The online version of this article has a Supplementary Appendix. BackgroundFollowing a clinical evaluation of deferasirox (Exjade ® ) it was concluded that, in addition to baseline body iron burden, ongoing transfusional iron intake should be considered when selecting doses. The 1-year EPIC study, the largest ever investigation conducted for an iron chelator, is the first to evaluate whether fixed starting doses of deferasirox, based on transfusional iron intake, with dose titration guided by serum ferritin trends and safety markers, provides clinically acceptable chelation in patients (aged ≥2 years) with transfusional hemosiderosis from various types of anemia. Design and MethodsThe recommended initial dose was 20 mg/kg/day for patients receiving 2-4 packed red blood cell units/month and 10 or 30 mg/kg/day was recommended for patients receiving less or more frequent transfusions, respectively. Dose adjustments were based on 3-month serum ferritin trends and continuous assessment of safety markers. The primary efficacy end-point was change in serum ferritin after 52 weeks compared with baseline. ResultsThe 1744 patients enrolled had the following conditions; thalassemia (n=1115), myelodysplastic syndromes (n=341), aplastic anemia (n=116), sickle cell disease (n=80), rare anemias (n=43) and other transfused anemias (n=49). Overall, there was a significant reduction in serum ferritin from baseline (-264 ng/mL; P<0.0001), reflecting dosage adjustments and ongoing iron intake. The most common (>5%) adverse events were gastrointestinal disturbances (28%) and skin rash (10%). ConclusionsAnalysis of this large, prospectively collected data set confirms the response to chelation therapy across various anemias, supporting initial deferasirox doses based on transfusional iron intake, with subsequent dose titration guided by trends in serum ferritin and safety markers (clinicaltrials.gov identifier: NCT00171821).

An antithrombin III mutation database was collated and published in L99L by a group of investigators working on the molecular basis of antithrombin III deficiency (1). Soon after, under the auspices of the ISTH SSC, an Antithrombin III Working Party was formed of those involved in the preparation of the database, with the instruction to report to the "Thrombin and its Inhibitors" SSC on the developments in this and related areas. This document is one outcome of the work of the Antithrombin III Working Party and is a partial report of the deliberations of the "Thrombin and its Inhibitors" SSC Meeting held in Munich, July 1992. Other items discussed at this meeting included the nomenclature of the plasma coagulation inhibitors. Three alternative names were considered for this inhibitor, antithrombin III, antithrombin and thrombin inhibitor I. No unanimous view emerged regarding the name, other than the rejection of the term thrombin inhibitor I. For this report, the historical name antithrombin III will be used, despite the preference for anti. thrombin by the majority of the authors of this database. This is in deference to the journal, Thrombosis and Haemostasis, pending any final decision of the SSC regarding nomenclature. The intention behind the production and updating of the antithrombin III database has been to provide a readily accessible and up-to-date source of known mutations of antithrombin III. The complex effects of some mutations on structure/function relationships of the protein can only be indicated. For more information on this and on possible mechanisms involved in gene mutation (see below for brief consideration of mutations involving CpG dinucleotides), the reader is referred to the original papers and to several reviews in this area (2-6).

A study of the molecular pathology of beta thalassaemia in the Asian Indian immigrant population in the U.K. included 37 patients with thalassaemia major and 14 with thalassaemia intermedia. Using a combination of oligonucleotide probe hybridization and restriction endonuclease analysis the mutations in 100/102 (98%) of the beta thalassaemia genes were characterized. Nine different types were found, of which six are associated with beta zero, one with severe beta+ and two with mild beta+ thalassaemia. Comparison of the beta-globin gene cluster haplotypes, alpha globin genotypes and beta gene mutations of the thalassaemia major group with the thalassaemia intermedia group suggests that the co-inheritance of a high Hb F determinant associated with the - + - + + 5' beta haplotype and the inheritance of a mild beta-thalassaemia mutation are the major ameliorating factors of disease severity in Asian Indians. In comparison with other population groups. beta thalassaemia in Asian Indians is not associated with one or two predominant mutations. Despite this, prenatal diagnosis by direct detection is possible in the majority of families by restriction analysis and a limited number of oligonucleotide probes since the majority of severely affected individuals are homozygous for a single mutation. The characterization of these mutations should be useful for the planning of prenatal diagnosis programmes for beta thalassaemia in other Asian Indian communities.