Abciximab (ReoPro) as a Therapeutic Intervention for Sickle Cell Vaso-Occlusive Pain Crisis

Sickle cell disease (SCD) is one of the more common genetic diseases worldwide, affecting approximately 1 in 500 African-Americans and 1 in 1000 Hispanic-Americans. A single amino acid substitution decreases the solubility of deoxygenated hemoglobin, leading to polymer formation and subsequent distortion of erythrocyte shape from the normal biconcave disc into a relatively rigid crescent or sickle shape. Initially reversible, the polymer formation and shape distortion eventually becomes permanent. Clinical manifestations of sickle cell disease relate both to increased clearance of these misshapen erythrocytes (causing a chronic hemolytic anemia) as well as occlusion of small (and sometimes large) blood vessels.

Vaso-occlusive phenomena are responsible for much of the acute morbidity of sickle cell disease, including episodes of pain resulting from bone infarcts, splenic infarction with a secondary increased risk of infection, and a relatively high incidence of ischemic stroke (~10% in the first 2 decades of life). In addition, chronic and cumulative ischemic episodes contribute to long-term morbidity (including avascular necrosis of bone, retinopathy, renal insufficiency, and pulmonary hypertension) and a significantly shortened life span. Vaso-occlusive pain crises often require hospitalization for the administration of parenteral narcotics; the average duration of hospitalization is 4-5 days, and a significant proportion of patients experience multiple crises per year. In most episodes, pain continues to intensify over the first 2-3 days before beginning to abate, suggesting that there is ongoing extension of tissue damage for some time following initiation of the episode; also, many patients will develop additional foci of pain even during the course of hospitalization.

While direct mechanical blockage of small vessels by sickled erythrocytes is undoubtedly an important factor in vaso-occlusion, there are other secondary phenomena that are likely to contribute to these episodes, including increased erythrocyte adhesion to the endothelium of post-capillary venules. SCD patients also exhibit chronic pro-coagulation changes in soluble clotting factors, as well as increased platelet number and activation. The relative contribution of these various changes to the pathophysiology of vaso-occlusive crises is unclear. One published study showed that the antiplatelet drug ticlopidine decreased frequency, duration, and severity of pain crises in SCD patients, suggesting that the increase in platelet activation does indeed contribute to vaso-occlusion.

Current therapy for vaso-occlusive pain crises is mostly supportive (maintaining adequate hydration and oxygenation and administering pain medication). With the possible exception of exchange transfusion-a procedure with significant potential morbidity-there is no therapy that directly targets the vaso-occlusion.

Abciximab (ReoPro) is the Fab fragment of the chimeric human-mouse monoclonal antibody 7E3. It avidly binds to both glycoprotein IIb/IIIa and to integrin αvβ3, and so would potentially inhibit both erythrocyte binding to vascular endothelial as well as platelet adhesion, thus targeting two separate mechanisms that are felt to be components of the vaso-occlusive phenomenon in SCD.

The relatively prolonged course of most pain crises-which typically involves increasing intensity of pain and often development of new areas of pain over the first few days-suggests that treatment during the early phases of a crisis might be effective in ameliorating the course of the episode, resulting not only in decreased acute morbidity but possibly also in less long-term tissue damage. The study hypothesis is that administration of abciximab early in the course of a vaso-occlusive sickle cell pain crisis will reduce the median length of hospitalization without an accompanying increase in bleeding or other serious complications.

Participants will be randomized in a double blind fashion to receive either abciximab (ReoPro) or placebo intravenously over 12 hours. Randomization will be stratified by sickle cell genotype: Sickle Cell Anemia (SS) vs. Sickle-Hemoglobin C Disease (SC). All patients will receive standard supportive care, including hydration, supplemental oxygen as needed to maintain oxygen saturation >92%, scheduled use of NSAIDS, and narcotics titrated to effect.