Sherri A. Zimmerman

Childhood ITP: 12 months follow‐up data from the prospective registry I of the Intercontinental Childhood ITP Study Group (ICIS)

Acute and chronic idiopathic thrombocytopenic purpura (ITP) is traditionally based on the duration of thrombocytopenia at the cut‐off point of 6 months after diagnosis. Registry I evaluated the diagnosis, definition, management, and follow‐up of childhood ITP. This report focuses on children with thrombocytopenia persisting more than 6 months.

Erythrocyte autoantibodies in paediatric patients with sickle cell disease receiving transfusion therapy: frequency, characteristics and significance

The formation of erythrocyte autoantibodies following transfusion therapy has been described in case reports and small series. To determine the frequency, serological characteristics, and clinical significance of this phenomenon in paediatric patients with sickle cell disease, we analysed the patient database at the Duke University Pediatric Hematology Clinic. We identified children who received multiple erythrocyte transfusions, then reviewed clinical records to identify children who developed erythrocyte autoantibodies in association with transfusions. Among 184 paediatric patients who received multiple erythrocyte transfusions, 14 children (7.6%) developed warm (IgG) erythrocyte autoantibodies. Median transfusion exposure at the time of autoantibody formation was 24 erythrocyte units, range 3–341 units. The autoantibody reacted as a panagglutinin in 11 cases but had anti‐e specificity in three patients. Surface complement also was detected in five patients. Clinically significant haemolysis was documented in four patients, each of whom had both surface IgG and C3 detected. The development of erythrocyte autoantibodies was associated with the presence of erythrocyte alloantibodies. Formation of warm erythrocyte autoantibodies in association with transfusions is not rare in paediatric patients with sickle cell disease. Clinicians should be aware of this complication and recognize that the presence of surface C3 is often associated with significant haemolysis.

Influence of bilirubin uridine diphosphate-glucuronosyltransferase 1A promoter polymorphisms on serum bilirubin levels and cholelithiasis in children with sickle cell anemia

Purpose Genetic mutations in the uridine diphosphate (UDP)–glucuronosyltransferase 1A (UGT1A) enzyme promoter have been associated with unconjugated hyperbilirubinemia and Gilbert syndrome. The effects of UGT1A promoter polymorphisms on serum bilirubin levels and symptomatic gallstone formation were studied in a cohort of children with sickle cell anemia (SCA). Methods The UGT1A promoter genotype was determined for 115 consecutive children with SCA. Steady-state laboratory parameters and previous cholecystectomy for symptomatic gallstones were recorded retrospectively, then analyzed according to UGT1A genotype. Results Children with SCA had a lower frequency of the normal (TA) 6 UGT1A promoter allele (0.413) than the abnormal (TA) 7 allele (0.461). A previously described shorter (TA) 5 allele (frequency 0.074) and longer (TA) 8 allele (frequency 0.052) were also observed. Children with the 7/7 UGT1A genotype had a significantly higher mean bilirubin level (5.8 ± 3.1 mg/dL) than those with the 6/6 (2.4 ± 0.8 mg/dL) or 6/7 genotype (3.0 ± 1.1 mg/dL;P < 0.001 by analysis of variance). Patients with the 7/7 genotype were more likely to have previous cholecystectomy (87.5%) than those with the 6/6 (35.7%) or the 6/7 genotype (36.1%;P = 0.002 by &khgr; 2 ). Conclusions Genetic variation in the UGT1A promoter significantly influences serum bilirubin levels and the development of symptomatic cholelithiasis in children with SCA. The UGT1A promoter polymorphisms represent an important nonglobin genetic modifier of clinical disease expression in SCA.

GENITOURINARY COMPLICATIONS OF SICKLE CELL DISEASE

PURPOSE In the last half century the molecular biology, pathophysiology and natural history of sickle cell disease have been well defined. Sickle cell disease causes microvascular occlusion, which is manifested in most organ systems. The genitourinary tract is most commonly affected by hematuria, urinary tract infection and priapism but other more serious sequelae have been identified. MATERIALS AND METHODS We performed a computerized MEDLINE search from 1965 to the present and a bibliographic review of cross references. These references were analyzed for meaningful findings and case reports. RESULTS The diagnosis and management of sickle cell disease have advanced rapidly with a significant increase in the life expectancy of affected patients and recognition of a greater number of genitourinary complications. Renal function may be mildly altered or lost completely. Patients with sickle cell disease are at increased risk for urinary tract infection. Priapism is a painful complication of sickle cell disease that is poorly understood and challenging to treat and prevent. Testicular infarction has also been noted. Furthermore, renal medullary carcinoma, a highly lethal tumor, develops almost exclusively in young patients with sickle cell trait. CONCLUSIONS Heightened awareness of the genitourinary complications of sickle cell disease may prevent end stage disease, including renal failure and impotence. New forms of therapy for sickle cell disease, such as hydroxyurea, may prevent these complications in the future.

Inherited DNA mutations contributing to thrombotic complications in patients with Sickle cell disease

Thrombosis may play an important role in the pathophysiology of certain complications of sickle cell disease (SCD), including stroke and avascular necrosis (AVN). Currently there is no laboratory or clinical parameter that can identify patients who are at highest risk of developing these thrombotic complications. We hypothesized that some patients with SCD have an inherited hypercoagulable state that results in an increased risk of developing stroke or AVN. We examined the role of two common inherited thrombophilic mutations that, in other populations, have been associated with arterial and venous thrombosis and are amenable to screening with DNA restriction enzyme analysis. The C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene and the C1565T mutation in the platelet glycoprotein IIIa (GPIIIa) gene were evaluated. We analyzed genomic DNA from 86 children and adults with SCD, including 16 patients with a history of a clinical stroke and 14 patients with AVN, for the presence of these mutations. The C677T MTHFR mutation was found in 19% of patients with stroke, 14% of patients with AVN, and 14% of patients with neither complication (P = NS). The C1565T GPIIIa mutation was found in 25% of patients with stroke, 14% of patients with AVN, and 18% of patients with neither complication (P = NS). Although each of these mutations is relatively common in patients with SCD, neither is independently associated with an increased risk of developing stroke or AVN. Am. J. Hematol. 59:267–272, 1998.

A pilot study of hydroxyurea to prevent chronic organ damage in young children with sickle cell anemia.

Hydroxyurea improves laboratory parameters and prevents acute clinical complications of sickle cell anemia (SCA) in children and adults, but its effects on organ function remain incompletely defined.

Clinical significance of the antinuclear antibody test in selected children with idiopathic thrombocytopenic purpura.

PURPOSE To determine the clinical significance of the antinuclear antibody (ANA) test in selected children with idiopathic thrombocytopenic purpura (ITP). METHODS The study was conducted through retrospective chart review and long-term follow-up by telephone interview. RESULTS Of 87 children with ITP who had an ANA performed, 25 had a positive titer (median = 1:160, range: 1:40 to 1:2,560). Children with a positive ANA were more likely to be older girls who developed chronic ITP, but there was no correlation with family history of autoimmune disease, initial hemoglobin concentration, or initial platelet count. With an average follow-up of more than 5 years, more children with a positive ANA developed further autoimmune symptoms than those with a negative ANA (36% vs. 0%, p < 0.001). Nine children with a positive ANA developed additional autoimmune symptoms, including five with clinical criteria sufficient for the diagnosis of systemic lupus erythematosus (SLE). Autoantibodies to dsDNA were more prevalent in the children with progression of autoimmune symptoms (57% vs. 0%, p = 0.04). The presence of any autoantibody in addition to the ANA, including dsDNA, SS-A/Ro, SS-B/La, Smith Antigen (Sm), nuclear ribonucleoprotein (nRNP), or cardiolipin was more common in children who had further autoimmune symptoms (75% vs. 0%, p = 0.003). CONCLUSIONS The ANA is a useful screening test in a subset of children with ITP, especially older girls with chronic ITP, who are at risk for the development of generalized autoimmune disease. Children with ITP and a positive ANA should receive careful follow-up.

Childhood autoimmune cytopenia secondary to unsuspected common variable immunodeficiency

Immune thrombocytopenic purpura and autoimmune hemolytic anemia are typically idiopathic processes without underlying systemic illness. Four children with autoimmune cytopenia had low immunoglobulin levels that led to the diagnosis of common variable immunodeficiency. Routine screening of immunoglobulins is suggested for children with chronic or recurrent immune thrombocytopenic purpura and autoimmune hemolytic anemia.

Clinical manifestations of hematologic and oncologic disorders in patients with Down syndrome

Hematologic abnormalities are common in individuals with Down syndrome (DS). Increased erythrocyte mean corpuscular volume (MCV) is frequently found among DS infants and remains elevated throughout life in two‐thirds of patients, making interpretation of red cell indices for diagnosis of nutritional anemias or bone marrow failure disorders more challenging. Transient myeloproliferative disorder (TMD) associated with pancytopenia, hepatosplenomegaly, and circulating immature WBCs, is found almost exclusively in DS infants with an incidence of approximately 10%. In most cases, TMD regresses spontaneously within the first 3 months of life, but in some children, it can be life threatening or even fatal. Despite the high rate of spontaneous regression, TMD can be a preleukemic disorder in 20–30% of children with DS. The types of malignancy, response to therapy, and clinical outcome in children with DS are also unique. There is an increased risk of leukemia with an equal incidence of lymphoid and myeloid leukemia. Acute megakaryocytic leukemia (AMKL) subtype is the most common form of acute myeloid leukemia (AML) in this setting, and is uncommon in children without DS. Somatic mutations of the gene encoding the hematopoetic growth factor GATA1 have been shown to be specific for TMD and AMKL in children with DS. Myelodysplastic syndrome can precede AML. Children with DS and leukemia are more sensitive to some chemotherapeutic agents such as methotrexate than other children which requires careful monitoring for toxicity. Although the risk for leukemia is higher in individuals with DS, these patients have a lower risk of developing solid tumors, with the exception of germ cell tumors, and perhaps retinoblastoma and lymphoma.

Hemoglobin S/OARAB: Thirteen new cases and review of the literature

Hemoglobin S/OArab (Hb S/OArab) is a rare compound heterozygous hemoglobinopathy characterized by the presence of two variant β‐globin chains: β6Glu → Val (Hb S) and β121Glu → Lys (Hb OArab). The diagnosis of Hb S/OArab requires electrophoresis on both cellulose acetate and citrate agar, since Hb OArab co‐migrates with Hb C at alkaline pH and close to Hb S at acidic pH. To date only case reports and small series of patients with Hb S/OArab have been described. To better characterize the clinical and laboratory aspects of this unusual disorder, we reviewed the Duke University Medical Center experience. We identified 13 African‐American children and adults with Hb S/OArab ranging in age from 2.7 to 62.5 years. All patients had hemolytic anemia with a median Hb of 8.7 gm/dL (range 6.1–9.9 gm/dL), and a median reticulocyte count of 5.8% (range 1.2–10.3%). The peripheral blood smear typically showed sickled erythrocytes, target cells, polychromasia, and nucleated red blood cells. All 13 patients have had significant clinical sickling events including acute chest syndrome (11), recurrent vasoocclusive painful events (10), dactylitis (7), gallstones (5), nephropathy (4), aplastic crises (2), avascular necrosis (2), leg ulcers (2), cerebrovascular accident (CVA) (1), osteomyelitis (1), and retinopathy (1). Four patients have died, including two from pneumococcal sepsis/meningitis at ages 5 and 10 years, one of acute chest syndrome at age 14 years, and one of multiorgan failure at age 35 years. We conclude that Hb S/OArab disease is a severe sickling hemoglobinopathy with laboratory and clinical manifestations similar to those of homozygous sickle cell anemia. Am. J. Hematol. 60:279–284, 1999.