and obstruct blood flow leading to ischemia, organ damage and ultimately, death. Thepathophysiology of SCO is due in part to the increase in blood viscosity caused by hemoglobin S (HbS).Chronic transfusions markedly reduce sickle episodes and protect against recurring stroke and acute chestsyndrome, presumably by reducing HbS and improving viscosity. However, the optimal reduction in HbSneeded to prevent complications is not known. Our preliminary data suggests that changes in HbS andhematocrit that improve arterial flow may be detrimental in low shear flow areas like the cerebral cortex andheart. The effect of changes in blood viscosity on high and low shear flow and oxygen delivery has notbeen measured in humans with SCO.Goals: This project will determine the relation between prefrontal cerebral cortex oxygen delivery, cerebralarterial flow and blood viscosity and %HbS. Furthermore, we want to validate easily determined,noninvasive measures of regional oxygen delivery and perfusion that could be clinical surrogates forconsequences of sickling for management and for testing new therapies.
AIMS : We will 1) determine the relation of oxygen delivery and blood flow in regions of high and low shear toblood viscosity in chronically transfused patients over a wide range of HbS% and during the change in %HbSthat occurs during simple or exchange transfusion, 2) determine if total nighttime hypoxia and loss of heartrate variability, a measure of autonomic dysregulation, are surrogates for the effects of disordered viscosity,and 3) if pre-frontal cerebral oxygen content, nighttime hypoxia and autonomic function improve in parallelwith improvement in exercise tolerance and pain-free days after dietary supplementation with glutamine.
Aim 3 will be done in collaboration with the randomized glutamine trial proposed in Project 2B (PI:Niihara).Relevance: This research will test assumptions about the role of viscosity on regional blood flow and oxygendelivery by direct measurement in humans and provide information that will be critical for optimization oftransfusion therapy in sickle cell disease. Furthermore, it will validate easily performed non-invasivemeasures related to sickling that be very useful in monitoring disease course and testing new treatments.
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