Sickle cell disease is the most common hemoglobinopathy in the world, and, in the UnitedStates, affects approximately 1 in 360 African Americans and 1 in 1200 Latinos. Small vesselocclusion, or vaso-occlusion, is the primary pathology leading to clinical complications of thisdisease. The most frequent manifestation of vaso-occlusion is the acute pain episode (crisis),which often requires hospitalization and narcotic use, thus exacting an economic, social, andpsychological toll on afflicted individuals. Standard of care is inadequate, there being no specifictherapies that target ongoing acute pain episodes. Mouse models have shown that leukocytes adherent to blood vessel endothelium play acrucial role in vaso-occlusion, probably through their subsequent interaction with sickle red bloodcells. Further work has shown that intravenous gammaglobulin (IVIG) administered either prior to orafter the induction of vaso-occlusion rapidly and dramatically reduces leukocyte adhesion toendothelium and subsequent red cell interactions, leading to a marked increase in survival. Based on this work , we propose to conduct a randomized, double-blind, placebo-controlled, dose-escalation Phase I-II trial to study the safety and efficacy of a single dose of IVIGcompared to normal saline placebo administered to patients with sickle cell anemia admitted to thehospital with an uncomplicated acute pain episode. A total of 52 subjects will be enrolled. Wehypothesize that IVIG will act quickly to reduce vaso-occlusion and thus pain scores, narcotic use,and length of hospitalization. We will also investigate the physiological effects of IVIG in patientswith sickle cell disease by measuring the adhesion receptors involved in leukocyte adherence toendothelium and red blood cell-leukocyte interactions, microcirculatory blood flow, and serummarkers of hemolysis. Completion of this trial will allow us to submit by the end of the grant period an NIHapplication to expand this trial into a Phase III trial or to test, in Phase I-II trials, newly identifiedagents that interfere with the molecular mechanism of vaso-occlusion.
Developing new treatments for acute pain episodes in sickle cell disease is relevant because they are the most frequent manifestation in sickle cell disease and are associated with long-term morbidity, yet there are currently no specific therapies for ongoing episodes. Intravenous gammaglobulin may represent the first specific therapy for ongoing acute pain episodes.
| Manwani, Deepa; Chen, Grace; Carullo, Veronica et al. (2015) Single-dose intravenous gammaglobulin can stabilize neutrophil Mac-1 activation in sickle cell pain crisis. Am J Hematol 90:381-5 |
| Shi, Patricia Ann; Manwani, Deepa; Olowokure, Olugbenga et al. (2014) Serial assessment of laser Doppler flow during acute pain crises in sickle cell disease. Blood Cells Mol Dis 53:277-82 |
