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

Abstract

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 in haemoglobinopathy teams and the national blood 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 and advice should be obtained for the management of patients with complex transfusion requirements (Grade 1C). state between genotypes and between with the & are in in in and in SC and Blood is to that some patients with have state of up to or & Serjeant, should be because of the oxygen of haemoglobin the state is appropriate to the individual and is not in an indication for and should be in their clinical in of haemolysis and red cell which may be in the cause of acute in by from state should prompt a for the and the need for transfusion 2014) but may be in the of such as or 2003). A in should also prompt further The decision to transfuse a patient with SCD, whether for anaemia or for complications of SCD, must into account the of anaemia to the state haemoglobin concentration and overall clinical (Grade 1C). from are related to the proportion of red cells HbS (%HbS) in may be by the transfusion, but all controlled studies have a transfusion of HbS with is in rates of et al, & et al, acute chest syndrome, and (DeBaun et al, However, other randomised trials have of rates in transfused et al, and perioperative complications in surgical patients transfused (Howard et al, studies used of in acute chest syndrome et al, et al, et al, The on including the the sickle of the acute and clinical to the a a of HbS is in acute such as acute chest syndrome, acute and multi-organ failure syndrome 2006), and in patients transfusions for of such as et al, et al, et al, & et al, In a may be In acute anaemia, it is to a simple transfusion to the state a Specialist advice should be sought for individual is a and any in must be without increasing the adverse including have reported from (Royal & Seeler, 1978; Serjeant, et al, 2013). The transfusion and should be into account the in any given In patients with are not on chronic the should not or if the (see section should be not to for sickle cell patients with state transfused the may be at a if the HbS is in these the patient has a percentage of haemoglobin and the risk of hyperviscosity is these the should be on an individual and on the In patients with sickle cell anaemia, transfusion to HbS prevent or acute sickle complications and complications in transfused patients. and HbS should be into consideration in the in order to avoid In sickle cell anaemia patients with and not on regular the should not if is The can be at a in transfused patients or if is but should be to Patients with should not be transfused their state (Grade 1C). SCD patients may so transfusion issues should be including any recent previous haemolytic transfusion reactions, and alloantibody should blood and blood group with The transfusion must clearly state that the patient has SCD so that special transfusion requirements are patients to a hospital from their hospital should be for their transfusion red cell and history of The patient may have a card of their and/or Red cell units have to be from the Blood and this may for with should be to all of SCD and to prevent the development of complications for which transfusion may be A transfusion history should be obtained in all SCD patients requiring transfusion, whether elective or emergency. of the red cell and any red cell antibodies (current and should have systems in to transfusion to clearly for sickle cell patients. Close communication is essential between clinical and laboratory teams so that appropriate blood is given (Grade 1C). Transfusion has of alloimmunisation, iron overload and can cause major difficulties (Vichinsky, (see section and should be undertaken with consideration of such as is essential that both and transfused patients are for iron overload and is an of iron overload as it for a (Porter & Huehns, in with may be in iron levels are significant et al, of iron concentration using is for patients with or iron a testing of has may the risk is in the UK et al, All SCD patients should be hepatitis B whether or not they are on regular transfusions and testing should be undertaken for if transfused SCD patients should be for iron overload with at iron should be performed for with or iron transfused patients should also be for iron overload as of their 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). that are between simple or exchange transfusion are transfusion is the for the transfusion is to prevent or the of anaemia aplastic Exchange transfusion the of sickle cells and their by red cells and is the where an or in complications of SCD is without an increase in blood viscosity acute chest The viscosity of sickle red cells is that of red and the risk of hyperviscosity at a given is on the and the et al, et al, et al, et al, 2006). viscosity oxygen delivery and the et al, & The viscosity of sickle red cells is but not by the presence of red cells 2006). transfusion to a in and any in oxygen capacity is by increased blood viscosity et al, et al, et al, 2006). Exchange transfusion cells and blood viscosity et al, the is to state or is for other as exchange transfusion is red cells oxygen at but in sickle cell anaemia it is at because of the viscosity of sickle red cells 2006). In such it is to a of without an in to (see section The of iron on the of transfusion used (Porter & 2013). transfusion iron exchange transfusion et al, et al, et al, et al, et al, 2001; et al, in exchange transfusion on the between the of red cells removed and given and is by the of exchange or as as and and exchange transfusion (Porter & 2013). manual exchange transfusions may the of iron by approximately to simple transfusion (Porter & Huehns, 1987) but automated can or negative iron et al, The of alloimmunisation in SCD is on a of including the of units transfused (Rosse et al, 1990; Vichinsky et al, exchange transfusion red cell units chronic exchange or simple transfusion procedures et al, However, a of on chronic transfusions reported a of alloimmunisation for on automated to on simple transfusions blood was in the group et al, increased alloimmunisation with exchange transfusion may be and should not be from likely to from access is a in a of adult patients with SCD and may be for automated exchange where access is essential to exchange can be performed using a but it is can be performed using two in a and manual exchange can be performed using but term may be et al, 2013). venous have a SCD patients with other patient et al, et al, et al, et al, 2012; et al, rates have reported in in et al, and in where a was used et al, may be for chronic automated but there is their resources are for exchange transfusion simple transfusion in relation to and automated exchange are simple transfusion but the increased may be by hospital and requirement for iron et al, 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 and venous access exchange should be available to all patients and not be by resources (Grade 1C). manual and automated exchange transfusions are in the emergency for with acute sickle complications (Janes et al, 1997; Vichinsky et al, et al, as in the for elective indications et al, et al, et al, 1999; et al, et al, 2013). The of blood and the can be The of these two to of complications, blood and clinical a were in a et al, has manual red cell exchange and is the where reduces manual exchange because and cells are to the patient et al, The around with venous access et al, et al, 1997; Lawson et al, and is et al, in up to transfusion et al, also or iron et al, red cell exchange is for both et al, 1999; et al, et al, and (Janes et al, 1997; Lawson et al, 1999; et al, et al, may and with the of units of blood but is by the of the et al, may also et al, so should be addressed and may need to be a of blood and where this is of the blood the with donor blood prior to may be may also be used for patients have their state simple transfusion be given prior to access can be a in order to rates and access may be chronic automated some centres but these special because of the of and should be used other are not The of cell and/or trained for automated red cell exchange in SCD is so trained staff may not be available working exchange transfusions may be in these and is In of manual exchange transfusion, that all patients with SCD should have access to automated exchange transfusion at a The of automated exchange transfusion have in a recent guidance by the for and has the of the for automated red cell exchange in the of sickle cell patients regular transfusions A manual red cell exchange to exchange of the blood should be a of blood that transfused and up the with a adult exchange the of red cell units with transfusion of this increase the by and may the of units at the of the (Porter & Huehns, and may need to the transfusion can be performed in any or but requires the to have with the In of and in reversing the acute complications of SCD, it is that all hospitals likely to admit SCD patients have trained staff to the in an emergency as a have a that is to We that manual red cell exchange transfusion be a requirement of haematology All hospitals that are likely to admit SCD patients should have staff trained in manual exchange procedures and clearly identified manual exchange as this can be lifesaving in emergency situations (Grade 1C). exchange transfusion should be available at all centres and all patients with SCD should have access to it (Grade 1C). is in SCD et al, in an increased of haemolytic reactions & Cohen, 2013). in antigen between and and contribute to increased rates of alloimmunisation et al, 1990). The of Rh- and units has alloimmunisation and haemolytic transfusion reactions, but that are on but not by serological et al, & et al, 2013; et al, 2013; O'Suoji et al, 2013). alloimmunisation a in alloantibody it may by (Rosse et al, the need for automated systems should be used for typing to the of and should be of If an alloantibody is should be If the patient is to have a red cell should be to the presence of further alloantibodies et al, 2013). should be sent to a red cell laboratory if there is in or clinically significant patients not on a regular transfusion it is that be of transfusion to whether or not any antibodies have et al, studies should be performed using blood in of the transfusion the patient has transfused et al, 2013). The should be available for at days transfusion to in the of an acute transfusion patient for days transfusion may be for investigation of transfusion reactions et al, 2013). extended including should be performed on all patients at If the patient is then typing should be performed et al, 2013). If the patient has not transfused then this can be undertaken the needs by & et al, an appropriate in emergency, the should be prior to transfusion et al, 2013). The Blood and is a to extended including and on haemoglobinopathy patients. a red cells should be for and antigens (Vichinsky, 2001; Vichinsky et al, 2001; et al, 2013). possible, blood should be selected for patients are as et al, 2013). If blood is then blood can be used if Red cells should be HbS negative et al, 2013). If there are clinically significant red cell antibodies (current or historical) then the red cells selected should be negative for the corresponding Red cells should be days old for simple transfusion and, if possible, <7 days old for exchange may not be in for the units available should be used et al, 2013). haemolytic reactions may be due to in SCD as for antigens but an to blood et al, 2013). All sickle cell patients should be with a card their red cell and, in particular, information as to whether they have an must be given to the patient as to to the card (Vichinsky, can communication of and alloantibodies between the Blood in is using the for Red access to by hospitals If transfusion is needed, patients with SCD must 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 antigen typing performed, which may assist with further serological testing and selection of red cell units if haemolytic reactions or there are complex transfusion requirements (Grade 1C). Blood provided for SCD patients should be HbS negative and, where possible, 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 they have ‘special requirement’ and, in particular, information as to whether they have an (Grade 2C). or antibodies to rare antigens not in can cause in The development of and can be to antigens is further by in this blood group in of et al, et al, The C or and or are by two and and in C and antigens can in alloimmunisation in these patients but the clinical can be The patients to have because serological testing as for the corresponding However, testing the antigen that the is an alloantibody et al, may be to this and provision of red cells et al, 2013). Red cell alloimmunisation clinical risk due to in as as increased for haemolytic transfusion and communication between all teams is this with the Blood for rare blood from and units where The are to blood in a and to minimise the from Patients are difficult to transfuse should have a plan the transfusion a plan for emergency transfusion, the of the and a to a Blood In hospital transfusion access to Specialist for of serological can the need for transfusions and should be et al, Patients with multiple red cell alloantibodies or antibodies to rare antigens need a clear agreed plan because blood may be difficult to source in the elective or emergency setting. Close liaison between all clinical teams, the hospital transfusion laboratory and the Blood is essential to ensure appropriate provision of blood (Grade 1C). Sickle cell patients are at increased risk of haemolytic transfusion reactions due to a of red cell alloimmunisation, previous red cell antibodies that are increased of transfusion out of and transfusion in multiple of haemolytic transfusion reactions in SCD patients. reported are which are with the of a and of the transfused red cells The of is a syndrome in which as the of both transfused and red in and life-threatening anaemia without antibodies et al, 1997; reactions are due to in patients and are in SCD, in of transfused patients & Patients with a of and anaemia, days transfusion, which may be by is clear laboratory evidence of haemolysis and of the transfused red cells a in a and alloantibodies identified in the or red cell is a The in the to the investigation of a haemolytic transfusion are in may the services of a red cell If the of the alloantibody be and further transfusion is the provision of extended antigen blood should be transfusion should be unless anaemia is is a of haemolytic transfusion which can cause life-threatening acute anaemia et al, 1997; et al, 1997; et al, et al, et al, et al, with SCD were reported to of Transfusion in & Cohen, and in et al, 2013). The of in the UK was reported in & Cohen, The are sickle and et al, 1997; et al, et al, for with disease and clinical et al, The is negative and red cell alloantibodies are not on serological alloantibodies are identified in cases, their may be 1997; et al, et al, transfusion, with may to further haemolysis and a or et al, et al, but must not be in patients with life-threatening the of anaemia and of In further transfusion should be In cases, of and may the anaemia and haemolysis et al, et al, of and may be et al, In further transfusion may be to prevent from this should be given with and et al, may also if transfusion is but this is of may be by the of and prior to transfusions et al, et al, et al, et al, et al, and et al, 2016) have used in but further is to their A on sickle cell patients with a history of has that may minimise the risk of further alloimmunisation and but not prevent haemolysis in all patients et al, should be obtained from the patient before is used 2013). is in SCD patients and has a reported of et al, 1999; can the presence of alloantibodies and cause clinically significant haemolysis & et al, 1999; et al, et al, to & et al, the increasing and of it is clear that are in alloantibodies due to that are of haemolytic reactions et al, All clinicians managing patients with SCD must 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 Haemovigilance Schemes (Grade 1C). guideline be reviewed of of the All were in evidence and writing the We are to for the of the have a of the advice and information in these guidelines is to be and at the of to the the British Society for Haematology the any for the of these