Aims of blood transfusion

The aim of blood transfusion in thalassaemia is to deliver a safe and effective transfusion regimen whilst minimising the burden of transfusion therapy on everyday life.

An effective transfusion regimen will result in:

• Good growth and development
• Good energy levels
• Sufficient suppression of intra and extramedullary haematopoiesis

A safe transfusion regimen will

• Use a product that is collected, tested, selected, issued and administered adherent to established quality and safety regulations and guidance
• Be administered by staff trained in blood transfusion
• Involve informed patient consent
• Be performed in a system with a good haemovigilance structure

Haemovigilance

“Haemovigilance is the set of surveillance procedures covering the entire blood transfusion chain, from the donation and processing of blood and its components, through to their provision and transfusion to patients, and including their follow-up”.

It includes the monitoring, reporting, investigation and analysis of adverse events related to the donation, processing and transfusion of blood, and taking action to prevent their occurrence or recurrence. The reporting systems play a fundamental role in enhancing patient safety by learning from failures and then putting in place system changes to prevent them in future.

The haemovigilance system should involve all relevant stakeholders and should be coordinated between the blood transfusion service, hospital clinical staff and transfusion laboratories, hospital transfusion committees, the national regulatory agency and national health authorities.

The resulting modifications to transfusion policies, standards and guidelines, as well as improvements to processes in blood services and transfusion practices in hospitals, lead to improved patient safety” (WHO, 2021b).

Good haemovigilance is key to the delivery of safe and effective transfusion in any setting and must be in place in the delivery of blood transfusion to those with thalassaemia.

Blood donation

To safeguard the health of patients with thalassaemia, blood should be obtained from carefully selected voluntary, non-remunerated donors and should be collected, processed, stored and distributed, by dedicated blood transfusion centres with established quality assurance systems in place.

Adherence to the directives from the European Union (EU), World Health Organisation (WHO), American Association of Blood Banks (AABB) or other international groups, with additional consideration of national needs, resources and prevalence of infectious agents, should safeguard the quality of blood transfusion services particularly to prevent transfusion transmitted infections (TTI). Clearly patients who have repeated donor exposure are at greater risk of such infection. Blood donation practices, donor selection (e.g., through questionnaires) and specific product screening for hepatitis B, hepatitis C, HIV, syphilis and, in some countries, other infectious diseases such as HTLV I/II, malaria, toxoplasma, Hepatitis A, Hepatitis E, West Nile virus and Chagas disease constitute some of the most important strategies that contribute to the safety and adequacy of blood. For more information on EU directives visit https://www.edqm.eu/en/blood-transfusion-mission.html while additional WHO guidelines and American Standards are available at https://www.who.int/bloodsafety/gcbs/structure/en/ and https://www.aabb.org/standards-accreditation/standards.

Blood component specification

 

Leucodepletion

Reduction to 1 X 10^6/l or less leucocytes per unit is considered the critical threshold for eliminating adverse reactions attributed to contaminating white cells (Table 1) (Klein, Spahn & Carson, 2007) and in countries where variant Creutzfeld Jakob Disease was prevalent (e.g. the United Kingdom), it is universally used for all cellular products to decrease the risk of transmission through blood products.

Table 1

Adverse effects of leucocytes in blood products.

• Pre-storage filtration of whole blood is the preferred method for leuco-reduction. This method of leucocyte removal offers high efficiency filtration and provides consistently low residual leucocytes in the processed red cells and high red cell recovery. Packed red cells are obtained by centrifugation of the leucodepleted whole blood.
• Pre-transfusion, laboratory filtration refers to the filtration at the blood bank laboratory of packed red cells, prepared from donor whole blood.
• Bedside filtration refers to the packed red cell unit that is filtered at the bedside at the time of transfusion. This method may not allow optimal quality control because the techniques used for bedside filtration may be highly variable.

Storage of Donor Red Cell Units

The anticoagulant preservative solutions used in blood collection (Table 2) have been developed to prevent coagulation and to permit storage of red cells without loss of metabolic integrity. All of these solutions contain sodium citrate, citric acid and glucose, and some of them also contain adenine, guanosine and phosphate (e.g., CPD-A). As shown in Table 2, the introduction of additives such as AS-1, AS-3 and AS-5 permits storage of red cells for up to 42 days.

Table 2

Storage time for anticoagulant-preservative solutions with and without additive solution.

The maximum duration of storage, as noted on each unit varies with the type of preparation. However, all of the storage solutions should achieve a mean 24-hour post-transfusion survival of no less than 75% of the transfused red cells. The actual half-life of donor red cells after transfusion is not routinely tested for different additives and for different lengths of storage.

The haemoglobin oxygen release function which is extremely important in thalassaemia major is impaired during normal storage due to progressive loss of 2, 3-biphosphoglycerate (2, 3-BPG, previously known as 2, 3- diphosphoglycerate, DPG). However, the rapid repletion of 2,3-BPG after transfusion generally compensates for the loss of function during storage.

In TDT, decreased recovery and a shortened red cell half-life may increase transfusion requirements and as a consequence the rate of transfusional iron overload; the current practice is to use red cells stored in additive solutions for less than two weeks where this is available and does not lead to an unacceptable delay in transfusion.

Compatibility Testing

Development of one or more specific red cell antibodies (alloimmunisation) is an important complication of chronic transfusion therapy (Thompson et al., 2011; Singer et al., 2000; Spanos et al., 1990). However, the prevalence of alloantibodies varies widely among centers and may be related to the homogeneity of thepopulation, strategies for antigen matching and other factors. It is important to monitor patients carefully for the development of new antibodies. Anti-E, anti-C and anti-Kell alloantibodies are the most common. However, 5-10% of patients develop alloantibodies against other erythrocyte antigens or develop warm or cold antibodies of unidentified specificity.

It is recommended that:

Box

Before embarking on transfusion therapy, patients should have extended red cell antigen typing that includes at least A, B, O, C, c, D, E, e, and Kell, (though preferably a full red cell phenotype/genotype panel) If the patient is already transfused, (more...)

It may be appropriate to extend antigen matching in line with specific local population requirements (Cheng, Lee & Lin, 2012).

Most blood banks currently perform a screen for new antibodies and an IAT (indirect antiglobulin test) crossmatch before each transfusion. Where patients are not pregnant and have no history of alloimmunisation, a newer approach in which the initial approach known as an electronic issue may be used. Here, in eligible patients with a negative antibody screen, blood is issued without an IAT crossmatch being performed. This is only appropriate in blood banks that adhere to strict regulations regarding computer systems, sample labelling and other critical issues (Milkins et al., 2013). Using either approach, new clinically significant antibodies must be identified so that blood lacking the corresponding antigen(s) is selected.

A complete and detailed record of antigen typing, current and historical red cell antibodies and transfusion reactions should be maintained for each patient, and should be readily available if the patient is transfused at a different centre. Transfusion of blood from first-degree relatives should be avoided because of the risk of developing antibodies that might adversely affect the outcome of a later stem cell transplant and the risks of transfusion associated graft versus host disease. The length of time between the sample acquisition and antibody screen and the transfusion of blood for regularly transfused patients is usually 72 hours but may be as long as one week in centres with full Rh and Kell antigen matching in patients who are regularly transfused (Trompeter et al., 2015). In patients who are irregularly transfused or start transfusion later in life (Table 3) the risk of allomunisation may be greater (Spanos et al., 1990; Michail-Merianou et al., 1987, see Table 3), so that the interval between sample forantibody screen and transfusion should preferably not be longer than 72h.

Table 3

Age and alloimmunisation in thalassaemia.

Criteria for initiating transfusion therapy

For deciding whom to transfuse, the following should be included in the investigations:

• Confirmed diagnosis of thalassaemia.
• Laboratory criteria:

  -

  Haemoglobin level (Hb) <70 g/l on 2 occasions, > 2 weeks apart (excluding all other contributory causes such as infections) AND/OR

• Clinical criteria irrespective of haemoglobin level:

  >

  Significant symptoms of anaemia

  >

  Poor growth / failure to thrive

  >

  Complications from excessive intramedullary haematopoiesis such as pathological fractures and facial changes

  >

  Clinically significant extramedullary haematopoiesis

The decision to initiate a long-term transfusion regimen should be based on a definitive diagnosis of transfusion dependent thalassaemia. This diagnosis should consider the molecular defect, the severity of anaemia on repeated measurements, the level of ineffective erythropoiesis, and clinical criteria such as failure to thrive or significant symptoms or bone changes. It must be established that the severity of anaemia is not transient to issues such an infection, in which case a one-off transfusion may be sufficient.

The initiation of regular transfusion therapy for severe thalassaemia genotypes usually occurs in the first two years of life and is in this setting usually due to severe anaemia or significant anaemia with accompanying symptoms such as not being able to feed or failure to thrive. Some patients with milder forms of thalassaemia who only need sporadic transfusions in the first two decades of life may later need regular transfusions because of a falling haemoglobin level or the development of serious complications.

Transfusion thresholds and frequency

The recommended treatment for transfusion dependent thalassaemia is lifelong regular blood transfusions, usually administered every two to five weeks, to maintain the pre-transfusion haemoglobin level 95-105 g/l. This transfusion regimen promotes normal growth, allows normal physical activities, adequately suppresses bone marrow activity in most patients, and minimizes transfusional iron accumulation (Cazzola et al., 1997, 1995). A higher target pre-transfusion haemoglobin level of 110-120 g/l may be appropriate for patients with heart disease, clinically significant extramedullary haematopoeisis or other medical conditions, and for those patients who do not achieve adequate suppression of bone marrow activity at the lower haemoglobin level. Sometimes back pain occurs prior to blood transfusion and may also respond to a higher pre-transfusion haemoglobin level. Although shorter intervals between transfusions may reduce overall blood requirements, the choice of interval must consider other factors such as the patient’s school or work schedule and other lifestyle issues.

The schedule outlined above has been shown to minimize iron loading while suppressing bone marrow expansion in Italian patients with thalassaemia major (Cazzola et al., 1997, 1995). The optimal regimen with other transfusion dependent phenotypes such a E-Beta thalassaemia has not been formally studied and may not be the same, as there is some evidence that lower haemoglobin values may be tolerated in patients with E-Beta thalassaemia. However, in the absence of prospective data to show that low transfusion regimens achieve the same outcomes in such patients, the same approach as for other patients is currently recommended.

Volume to be transfused

It is difficult to make clear recommendations regarding the volume of blood to be infused as the number of red cells per unit and the haematocrit will differ depending on local policies. These relate to the acceptable haematocrit of the donors, the volume collected at donation, whether it is whole or packed red cells and the type of anticoagulant used (see Table 4). To limit donor exposure, a certain number of units (e.g. one or two) rather than a particular volume of blood is ordered. Younger children may require a fraction of a unit to avoid under- or over-transfusion. For such children or for others who may need a specific volume, the following calculations is generally be used:

Table 4

Guidelines for choosing how much blood to transfuse.

(i) (Desired – actual Hb (g/l)) x weight (kg) x 0.3 = ml to be transfused assuming the haematocrit of the unit is 0.58 (Davies et al., 2007)

The right regimen is one in which the haematological targets are met and that achieve the clinical aims of the transfusion regimen.

As an example, using the above Guidelines (Table 4), in order to raise haemoglobin level by 4g/l in a patient weighing 40 kg and receiving blood with a haematocrit of 60%, 800 ml would be required. This calculation assumes a blood volume of 70 ml/kg body weight.

Post transfusion haemoglobin can be measured when evaluating the effects of changes in the transfusion regimen, the degree of hypersplenism, or unexplained changes in response to transfusion.

To achieve pre-transfusion haemoglobin of 90-105 g/l it is often usual to aim for a post transfusion haemoglobin of 130-150g/l. This overall approach to transfusion has been shown to promote normal growth, to allow normal physical activities, to adequately suppress bone marrow activity and to minimize transfusional iron accumulation in most patients (Cazzola et al., 1997).

Although erythrocytapheresis, or automated red cell exchange, has been shown to reduce net red cells infused, and thus the rate of transfusional iron loading (Friedman et al., 2003; Berdoukas, Kwan & Sansotta, 1986), its use may be limited due to a two- to three-fold increase in donor blood utilization and donor exposure resulting in increased costs, and increased risk of transmission. Thalassaemia settings audits have not shown to date the benefit seen in sickle cell disease. Lastly, there are financial constraints with such a procedure and logistic issues surrounding the need for suitable venous access.

Rate of transfusion

The rate of transfusion has not been subjected to a prospective study and again will depend on the component issued. Leucodepletion decreases systemic reactions, packed cells are smaller volume. British Society of Haematology Guidelines state that for adults, a unit of blood (here, packed red cells of a mean volume of 260ml) can be infused over 90 minutes, however, the clinical state of the patient needs to be ascertained to see whether this is suitable. However, an ongoing study in two London thalassaemia centres suggests that in very carefully selected adults >45kg, free of cardiac disease and receiving up to 3 units of mean volume of 260ml can be administered at the rate of one unit per hour. Particular caution should be taken with smaller patients, particularly children, patients with cardiac failure or very low initial haemoglobin levels.

There are international guidelines regarding the keeping of transfusion records (e.g. EU directives). Historically for patients with thalassaemia additional records would be kept. These included the volume or weight of the administered units, the haematocrit of the units or the average haematocrit of units with similar anticoagulant-preservative solutions, and the patient’s weight. With this information, it was possible to calculate the annual blood requirements as volume of transfused blood or pure red cells (haematocrit 100%) per kg of body weight. The latter (pure red cells per kg of body weight) when multiplied by 1.08, the estimated amount of iron per ml of RBC (see Chapter 3: Iron Overload and Chelation), yields an approximate value for the amount of transfusional iron that the patient receives per kilogram of body weight in a year. Figure 1 shows a detailed example of how the daily rate of iron loading (mg/kg/day) is calculated. The rate of transfusional iron loading may be very important in choosing the appropriate dose of an iron chelator among other indicators of iron overload. For example, the recommended dose of the chelator deferasirox is based in part on the daily or annual rate of transfusional iron loading. Nowadays, this level of calculation is not often done, although may be useful in situations where there has been a change in blood requirement, development of hypersplenism or where access to accurate MRI measurements of iron loading is poor.

Figure 1

Calculation of annual blood requirements and transfusional iron loading.

Transfusion and the spleen

The transfusion requirements in unsplenectomised patients are generally higher than splenectomised patients. In a study of thalassaemia major patients who required more than 250 ml of packed red cells/kg/yr, splenectomy decreased the annual iron loading by an average of 39% (Graziano et al., 1981).

Average transfusion requirements are about 30% higher in unsplenectomised (0.43 mg/kg/day) than splenectomised thalassaemia major patients (0.33 mg/kg/day) (Cohen, Glimm & Porter, 2008). With modern chelation regimes, this is seldom a justification for splenectomy unless blood transfusion rates increase into unmanageable ranges, in the context of an enlarging spleen. Hypertransfusion decreases the rate of splenic enlargement (O’Brien, Pearson & Spencer, 1972) and the introduction of a hypertransfusion regimen may diminish the extent to which the spleen contributes to an increased blood transfusion requirement (Modell, 1977) thus preventing the need for a splenectomy.

Specific thresholds of annual transfusion requirements that would lead to consideration of splenectomy are difficult to establish because earlier studies did not specify the haematocrit levels of the transfused blood and because the potential reduction in transfusional iron loading after splenectomy must be weighed against the long-term consequences of asplenia including sepsis, thrombosis and pulmonary hypertension. With access and tolerance to good chelation regimens, splenectomy is not often needed for iron control. Nevertheless, as the annual transfusion requirements rise above 200 ml/kg/year of pure red cells, splenectomy may be considered as one of several strategies to reduce transfusion requirements.

Adverse Reactions

Blood transfusion exposes the patient to a variety of risks and adverse events (see Table 5). Thus, it is vital to continue to improve blood safety and to find ways of reducing transfusion requirements and the number of donor exposures. Equally adverse events reporting should be embedded within the haemovigilance framework. The Serious Hazards of Transfusion (SHOT) yearly reports are an excellent resource for those interested in adverse events, and are frequently accompanied by a chapter on haemoglobinopathies (SHOT, 2021).

Table 5

Broad categorization of immune-mediated transfusion reactions and reported frequencies.

Non-haemolytic febrile transfusion reactions were common in past decades, but have been dramatically reduced by leuco-reduction, especially pre-storage leuco-reduction, which sharply reduces cytokine accumulation and leucocyte alloimmunization. In the absence of effective leuco-reduction, patients experiencing such reactions should be given antipyretics before their transfusions. Since fever may accompany a haemolytic transfusion reaction or the administration of a unit with bacterial contamination, these other causes should always be considered in a patient who develops fever during administration of red cells.

Allergic reactions are usually due to plasma proteins and range from mild to severe. Milder reactions include urticaria, itching and flushing, and they are generally mediated by IgE. More severe reactions, such as stridor, bronchospasm, hypotension or other symptoms of anaphylaxis may occur, especially in patients with IgA deficiency and anti-IgA antibodies. Allergic reactions have been reported in patients s who receive units of blood from donors who have been exposed to something that the patient is allergic to e.g. a donor eating strawberries donating blood to someone who is allergic to strawberries.

Occasional mild allergic reactions often can be prevented using antihistamines or corticosteroids before transfusion. Recurrent allergic reactions can be markedly reduced by washing the red cells to remove the plasma. Patients with IgA deficiency and severe allergic reactions may require blood from IgA -deficient donors.

Acute haemolytic reactions begin within minutes or sometimes hours of initiating a transfusion and are characterized by the abrupt onset of fever, chills, lower back pain, a sense of impending death, dyspneoa, haemoglobinuria and shock. These unusual reactions most commonly arise from errors in patient identification or blood typing and compatibility testing. The risk of receiving the wrong blood is greater for a patient with thalassaemia who travels to another centre or is admitted to a hospital not familiar with his/her case and medical history. Haemolytic reactions in these patients can still be avoided by (1) the use of optimal methods for identifying the patients and labeling of the sample when blood is obtained for crossmatch, (2) proper linkage of the sample to the donor unit in the blood bank, (3) adherence to standard protocols for screening for antibodies and carrying out the necessary compatibility protocols (4) use of multiple patient identifiers before transfusing the blood. In many transfusion units, two staff members check the identification of the unit and the recipient prior to beginning the transfusion although this has been replaced in resource rich countries by electronic forms of patient identification. If signs and symptoms suggest an acute haemolytic reaction, the transfusion should be stopped immediately and intravenous fluids should be administered to maintain intravascular volume. Diuretics may help to preserve renal function. Disseminated intravascular coagulation (DIC) may require additional measures such as heparin. The identification of the patient and the donor unit should be re-checked. The blood bank should also be alerted to the possibility of an undetected alloantibody.

Alloimmunisation, as described above, is a common complication of transfusion therapy, occurring in as many as 10-20% of patients with thalassaemia. Alloimmunisation is more common in children who begin transfusion therapy after 1-3 years of age than in those who begin transfusion therapy earlier. This may reflect the fact that such people are often transfused in an emergency (therefore often not at the hospital where they are known to have thalassaemia and therefore inadequately matched) or when immune activated i.e. when they are unwell. Some evidence also suggests that new alloantibodies develop more frequently after splenectomy (Thompson et al., 2011). The use of extended antigen matched donor blood is effective in reducing the rate of alloimmunisation.

Delayed transfusion reactions usually occur 5-14 days after transfusion and are characterized by unexpected levels of anaemia, as well as malaise and jaundice. These reactions may be due to an alloantibody that was not detectable at the time of transfusion or to the development of a new antibody. A sample should be sent to the blood bank to investigate the presence of a new antibody and to repeat cross-matching of the last administered unit(s).

Autoimmune haemolytic anaemia is a very serious complication of transfusion therapy that usually but not always occurs in patients with alloantibodies (Ameen et al., 2003) although may be unrelated to transfusion. Even red cells from seemingly compatible units (i.e., those units that do not contain the antigen to which there is a known alloantibody) may demonstrate markedly shortened survival, and the haemoglobin concentration may fall well below the usual pre-transfusion level because of destruction of both the donor’s and the recipient’s red cells. The serologic evaluation by the blood bank usually shows an antibody that reacts with a wide range of test cells and fails to show specificity for a particular antigen. Steroids, immunosuppressive drugs and intravenous immunoglobulins are used for the clinical management of this complication (British Society for Haematology, 2016; Hill et al., 2017; Jäger et al., 2020).

Autoimmune haemolytic anaemia occurs more frequently in patients who begin transfusion therapy later in life (Rebulla & Modell, 1991), and this complication should be carefully considered before instituting transfusion therapy for teenagers and adults with thalassaemia intermedia.

Transfusion-related acute lung injury (TRALI) is a potentially severe complication that is usually caused by specific anti-neutrophil or anti-HLA antibodies that activate the patient’s neutrophils, but may also be due to non-antibody related accumulation of pro-inflammatory mediators during storage of donor red cells (Vlaar & Juffermans, 2013; Swanson et al., 2006). This complication is characterized by dyspnoea, tachycardia, fever and hypotension during or within six hours of transfusion. Hypoxemia is present and the chest radigraph shows bilateral infiltrates typical of pulmonary oedema although there is no reason to suspect volume overload. Management includes oxygen, administration of steroids and diuretics, and, when needed, assisted ventilation.

Transfusion-associated graft versus host disease (TA-GVHD) is caused by viable lymphocytes in donor red cell units. It is a rare but often fatal complication of transfusion. Immunosuppressed patients are at particular risk, but TA-GVHD may also occur in immunocompetent recipients of red cells from a haploidentical donor such as a family member. TA-GVHD usually occurs within 1-4 weeks of transfusion and is characterized by fever, rash, liver dysfunction, diarrhoea and pancytopenia due to bone marrow failure. To reduce the risk of TA-GVHD, donated blood from a family member should be avoided or if used should always be irradiated before transfusion. Leucodepletion alone is inadequate for the prevention of this complication.

Transfusion-associated circulatory overload (TACO) may occur in the presence of recognized or unrecognized cardiac dysfunction, or when the rate of transfusion is inappropriately fast. Signs and symptoms include dyspnoea and tachycardia, and the chest radiograph shows the classic findings of pulmonary oedema. Treatment focuses on volume reduction and cardiac support, as required.

Transfusion transmitted infections (TTI) including viruses, bacteria and parasites, are a major risk in blood transfusion (see Chapter 7: Infections). Blood traceability rules are important and enshrined in law in several countries so that “look back” can occur when blood is contaminated (ref EU directive). Even in countries where residual risk of transmission through blood transfusion of clinically significant pathogens (HIV, HBV, HCV and syphilis) has been reduced to minimal levels, problems continue to exist or emerge because:

• Laboratory tests may fail to identify viruses during the window period or because of imperfect sensitivity
• The clinical significance of newly identified infectious agents is not always completely clarified and donors are not screened for these agents
• Newly emerging infectious agents such as coronaviruses, hepatitis E, highly virulent influenza strains and prions may constitute serious threats.
• There is currently no evidence that SARS-COV-2 is transmitted by blood transfusions, however, donor deferral due to recent illness or the logistics of donation during a pandemic has affected blood stocks in many countries.
• Absence of widely accepted or routinely used tests for bacterial, viral and other pathogens (e.g., Yersinia enterocolitica, hepatitis A, toxoplasmosis, malaria and babesiosis).

Although the standard of care to prevent TTI is through donor specific questionnaire and sample screening, there is growing interest in the use of pathogen inactivation/reduction technologies. These have enjoyed greater development in platelet and plasma products and there are ongoing studies in the use of such technologies for red cell products (please see chapter on ‘Infectious disease’).

In many regions of the developing world in which thalassaemia is most common, continued transmission of hepatitis B, hepatitis C and HIV underscores the importance of promoting the quality of national blood transfusion services, including voluntary blood donations, careful donor selection and donor blood screening, and the consistent use of immunizations such as hepatitis B vaccine.

Box

Summary and Recommendations.

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