complete the survey via SurveyMonkey between March 2018 and May 2018.Respondents were asked to provide data regarding 10-16 year olds (PRh) and 16-25 year olds (ARh).Results: Thirteen (62%) PRh and 11 (52%) ARh consultants completed all or most of the survey.Table 1 summarises the core survey questions.PRh and ARh respondents reported referring fewer 10-25 year olds to psychology support services (dedicated, general and community psychology services) than they would have done if there were unlimited psychology support resource available.The types of support offered (urgent triage/assessment; one to one therapy; group therapy; advice, support and training of MDT) and the numbers of therapy sessions typically provided by psychology services varied widely between centres represented by respondents.Conclusion: Access to psychology services for young people with rheumatic and musculoskeletal disease varies significantly between paediatric and adult rheumatology centres as well as between paediatric centres and between adult centres.Current psychology service provision for 10-25 year olds was reported as inadequate.We plan to study psychosocial factors around the time of transfer from paediatric to adult rheumatology services to enable scarce NHS psychological support services to be better targeted.
Thrombocytopenia is defined as a platelet count less than 150 × 109/L. However, a platelet count of 10–20 × 109/L (20–30 × 109/L in a neonate) and possibly lower, is adequate to maintain haemostasis in the absence of coagulopathy, and spontaneous bleeding is unlikely. Causes of thrombocytopenia are diverse and can be related to either inadequate production or increased consumption, or a combination of both. In most cases, a careful history and examination of the blood film is sufficient to determine the cause of thrombocytopenia. The most common cause in the intensive care setting is sepsis. The underlying cause should be investigated and treatment should only be given to treat or prevent bleeding. Treatment involves platelet transfusions, if non-immune mediated or immune suppression if immune-mediated. This chapter will describe the causes of neonatal and paediatric thrombocytopenia and an approach to the diagnosis and management.
Summary We retrospectively analysed the outcome of consecutive children with idiopathic severe aplastic anaemia in the United Kingdom who received immunosuppressive therapy ( IST ) or matched unrelated donor ( MUD ) haematopoietic stem cell transplantation ( HSCT ). The 6‐month cumulative response rate following rabbit antithymocyte globulin ( ATG )/ciclosporin ( IST ) was 32·5% (95% CI 19·3–46·6) ( n = 43). The 5‐year estimated failure‐free survival ( FFS ) following IST was 13·3% (95% confidence interval [ CI ] 4·0–27·8). In contrast, in 44 successive children who received a 10‐antigen ( HLA ‐A, ‐B, ‐C, ‐ DRB 1, ‐ DQB 1) MUD HSCT there was an excellent estimated 5‐year FFS of 95·01% (95% CI 81·38–98·74). Forty of these children had failed IST previously. HSCT conditioning was a fludarabine, cyclophosphamide and alemtuzumab ( FCC ) regimen and did not include radiotherapy. There were no cases of graft failure. Median donor chimerism was 100% (range 88–100%). A conditioning regimen, such as FCC that avoids total body irradiation is ideally suited in children. Our data suggest that MUD HSCT following IST failure offers an excellent outcome and furthermore, if a suitable MUD can be found quickly, MUD HSCT may be a reasonable alternative to IST .
Blood transfusion in the management of sickle cell disease (SCD) can be lifesaving and reduces disability. However, it may cause morbidity, including alloimmunisation and iron overload (Rosse et al, 1990; Vichinsky et al, 1990; Ballas, 2001; Darbari et al, 2006), and mortality (Royal & Seeler, 1978; Serjeant, 2003). A paucity of randomised controlled clinical trials has resulted in wide variations in clinical practice. However, recent randomised studies have addressed some of the outstanding issues around indications to prevent some chronic complications (DeBaun et al, 2014) and to prevent perioperative acute complications, such as acute chest syndrome (Howard et al, 2013). We have reviewed the evidence and developed two linked guidelines on transfusion in SCD; Part I relates to general principles and laboratory aspects, whereas Part II addresses indications for transfusion in SCD. Here the term SCD refers to all genotypes of the disease and sickle cell anaemia to the homozygous state (SS). The writing group was selected by the British Committee for Standards in Haematology (BCSH) General Haematology and Transfusion Task Forces with input from other experts in haemoglobinopathy. PubMed, MEDLINE and Embase were searched systematically for publications on red cell transfusion in SCD from 1960 to May 2016 using a combination of search terms related to: (i) sickle cell (including sickle, sickle cell, SCD, sickle cell anaemia, haemoglobin SC disease, sickle cell crisis), (ii) transfusion (including transfusion, blood transfusion, red cell transfusion), (iii) transfusion indications [including aplastic crisis, parvovirus, sequestration (splenic, liver, hepatic), acute chest syndrome, stroke, silent cerebral infarcts, multi-organ failure, girdle syndrome, intrahepatic cholestasis, surgery, pregnancy] and (iv) transfusion complications (including alloimmunisation, haemolytic transfusion reactions, iron overload, viral infections). Opinions were also sought from experienced haematologists with a special interest in the care of SCD patients. The guideline was reviewed by the members of the General Haematology Task Force of the BCSH prior to being sent to a sounding board of approximately 50 UK haematologists, the BCSH and the British Society for Haematology (BSH) Committee. Comments were incorporated where appropriate. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria are specified in the BCSH guidance pack http://www.bcshguidelines.com/BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION/43_GRADE.html and the GRADE working group website http://www.gradeworkinggroup.org. The decision to top up or exchange transfuse an adult or paediatric patient with sickle cell disease (SCD) needs the input of a clinician with appropriate experience. Specialist advice should be obtained for the management of patients with complex transfusion requirements (Grade 1C). Transfusion in SCD requires careful consideration of both the haemoglobin concentration (Hb) and/or percentage of sickle haemoglobin (%HbS) in order to ensure maximal oxygen delivery to tissues without increasing overall blood viscosity to detrimental levels (Grade 1C). A transfusion history should be obtained in all SCD patients requiring transfusion, whether elective or emergency. Close communication is essential between clinical and laboratory teams so that appropriate blood is given (Grade 1C). Individuals with SCD are high-risk surgical patients. Close liaison between all clinical teams is essential with preoperative optimisation and appropriate postoperative care, whether transfused or not (Grade 1C). Virology testing [hepatitis B, hepatitis C and human immunodeficiency virus (HIV)] should be undertaken at presentation and hepatitis B vaccination should be given to all patients with SCD, irrespective of previous or prospective planned transfusions. SCD patients on regular transfusions should be screened annually for hepatitis B, hepatitis C and HIV (Grade 1C). The choice of transfusion method, i.e., simple (top up) or exchange, should be based on clinical judgement of individual cases, taking into account the indication for transfusion, the need to avoid hyperviscosity and minimise alloimmunisation, maintenance of iron balance, venous access issues and available resources (Grade 1C). All hospitals that are likely to admit SCD patients should have staff trained in manual exchange procedures and clearly identified manual exchange procedures, as this can be lifesaving in emergency situations (Grade 1C). Large referral centres managing patients with SCD should have facilities and trained staff for automated exchange transfusion (Grade 1C). If transfusion is needed, patients with SCD should be given ABO-compatible, extended Rh- and Kell-matched units. If there are clinically significant red cell antibodies (current or historical) then the red cells selected should be negative for the corresponding antigens (Grade 1C). Patients with SCD must also have extended red blood cell (RBC) antigen typing performed, which may assist with further serological testing and selection of red cell units if there are haemolytic reactions and complex transfusion requirements (Grade 1C). Blood provided for SCD patients should be HbS negative and, where possible, should be <10 days old for simple transfusion and <7 days old for exchange transfusion but older blood may be given if the presence of red cell antibodies makes the provision of blood difficult (Grade 1C). All patients with SCD should carry a transfusion card indicating that they have 'special requirement' and, in particular, giving information of any alloantibody (Grade 2C). Patients with multiple red cell alloantibodies or antibodies to rare antigens need a clear agreed plan given that blood may be difficult to source in the elective or emergency setting. Close liaison between all clinical teams, the hospital transfusion laboratory and the national blood service is essential to ensure appropriate provision of blood (Grade 1C). All clinicians managing patients with SCD should be aware of the risk of haemolytic transfusion reactions to ensure prompt recognition and management. Close liaison is needed with haemoglobinopathy specialists and blood services for investigation and management (Grade 1C). Any adverse events or reactions related to transfusion should be appropriately investigated and reported to local risk management systems and to UK Haemovigilance Schemes (Grade 1C). Red cell (RBC) transfusion in SCD may be necessary in the management of acute complications or electively to prevent the development or progression of chronic complications. In both settings, transfusion may be administered by simple (top up) transfusion or by exchange transfusion (where patient red cells are removed and replaced with donor red cells). Exchange transfusion can be performed manually (Porter & Huehns, 1987) or with an automated cell separator (Janes et al, 1997; Lawson et al, 1999; Kuo et al, 2015; Tsitsikas et al, 2016) (see section 6). The major goals of transfusion in SCD are (i) improving oxygen-carrying capacity by correcting anaemia and (ii) preventing or reversing complications of SCD related to vaso-occlusion and haemolysis (by decreasing the proportion of HbS in relation to HbA). Sickle cell disease patients are at risk of haemolytic transfusion reactions due to increased rates of alloimmunisation (Rosse et al, 1990; Vichinsky et al, 1990). Poor communication may contribute to the failure to meet special transfusion requirements because these patients tend to be transfused out of hours, or at hospitals where their previous history is unknown (Vichinsky, 2012; Bolton-Maggs & Cohen, 2013; O'Suoji et al, 2013). Co-existing morbidities increase susceptibility to circulatory overload and the requirement for phenotyped blood can pose logistical difficulties (Flickinger, 2006). Expert haematology advice must be sought before a decision is made to transfuse, unless in an emergency, such as life-threatening acute blood loss. Complex patients should be discussed with consultants in specialist haemoglobinopathy teams and the national blood service. The decision to transfuse or exchange transfuse an adult or paediatric patient with sickle cell disease (SCD) needs the input of a clinician with appropriate experience and specialist advice should be obtained for the management of patients with complex transfusion requirements (Grade 1C). Steady state Hb varies between genotypes and between individuals with the same genotype (Serjeant & Serjeant 2001). Typical values are 60–90 g/l in SS, 70–90 g/l in S/βo thalassaemia, 90–120 g/l in S/β+ thalassaemia and 90–140 g/l in SC (National Heart, Lung, and Blood Institute [NHLBI] 2014). It is important to remember that some patients with SS have steady state Hb concentrations of up to 130 g/l or higher (Serjeant & Serjeant, 2001). It should be noted that, because of the low oxygen affinity of haemoglobin S, the steady state Hb is appropriate to the individual and is not in itself an indication for transfusion. Each patient's baseline Hb and reticulocyte count should be documented in their clinical record. Changes in reticulocyte level reflect amounts of haemolysis and red cell production, which may be helpful in identifying the cause of worsening anaemia. An acute drop in Hb by >20 g/l from steady state should prompt a review for the aetiology and the need for transfusion (NHLBI, 2014) but may be tolerated in the absence of additional pathologies such as cardiovascular instability or hypoxia. (Serjeant, 2003). A chronic, progressive decrease in Hb should also prompt further investigation. The decision to transfuse a patient with SCD, whether for worsening anaemia or for complications of SCD, must take into account the degree of anaemia relative to the patient's steady state haemoglobin concentration and overall clinical condition (Grade 1C). Complications from sickling are related to the proportion of red cells containing HbS (%HbS) (or HbS+C in SC). These risks may be minimised by reducing the %HbS through transfusion, but no single %HbS target covers all indications. Randomised controlled studies have shown a transfusion target of HbS ≤30% (compared with no transfusion) is effective in reducing incidence rates of stroke (Adams et al, 1998; Adams & Brambilla, 2005; DeBaun et al, 2014), vaso-occlusive crises, acute chest syndrome, priapism and new symptomatic avascular necrosis (DeBaun et al, 2014). However, other randomised trials have shown higher targets of <35% and<50% reduced pain rates in prophylactically transfused pregnant women (Koshy et al, 1988) and perioperative complications in surgical patients transfused preoperatively (Howard et al, 2013), respectively. Some observational studies used %HbS targets of 25–40% in acute chest syndrome (Maitre et al, 2000; Lombardo et al, 2003; Velasquez et al, 2009). The post-transfusion %HbS target depends on several factors, including the indication, the patient's background sickle history, severity of the acute illness, organ dysfunction, and clinical response to the initial transfusion. As a pragmatic approach, a target of HbS <30% is recommended in acute syndromes, such as severe acute chest syndrome, acute stroke and multi-organ failure syndrome (Swerdlow, 2006), and in patients receiving long-term transfusions for prevention of problems, such as stroke (Wang et al, 1991; Pegelow et al, 1995; Adams et al, 1998; Adams & Brambilla, 2005; DeBaun et al, 2014). In very sick patients, a lower %HbS may be desirable. In acute anaemia, it is usually sufficient to give a simple transfusion back to the steady state Hb (Telen, 2001) rather than use a %HbS target. Specialist advice should be sought for individual cases. Hyperviscosity is a potential problem and any decrements in %HbS must be achieved without increasing the haematocrit unduly. Serious adverse events, including death, have been reported from over-transfusion (Royal & Seeler, 1978; Serjeant, 2003; Raj et al, 2013). The patient's baseline Hb, transfusion status and %HbS should be taken into account when determining the target post-transfusion Hb in any given situation. In SS patients with baseline Hb <90 g/l who are not on chronic transfusions, the post-transfusion Hb should not exceed 100 or 10–20 g/l above baseline, particularly if the post-transfusion %HbS exceeds 30% (see section 5.2). Care should be taken not to exceed baseline Hb values for sickle cell patients with high steady state Hb (>100 g/l). For chronically transfused patients, the post-transfusion Hb may be set at a higher level if the pre-transfusion HbS is low; in these circumstances, the patient has a higher percentage of normal affinity haemoglobin A, and the risk of hyperviscosity is consequently lower. For these patients, the post-transfusion Hb should be decided on an individual basis and will depend on the %HbS. In patients with sickle cell anaemia, transfusion to HbS <30% will prevent or reverse most acute sickle complications and significantly reduce long-term complications in chronically transfused patients. Baseline Hb and % HbS should be taken into consideration in setting the target post-transfusion Hb in order to avoid hyperviscosity. In sickle cell anaemia patients with baseline Hb <90 g/l and not on regular transfusions, the post-transfusion Hb should not exceed 100 g/l, particularly if %HbS is greater than 30%. The post-transfusion Hb can be set at a higher target in chronically transfused patients or if %HbS is low, but should be individualised to each patient. Patients with high baseline Hb (>100 g/l) should not be transfused above their steady state Hb (Grade 1C). Acutely ill SCD patients may deteriorate rapidly so transfusion issues should be considered early, including any recent transfusions, previous haemolytic transfusion reactions, and alloantibody formation. Baseline investigations should include: full blood count, reticulocyte count, and blood group with antibody screen. The transfusion request form must clearly state that the patient has SCD so that special transfusion requirements are met. For patients presenting to a different hospital from usual, their primary hospital should be contacted for their baseline Hb, reticulocyte count, transfusion history, red cell phenotype/genotype and history of alloantibodies. The patient may have a card bearing details of their phenotype and/or alloantibodies. Red cell units usually have to be ordered from the National Blood Service and this may introduce delay, especially for individuals with alloantibodies. Meticulous attention should be paid to all aspects of SCD management, particularly adequate analgesia, hydration and incentive spirometry, to help prevent the development of critical organ complications for which transfusion may be required. A transfusion history should be obtained in all SCD patients requiring transfusion, whether elective or emergency. This includes details of the patient's red cell phenotype and any red cell antibodies (current and historical). Hospitals should have robust systems in place to enable transfusion laboratories to clearly identify samples for sickle cell patients. Close communication is essential between clinical and laboratory teams so that appropriate blood is given (Grade 1C). Transfusion has risks of alloimmunisation, iron overload and transfusion-transmitted infections. Alloimmunisation can cause major difficulties (Vichinsky, 2001) (see section 8) and early review should be undertaken with consideration of alternative treatments, such as hydroxycarbamide. It is essential that both intermittently and regularly transfused patients are monitored for iron overload and treated accordingly (NHLBI, 2014). Ferritin is an unreliable marker of iron overload as it remains elevated for weeks after a painful crisis (Porter & Huehns, 1987). Furthermore, changes in ferritin with chelation therapy may be absent even when changes in hepatic iron levels are significant (Vichinsky et al, 2007). Therefore assessment of liver iron concentration using validated non-invasive magnetic resonance imaging techniques is recommended for patients with suspected or documented transfusional iron overload; a testing frequency of every 1–2 years has been suggested (NHLBI, 2014). Transfusion-transmitted infections may occur, though the risk is currently very low in the UK (Watkins et al, 2012). All SCD patients should be immunised against hepatitis B whether or not they are on regular transfusions (Sickle Cell Society, 2008) and annual testing should be undertaken for transfusion-transmitted viruses if transfused. Chronically transfused SCD patients should be regularly monitored for iron overload with serum ferritin at least every 3 months; liver iron measurements should be performed every 1–2 years for those with suspected or proven iron overload. Intermittently transfused patients should also be monitored for iron overload as part of their routine care (Grade 1C). Virology testing [hepatitis B, hepatitis C and human immunodeficiency virus (HIV)] should be undertaken at presentation and hepatitis B vaccination should be given to all patients with SCD irrespective of previous or prospective planned transfusions. SCD patients on regular transfusions should be screened annually for hepatitis B, hepatitis C and HIV (Grade 1C). Factors that are important when deciding between simple or exchange transfusion are outlined below. Simple transfusion is preferable when the primary reason for the transfusion is to prevent or reverse the effects of severe anaemia (e.g. aplastic crisis). Exchange transfusion allows the removal of sickle cells and their replacement by normal red cells and is the preferred option where an immediate or sustained reduction in complications of SCD is required without an undesirable increase in blood viscosity (e.g. severe acute chest syndrome). The viscosity of sickle red cells is much higher than that of normal red cells, and the risk of hyperviscosity at a given Hb is dependent on the %HbS and the haematocrit (Anderson et al, 1963; Chien et al, 1970; Schmalzer et al, 1987; Alexy et al, 2006). Increased viscosity compromises oxygen delivery and exacerbates the sickling process (Schmalzer et al, 1987; Ballas & Mohandas, 2004). The viscosity effect of sickle red cells is reduced but not eliminated by the presence of normal red cells (Swerdlow, 2006). Simple transfusion leads to a rise in haematocrit, and any increment in oxygen carrying capacity is offset by increased blood viscosity (Schmalzer et al, 1987; Wayne et al, 1993; Alexy et al, 2006). Exchange transfusion removes HbS-containing cells and decreases blood viscosity (Schmalzer et al, 1987). When the pre-transfusion Hb is close to steady state or is high for other reasons (such as SC) exchange transfusion is preferred. Normal red cells support maximum oxygen transport at Hb 140–160 g/l, but in untransfused sickle cell anaemia patients, it is lower at 100–110 g/l because of the higher viscosity of sickle red cells (Swerdlow, 2006). In such patients, it is unwise to exceed a post-transfusion Hb target of 100–110 g/l, without an accompanying reduction in %HbS to less than 30% (see section 4.5). The rate of iron accumulation depends on the type of transfusion used (simple versus exchange) (Porter & Garbowski, 2013). Simple transfusion inevitably causes greater positive iron balance than exchange transfusion (Cohen et al, 1992; Kim et al, 1994; Adams et al, 1996; Hilliard et al, 1998; Harmatz et al, 2000; Olivieri, 2001; Brown et al, 2009). Iron accumulation in exchange transfusion depends on the difference between the numbers of red cells removed and those given and is influenced by the type of exchange (manual or automated), as well as Hb and %HbS values pre- and post- exchange transfusion (Porter & Garbowski, 2013). Chronic manual exchange transfusions may decrease the rate of iron loading by approximately 40% relative to simple transfusion (Porter & Huehns, 1987) but automated exchanges can achieve neutral or even negative iron balance (Kim et al, 1994). The rate of alloimmunisation in SCD is dependent on a number of factors including the number of units transfused (Rosse et al, 1990; Vichinsky et al, 1995). Automated exchange transfusion programmes consume more red cell units than chronic partial exchange or simple transfusion procedures (Hilliard et al, 1998). However, a retrospective study of children on chronic transfusions reported a significantly lower rate of alloimmunisation for those on automated apheresis compared to children on simple transfusions even though blood consumption was significantly higher in the erythrocytapheresis group (Wahl et al, 2012). Concerns about increased alloimmunisation with exchange transfusion may be unjustified and erythrocytapheresis should not be withheld from those likely to benefit from it. Venous access is a problem in a substantial number of adult patients with SCD and may be particularly problematic for automated exchange where good vascular access is essential to maintain flow rates. Manual exchange can be performed using a single line, but it is slow. It can only be performed isovolaemically using two lines in a two-arm technique. Automated and manual exchange can be performed using peripheral cannulae, but short term femoral line insertion may be required (Billard et al, 2013). Indwelling central venous catheters have a high complication rate, particularly infection, among SCD patients compared with other patient groups (McCready et al, 1996; Jeng et al, 2002; Wagner et al, 2004; Alkindi et al, 2012; Shah et al, 2012). Lower complication rates have been reported in one small study in children (Bartram et al, 2011) and in another study where a particular implantable device was used (Raj et al, 2005). Dual lumen ports may be considered for chronic automated exchanges but there is limited data regarding their long-term use. More resources are required for exchange transfusion than simple transfusion especially in relation to staffing and equipment. Chronic automated exchange programmes are much more expensive than simple transfusion programmes but the increased costs may be offset by fewer hospital visits and reduced requirement for iron chelation therapy (Hilliard et al, 1998). The choice of transfusion method, simple or exchange, should be based on clinical judgement of individual cases, taking in account the indication for transfusion and the need to avoid hyperviscosity and minimise alloimmunisation, maintenance of iron balance and venous access issues. Automated exchange should be available to all patients and not be limited by resources (Grade 1C). Both manual and automated exchange transfusions are suitable in the emergency setting for inpatients with acute sickle complications (Janes et al, 1997; Vichinsky et al, 2000; Velasquez et al, 2009) as well in the outpatient setting for elective indications (Vichinsky et al, 1995; Adams et al, 1998; Singer et al, 1999; Raj et al, 2005; Billard et al, 2013). The volume of blood exchanged and the target final Hb can be adjusted. The ability of these two methods to achieve pre-defined haematological targets, rate of complications, blood usage and clinical outcome over a 1-year period were compared in a retrospective observational cohort study (Kuo et al, 2015). This has advantages over manual red cell exchange and is the preferred technique where available. It reduces %HbS faster than manual exchange because plasma, platelets and white cells are returned to the patient (Lawson et al, 1999). The procedure takes around 2 h with good venous access (Kim et al, 1994; Janes et al, 1997; Lawson et al, 1999) and is well tolerated (Lawson et al, 1999). Additionally, its effectiveness in reducing %HbS allows up to 6-weekly transfusion intervals (Kalff et al, 2010). It also limits or eliminates iron accumulation (Kim et al, 1994). Automated red cell exchange is suitable for both children (Singer et al, 1999; Velasquez et al, 2009; Billard et al, 2013) and adults (Janes et al, 1997; Lawson et al, 1999; Kozanoglu et al, 2007; Kalff et al, 2010). Hypocalcaemia may occur and increases with the number of units of blood transfused, but is easily prevented by the intravenous administration of calcium during the procedure (Lawson et al, 1999). Dilutional thrombocytopenia may also occur (Tsitsikas et al, 2016). Fluid shifts occur during apheresis so hydration status should be addressed pre-procedure; anti-hypertensive medications and diuretics may need to be withheld. Apheresis machines pool a fixed volume of blood ex vivo and where this is >15% of the patient's total blood volume, priming the machine with donor blood prior to apheresis may be useful. This approach may also be used for patients who have Hb >20% below their steady state Hb; alternatively, simple transfusion could be given prior to apheresis. Venous access can be a challenge in order to achieve adequate flow rates and femoral access may be required. For chronic automated apheresis, some centres use indwelling double lumen Vortex® ports (AngioDynamics, Latham, NY, USA), but these require special attention because of the risks of infection and thrombosis. These should be used only when other approaches are not possible. The availability of cell separators and/or trained operators for automated red cell exchange in SCD is limited nationally so trained staff may not be available outside normal working hours. Manual exchange transfusions may be more practical in these circumstances and is more widely available. In view of its advantages over manual exchange transfusion, we recommend that all patients with SCD should have access to automated exchange transfusion at a specialist centre. The advantages of automated exchange transfusion have been recognised in a recent medical technology guidance published by the National Institute for Health and Care Excellence (NICE, 2016). NICE has recommended the use of the Spectra Optia Apheresis System (Terumo BCT, Lakewood, CO, USA) for automated red cell exchange in the treatment of sickle cell patients who require regular transfusions (NICE, 2016). A manual red cell exchange typically aims to exchange about one-third of the patient's blood volume thereby achieving about 30% HbA. This should be done isovolaemically, typically removing a larger volume of blood than that transfused and making up the volume difference with 0·9% sodium chloride (normal saline). Although practices vary, a typical adult exchange would involve the removal of 4 red cell units with transfusion of 3 units; this will increase the Hb by 10–20 g/l and may require the removal of additional units at the end of the procedure (Porter & Huehns, 1987). This takes several hours and may need repeating to achieve the desired transfusion targets. Manual exchanges can be performed in any ward or day unit setting but requires the operator to have familiarity with the procedure. In view of its simplicity and effectiveness in reversing the acute complications of SCD, it is imperative that all hospitals likely to admit SCD patients have trained staff to perform the procedure in an emergency or, as a minimum, have a written protocol that is easy to follow. We recommend that manual red cell exchange transfusion be a requirement of specialist haematology training. All hospitals that are likely to admit SCD patients should have staff trained in manual exchange procedures and clearly identified manual exchange protocols, as this can be lifesaving in emergency situations (Grade 1C). Automated exchange transfusion should be available at all specialist centres and all patients with SCD should have access to it (Grade 1C). Alloimmunisation is common in SCD (Yazdanbakhsh et al, 2012), resulting in an increased frequency of haemolytic reactions (Bolton-Maggs & Cohen, 2013). Significant differences in RBC antigen frequencies between Caucasian donors and African and Afro-Caribbean recipients contribute to increased rates of alloimmunisation (Vichinsky et al, 1990). The use of Rh- and K- matched units has reduced alloimmunisation and haemolytic transfusion reactions, but sensitisation continues against Rh variants that are identifiable on molecular genotyping but not by serological methods (Lasalle-Williams et al, 2011; Noizat-Pirenne & Tournamille, 2011; Chou et al, 2013; Miller et al, 2013; O'Suoji et al, 2013). Following alloimmunisation a rapid reduction in alloantibody titre means it may become undetectable by routine antibody screening (Rosse et al, 1990), hence the need for accurate records. Fully automated systems should be used for ABO typing to mitigate the risks of interpretation and transcription error. Antibody screening should always be part of pre-transfusion testing. If an alloantibody is detected its specificity should be determined. If the patient is known to have formed a red cell alloantibody, each new sample should be fully tested to exclude the presence of further alloantibodies (Milkins et al, 2013). Samples should be sent to a red cell reference laboratory if there is difficulty in antibody identification or excluding clinically significant antibodies. For patients not on a regular transfusion programme, it is recommended that antibody screening be repeated after every episode of transfusion to document whether or not any new antibodies have formed (Milner et al, 1985). Serological studies should be performed using blood collected no more than 72 h in advance of the transfusion when the patient has been recently transfused (Milkins et al, 2013). The pre-transfusion sample should be available for at least 3 days after transfusion to allow repeat ABO grouping in the event of an a
Accurate diagnosis of rare inherited anaemias is challenging, requiring a series of complex and expensive laboratory tests. Targeted next-generation-sequencing (NGS) has been used to investigate these disorders, but the selection of genes on individual panels has been narrow and the validation strategies used have fallen short of the standards required for clinical use. Clinical-grade validation of negative results requires the test to distinguish between lack of adequate sequencing reads at the locations of known mutations and a real absence of mutations. To achieve a clinically-reliable diagnostic test and minimize false-negative results we developed an open-source tool (CoverMi) to accurately determine base-coverage and the 'discoverability' of known mutations for every sample. We validated our 33-gene panel using Sanger sequencing and microarray. Our panel demonstrated 100% specificity and 99·7% sensitivity. We then analysed 57 clinical samples: molecular diagnoses were made in 22/57 (38·6%), corresponding to 32 mutations of which 16 were new. In all cases, accurate molecular diagnosis had a positive impact on clinical management. Using a validated NGS-based platform for routine molecular diagnosis of previously undiagnosed congenital anaemias is feasible in a clinical diagnostic setting, improves precise diagnosis and enhances management and counselling of the patient and their family.
We report the incidence and outcome of venous thrombosis (VT) in the UK acute lymphoblastic leukaemia (ALL) 2003 trial. VT occurred in 59/1824 (3.2%) patients recruited over 5 years with 90% occurring during a period of Asparagine depletion. Pegylated Escherichia Coli Asparaginase (Peg-ASP) 1000 units/m(2) was used throughout. Thirty-four children received further Peg-ASP, most with concurrent heparin prophylaxis. There were no episodes of bleeding or recurrent thrombosis. Optimal Asparagine depletion is central to success of modern regimes for treatment of ALL. This report confirms a significant risk of thrombosis with such therapy, but demonstrates that re-exposure to Asparaginase is feasible and safe.
Audit of follow-up of neutropenia in children, in terms of blood tests, in a single institution was found to be variable. This can potentially lead to significant underlying conditions being missed and standardising follow-up blood tests is important. As a quality improvement project we wrote a guideline (figure 1), re-audited and present our findings.
Methods
All neutrophil counts less than 1x109/L in under 16 year olds were retrospectively collected from a single tertiary hospital over a 1-year period, as well as diagnoses and available follow-up results. Children with underlying conditions known to have haematological sequelae were excluded, as were counts requested from the haematology/oncology and neonatal units. An evidence- and locally consensus-based guideline was written and ratified, advising repeat counts within 4-6 weeks and that well children of Afro-Caribbean heritage did not require follow-up.1 A further 6 months of data were collected approximately 2 months after introduction of the guideline with the same exclusion criteria as above.
Results
56 children with neutropenia were identified over a 1-year period on initial analysis, with 111 full blood counts (FBC) performed between them. 36% (n=20) of children did not have a repeat FBC and 48% (n=27) did not have a normal neutrophil count (>1) recorded, even if checked more than once (figure 2). The average number of days before a 'normal' result was obtained was 18 in those who had repeat FBC. 3 new cases of autoimmune neutropenia (AIN) were identified in this time period; these were excluded from analysis since a normal FBC was not recorded. Following implementation of the new guideline, repeat analysis over a 6-month period was performed, with the same exclusions as the initial analysis. 36 children were identified; 25% (n=9) did not have a repeat FBC, and 36% (n=13) did not have a normal count documented. 72% had a repeat count within 6 weeks. The average number of days until normal count was recorded was 15, and 1 new case of AIN was identified, receiving a repeat FBC within the suggested 4-6 week time frame.
Conclusion
Local assessment of current practice with isolated neutropenia in children confirmed a variety of follow-up approaches, with almost 1 in 2 cases not having a normal count recorded. Introduction of a pragmatic guideline improved retesting rates (64% vs 75%). We noted a 3-5% incidence of newly identified significant diagnoses, highlighting the importance of standardising practice. The advocated 4-6 week gap before retesting FBC was supported by preliminary and repeat analysis; most counts in our datasets normalised in approximately 2-3 weeks, and although the gap could be reduced, 4-6 weeks strikes a balance between rational testing and safety. Our data however may be incomplete for those children who were from neighbouring hospitals and repatriated before repeat counts, and the re-audit was of a shorter period. More complete coding of ethnicity would also enable a better evaluation of repeat counts in different ethnic groups.
Reference
Thomas AE, et al. A step-by-step approach to paediatric neutropenia. Paediatrics Child Health 2017;27:11.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)