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Blood transfusion is an integral component in the management of children and adults with sickle cell disease (SCD). Concerns about blood safety due to the high risk of bloodborne infections in sub-Saharan Africa limits the application of this cost-effective strategy in the management of individuals with SCD. In a single-centre, retrospective, longitudinal study in southwest Nigeria, we hypothesised that the use of stringent blood donor selection, along with very sensitive enzyme-linked immunosorbent assay (ELISA) screening methods would reduce transfusion-transmitted infections (TTIs). Among 45 002 eligible blood donors at the Lagos University Teaching Hospital in Nigeria, over a 5-year review period (2015-2019), the seroprevalence rate of viral TTIs was 9.83%. The seroprevalence rates for human immunodeficiency, hepatitis B, and hepatitis C viruses were 1.37%, 6.2%, and 2.25% respectively. Among 172 children with SCD, 71% (122/172) on regular blood transfusion and 29% (50/172) who had never been transfused or had less than two transfusions per lifetime, none acquired any TTIs using our enhanced screening approach during the study period. Thus, safe blood transfusion practices can be provided for children with SCD in sub-Saharan Africa with the use of stringent donor selection protocols and fourth-generation ELISA kits for TTI screening.

Summary Pathogen‐reduced (PR) platelets are routinely used in many countries. Some studies reported changes in platelet and red blood cell (RBC) transfusion requirements in patients who received PR platelets when compared to conventional (CONV) platelets. Over a 28‐month period we retrospectively analysed platelet utilisation, RBC transfusion trends, and transfusion reaction rates data from all transfused adult patients transfused at the Yale‐New Haven Hospital, New Haven, CT, USA. We determined the number of RBC and platelet components administered between 2 and 24, 48, 72 or 96 h. A total of 3767 patients received 21 907 platelet components (CONV = 8912; PR = 12 995); 1,087 patients received only CONV platelets (1578 components) and 1,466 patients received only PR platelets (2604 components). The number of subsequently transfused platelet components was slightly higher following PR platelet components (P 0·05). Septic transfusion reactions (N = 5) were seen only after CONV platelet transfusions (P = 0·011). These results provide evidence for comparable clinical efficacy of PR and CONV platelets. PR platelets eliminated septic transfusion reactions without increased risk of other types of transfusions with only slight increase in platelet utilisation.

Post-transfusion hyperhaemolysis syndrome (PTHS) is a rare life-threatening transfusion complication reported mainly in sickle cell patients. Its pathogenesis is poorly understood. Antibody-mediated haemolysis and bystander effect have been proposed as putative mechanisms, but in half of cases, red cell antibodies are undetectable, and PTHS develops despite transfusion of cross-matched compatible RBC. An alternate hypothesis proposes activated macrophages as the main drivers of red cell destruction through direct phagocytosis. We report the histopathological findings of two patients with PTHS showing extensive macrophage expansion and erythrophagocytosis, supportive of macrophage activation driving PTHS. This supports a possible role for novel therapies that target macrophage activation.

Sickle cell disease is one of the commonest serious inherited diseases in the world, and red cell transfusion is still one of the few effective treatments for acute and chronic complications. Transfusion corrects anaemia and dilutes out the number of red cells able to cause vaso-occlusion and vascular damage. Urgent red cell transfusions are used to correct acute anaemia, treat acute chest syndrome and patients with acute neurological symptoms. We use elective transfusions preoperatively for moderate risk surgery, and in some pregnant women. There is good evidence for the use of long-term regular transfusions in primary stroke prevention, with the aim of keeping the percentage of sickle haemoglobin below 30%. Long-term transfusions are also used in secondary stroke prevention, and the management of progressive organ damage, including renal impairment and pulmonary hypertension. Blood needs to be matched for ABO, RH and Kell, although alloantibodies may still develop and require more careful, extended cross-matching. Delayed haemolytic transfusion reactions are relatively common, difficult to diagnose and manage, and potentially fatal.

Summary Anaemia is the commonest cytopenia seen in patients with myelodysplastic syndrome (MDS), and the majority of patients will require transfusion support at some point. Blood transfusions are rich in iron, which leads to the accumulation of body iron over time. It is accepted that this ultimately causes end organ damage and may impact on both morbidity and mortality. In addition, recent data has increased our interest in the subject with regard to the potential impact on stem cell transplant outcome and an anti-leukaemic effect of iron chelation therapy. There is still debate over which patients should receive iron chelation therapy, but the emergence of new diagnostic and prognostic markers in MDS may help decision making in the clinic setting.

Blood transfusion plays a prominent role in the management of patients with sickle cell disease (SCD), but causes significant iron overload. As transfusions are used to treat the severe complications of SCD, it remains difficult to distinguish whether organ damage is a consequence of iron overload or is due to the complications treated by transfusion. Better management has resulted in increased survival, but prolonged exposure to iron puts SCD patients at greater risk for iron-related complications that should be treated. The success of chelation therapy is dominated by patient adherence to prescribed treatment; thus, adjustment of drug regimens to increase adherence to treatment is critical. This review will discuss the current biology of iron homeostasis in patients with SCD and how this informs our clinical approach to treatment. We will present the clinical approach to treatment of iron overload at our centre using serial assessment of organ iron by magnetic resonance imaging.

Transfusional iron overload represents a substantial challenge in the management of patients with sickle cell disease (SCD) who receive chronic or episodic red blood cell transfusions. Iron-induced cardiomyopathy is a leading cause of death in other chronically transfused populations but rarely seen in SCD. Study objectives were to: (i) examine the extent of myocardial and hepatic siderosis using magnetic resonance imaging (MRI) in chronically transfused SCD patients, and (ii) evaluate the relationship between long-term (over the 5 years prior to enrolment) mean serum ferritin (MSF), spot-ferritin values and liver iron content (LIC) measured using MRI and liver biopsy. Thirty-two SCD patients (median age 15 years) with transfusional iron overload were recruited from two U.S. institutions. Long-term MSF and spot-ferritin values significantly correlated with LIC by MRI-R2* (r = 0·77, P

Glanzmann thrombasthenia (GT) is caused by inherited defects of the α

Transcranial Doppler (TCD) With Transfusions Changing to Hydroxyurea (TWiTCH) trial is a randomized, open-label comparison of hydroxycarbamide (also termed hydroxyurea) versus continued chronic transfusion therapy for primary stroke prevention in patients with sickle cell anaemia (SCA) and abnormal TCD. Severity and location of iron overload is an important secondary outcome measure. We report the baseline findings of abdominal organ iron burden in 121 participants. At enrollment, patients were young (9·8 ± 2·9 years), predominantly female (60:40), and previously treated with transfusions (4·1 ± 2·4 years) and iron chelation (3·1 ± 2·1 years). Liver iron concentration (LIC; 9·0 ± 6·6 mg/g dry weight) and serum ferritin were moderately elevated (2696 ± 1678 μg/l), but transferrin was incompletely saturated (47·2 ± 23·6%). Spleen R2* was 509 ± 399 Hz (splenic iron ~13·9 mg/g) and correlated with LIC (r(2) = 0·14, P = 0·0008). Pancreas R2* was increased in 38·3% of patients but not to levels associated with endocrine toxicity. Kidney R2* was increased in 80·7% of patients; renal iron correlated with markers of intravascular haemolysis and was elevated in patients with increased urine albumin-creatinine ratios. Extra-hepatic iron deposition is common among children with SCA who receive chronic transfusions, and could potentiate oxidative stress caused by reperfusion injury and decellularized haemoglobin.

Summary Delayed haemolytic transfusion reactions (DHTR) are potentially life-threatening complications in patients with sickle cell disease (SCD). Between 1 August 2008 and 31 December 2013, 220 of 637 adult patients in our centre had at least one red blood cell (RBC) transfusion in 2158 separate transfusion episodes. Twenty-three DHTR events occurred in 17 patients (13 female) including 15 HbSS, one HbSC and one HbSβ0 thalassaemia, equating to a DHTR rate of 7·7% of patients transfused. Mean interval from RBC transfusion to DHTR event was 10·1 ± 5·4 d, and typical presenting features were fever, pain and haemoglobinuria. Twenty of the 23 (87·0%) DHTR episodes occurred following transfusion in the acute setting. Notably, 11/23 (47·8%) of DHTRs were not diagnosed at the time of the event, most were misdiagnosed as a vaso-occlusive crisis. 16/23 DHTRs had ‘relative reticulocytopenia’, which was more common in older patients. Seven of 23 episodes resulted in alloantibody formation, and three caused autoantibody formation. DHTRs are a severe but uncommon complication of RBC transfusion in SCD and remain poorly recognized, possibly because they mimic an acute painful crisis. Most of the DHTRs are triggered by RBC transfusion in the acute setting when patients are in an inflammatory state.

Serial phlebotomy was performed on sixty children with sickle cell anaemia, stroke and transfusional iron overload randomized to hydroxycarbamide in the Stroke With Transfusions Changing to Hydroxyurea trial. There were 927 phlebotomy procedures with only 33 adverse events, all of which were grade 2. Among 23 children completing 30 months of study treatment, the net iron balance was favourable (-8·7 mg Fe/kg) with significant decrease in ferritin, although liver iron concentration remained unchanged. Therapeutic phlebotomy was safe and well-tolerated, with net iron removal in most children who completed 30 months of protocol-directed treatment.

Despite the significance of red blood cell (RBC) alloimmunization, the lack of standardized registries in the US has prevented the completion of large studies. Data from 3.5 years of the Recipient Epidemiology and Donor Evaluation Study-III (REDS-III) recipient database, containing information from 12 hospitals, were studied. A RBC alloantibody responder had an antibody identified at any point during the study, and a non-responder had a negative antibody screen at least 15 days post-RBC transfusion. Demographics, blood type, ICD9/10 codes, and other potential correlates were evaluated. Of 319 177 (2.07%) screened patients, 6597 had a total of 8892 clinically significant RBC alloantibodies identified, with 75% being in the Rh or Kell families. Alloimmunization was more common in females (2.38%) than males (1.68%), and in RhD negative (2.82%) than RhD positive (1.94%) patients. Age, sex, RhD status and race were associated with being a responder, and certain diagnoses (including sickle cell disease or trait, systemic lupus erythematosus, rheumatoid arthritis and myelodysplastic syndrome) were more common among responders than non-responders. Data collected in this multi-centre recipient database provide the largest RBC alloimmunized patient cohort studied in the US, with previously known demographic and disease associations of responder status confirmed, and new associations identified.

Plasma transfusions may result in transfusion reactions. We used the International Surveillance of Transfusion-Associated Reactions and Events (ISTARE) database, containing yearly reported national annual aggregate data on transfusion reactions from participating countries, to investigate risks of plasma transfusion reactions and compare transfusion reaction risks for different plasma types. We calculated risks for plasma transfusion reactions and compared transfusion reaction risks between plasma types using random effects regression on repeated measures. The ISTARE database contains data from 23 countries, reporting units issued and/or transfused and transfusion reactions observed for some portion of 7 years (2006-2012). Interquartile ranges (IQRs) of plasma transfusion reaction risks were: allergic reactions (5·6-72·2 reactions/105 units transfused); febrile non-haemolytic transfusion reactions (0-9·1); transfusion-associated circulatory overload (0-1·9); transfusion related acute lung injury (TRALI) (0-1·2); and hypotensive reactions (0-0·6). Apheresis plasma was associated with more allergic reactions [odds ratio (OR) = 1·29 (95% confidence interval: 1·19-1·40)] and hypotensive reactions [OR = 2·17 (1·38-3·41)] than whole blood-derived plasma. Pathogen-inactivated plasma was associated with fewer transfusion reactions than untreated plasma.

Evidence to support many blood transfusion policies and practices in sub-Saharan Africa (SSA) is weak or lacking. SSA cannot extrapolate from wealthy countries’ research findings because its environment, users and structures are very different and SSA has critical blood shortages. SSA needs to generate its own evidence but research funds are very scarce and need to be carefully targeted to match need. This study aimed to define this need by determining research priorities for blood services in SSA. Thirty-five stakeholders representing diverse blood services’ interests and expertise participated in a workshop. An adapted ‘consensus development method’ was used to identify, agree and justify research priorities under five themes through small group and plenary discussion, and cumulative voting. Research priorities covered traditional research areas, such as clinical use of blood and infection screening, but also highlighted many new, under-researched topics, mostly concerning blood service ‘systems’, such as economics, blood components and regulation. Lack of electronic information management systems was an important hindrance to the blood services’ ability to generate robust research data. This study has identified and prioritised novel research that will help blood services in SSA to address their own needs including their most urgent problem: the lack of access to adequate blood supplies. To catalyse this research blood services in SSA need to enhance their capacity to conduct, commission and manage research and to strengthen their collaborations within and beyond Africa.

This review outlines the effectiveness and safety of 10 different regimens for controlling iron overloading in thalassaemia major (TM). For each treatment, the strength of the evidence was documented according to the guidelines of the American College of Cardiology and the American Heart Association. Serum ferritin (SF), liver iron concentration (LIC), heart T2* signal, heart damage and survival were used to assess effectiveness. Five chelation regimens out of 10 showed Level A Evidence in controlling iron overloading, as determined by SF levels and LIC. Three out of 10 chelation regimens were able to control heart iron levels, as determined by T2* signals with Level A Evidence. Two chelation regimens were able to improve/reverse heart damage and four increased of survival with Level B Evidence. These advances mean that the current survival of TM patients is now similar to that of thalassaemia intermedia patients.

'Wrong blood in tube' (WBIT) errors, where the blood in the tube is not that of the patient identified on the label, may lead to catastrophic outcomes, such as death from ABO-incompatible red cell transfusion. Transfusion is a multistep, multidisciplinary process in which the human error rate has remained unchanged despite multiple interventions (education, training, competency testing and guidelines). The most effective interventions are probably the introduction of end-to-end electronic systems and a group-check sample for patients about to receive their first transfusion, but neither of these eradicates all errors. Further longer term studies are required with assessment before and after introduction of the intervention. Although most focus has been on WBIT in relation to blood transfusion, all pathology samples should be identified and linked to the correct patient with the same degree of care. Human factors education and training could help to increase awareness of human vulnerability to error, particularly in the medical setting where there are many risk factors.

Thalassaemia is characterized by ineffective erythropoiesis and anaemia, which can precipitate bone marrow expansion and extramedullary haematopoiesis. The mainstays of treatment are blood transfusion and chelation therapy, which can cause an array of complications. Only recently, however, has pain been recognized as a clinical component of thalassaemia (Trachtenberg, et al 2010). Sixty-nine per cent of 265 participants in the Thalassaemia Clinical Research Network (TCRN) Thalassaemia Longitudinal Cohort reported bodily pain (Trachtenberg, et al 2010). Additionally, 34% of transfused thalassaemia patients participating in the TCRN Low Bone Mass Observational Study reported that transfusions helped reduce or eliminate their pain (Vogiatzi, et al 2009). We hypothesized that the effects of ineffective erythropoiesis are mitigated by transfusion and thus incidence of pain will vary throughout the transfusion cycle. The Assessment of Pain Survey study, conducted by the TCRN, was initiated to address increasing reports of pain. The primary aim of this substudy was to assess whether reports of pain vary over the transfusion cycle. Secondary aims were to assess whether the length of the transfusion cycle affects the level of pain and whether pain varies by pre-transfusion haemoglobin (Hb) level and reticulocyte count. The TCRN of the National Heart, Lung and Blood Institute is a clinical research network, funded by the National Institutes of Health (Appendix 1). The protocol was approved by the TCRN Data and Safety Monitoring Board and by the ethical review boards of all TCRN institutions. All participants signed informed consent. Transfusion-dependent subjects (≥8 transfusions within the last 12 months) with β-thalassaemia or Hb E β-thalassaemia participating in the Assessment of Pain Survey study who reported at least mild pain in the last month as measured by Brief Pain Inventory (BPI; Cleeland 2009) were enrolled. The BPI provides information on the intensity of pain and the degree to which pain interferes with function. It has been used previously to assess pain in osteoporotic thalassaemia patients and its use has been validated in cancer patients (Cleeland 2009; Dworkin, et al 2005; Keller, et al 2004; Tan, et al 2004). Subjects were stratified into two cohorts: age 18–29 years vs. 30+ years. Stratification was chosen based on observation that patients aged 30+ years tend to have more pain than younger patients (Haines, et al 2013). Target enrolment was 25–35 subjects. Subjects completed a daily pain assessment during three non-consecutive transfusion cycles, separated by at least three months and no more than four months apart. Subjects were transfused according to their clinical need; cycles lasted two to four weeks. Transfusion cycles were not altered for participation. Daily pain was assessed using the BPI Short Form (BPI-SF) by daily telephone call provided by Interactive Performance Technologies in association with Telecare Management of Pain (Cambridge, MA). The BPI-SF consists of 10 questions in which participants rate their worst, least and average pain in the past 24 h on a scale of 0–10 where 0 is “No pain” and 10 is “Pain as bad as you can imagine”. Variation over the transfusion cycle was modelled with repeated measures logistic regression (for pain prevalence) or regression (for pain severity) of time in pain, controlling for age, sex and transfusion cycle. An autoregressive [AR(1)] variance structure was assumed. Time was measured as percentage of transfusion cycle completed and quadratic effects of time were utilized. Length of transfusion cycle, pre-transfusion Hb level and reticulocyte counts were added to the model. Repeated measures models, controlling for age, were used to test for differences in reported causes of pain between patients reporting frequent (≥50% of study days) vs. infrequent pain. Thirty-two subjects enrolled, 56% were female, the mean age was 31.8 years (range, 18 – 55), and 59% were Caucasian. The average pre-transfusion Hb was 101 g/l (range, 73–128 g/l) and the average length of transfusion cycle was 23 days. Pain prevalence and severity increased with age (p 0.4), or differences over the three transfusion cycles (p>0.5). Thirty-four per cent of subjects reported pain on at least 50% of study days, confirming that pain is an important problem. Table I Pain prevalence, severity, and treatment over the thalassaemia transfusion cyclea. There was a non-significant trend towards lower prevalence of pain midway through the transfusion cycle compared to immediately pre-transfusion (31.3 vs. 42.2%, p=0.14; Figure 1, Table I). Pain reduction was more pronounced among subjects transfused less frequently (>4 weeks) (13.6 vs. 40.9%, p=0.026 for effect of length of transfusion cycle; Table I) whilst, there was no apparent variation among subjects transfused more frequently (≤2 week cycle); Table I). As fluctuation in Hb levels is greater with longer transfusion cycles, these effects may reflect improvement in anaemia and/or ineffective erythropoiesis. Figure 1 Pain prevalence over the thalassaemia transfusion cycle. Unexpectedly, prevalence of pain correlated with higher, not lower, pre-transfusion Hb (p=0.013) and also a lower reticulocyte count (p=0.05). Subjects transfused more frequently also reported more severe average pain compared to those with a longer transfusion cycle (3.8/10 for ≤2 week cycles vs. 0.7/10 for >4 weeks; p=0.031 for length of cycle). Although higher Hb could contribute to pain, it is also possible that patients are transfused more frequently in response to chronic pain or other complications. Nevertheless, it is likely that pain is multifactorial. Use of pain medications/treatments varied from 25–35% over the transfusion cycle (15–18% for those aged 18–29 years, 35–51% aged 30+ years; 14–32% for those transfused frequently, 40–50% transfused infrequently). Furthermore, midway through the transfusion cycle, pain severity was greater among subjects with frequent pain (5.1/10 vs. 0/10, p

Summary Pyruvate kinase (PK) deficiency is an iron-loading anaemia characterized by chronic haemolysis, ineffective erythropoiesis and a requirement for blood transfusion in most cases. We studied 11 patients from 10 unrelated families and found nine different disease-causing PKLR mutations. Two of these mutations - the point mutation c.878A>T (p.Asp293Val) and the frameshift deletion c.1553delG (p.(Arg518Leufs*12)) - have not been previously described in the literature. This frameshift deletion was associated with an unusually severe phenotype involving neonatal hyperferritinaemia that is not typical of PK deficiency. No disease-causing mutations in genes associated with haemochromatosis could be found. Inappropriately low levels of hepcidin with respect to iron loading were detected in all PK-deficient patients with increased ferritin, confirming the predominant effect of accelerated erythropoiesis on hepcidin production. Although the levels of a putative hepcidin suppressor, growth differentiation factor-15, were increased in PK-deficient patients, no negative correlation with hepcidin was found. This result indicates the existence of another as-yet unidentified erythroid regulator of hepcidin synthesis in PK deficiency.

Summary The Serious Hazards of Transfusion (SHOT) UK confidential haemovigilance reporting scheme began in 1996. Over the 16 years of reporting, the evidence gathered has prompted changes in transfusion practice from the selection and management of donors to changes in hospital practice, particularly better education and training. However, half or more reports relate to errors in the transfusion process despite the introduction of several measures to improve practice. Transfusion in the UK is very safe: 2·9 million components were issued in 2012, and very few deaths are related to transfusion. The risk of death from transfusion as estimated from SHOT data in 2012 is 1 in 322 580 components issued and for major morbidity, 1 in 21 413 components issued; the risk of transfusion-transmitted infection is much lower. Acute transfusion reactions and transfusion-associated circulatory overload carry the highest risk for morbidity and death. The high rate of participation in SHOT by National Health Service organizations, 99·5%, is encouraging. Despite the very useful information gained about transfusion reactions, the main risks remain human factors. The recommendations on reduction of errors through a ‘back to basics’ approach from the first annual SHOT report remain absolutely relevant today.

Summary Tremendous progress has been made in the care of individuals with sickle cell over the past several decades. Major successes have been comprehensive infection prophylaxis, prediction and prevention of stroke, and better transfusion care, the latter including both prevention of alloimmunization and treatment of iron overload. However, definitive therapies remain limited to hydroxycarbamide (hydroxyurea) and stem cell transplantation, both of which have been in use for at least two decades. Despite knowing the progressive natural history of the disease with organ dysfunction, failure, and ultimately death at a young age, definitive therapies are considered for only a small proportion of individuals. Consequently, while life expectancy has improved dramatically from the last century, the ongoing pace of advancement has slowed or stalled. We believe that it is time to broaden the use of definitive therapy for those with asymptomatic disease, being cautiously more aggressive in our approach.

Keywords: iron overload; chelation therapy; non-transfusion-dependent thalassaemia; liver iron concentration; serum ferritin

Calculations of blood group antigen immunogenicity have been based on antigen and antibody frequencies in transfused populations, with the assumption of a single red blood cell (RBC) unit exposure per patient. Given that patients are usually transfused >1 RBC unit, antigen exposures will be greater than assumed, resulting in inaccurate immunogenicity calculations. As such, the goal of this study was to modify the calculation to correct for RBC exposures. To further improve accuracy, we used an empirically-derived immunogenicity for the reference antigen, K, in calculations of absolute immunogencity and eliminated anamnestic and pre-existing antibodies (i.e., antibodies induced outside the study site) from the calculation. Alloantibody numbers for the top 12 specificities and mean RBCs (MRBC) transfused per patient were obtained from the records of a hospital transfusion service. A revised immunogenicity calculation, incorporating a correction for MRBC, was developed. This correction resulted in up to a 4-fold increase in the immunogenicity of relatively high frequency antigens, with smaller increases for lower frequency antigens, yielding the following revised immunogenicity ranking: K>Jk(a) >Lu(a) >E>P1>c>M>Le(b) >C>Le(a) >Fy(a) >S. Use of an empirical value for K immunogenicity resulted in a 1·9-fold increase in absolute immunogenicities for all antigens. In summary, the calculation of blood group antigen immunogenicity has been further refined.

Non-haemolytic transfusion reactions are the most common type of transfusion reaction and include transfusion-related acute lung injury, transfusion-associated circulatory overload, allergic reactions, febrile reactions, post-transfusion purpura and graft-versus- host disease. Although life-threatening anaphylaxis occurs rarely, allergic reactions occur most frequently. If possible, even mild transfusion reactions should be avoided because they add to patients' existing suffering. During the last decade, several new discoveries have been made in the field of allergic diseases and transfusion medicine. First, mast cells are not the only cells that are key players in allergic diseases, particularly in the murine immune system. Second, it has been suggested that immunologically active undigested or digested food allergens in a donor's blood may be transferred to a recipient who is allergic to these antigens, causing anaphylaxis. Third, washed platelets have been shown to be effective for preventing allergic transfusion reactions, although substantial numbers of platelets are lost during washing procedures, and platelet recovery after transfusion may not be equivalent to that with unwashed platelets. This review describes allergic transfusion reactions, including the above-mentioned points, and focusses on their incidence, pathogenesis, laboratory tests, prevention and treatment.

Although acute non-haemolytic febrile or allergic reactions (ATRs) are a common complication of transfusion and often result in little or no morbidity, prompt recognition and management are essential. The serious hazards of transfusion haemovigilance organisation (SHOT) receives 30-40 reports of anaphylactic reactions each year. Other serious complications of transfusion, such as acute haemolysis, bacterial contamination, transfusion-related acute lung injury (TRALI) or transfusion-associated circulatory overload (TACO) may present with similar clinical features to ATR. This guideline describes the approach to a patient developing adverse symptoms and signs related to transfusion, including initial recognition, establishing a likely cause, treatment, investigations, planning future transfusion and reporting within the hospital and to haemovigilance organisations. Key recommendations are that adrenaline should be used as first line treatment of anaphylaxis, and that transfusions should only be carried out where patients can be directly observed and where staff are trained in manging complications of transfusion, particularly anaphylaxis. Management of ATRs is not dependent on classification but should be guided by symptoms and signs. Patients who have experienced an anaphylactic reaction should be discussed with an allergist or immunologist, in keeping with UK resuscitation council guidelines.

The identification of variant Creutzfeldt-Jakob disease (vCJD) in the UK in 1996 led to significant concerns about the possibility of secondary transmission, however the prevalence of subclinical vCJD and risks of vCJD transmission by plasma are not known. In the UK, public health precautions have been implemented in all recipients of coagulation factor concentrates manufactured from UK plasma pools between 1980 and 2001. The recent demonstration of abnormal prion protein in a spleen sample at autopsy of a UK haemophilic patient who received coagulation factor concentrates to which a donor incubating vCJD had contributed most likely represents the first case of vCJD transmission by coagulation factor concentrates. We review the uncertainties that surround risk of vCJD transmission by coagulation factor concentrates, the challenges in dealing with undefined risks, the rationale behind current policies and the implementation of vCJD surveillance and risk management measures in bleeding disorder patients in the UK.

Summary The transfusion of blood products can result in a variety of consequences, including transfer of pathogens and the induction of immune responses, such as the almost invariably fatal transfusion-associated graft-versus-host disease (TA-GVHD). Exposure of blood products to c-irradiation is currently the standard of care for the prevention of TA-GVHD. Regulatory, technical and clinical challenges associated with the use of c-irradiators are driving efforts to develop alternatives. Initially, pathogen reduction methods were developed to reduce the risk of microbial transmission by blood components. Through modifications of nucleic acids, these technologies interfere with the replication of both pathogens and leucocytes. These methods have been found to be as effective as c-irradiation in preventing T lymphocyte proliferation and TA-GVHD responses. Additional benefits of pathogen reduction protocols potentially include inhibition of antigen presentation, cytokine production and activation of lymphocytes.

To date, there is a lack of long-term safety and efficacy data for iron chelation therapy in transfusion-dependent patients with sickle cell disease (SCD). To evaluate the long-term safety and efficacy of deferasirox (a once-daily oral iron chelator), patients with SCD completing a 1-year, Phase II, randomized, deferoxamine (DFO)-controlled study entered a 4-year extension, continuing to receive deferasirox, or switching from DFO to deferasirox. Average actual deferasirox dose was 19·4 ± 6·3 mg/kg per d. Of 185 patients who received at least one deferasirox dose, 33·5% completed the 5-year study. The most common reasons for discontinuation were withdrawal of consent (23·8%), lost to follow-up (9·2%) and adverse events (AEs) (7·6%). Investigator-assessed drug-related AEs were predominantly gastrointestinal [including nausea (14·6%), diarrhoea (10·8%)], mild-to-moderate and transient in nature. Creatinine clearance remained within the normal range throughout the study. Despite conservative initial dosing, serum ferritin levels in patients with ≥ 4 years deferasirox exposure significantly decreased by -591 μg/l (95% confidence intervals, -1411, -280 μg/l; P = 0·027; n = 67). Long-term deferasirox treatment for up to 5 years had a clinically acceptable safety profile, including maintenance of normal renal function, in patients with SCD. Iron burden was substantially reduced with appropriate dosing in patients treated for at least 4 years.

Cardiac and endocrine disorders are common sequelae of iron overload in transfused thalassaemia patients. Combined chelation with desferrioxamine (DFO) and deferiprone (DFP) is well tolerated and produces an additive/synergistic effect superior to either drug alone. 52 thalassaemia major patients were transitioned from DFO to combined chelation with DFO and DFP. Serum ferritin, cardiac and hepatic iron levels were monitored regularly for up to 7 years, as were cardiac and endocrine function. Patients' iron load normalized, as judged by ferritin and cardiac and hepatic magnetic resonance imaging findings. In all 12 patients receiving treatment for cardiac dysfunction, symptoms reversed following combined chelation, enabling nine patients to discontinue heart medications. In the 39 patients with abnormal glucose metabolism, 44% normalized. In 18 requiring thyroxine supplementation for hypothyroidism, 10 were able to discontinue, and four reduced their thyroxine dose. In 14 hypogonadal males on testosterone therapy, seven stopped treatment. Of the 19 females, who were hypogonadal on DFO monotherapy, six were able to conceive. Moreover, no patients developed de novo cardiac or endocrine complications. These results suggest that intensive combined chelation normalized patients' iron load and thereby prevented and reversed cardiac and multiple endocrine complications associated with transfusion iron overload.

There have been four highly probable instances of variant Creutzfeldt-Jakob disease (vCJD) transmission by non-leucocyte depleted red cell concentrates and it is now clear that the infectious agent is transmissible by blood components. To date there in no reported evidence that the infectious agent has been transmitted by fractionated plasma products, e.g. factor VIII concentrate. This review outlines current and potential risk management strategies including donor deferral criteria, the potential for donor screening, blood component processing and prion reduction filters, plasma product manufacture and the difficulties in identification and notification of those considered 'at risk of vCJD for public health purposes'.

A platelet cross-matching procedure has been assessed for selecting compatible donors for alloimmunized patients. This confirms the clinical value of combining an indirect platelet immunofluorescence test (PIFT) with a lymphocytotoxicity test (LCT) in predicting the survival of single-donor platelets. There was good agreement between the PIFT cross-match and post-transfusion platelet recovery. Compatibility in the LCT alone was insufficient for platelet donor selection, as this test did not detect all antibodies affecting platelet survival. Positive LCT and PIFT cross-matches indicated the presence of HLA antibodies. Inclusion of an indirect lymphocyte immunofluorescence test (LIFT) helped to classify the platelet antibody when the LCT cross-match was negative. In such cases, parallel positive findings with the LIFT and PIFT suggested a cytotoxic-negative antibody of probable HLA specificity active against platelets. Disparity between the LIFT and PIFT was also observed; a strongly positive PIFT along with a weak reaction in the LIFT suggested that a platelet-specific antibody was responsible for the poor platelet survival in these cases. This study has also shown the presence in multitransfused patients of LIFT-positive antibodies not reacting in the LCT and PIFT, which do not affect the survival of transfused platelets. A positive granulocyte cross-match was demonstrated in patients with febrile rigors associated with compatible platelet transfusions. Splenectomy and steroids may improve the survival of incompatible platelets depending on the nature of the platelet antibody.

Vitamin D25-OH and D1-25OH levels were compared with cardiac R2* (1/T2*), left ventricular ejection fraction (LVEF), age, ferritin and liver iron in 24 thalassaemia major patients. Vitamin D25-OH levels were reduced in 13/24 patients while vitamin D1-25OH levels were often elevated. Vitamin D25-OH levels decreased with age (r(2) = 0.48) and with liver iron (r(2) = 0.20). Cardiac R2* was inversely related with the ratio of D25-OH to D1-25OH levels (r(2) = 0.42). LVEF was also proportional to the D25-OH/D1-25OH ratio (r(2) = 0.49). Vitamin D deficiency may be associated with cardiac iron uptake and ventricular dysfunction in thalassaemia major patients.

The ability to quantitate transfusional iron overload is crucial for determining the need for and the efficacy of chelation therapy in patients with long-standing transfusion-dependent anaemias. We evaluated the usefulness of some indirect measures of iron overload in estimating the iron concentration in the liver--the most important iron storage organ--in 26 non-chelated adult non-thalassaemic patients. Liver iron concentration was determined non-invasively by magnetic resonance imaging (MRI). The standard error of the estimated liver iron concentration was 80 mumol Fe/g dried liver tissue when using the number of transfused blood units, and 93 mumol Fe/g when using a serum ferritin assay. Follow-up in 11 patients (12-48 months) revealed that serum ferritin is a poor measure of the liver iron concentration during iron chelation. However, this discrepancy was individually different and seemed to be dependent on the erythropoietic marrow activity. By monitoring the liver iron concentration by MRI, we compared the efficacy of chelation with desferrioxamine given either by subcutaneous continuous infusions or by bolus injections. Depletion of liver iron stores could be achieved efficiently by both regimens.

Transfusion therapy is effective in the prevention and treatment of many complications of sickle cell disease (SCD). However, its benefits must be balanced against its risks, including delayed haemolytic transfusion reactions (DHTR). Not only is the relative rate of alloimmunization higher in patients with SCD than in other patient populations, but attendant risks associated with DHTR are even greater in SCD. Clinicians' awareness of DHTR events is poor because symptoms of DHTR mimic acute vaso-occlusive pain and immunohaematology findings are often negative. Transfusions delivered in the acute rather than elective setting appear to confer a higher risk of DHTR. Management of DHTR in SCD depends on the clinical severity, ranging from supportive care to immunosuppression, and optimization of erythropoiesis. DHTR must be considered in any recently transfused patient presenting with acute sickle cell pain. Meticulous documentation of transfusion and immunohaematology history is key. We anticipate an increase in DHTR events in SCD patients with the increasing use of red blood cell transfusion therapy.

Summary The level of circulating platelet-, erythrocyte-, leucocyte- and endothelial-derived microparticles detected by high-sensitivity flow cytometry was investigated in 37 β-thalassaemia major patients receiving a regular transfusion regimen. The phospholipid procoagulant potential of the circulating microparticles and the microparticle-dependent tissue factor activity were evaluated. A high level of circulating erythrocyte- and platelet-microparticles was found. In contrast, the number of endothelial microparticles was within the normal range. Platelet microparticles were significantly higher in splenectomized than in non-splenectomized patients, independent of platelet count (P

Iron-overload associated endocrinopathy is the most frequently reported complication of chronic transfusion therapy in patients with thalassaemia (Thal). This study compared iron-overloaded subjects with Thal (n = 142; 54%M; age 25.8 +/- 8.1 years) and transfused sickle-cell disease (Tx-SCD; n = 199; 43%M, 24.9 +/- 13.2 years) to non-transfused SCD subjects (non-Tx-SCD; n = 64, 50%M, 25.3 +/- 11.3 years), to explore whether the underlying haemoglobinopathy influences the development of endocrinopathy. Subjects were recruited from 31 centres in the USA, Canada and the UK. Subjects with Thal had more evidence of diabetes (13% vs. 2%, P < 0.001), hypogonadism (40% vs. 4%, P < 0.001), hypothyroidism (10% vs. 2%, P =

Blood transfusion therapy is life-saving for patients with beta-thalassaemia and sickle cell disease (SCD), but often results in severe iron overload. This pilot study examined whether the biomarkers of tissue injury or inflammation differ in these two diseases. Plasma malondialdehyde (MDA) was significantly increased 1.8-fold in thalassaemia relative to control patients. In contrast, MDA in SCD was not significantly different from controls. In multivariate analysis, the strongest predictors of elevated MDA were liver iron concentration (P < 0.001) and specific diagnosis (P = 0.019). A significant 2-fold elevation of non-transferrin bound iron (NTBI) was observed in thalassaemia relative to SCD. NTBI was not a significant predictor of high MDA in multivariate analysis. SCD patients showed a significant 2.2-fold elevation of the inflammatory marker interleukin (IL)-6 relative to controls, and a 3.6- and 1.7-fold increase in IL-5 and IL-10 relative to thalassaemia. Although alpha-tocopherol was significantly decreased by at least 32% in both thalassaemia and SCD, indicating ongoing oxidant stress and antioxidant consumption, gamma-tocopherol, a nitric oxide-selective antioxidant, was increased 36% in SCD relative to thalassaemia. These results demonstrate that thalassaemia patients have increased MDA and circulating NTBI relative to SCD patients and lower levels of some cytokines and gamma-tocopherol. This supports the hypothesis that the biology of SCD may show increased inflammation and increased levels of protective antioxidants compared with thalassaemia.

Some patients with β thalassaemia experience non-progressive creatinine increases with deferasirox, mostly within normal limits; the mechanisms involved are not fully elucidated. The effects of deferasirox on renal haemodynamics, including glomerular filtration rate (GFR) and renal plasma flow (RPF), were investigated in a Phase I, open-label study in β thalassaemia major patients with iron overload. Patients received deferasirox 30 mg/kg/d up to Week 8, followed by a 2-week washout period, and extended treatment up to Week 104 with a 4-week washout period. In the short-term study (n = 11), mean GFR and RPF declined from baseline to Week 8 (mean [%] change:-9·2 [-9·5%] and -105·7 ml/min [-17·8%], respectively). A similar pattern was observed during the long-term study (n = 5); mean GFR and RPF decreased up to Week 52 (-19·1 [-17·7%] and -155·6 ml/min [-26·1%]), with similar change at Week 104 (-18·4 [-17·2%] and -115·9 ml/min [-19·6%]). Measures returned to baseline values after each washout. Serum creatinine and creatinine clearance followed a similar pattern. Effects of deferasirox on renal haemodynamics were mild and reversible for up to 2 years of treatment, with no progressive worsening of renal function over time. www.clinicaltrials.gov: NCT00560820.