Secondary erythrocytosis due to compound homozygosity, but not compound heterozygosity, for Hb Luton and α-thalassemia: a family study.

We describe the hematological and clinical features of homozygous Hb Luton (OMIM 141800.0172), a high affinity α-globin variant that has not been previously described in the homozygous state. The proband was found to have a high hemoglobin (Hb) concentration following a routine blood count prior to a planned appendectomy at the age of 16 years. Investigation showed that she was homozygous for both Hb Luton [α89(FG1)His→Leu (CAC>CTC), a high oxygen affinity Hb)] and homozygous for α(+)-thalassemia (α(+)-thal), while her mother, maternal aunt and half-brother were heterozygous for these conditions. Further investigation showed that she also had Gilbert's disease and Raynaud's syndrome. As far as we are aware, this is also the first reported family with a subject homozygous for both Hb Luton and α-thal so that the proband has no nomal α-globin. The parents of the proband are first cousins and originate from Pakistan.

Evaluation of the suitability of the World Health Organization International Reference Reagent for Hb A2 quantitation (89/666) for continued use.

INTRODUCTION: The accurate determination of Hb A2 is a key marker when screening for a ß-thalassaemia carrier. Data from external quality assessment (EQA) exercises have shown a lack of alignment of Hb A2 quantitation both within and between methods. The only reference material available for Hb A2 quantitative assay at the time of writing is the World Health Organization International Reference Reagent (89/666; WHO IRR) prepared in the 1980s and not validated for all current methodologies. METHOD: The WHO IRR was analysed for Hb A2 concentration by 52 laboratories using a representative range of high-performance liquid chromatography and capillary electrophoresis analysers. The results of the analysis were compared to those of a whole blood EQA specimen of similar Hb A2 concentration, distributed in the same week. RESULTS: The mean Hb A2 value obtained for the WHO IRR was 5.17%, compared to the assigned value of 5.3%. The range of results returned was wide (4.0%-6.2%), with differences in the results observed by between and within analyser groups. A similar range of results was seen with the whole blood sample, although the bias observed between analyser types was different from that seen with the WHO IRR. CONCLUSION: The results may indicate a lack of commutability of the WHO IRR material, resulting from deterioration, matrix effects or changes in reagent formulation or calibration parameters. Further examination of the suitability of the WHO IRR (89/666) for continued use is required.

Clinical outcomes in children with sickle cell disease living in England: a neonatal cohort in East London.

BACKGROUND AND OBJECTIVES: We investigated outcomes in a UK neonatal cohort as a benchmark for care of children with sickle cell disease (SCD). DESIGN AND METHODS: Two-hundred and fifty-two children (180 with hemoglobin [Hb] SS, 64 with HbSC, and 8 with HbS/beta thalassemia), identified during 1983-2005 by universal birth screening in East London, were followed in a hospital and community-based program which included penicillin V prophylaxis from 3 months of age, 23-valent pneumococcal polysaccharide vaccine from 1993, conjugate pneumococcal vaccine from 2002 and transcranial Doppler screening from 1991. RESULTS: At the end of 2005, there were 2158 patient years of observation. The median age of the patients was 7.8 (interquartile range 3.3-13.0) years, and 2.8% of those enrolled had been lost to follow-up. The estimated survival of children with HbSS at 16 years was 99.0% (95% confidence interval, CI, 93.2 to 99.9%) and pneumococcal sepsis rate was 0.3 (95% CI 0.1-0.8) episodes per 100 patient-years. The risk of overt stroke was 4.3% (95%CI 1.5 to 11.4%) and could be further reduced by transcranial Doppler screening from infancy and transfusing all children with high-risk scans. No deaths, strokes or episodes of pneumococcal sepsis were observed in children with HbSC or HbS/beta thalassemia. The mortality rates from HbSS were significantly lower than those in other reported cohorts. INTERPRETATION AND CONCLUSIONS: Mortality in childhood SCD can virtually be eliminated in a well-resourced health service setting linking community-based care with a specialized, hospital-based center. SCD continues to cause substantial morbidity from acute complications and chronic organ damage. We recommend setting up of clinical networks to optimize the management of SCD.

Hb Bart's in cord blood: an accurate indicator of alpha-thalassemia.

We quantified Hb Bart's (gamma4) levels by high performance liquid chromatography (HPLC) in 103 fresh cord blood samples from Homerton Hospital, East London, UK. The alpha-globin gene arrangement was determined by Southern blot hybridization and genomic sequence analysis of the alpha-globin genes. The cord blood Hb Bart's levels ranged from 0.5 to 11.9% of total hemoglobin (Hb) and were arranged into three categories: i) levels below 1.5%; ii) levels between 1.5 and 5.7%; iii) levels above 6.1%. These corresponded to a normal alpha-globin genotype, a single deleted/inactivated alpha-globin gene and two deleted/inactivated alpha-globin genes, respectively. The study identified the 3.7 kb and 20.5 kb alpha-thalassemia (thal) deletions, three non deletional alpha-thal mutations and a novel alpha-globin gene rearrangement. Hb Bart's screening of fresh umbilical cord blood is an effective method to evaluate globin chain imbalance. This strategy could be utilized to screen populations for the incidence of alpha-thal and also to identify rare or new molecular lesions that reduce alpha-globin gene expression.

Windy weather and low humidity are associated with an increased number of hospital admissions for acute pain and sickle cell disease in an urban environment with a maritime temperate climate.

Sickle cell disease (SCD) is characterised by intermittent episodes of acute severe pain, related to vaso-occlusion. Environmental factors are thought to play an important role, and studies in tropical countries have suggested that cold and rainy seasons are associated with increased episodes of acute pain. We have studied retrospectively the number of admissions with acute pain and SCD to King's College Hospital, London, together with daily meteorological records collected locally. Data from 1400 d and 1047 separate admissions were analysed. Increased admissions were significantly associated with increased wind speed and low humidity, but showed no relationship to temperature, rainfall or barometric pressure. The strongest effect was for (maximum wind speed)/humidity, with 464 admissions on days in the lowest two quartiles of this parameter and 582 in the highest quartiles. The effect of high wind and low humidity is likely to be related to skin cooling.