Bernard A. Davis

Myocardial iron clearance during reversal of siderotic cardiomyopathy with intravenous desferrioxamine: a prospective study using T2* cardiovascular magnetic resonance.

Heart failure from iron overload causes 71% of deaths in thalassaemia major, yet reversal of siderotic cardiomyopathy has been reported. In order to determine the changes in myocardial iron during treatment, we prospectively followed thalassaemia patients commencing intravenous desferrioxamine for iron‐induced cardiomyopathy during a 12‐month period. Cardiovascular magnetic resonance assessments were performed at baseline, 3, 6 and 12 months of treatment, and included left ventricular (LV) function and myocardial and liver T2*, which is inversely related to iron concentration. One patient died. The six survivors showed progressive improvements in myocardial T2* (5·1 ± 1·9 to 8·1 ± 2·8 ms, P = 0·003), liver iron (9·6 ± 4·3 to 2·1 ± 1·5 mg/g, P = 0·001), LV ejection fraction (52 ± 7·1% to 63 ± 6·4%, P = 0·03), LV volumes (end diastolic volume index 115 ± 17 to 96 ± 3 ml, P = 0·03; end systolic volume index 55 ± 16 to 36 ± 6 ml, P = 0·01) and LV mass index (106 ± 14 to 95 ± 13, P = 0·01). Iron cleared more slowly from myocardium than liver (5·0 ± 3·3% vs. 39 ± 23% per month, P = 0·02). These prospective data confirm that siderotic heart failure is often reversible with intravenous iron chelation with desferrioxamine. Myocardial T2* improves in concert with LV volumes and function during recovery, but iron clearance from the heart is considerably slower than from the liver.

Noncontrast myocardial T1 mapping using cardiovascular magnetic resonance for iron overload

To explore the use and reproducibility of magnetic resonance‐derived myocardial T1 mapping in patients with iron overload.

Recent Insights into Interactions of Deferoxamine with Cellular and Plasma Iron Pools: Implications for Clinical Use

Abstract: Despite the availability of deferoxamine (DFO) for more than three decades, its rates of interaction with cellular iron pools in different tissues, and the effects of its pharmacokinetics on the interaction with plasma iron pools, remain incompletely understood. The positive charge of DFO, together with the negative resting potential in vertebrate cells, favors cellular uptake, whereas the low lipophilicity and high molecular weight counter this effect. The findings presented suggest a facilitated uptake of DFO into hepatocytes, being several hundred‐fold faster than into red cells. Antibodies that selectively recognize ferrioxamine (FO) show that initial hepatocellular iron chelation is cytosolic, but later transposes to lysosomal and ultimately canalicular compartments. Strong FO staining is visible in myocytes within 4‐8 h after commencing a subcutaneous DFO infusion, indicating effective chelation of myocyte iron. A methodology was developed to study the interaction of DFO and its metabolites with plasma iron pools by stabilizing DFO with aluminum ions, thereby preventing iron shuttling from non‐transferrin‐bound iron (NTBI) onto DFO after plasma collection. DFO removes only about a third of NTBI rapidly, and NTBI is rarely cleared completely. Increasing DFO dosing does not increase NTBI removal, but instead leads to a greater rebound in NTBI on cessation of intravenous infusion. Thus, intermittent infusions of high‐dose DFO are less desirable than continuous infusions at low doses, particularly in high‐risk patients. Here the benefits of continuous DFO on heart function occur before changes in T2*‐visible storage iron, consistent with early removal of a toxic labile iron pool within myocytes.

Guideline on the management of acute chest syndrome in sickle cell disease

1. Department of Haematology, Guy’s and St Thomas’ NHS Foundation Trust 2. Lane Fox Respiratory Unit, St Thomas’ Hospital, Guy’s and St Thomas’ NHS Foundation Trust 3. Department of Haematology, North Middlesex Hospital 4. Department of Paediatric Haematology, Bristol Royal Hospital for Children 5. Department of Haematological Medicine, King’s College Hospital 6. Department of Haematology, Whittington Hospital

Results of Long Term Iron Chelation Treatment with Deferoxamine

Deferoxamine (DFO), a naturally occurring, hexadentate siderophore derived fromStreptomyces pilosuswas discovered by chance in 1960. During earlier work by the Swiss Federal Institute of Technology and Ciba Ltd on isolation of the iron-containing antibiotic ferrimycin fromStreptomyces griseoflavusit had become apparent that the antibiotic effect of ferrimycin was abolished by culture filtrates from other actinomycetes (Zahner, 1992). Further work revealed that one of the main ferrimycin antagonists was ferrioxamine B, the principal siderophore produced byStreptomyces pilosus(Zahner, 1992). Following its isolation by Bickel in May 1960, ferrioxamine B was initially investigated as a potential iron donor in iron deficient subjects. However, when preliminary studies in a human volunteer revealed that it was excreted intact in the urine without losing or exchanging its iron, the idea arose that an iron-free ferrioxamine might potentially chelate iron and eliminate it in the urine in the form of ferrioxamine. Later that year, the iron-free preparation, deferoxamine B (DFO) was synthesised by Bickel (Keberle, 1992). Afterin vitroandin vivopre-clinical studies had shown it to be a powerful and specific chelator of storage iron, DFO was successfully tested in a patient suffering from severe hemochromatosis in 1961 and introduced into clinical use the following year, initially as an antidote to acute iron poisoning (Keberle, 1992).

Prospective study of histomorphometry, biochemical bone markers and bone densitometric response to pamidronate in β-thalassaemia presenting with osteopenia-osteoporosis syndrome

This study aimed to evaluate bone remodelling disorders in thalassaemia by using pamidronate (PD) infusion with or without hormone replacement therapy (HRT) as a diagnostic‐therapeutic tool. In this prospective study, 24 adult thalassaemia major (TM) and 10 thalassaemia intermedia (TI) patients received either PD and HRT or HRT only (controls) for 3 years. Eugonadal patients with TI had PD only. Bone remodelling was assessed by dual energy X ray absorptiometry (DXA scan), type 1‐collagen biochemical bone markers (BBM) and histomorphometry of iliac crest biopsy before and after PD. As a group, thalassaemics had a significant improvement in spinal and femoral bone mineral density Z scores following PD (P < 0·01) compared to the controls. Although BBM were comparable pre‐therapy, they were significantly lower in the PD cohort (P < 0·001) compared to the control group. All patients had osteopenia, diminished osteoid formation and bone volume on histomorphometry pre‐therapy with high turnover bone disease (HTO) in TM and low‐turnover disease (LTO) in TI. In TM, bone volume improved significantly, whereas TI patients showed little or no response to PD. In conclusion, histomorphometry data suggest that TM patients have a distinct pathology of high turnover bone disease compared to TI patients, who have low‐turnover disease.

Retinoic Acid Syndrome: Pulmonary Computed Tomography (CT) Findings

We report the pulmonary computed tomography (CT) findings in three patients with acute promyelocytic leukaemia who developed the retinoic acid syndrome following all-trans retinoic acid (ATRA) therapy. The most consistent CT findings were small, irregular peripheral nodules in the lung fields and pleural effusions. Two of the patients also showed evidence of reticular and ground glass shadowing as well as abnormal anterior mediastinal soft tissue. We report for the first time an association between ATRA and pneumothorax. We conclude that routine CT scanning may provide a sensitive means of early detection or monitoring of the syndrome and thereby may facilitate its management.

Guidelines on red cell transfusion in sickle cell disease Part II: indications for transfusion

Bernard A. Davis, Shubha Allard, Amrana Qureshi, John B. Porter, Shivan Pancham, Nay Win, Gavin Cho and Kate Ryan, on behalf of the British Society for Haematology Whittington Health, Barts Health NHS Trust & NHS Blood and Transplant, London, Oxford University Hospitals NHS Foundation Trust, Oxford, University College London Hospitals NHS Foundation Trust, London, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, NHS Blood and Transplant, London, and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK

Guidelines on red cell transfusion in sickle cell disease. Part I: principles and laboratory aspects

Bernard A. Davis, Shubha Allard, Amrana Qureshi, John B. Porter, Shivan Pancham, Nay Win, Gavin Cho, Kate Ryanon behalf of the British Committee for Standards in Haematology Whittington Health, Barts Health NHS Trust & NHS Blood and Transplant, London, Oxford University Hospitals NHS Foundation Trust, Oxford, University College London Hospitals NHS Foundation Trust, London, Sandwell and West Birmingham Hospitals NHS Trust, Birmingham, NHS Blood and Transplant, London, and Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK

History of myocardial iron loading is a strong risk factor for diabetes mellitus and hypogonadism in adults with β thalassemia major

Endocrinopathies are common complications of transfusional hemosiderosis among patients with β thalassemia major (TM). Previous studies had shown associations between some endocrinopathies and iron overload of the myocardium, liver and/or endocrine organs as assessed by MRI techniques. This retrospective analysis of 92 patients with TM (median age 36 yr) from a tertiary adult thalassemia unit in UK aimed to determine independent risk factors associated with endocrinopathies among these patients. Unlike previous studies, longitudinal data on routine measurements of iron load [worst myocardial and liver T2* values since 1999, worst LIC by MRI‐R2 since 2008 and average 10‐yr serum ferritin (SF)] up to April 2010 together with demographic features and age of initiating chelation were analyzed for associations with endocrinopathies. The most common endocrinopathies in this cohort were hypogonadism (67%) and diabetes mellitus (DM) (41%), and these were independently associated with myocardial T2* <20 ms (P < 0.001 and P = 0.008, respectively) and increased age (P = 0.002 and P = 0.016, respectively). DM and hypogonadism were independently associated with average SF >1250 μg/L (P = 0.003) and >2000 μg/L (P = 0.047), respectively. DM was also associated with initial detection of abnormal myocardial T2* at an older age (30 yr vs. 24 yr, P = 0.039). An abnormal myocardial T2* may therefore portend the development of DM and hypogonadism in patients with TM.