Sickle cell disease (SCD) is an inherited disorder of hemoglobin that causes normally flexible red blood cells to become very rigid and obstruct blood flow leading to ischemia, organ damage and ultimately, death. The pathophysiology of SCD 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 chest syndrome, presumably by reducing HbS and improving viscosity. However, the optimal reduction in HbS needed to prevent complications is not known. Our preliminary data suggests that changes in HbS and hematocrit that improve arterial flow may be detrimental in low shear flow areas like the cerebral cortex and heart. The effect of changes in blood viscosity on high and low shear flow and oxygen delivery has not been measured in humans with SCD. Goals: This project will determine the relation between prefrontal cerebral cortex oxygen delivery, cerebral arterial 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 for consequences 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 to blood viscosity in chronically transfused patients over a wide range of HbS% and during the change in %HbS that occurs during simple or exchange transfusion, 2) determine if total nighttime hypoxia and loss of heart rate 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 parallel with 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).

Public Health Relevance

This research will test assumptions about the role of viscosity on regional blood flow and oxygen delivery by direct measurement in humans and provide information that will be critical for optimization of transfusion therapy in sickle cell disease. Furthermore, it will validate easily performed non-invasive measures related to sickling that be very useful in monitoring disease course and testing new treatments.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Specialized Center--Cooperative Agreements (U54)
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Special Emphasis Panel (ZHL1)
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Children's Hospital of Los Angeles
Los Angeles
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