J. Paul Scott

Bone marrow transplantation for sickle cell disease

BACKGROUND We investigated the risks and benefits of allogeneic bone marrow transplantation in children with complications of sickle cell disease. METHODS Twenty-two children less than 16 years of age who had symptomatic sickle cell disease received marrow allografts from HLA-identical siblings between September 1991 and April 1995. The indications for transplantation included a history of stroke (n = 12), recurrent acute chest syndrome (n = 5), and recurrent painful crises (n = 5). Patients were prepared for transplantation with busulfan, cyclophosphamide, and antithymocyte globulin. RESULTS Twenty of the 22 patients survived, with a median follow-up of 23.9 months (range, 10.1 to 51.0), and 16 patients had stable engraftment of donor hematopoietic cells. In three patients the graft was rejected and sickle cell disease recurred; in a fourth patient graft rejection was accompanied by marrow aplasia. In 1 of the 16 patients with engraftment, there was stable mixed chimerism. Two patients died of central nervous system hemorrhage or graft-versus-host disease. Kaplan-Meier estimates of survival and event-free survival at four years were 91 percent and 73 percent, respectively. Among patients with a history of acute chest syndrome, lung function stabilized; among patients with prior central nervous system vasculopathy who had engraftment, stabilization of cerebrovascular disease was documented by magnetic resonance imaging. CONCLUSIONS Allogeneic stem-cell transplantation can be curative in young patients with symptomatic sickle cell disease.

Hydroxyurea therapy in children severely affected with sickle cell disease

HYPOTHESIS The major clinical manifestations of sickle cell disease (SCD) are hemolytic anemia, predisposition to infection, and recurrent vaso-occlusive episodes resulting in pain, organ dysfunction, or both. There has been no satisfactory treatment for children with recurrent severe painful episodes caused by SCD. Hydroxyurea is an antimetabolite drug shown in adults with SCD to increase fetal hemoglobin levels and reduce the symptoms of SCD. We hypothesized that hydroxyurea therapy in children with severe (defined as > or = 3 vaso-occlusive events per year) SCD could improve hematologic parameters and reduce vaso-occlusive events. OBJECTIVE To assess the safety and efficacy of hydroxyurea for the treatment of severe SCD in children. STUDY DESIGN After obtaining informed consent, we initiated hydroxyurea therapy at a dosage of 10 to 20 mg/kg per day in 15 patients with severe SCD (hemoglobin SS, hemoglobin SS-alpha thalassemia, or hemoglobin S-beta0-thalassemia). Doses were escalated as tolerated. Patients were monitored with bimonthly physical examinations and monthly laboratory measures. To assess the impact of hydroxyurea on clinical symptoms, we recorded the number of inpatient days for each patient during the period of treatment and compared it with the number of inpatient days for the 12- to 24-month period before institution of hydroxyurea therapy, using the subject as his or her own control subject. RESULTS Thirteen patients received hydroxyurea for a median of 24 months (range, 6 to 39 months). The mean dose of hydroxyurea was 21.4 +/- 5.2 mg/kg. Treatment with hydroxyurea induced statistically significant increases in the total hemoglobin concentration, mean corpuscular volume, and percentage of hemoglobin F, and a decrease in the serum concentration of bilirubin. Toxic effects included three episodes of a reversible myelotoxic reaction, two of which required transfusion of packed erythrocytes. For the entire group, hospitalization decreased from a prehydroxyurea median of 3.9 +/- 2.0 days per month to 1.1 +/- 2.1 days per month of therapy (p = 0.09). For those subjects (n = 10) completing at least 1 year of treatment, the decrease in hospitalization from 4.1 +/- 2.2 to 1.0 +/- 1.7 days per month was significant (p = 0.03). CONCLUSIONS In this pilot trial, hydroxyurea treatment of severe SCD in children was associated with improved hematologic parameters, acceptable toxic effects, and a trend to reduced hospitalization. Hydroxyurea appears to be a safe and potentially effective agent for the treatment of severe SCD in children. A prospective, controlled trial to investigate the efficacy of hydroxyurea in children is therefore warranted.

Hydroxyurea therapy decreases the in vitro adhesion of sickle erythrocytes to thrombospondin and laminin

The adhesion of sickle erythrocytes to the vascular endothelium and subendothelial matrix probably contributes to the pathogenesis of vaso‐occlusive disease. The chemotherapeutic agent hydroxyurea (HU) decreases the frequency of vaso‐occlusive crises in patients with sickle cell disease. However, the exact mechanism(s) of HUs effect on vaso‐occlusive crises is not fully understood. The goal of this study was to determine the effect of HU therapy on the adhesion of sickle erythrocytes to the subendothelial matrix proteins thrombospondin (TSP) and laminin under conditions of flow in vitro. Erythrocytes from patients with severe sickle cell disease on HU therapy (n = 14) had significantly less adhesion to TSP (687 ± 92 erythrocytes/mm2, mean ± SE) than untreated patients with severe disease (n = 18, 1176 ± 117 erythrocytes/mm2, P = 0·003). In addition, there was significantly less adhesion of erythrocytes to immobilized laminin in patients treated with HU (1695 ± 293 erythrocytes/mm2) than in the untreated patients (2590 ± 296 erythrocytes/mm2, P = 0·02). Erythrocytes from an additional nine patients with severe sickle cell disease were studied both before and after initiation of HU therapy. Erythrocytes from these patients became less adhesive to both TSP (P = 0·001) and laminin (P = 0·01), a change that was sustained in most patients throughout the duration of the study (2 months to > 12 months). This study suggests that HU modulates the adhesive phenotype of sickle erythrocytes, an effect that may be in addition to, or independent of, other known effects of HU, such as an increase in fetal haemoglobin level.

Pulmonary, Gonadal, and Central Nervous System Status after Bone Marrow Transplantation for Sickle Cell Disease

We conducted a prospective, multicenter investigation of human-leukocyte antigen (HLA) identical sibling bone marrow transplantation (BMT) in children with severe sickle cell disease (SCD) between 1991 and 2000. To determine if children were protected from complications of SCD after successful BMT, we extended our initial study of BMT for SCD to conduct assessments of the central nervous system (CNS) and of pulmonary function 2 or more years after transplantation. In addition, the impact on gonadal function was studied. After BMT, patients with stroke who had stable engraftment of donor cells experienced no subsequent stroke events after BMT, and brain magnetic resonance imaging (MRI) exams demonstrated stable or improved appearance. However, 2 patients with graft rejection had a second stroke after BMT. After transplantation, most patients also had unchanged or improved pulmonary function. Among the 11 patients who had restrictive lung changes at baseline, 5 were improved and 6 had persistent restrictive disease after BMT. Of the 2 patients who had obstructive changes at baseline, 1 improved and 1 had worsened obstructive disease after BMT. There was, however, significant gonadal toxicity after BMT, particularly among female recipients. In summary, individuals who had stable donor engraftment did not experience sickle-related complications after BMT, and were protected from progressive CNS and pulmonary disease.

Neonatal aortic thrombosis: Recent experience

To evaluate the course, use of diagnostic modalities, management, and outcome of aortic thrombosis associated with umbilical artery catheterization, we reviewed 20 cases of aortic thrombosis diagnosed by ultrasonography (n = 16) or aortography (n = 4) over 4 years. Fourteen of 20 infants had severe perinatal asphyxia, suggesting that asphyxia predisposes to aortic thrombosis. Ultrasonography provided information about the size, location, and configuration of the thrombus and was useful in following thrombus size with therapy. Radionuclide renography-scintigraphy demonstrated abnormal renal function in all 11 patients scanned. Six patients with minor thrombosis (hypertension as the only sign) improved without specific therapy. Nine infants had moderate thrombosis (multiple signs but normal urine output); all survived with a variety of therapies; two were not given anticoagulant or fibrinolytic agents; three improved with heparin alone; and one had surgery without recurrence of the thrombus. Resolution of moderate thrombosis followed streptokinase therapy in two of three infants. All five babies with anuria from major thrombosis died. Hepatic infarction associated with aortic thrombosis was found in three of three autopsies.

Neurologic events after partial exchange transfusion for priapism in sickle cell disease

We describe six boys with homozygous sickle cell disease, aged 7 to 13 years, in whom acute, severe neurologic abnormalities developed 1 to 11 days after partial exchange transfusion was performed to treat priapism that was unresponsive to more conservative therapy. Hemoglobin levels were 10.5 to 13.4 gm/dl (mean 12.1 gm/dl), and hemoglobin S levels were 18% to 33% (mean 27%) before the onset of neurologic complications. Severe headache was the initial finding in five patients, four of whom had increased intracranial pressure and three of whom required tracheal intubation and hyperventilation. Four patients had seizures; three had focal neurologic deficits for more than 24 hours. Cerebral arteriography demonstrated vascular abnormalities, including irregularity, stenosis, and complete occlusion of vessels. Patients treated with regular erythrocyte transfusions had no recurrence of neurologic signs or symptoms when hemoglobin S levels were kept at 30% to 50%. The occurrence of serious neurologic complications after partial exchange transfusion in patients with homozygous sickle cell disease from three centers indicates the possibility of a causal relationship between the events. Early and thorough investigation of neurologic symptoms, especially severe headache, is warranted in this clinical setting.

Stroke with transfusions changing to hydroxyurea (SWiTCH): A phase III randomized clinical trial for treatment of children with sickle cell anemia, stroke, and iron overload†

Stroke occurs in 5–10% of children with sickle cell anemia (SCA) and has a high (>50%) risk of recurrence without therapy. Chronic monthly erythrocyte transfusions effectively prevent recurrent stroke, but their long‐term use is limited by serious side effects, including iron overload. An alternative to transfusion for secondary stroke prevention in SCA is needed, especially one that also improves the management of iron overload.

Partial splenectomy for hereditary spherocytosis: a multi-institutional review

BACKGROUND/PURPOSE Partial splenectomy has emerged as a surgical option for selected children with hereditary spherocytosis, with the goal of reducing anemia while preserving splenic function. This multi-institutional study is the largest series to date examining outcomes data for partial splenectomy in patients with hereditary spherocytosis. METHODS Data were collected retrospectively from 5 North American pediatric hospitals. Sixty-two children underwent partial splenectomy for hereditary spherocytosis between 1990 and 2008. RESULTS At 1 year following partial splenectomy, mean hemoglobin significantly increased by 3.0 ± 1.4 g/dL (n = 52), reticulocyte count decreased by 6.6% ± 6.6% (n = 41), and bilirubin level decreased by 1.3 ± 0.9 mg/dL (n = 25). Patients with poor or transient hematologic response were found to have significantly more splenic regeneration postoperatively compared with patients with a durable clinical response (maximal spleen dimension, 9.0 ± 3.4 vs 6.3 ± 2.2 cm). Clinically significant recurrence of anemia or abdominal pain led to completion splenectomy in 4.84% of patients. No patients developed postsplenectomy sepsis. CONCLUSIONS Our multi-institutional review indicates that partial splenectomy for hereditary spherocytosis leads to sustained and clinically significant improvement in hematologic profiles and clinical symptoms in most patients. Our data support partial splenectomy as an alternative for selected children with hereditary spherocytosis.

Heparin-induced thrombocytopenia in a child

We describe a case of thrombocytopenia and deep venous thrombosis in a boy who received heparin to maintain patency of a central venous catheter. Measurement of the release of serotonin labeled with carbon 14 confirmed the presence of heparin-induced thrombocytopenia. Children receiving heparin therapy should be monitored for the possibility of heparin-induced thrombocytopenia.

Patient-controlled analgesia for sickle cell pain crisis in a pediatric emergency department

Objective To determine whether a protocol to start patient-controlled analgesia (PCA) in the emergency department (ED-PCA) would shorten the length of time between narcotic bolus doses and PCA initiation as compared with standard inpatient initiation of PCA (IP-PCA). Also, to compare patient satisfaction and inpatient length of stay for the 2 groups. Methods To improve care, we developed a protocol to institute ED-PCA after an initial bolus dose of narcotics. This was a nonrandomized pilot study. Patient records were reviewed for location of PCA initiation, time from narcotic bolus to initiation of PCA, and length of stay. A brief patient/parent satisfaction survey was collected. Results Sixty-nine records were reviewed. Patients treated using the protocol had initiation of PCA therapy within 35 ± 7 minutes from the last bolus narcotic dose in the emergency department versus 211 ± 17 minutes for nonprotocol patients. Forty-eight of 50 patient surveys indicated preference for starting ED-PCA; 2 did not have a preference. No complications were identified in either group. Conclusions A protocol to initiate PCA for sickle cell patients in a pediatric emergency department shortened the time of its initiation and was preferred by patients.