Abciximab (ReoPro) as a Therapeutic Intervention for Sickle Cell Vaso-Occlusive Pain Crisis
Abciximab (ReoPro) as a Therapeutic Intervention for Sickle Cell Vaso-Occlusive Pain Crisis
The purpose of this study is to determine whether giving abciximab (ReoPro) to children with
 sickle cell disease who are hospitalized for acute pain crisis will improve their pain and
 shorten the time spent in the hospital, when compared with standard supportive care.
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.
Inclusion Criteria:

 1. Diagnosis of sickle cell disease (Hb SS, HbSC, HbS-β0-thalassemia)

 2. Age 5.00 to 24.99 years

 3. Pain consistent with vaso-occlusive crisis that meets the criteria for hospitalization
 and parenteral narcotics: moderate-severe pain unresponsive to oral medications
 (NSAIDS + narcotics) that has no alternative etiology (e.g., trauma)

 4. Platelet count >100,000

 5. INR <1.2, PTT < 40 seconds

 6. Negative urine pregnancy test for females of child-bearing potential, including any
 female ≥10 years of age

 7. Informed consent by patient (≥18 years of age) or parent (if patient <18 years of
 age); assent from patients 12-18 years of age

 8. Ability to start drug/placebo infusion within 16 hours of admission

 Exclusion Criteria:

 1. History of stroke (either ischemic or hemorrhagic)

 2. Currently receiving anticoagulation medication (heparin within 1 week, Coumadin within
 3 weeks) or medication with irreversible anti-platelet effect (e.g., aspirin,
 ticlopidine) within 14 days

 3. Red cell transfusion within 60 days

 4. Major surgery within 30 days

 5. Treatment with hydroxyurea within 30 days (due to evidence that hydroxyurea can
 reverse platelet activation in patients with SCD)

 6. Tmax ≥ 102.0o F without concomitant signs of infection, or ≥ 100.4o F with any finding
 suggestive of bacterial infection, including acute chest syndrome (fever, respiratory
 symptoms, and new infiltrate on chest X-ray)

 7. Active internal bleeding

 8. Known allergy to abciximab or murine proteins

 9. Recent (within 6 weeks) gastrointestinal or genitourinary bleeding of clinical
 significance

 10. Bleeding diathesis

 11. History of vasculitis

 12. Intracranial neoplasm, arteriovenous malformation or aneurysm

 13. Severe uncontrolled hypertension

 14. Patients who previously participated in the study must be excluded due to the
 increased risk of severe thrombocytopenia.