This project will test the ability of anti-inflammatory agents to block decrease in blood flow directly measured in the skin, deep tissue and bone marrow of subjects with sickle cell anemia. We hypothesize that therapeutic interventions that interrupt adhesive interactions between sickle erythrocytes, leukocytes, platelets and vascular endothelium will lessen the vaso occlusion, hemoglobin desaturations, and release of mediators of vascular damage induced by intermittent hypoxia. While sickle cell anemia (SCA) is thought of as acute episodes of marked red blood cell (RBC) sickling, sickle-related vaso occlusion occurs continually even dudng non-crisis periods. The cumulative effect of these processes is end-organ damage. Recent data from animal models underscore the importance of leukocyte adhesion to the vascular endothelium in the genesis of sickle vasoocclusion. It is therefore likely that therapies that interfere with the formation of the adhesive interactions between leukocytes, sickle red cells and vascular endothelium will decrease end-organ damage. RBC sickling is triggered by hypoxia. Sleep studies in SCD children demonstrate that 10 to 40 episodes of desaturation occur each night with oxygen saturation dropping to 75 to 85 percent. We directly measured decreases in blood flow in response to nitrogen-induced hypoxia in subjects with sickle cell disease. These decreases are six-times greater than normal controls (p<.001). We will develop this model of vaso occlusion in humans and extend the studies to include measurement of hypoxia-induced changes in inflammatory mediators, markers of vascular damage, and measures of deep tissue blood flow. These parameters will be measured in response to nitrogen-induced hypoxia as well as hypoxic episodes naturally occurring during sleep. We will then use anti-inflammatory agents to block the changes in blood flow and increase in markers of vascular damage after detailed characterization of the N2 challenge and sleep hypoxia models. If these agents are successful, we will have direct evidence in humans that inflammation plays a role in vaso occlusion. Furthermore, this model may serve to test candidate treatments for sickle cell disease. While not within the scope of the present proposal, we anticipate that therapeutic interventions that abrogate hypoxia-induced blood flow decreases and changes in markers of vascular damage detected in these human models will decrease frequency of crisis and lessen the degree of end-organ damage if tested in larger clinical trials.
| Detterich, Jon A; Sangkatumvong, Suvimol; Kato, Roberta et al. (2013) Patients with sickle cell anemia on simple chronic transfusion protocol show sex differences for hemodynamic and hematologic responses to transfusion. Transfusion 53:1059-68 |
