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Summary With the developing COVID‐19 pandemic, patients with inherited anaemias require specific advice regarding isolation and changes to usual treatment schedules. The National Haemoglobinopathy Panel (NHP) has issued guidance on the care of patients with sickle cell disease, thalassaemia, Diamond Blackfan anaemia (DBA), congenital dyserythropoietic anaemia (CDA), sideroblastic anaemia, pyruvate kinase deficiency and other red cell enzyme and membrane disorders. Cascading of accurate information for clinicians and patients is paramount to preventing adverse outcomes, such as patients who are at increased risk of fulminant bacterial infection due to their condition or its treatment erroneously self‐isolating if their fever is mistakenly attributed to a viral cause, delaying potentially life‐saving antibiotic therapy. Outpatient visits should be minimised for most patients, however some, such as first transcranial dopplers for children with sickle cell anaemia should not be delayed as known risk of stroke will outweigh the unknown risk from COVID‐19 infection. Blood transfusion programmes should be continued, but specific changes to usual clinical pathways can be instituted to reduce risk of patient exposure to COVID‐19, as well as contingency planning for possible reductions in blood available for transfusions. Bone marrow transplants for these disorders should be postponed until further notice. With the current lack of evidence on the risk and complications of COVID‐19 infection in these patients, national data collection is ongoing to record outcomes and eventually to identify predictors of disease severity, particularly important if further waves of infection travel through the population.

Frank iron deficiency has been associated with a wide range of cardiac and pulmonary abnormalities including non-ischaemic cardiomyopathy. Iron deficiency anaemia and isolated iron deficiency are well-defined adverse prognostic factors in non-ischaemic cardiac failure. Furthermore, iron-deficient patients in chronic heart failure with a serum ferritin of

Allogeneic haematopoietic stem cell transplant (HSCT) recipients are at increased risk of morbidity and mortality, often due to the development of acute or chronic graft-versus-host disease (GVHD). Low numbers or proportions of regulatory T cells (Tregs) have been reported in patients who develop GVHD. We undertook a systematic review of studies that reported the Treg composition of HSCT grafts in patients with haematological malignancies. Fourteen eligible studies were identified, eight of which stratified patients by Tregs (absolute dose or ratio to CD3+ or CD4+ cells). Meta-analyses showed that high levels of Tregs in the grafts were associated with improved overall survival [hazard ratio (HR) 0·42, 95% confidence interval (CI) 0·23-0·74, P = 0·003, 2 studies], with a significant reduction in non-relapse mortality (HR 0·30, 95% CI 0·14-0·64, P = 0·002, 2 studies) and a reduced risk of acute GVHD (relative risk (RR) 0·59, 95% CI 0·40-0·89, P = 0·01, 6 studies). The consistency of these findings strongly suggests that the Treg composition of HSCT grafts has a powerful effect on the success of allogeneic HSCT. The major challenge is to translate these findings into better selection of allografts and future donors to provide a substantial improvement in allogeneic HSCT outcomes and practice.

Summary Human induced pluripotent stem cells (hiPSCs) are being considered for use in understanding haematopoietic disorders and as a potential source of in vitro manufactured red cells. Here, we show that hiPSCs are able to recapitulate various stages of developmental erythropoiesis. We show that primitive erythroblasts arise first, express CD31+ with CD235a+, embryonic globins and red cell markers, but fail to express the hallmark red cell transcripts of adult erythropoiesis. When hiPSC-derived CD45+ CD235a− haematopoietic progenitors are isolated on day 12 and further differentiated on OP9 stroma, they selectively express CD36+ and CD235a+, adult erythroid transcripts for transcription factors (e.g., BCL11A, KLF1) and fetal/adult globins (HBG1/2, HBB). Importantly, hiPSC- and cord-derived CD36+ CD235a+ erythroblasts show a striking homology by transcriptome array profiling (only 306 transcripts with a 2Log fold change >1·5- or 2·8-fold). Phenotypic and transcriptome profiling of CD45+CD117+CD235a+ pro-erythroblasts and terminally differentiated erythroblasts is also provided, including evidence of a HbF (fetal) to HbA (adult) haemoglobin switch and enucleation, that mirrors their definitive erythroblast cord-derived counterparts. These findings provide a molecular roadmap of developmental erythropoiesis from hiPSC sources at several critical stages, but also helps to inform on their use for clinical applications and modelling human haematopoietic disease.

This special issue of the British Journal of Haematology highlights many leading haematological topics in Lower and Middle Income Countries (LMICs) or perhaps more engagingly – Global Haematology. The review articles are based, largely but not exclusively, on invited talks in Global Haematology given at the joint British Society of Haematology/International Society of Haematology Scientific Meeting held in Glasgow in 2016. These sessions reflect a growing emphasis on post-graduate medicine and haematology across the world. The realisation that specialist knowledge, research and care can now make a real contribution to health care in LMICs have allowed medical societies to reach out and encourage those working across Africa and Asia. Fittingly, both the American and British Societies of Haematology have recently developed programmes to encourage and support education, training and research in Global Haematology.

Philadelphia chromosome/BCR-ABL1 positive chronic myeloid leukaemia (CML) can be successfully treated with Glivec (Imatinib), which is available free of cost through the Glivec International Patient Assistance programme (GIPAP) to patients with proven CML without means to pay for the drug. We review the acquired mutations in the tyrosine kinase encoded by the BCR-ABL1 gene underlying Glivec failure or resistance in a cohort of 388 imatinib-treated CML patients (149 Female and 239 male) registered between February 2003 and June 2016 in Nepal. Forty-five patients (11 female 34 male) were studied; 18 different BCR-ABL1 mutations were seen in 33 patients. P-loop mutation, Kinase domain and A-loop mutations were seen in 9, 16 and 4 patients respectively. Other mutations were seen in five patients. A T315I mutation was the most common mutation, followed by F359V and M244V. Sixteen mutations showed intermediate activity to complete resistance to Glivec. Among the 45 patients evaluated for BCR-ABL1 mutations, 4 were lost to follow-up, 14 died and 27 are still alive. Among the surviving patients, 16 are receiving Nilotinib, 5 Dasatinib and 3 Ponatinib, while 3 patients were referred to India, one of who received allogenic bone marrow transplantation. Understanding the spectrum of further acquired mutations in BCR-ABL1 may help to choose more specific targeted tyrosine kinase inhibitors that can be provided by GIPAP.

Haematology and blood transfusion, as a clinical and laboratory discipline, has a far-reaching impact on healthcare both through direct patient care as well as provision of laboratory and transfusion services. Improvement of haematology and blood transfusion may therefore be significant in achieving advances in health in Africa. In 2005, Tanzania had one of the lowest distributions of doctors in the world, estimated at 2·3 doctors per 100 000 of population, with only one haematologist, a medical doctor with postgraduate medical education in haematology and blood transfusion. Here, we describe the establishment and impact of a postgraduate programme centred on Master of Medicine and Master of Science programmes to build the capacity of postgraduate training in haematology and blood transfusion. The programme was delivered through Muhimbili University of Health and Allied Sciences (MUHAS) with partnership from visiting medical and laboratory staff from the UK and complemented by short-term visits of trainees from Tanzania to Haematology Departments in the UK. The programme had a significant impact on the development of human resources in haematology and blood transfusion, successfully training 17 specialists with a significant influence on delivery of health services and research. This experience shows how a self-sustaining, specialist medical education programme can be developed at low cost within Lower and Middle Income Countries (LMICs) to rapidly enhance delivery of capacity to provide specialist services.

The Glivec International Patient Assistance Programme makes Glivec (Imatinib mesylate) available to Philadelphia chromosome/BCR-ABL1 positive patients with chronic myeloid leukaemia (CML) in Lower and Middle Income Countries (LMIC). We have established a large cohort of 211 CML patients who are eligible for Imatinib, in Kathmandu, Nepal. Thirty-one patients were lost to follow-up. We report on 180 CML patients with a median age of 38 years (range 9-81). Of these 180 patients, 162 underwent cytogenetic testing and 110 were investigated by reverse transcription polymerase chain reaction. One hundred and thirty-nine of the 180 patients (77·2%) had at least one optimal response. Taken together, our cohort has a 95% overall survival rate and 78% of the patients were still taking Glivec at a median time of 48·8 months (range 3-140 months). The number of patients who actually failed therapy, as defined by the LeukaemiaNet 2013 criteria, was 39 (21·7%). While our cohort has some differences with those in North America or Europe, we have shown Glivec is effective in inducing an optimal response in our patients in Nepal and that it is possible to deliver a clinical service for CML patients using tyrosine kinase inhibitors in resource-poor settings.

Fetomaternal alloimmune thrombocytopenia (FMAIT) is the most common cause of severe neonatal thrombocytopenia in otherwise well, term infants. First pregnancies are often severely affected. This descriptive, population-based national study was undertaken in order to inform the case for antenatal screening. Cases were identified using three sources and capture-recapture techniques used to generate a robust incidence estimate. One hundred and seventy three cases were identified between October 2006 and September 2008. An extra 20 cases were estimated from capture-recapture analysis, giving an estimated incidence of clinically detected FMAIT of 12??4 cases per 100???000 total births (95\%confidence interval: 10??7, 14??3). Fifty-two cases (30\%) were known at the start of pregnancy; 120 (70\%) were unknown (n=115) or unrecognized (n=5). Unknown cases were more likely to experience a haemorrhagic complication (67\% vs. 5\%) (P

Human induced pluripotent stem cells (hiPSCs), like embryonic stem cells, are under intense investigation for novel approaches to model disease and for regenerative therapies. Here, we describe the derivation and characterization of hiPSCs from a variety of sources and show that, irrespective of origin or method of reprogramming, hiPSCs can be differentiated on OP9 stroma towards a multi-lineage haemo-endothelial progenitor that can contribute to CD144(+) endothelium, CD235a(+) erythrocytes (myeloid lineage) and CD19(+) B lymphocytes (lymphoid lineage). Within the erythroblast lineage, we were able to demonstrate by single cell analysis (flow cytometry), that hiPSC-derived erythroblasts express alpha globin as previously described, and that a sub-population of these erythroblasts also express haemoglobin F (HbF), indicative of fetal definitive erythropoiesis. More notably however, we were able to demonstrate that a small sub-fraction of HbF positive erythroblasts co-expressed HbA in a highly heterogeneous manner, but analogous to cord blood-derived erythroblasts when cultured using similar methods. Moreover, the HbA expressing erythroblast population could be greatly enhanced (44·0 ± 6·04%) when a defined serum-free approach was employed to isolate a CD31(+) CD45(+) erythro-myeloid progenitor. These findings demonstrate that hiPSCs may represent a useful alternative to standard sources of erythrocytes (RBCs) for future applications in transfusion medicine.

Fetomaternal alloimmune thrombocytopenia (FMAIT) is the most common cause of severe neonatal thrombocytopenia in otherwise well, term infants. First pregnancies are often severely affected. This descriptive, population-based national study was undertaken in order to inform the case for antenatal screening. Cases were identified using three sources and capture-recapture techniques used to generate a robust incidence estimate. One hundred and seventy three cases were identified between October 2006 and September 2008. An extra 20 cases were estimated from capture-recapture analysis, giving an estimated incidence of clinically detected FMAIT of 12·4 cases per 100 000 total births (95%confidence interval: 10·7, 14·3). Fifty-two cases (30%) were known at the start of pregnancy; 120 (70%) were unknown (n=115) or unrecognized (n=5). Unknown cases were more likely to experience a haemorrhagic complication (67% vs. 5%) (P0·001) and more likely to have an intracranial haemorrhage (20% vs. 4%) (P=0·014) than known cases receiving antenatal management. In view of the incidence of severe disease identified, further assessment of the case for antenatal screening is important. There were a number of cases in which the significance of a history of FMAIT in a previous sibling was not recognized and there is a need to raise awareness of the importance of this diagnosis.