Audrey K. Brown

Pregnancy in sickle cell disease: experience of the Cooperative Study of Sickle Cell Disease.

Objective To determine the maternal and fetal outcomes of pregnancy in women with sickle cell disease. Methods The subjects were part of a cohort recruited from 19 centers for a prospective study of the clinical course of sickle cell disease. Each participant was evaluated using a structured protocol in which steady-state data and information on both sickle- and non-sickle-related events were colleted. The rates of antepartum and intrapartum complications were tallied for pregnancies carried to delivery. Fetal outcome was assessed according to gestational age, birth weight, and Apgar score. Differences among genotypes in event rates were assessed using Fisher exact test. Differences in gestational age and birth weight, and predictors of these outcomes, were assessed using analyses of covariance. Results Two hundred eighty-six of the 445 reported pregnacies proceeded to delivery. Non-sickle-related antepartum and intrapartum complication rates were comparable with those of African-American women who did not have sickle cell disease. One of the two deaths observed during this study was directly related to the presence of sickle cell disease. Rates of maternal morbidity from sickle cell disease were the same during pregancy as during the nonpregnant state. Ninety-nine percent of those pregnancies carried to delivery resulted in a live birth. Twenty-one percent of the infants born to women of the SS genotype were small for gestational age (SGA). Preclampsia and acute anemic events were identified as risk factors for SGA infants. Conclusion Those caring for women with sickle cell disease should support them if they desire to have children.

Hemoglobin Savannah (B6(24) β-glycine→valine): an unstable variant causing anemia with inclusion bodies

An abnormal hemoglobin, termed Hb Savannah, was found in red cell hemolysate of a young Caucasian girl with severe hemolytic anemia. The presence of this unstable variant became evident when inclusion bodies appeared rapidly upon exposure of red cells to redox dyes and a large percentage of hemoglobin in hemolysate precipitated on warming to 65°C. Treatment of the hemoglobin with p-hydroxymercuribenzoate (PMB) caused a rapid dissociation into monomers; starch-gel electrophoresis of PMB-treated hemoglobin showed the presence of abnormal β-chains. Data from structural studies of isolated β-chains indicated substitution of a valyl residue for the normally occurring glycyl residue at position 24, which corresponds to helical residue B6. A similar substitution but with an arginine replacing the glycyl residue has been observed in Hb Riverdale-Bronx. The glycine to valine substitution will change the relationship of the B and the E helices which results in extensive conformational changes in the β-chain. This change presumably causes an increased dissociation of the hemoglobin molecule into dimers and probably monomers, and a decreased stability of the αβ-dimers. The hemoglobin abnormality may be the result of a fresh mutation because the abnormality is not present in the parents nor in any of the seven siblings.

Metabolism of mucopolysaccharides in connective tissue. I. Studies of enzymes involved in glucuronide metabolism.

Details of the intermediary metabolism of mucopolysaccharides have been studied in microorganisms and some animal tissues (1). Wehave undertaken an exploration of enzymatic steps in the synthesis of mucopolysaccharides in extracts of the connective tissue which enter polyvinyl sponges inserted under the skin of guinea pigs and extracts of human synovial tissue obtained surgically. Uridine diphosphoglucuronic acid (UDPGA) is presumed to be the donor of glucuronic acid in the synthesis of acid mucopolysaccharides (1). This report concerns primarily the enzymatic steps involved in the synthesis of UDPGAfrom glucose, and other enzymes involved in the metabolism of glucuronides, including glucuronosyl transferase and beta-glucuronidase. Schematic outline of the actions of the enzymes studied is given in Table I.

Transient Neutropenia of Childhood

Patient characteristics and clinical course are described in 21 children with newly discovered neutropenia (absolute neutrophil count <1500/μl). Only children over age 3 months are included ; 19 of 21 were less than age 2 years. The majority had respiratory tract infections and 11 had been on various medications at the time neutropenia was discovered. Bacteria were isolated from the blood of three patients ( S. pneumoniae in two, H. influenzae in one) and from urine in one (E. coli). Respiratory syncytial virus was cultured from the nasopharynx of two patients. Opportunistic, gram-negative and staphyloccal infections did not occur. Neutrophil counts in all but one child returned to normal within 6 weeks of onset; half recovered within 7 days. Bone marrow examination was performed in 13 patients: maturation arrest at various stages in the myeloid series was noted in six, and seven had normal myeloid maturation. Bone marrow findings did not correlate with degree or duration of neutropenia. These observations indicate that previously well infants with isolated neutropenia generally have a benign clinical course, although three patients were ultimately proven to have significant chronic illness. Recommendations are made as to management.

Factors Affecting the Transcutaneous Measurement of Bilirubin: Influence of Race, Gestational Age, Phototherapy and Albumin Binding Capacity

Most previous studies in infants have found surprisingly good correlation between transcutaneous bilirubin indices and serum bilirubin indices and serum bilirubin levels.1–6 However, exact correlation between such measurements should not be expected since the instrument measures the yellowness of the skin and not the concentration of bilirubin in the blood. Many factors can influence the relationship between these two measurements, including race, gestational age, the rate of bilirubin accumulation as well as the bilirubin binding capacity, and other factors that affect the distribution of bilirubin between the intravascular and extravascular spaces. These influences preclude the use of any objective measurement of skin jaundice as a complete substitution or replacement for the measurement of serum bilirubin under all circumstances. Nevertheless, previous studies have tested the validity of transcutaneous bilirubinometry almost solely by comparing the degree of exact correlation with the serum value.

Hyperbilirubinemia in black infants. Role of glucose-6-phosphate dehydrogenase deficiency.

enzyme activity is actually increased. Since the initial descriptions from Greece in 1960, there have been several reports concerning the association of neonatal hyperbilirubinemia, and even kemicterus, with G6PD deficiency in many newborn populations throughout the world. Reports from Israel, China, Africa, and Thailand, for example, clearly demonstrate increased frequency and severity of neonatal hyperbilirubinemia, as well as kernicterus, in G6PD-deficient infants in these and other populations. In about 10 % of American black males, a G6PD deficiency, designated Gd A-, occurs and can be identified at birth. A similar en-

1319 BUFFY COAT TRANSFUSION: AN EFFECTIVE ALTERNATIVE IN SEVERELY ILL, GRANULOCYTE-DEPLETED NEWBORNS

Granulocyte transfusion may be life-saving in newborns with bacterial sepsis, neutropenia and severe depletion of the bone marrow mature neutrophil storage pool (NSP). Since a buffy coat is more readily available than granulocytes obtained by leukapheresis, we studied the efficacy of fresh (<24hrs), irradiated buffy coat transfusion in this high risk group. Bone marrow aspiration was done on 16 newborns with clinical sepsis and an absolute neutrophil count (ANC) <2000/mm3. Four were found to have severe depletion of NSP, i.e. (metas + bands + segs) <7% of nucleated cells, and were given 10cc/kg of a buffy coat preparation. Three of these infants received 0.5-1x 109 neutrophils/mm3/kg. Two had an increase to normal ANC within 12 hours and recovered from clinical sepsis. The rise in ANC continued and was far in excess of that predicted based on the number of granulocytes transfused. The third infant had a transient rise to 2350 neutrophils/mm3 6 hours post-transfusion, but subsequently remains neutropenic for 6+ weeks. A fourth infant whose buffy coat provided only 0.06 × 109 neutrophils/mm3/kg received a second transfusion from the same unit 12 hours later, recovered fully from neutropenia, and survived. Twelve infants with NSP >7% were not transfused; one of these had an NSP of 8.5% and expired. The remainder survived but remained neutropenic 4-16 days. Fresh buffy coat preparations appear to accelerate recovery from neutropenia and may improve survival in clinically septic NSP-depleted newborns.

TRANSIENT NEUTROPENIA OF CHILDHOOD

While neutropenia (ANC<1500) related to acute infections in children is well known, natural histroy and appropriate management are unclear. Clinical data on 22 children referred for neutropenia over a 13 mo. period were reviewed. Twenty patients were age 3 mos.-3 yrs. and 2 were age 11 yrs. ANC was <500/cmm in 18 patients. All patients were febrile at some point in their illness; the majority (13) had respiratory tract infection. Infectious agents were isolated in 6 patients (S. pneumo. 2, H.flu, 1, E.coli 1, RSV 2). Neutropenia may have been drug-related in 5 patients (carbamazepine 1, chloramphenicol 2, penicillin 1, ampicillin 1). Bone marrow aspiration, performed in 14 patients, was normal in 7; seven patients demonstrated maturation arrest.Recovery from neutropenia was documented in 20 patients; one child has remained neutropenic for 12 months and one was lost to follow-up. Ten recovered within 1 wk. of referral, whereas 10 remained neutropenic from 1 to 6 wks. Time to recovery could not be predicted based on any clinical or laboratory parameters available.These cases of childhood neutropenia appear to have been infection-related and 20/21 patients recovered. Superimposed bacterial infection did not occur even with ANC<500/cmm; empiric treatment with broad spectrum antibiotics was not instituted. Bone marrow evaluation, while useful in excluding infiltrative disorders and aplastic anemia, was not predictive of the rate of recovery.

PLATELET ASSOCIATED IMMUNE GLOBULIN|[lpar]|PAIg|[rpar]| IN THE COURSE OF CHILDHOOD IDIOPATHIC THROMBOCYTOPENIC PURPURA

Platelet associated immune globulin was studied during the course of ITP in 15 children; the microtiter solid phase immunoassay was used.Values in 10 patients with acute ITP were compared with those in 5 children with chronic ITP.At the onset,PAIgG was elevated in 9/10 children with acute ITP;8/10 had levels>70fg/pl (median PAIgG=91.7;normal=<5.2fg/pl) The one child with acute ITP whose PAIgG was normal recovered within two weeks.At recovery PAIgG levels had fallen below 10fg/pl(median 3.7 fg/pl) in 7/8;5/7 had normal levels.In contrast, 4/5 children whose disease became chronic, had lower levels of PAIgG (<16.7fg/pl).Only 1/5 chronic ITP patients had markedly elevated PAIgG. In 2 patients post-splenectomy, levels were normal even in transient periods of thrombocytopenia. In one patient,PAIgG rose dramatically to 75 fg/pl during an intercurrent viral illness. Another patients PAIgG levels rose transiently following treatment with IV gamma globulin; no change in the platelet count occurred.These findings suggest that PAIgG is usually higher at the onset of classic childhood ITP (acute) than in those children whose course becomes chronic although the levels are not individually predictive. The observed drop in PAIgG after splenectomy as well as the sharp rises noted during infection and gammaglobulin treatment deserve further study to help understand the relationship between thrombocytopenia and PAIgG.

PLATELET ASSOCIATED IMMUNE GLOBULINS IN PATIENTS TAKING CARBAMAZEPINE

Carbamazepine (Tegretol),a widely used anticonvulsant, is known to be associated with various hematologic toxicities including thrombocytopenia.Platelet associated immune globulin (PAIg) was measured in two children who were taking carbamazepine.PAIgG and PAIgM were significantly elevated in a patient with pancytopenia which developed 2 months after intitiation of the drug.Platelet counts and PAIg levels returned toward normal within 3 weeks of drug stoppage.PAIg was also found to be elevated in a second patient who had been on carbamazepine for 4 months and in whom there was no hematologic abnormality.There was no evidence of underlying autoimmune disorder in either patient.Elevated PAIg in patients on carbamazepine has not been reported. It appears that thrombocytopenia seen with carbamazepine adminstration may in some instances be due to production of specific antibody.Alternatively,the drug may induce a change in platelet membrane which allows adsorption of Ig.Investigation of this phenomenon could lead to a better understanding of the significance of PAIg in thrombocytopenia.