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Amid A, Lal A, Coates TD, et al., editors. Guidelines for the Management of α-Thalassaemia [Internet]. Nicosia (Cyprus): Thalassaemia International Federation; 2023.

Cover of Guidelines for the Management of α-Thalassaemia

Guidelines for the Management of α-Thalassaemia [Internet].

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Chapter 9BLOOD TRANSFUSION

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Introduction

In contrast to people with β-thalassaemia syndromes, individuals with α-thalassaemia are largely non-transfusion dependent. This is, in part, due to the intrauterine demise of patients with the most severe form of α-thalassaemia, haemoglobin Bart’s hydrops foetalis (or α-thalassaemia major), while other less severe forms of α-thalassaemia (e.g., most patients with haemoglobin H disease) are generally non-transfusion dependent. Nevertheless, episodic (on-demand) blood transfusion remains an important component of management for most patients with HbH disease. In some patients with more severe forms of HbH disease and all surviving patients with haemoglobin Bart’s hydrops foetalis, regular blood transfusion is the mainstay of treatment [1–4]. Furthermore, intrauterine blood transfusion can be the lifesaving intervention for foetuses with haemoglobin H hydrops foetalis or haemoglobin Bart’s hydrops foetalis syndromes [5, 6].

Overall, the general principles of transfusion in α-thalassaemia are based on those of β-thalassaemia. In this chapter, we do not intend to duplicate these recommendations, and readers and clinicians are encouraged to refer to Thalassaemia International Federation Guidelines for the Management of Transfusion Dependent Thalassaemia [7] for a more in-depth review and recommendations. Here, however, we provide an overview of these recommendations, but more specifically, we highlight some aspects of transfusion that are specific for α-thalassaemia.

Aims of blood transfusion in HbH disease and haemoglobin Bart’s hydrops foetalis syndrome (α-thalassaemia major)

In individuals with α-thalassaemia, blood transfusion can be required either on-demand or occasionally as part of a regular transfusion programme.

On-demand transfusions

Despite having moderate anaemia, most patients with HbH disease are asymptomatic and do not require transfusions. However, during periods of physiologic stress or illness, anaemia can become severe enough to necessitate on-demand transfusion [1–4]. These events can occur following an infection, febrile episode, an oxidative challenge, surgical procedure, or during pregnancy. Acute haemolytic episodes are more common in individuals with non-deletional forms of HbH disease, but they can also occur in those with deletional HbH disease, especially in younger children [4, 8]. Haemolysis can be brisk leading to acute haemodynamic compromise requiring urgent intervention [1]. Similarly, patients may experience an acute aplastic event following viral infections. Patients who require frequent on-demand transfusions may be considered for a disease-modifying approach (e.g., regular transfusion, splenectomy, or other novel treatments).

The decision to offer on-demand transfusion is based on a patient’s clinical status rather than a haemoglobin number. The underlying clinical indication, expected course of acute illness, and preference of patient or their caregivers plays a role. Most patients with an acute drop of haemoglobin to less than 60-70 g/L will benefit from correction of acute anaemia. On-demand transfusion can be considered during pregnancy to ensure normal development of the foetus and mother’s health [9, 10]. On-demand transfusion can also be offered to patients with more severe anaemia prior to surgeries as per discretion of the surgeon or anaesthesiologist.

If blood transfusion is required during an acute haemolytic event (or acute aplastic event), the haemoglobin should be increased to baseline, or slightly higher if it is expected that the haemolytic process is ongoing. In general, clinicians are advised not to expose patients to extra units of blood if not needed, but the patients’ clinical status should allow for transfusion of the whole unit so valuable donated blood is not discarded if the volume of transfusion does not exceed 20 ml/kg.

Patients with an acute event should be monitored closely to ensure indications for further transfusion have resolved. Supportive therapies should include adequate hydration to preserve renal function, but excessive hydration should be avoided to prevent volume overload. Addressing the underlying cause of an acute event is paramount.

Recommendations

  • Identify the underlying cause of an acute event (e.g., infection/inflammation/aplasia) and provide appropriate treatment. Empiric antibiotics with the coverage against encapsulated bacteria should be initiated in splenectomized patients with fever.
  • The decision to offer on-demand transfusion should be based on patient’s clinical status, underlying clinical indication of expected course of acute illness, and preference of patient or their caregivers.
  • The aim of blood transfusion is to restore patient’s haemoglobin to baseline or slightly higher.
  • Patients experiencing an acute event should be monitored closely to ensure indications for further transfusion have resolved.
  • Serial assessment of haemoglobin concentration, haemolytic markers, electrolytes, and renal function should be done, since continuing hemolysis could lead to worsening anaemia, electrolyte and acid-base disturbances, and renal damage.
  • Adequate hydration should be provided to maintain circulation and renal perfusion, but excessive hydration should be avoided to prevent volume overload.
  • Other supportive measures should be offered as needed (e.g. antipyretics).
  • If clinically indicated, on-demand transfusion can be offered prior to surgeries, or during pregnancy.

Regular transfusion programme

Regular blood transfusion is less commonly utilized in individuals with HbH disease. In general, individuals with deletional forms of HbH disease will rarely require starting regular transfusion unless there are associated disease modifiers or other aetiologies exacerbating their anaemia. In patients with non-deletional forms of HbH disease, regular blood transfusions are intended to improve the haemoglobin level in symptomatic patients, prevent or reduce the long-term sequelae of chronic haemolytic anaemia, suppress ineffective erythropoiesis, allow normal growth and development in children and adolescents, and improve an individual’s quality of life [1–4].

Severe anaemia can be observed from early childhood in patients with certain forms of non-deletional HbH disease (e.g., compound heterozygosity for α0-thalassaemia deletion and haemoglobin Pak Num Po [11], or haemoglobin Suan Dok α109leu→argα mutations). In the most severe forms of HbH disease, profound anaemia starts in utero leading to hydrops foetalis (e.g., due to interaction of α0-thalassaemia deletions and rare non-deletional mutations such as haemoglobin αCd 59Gly-Aspα (Adana), αΔCd 30α, αCd 66 Leu-Proα (Dartmouth), αCd 35Ser-Proα (Evora). Patients with this form of α-thalassaemia (HbH hydrops foetalis) require intrauterine and then regular lifelong transfusions, although, rarely, some patients may no longer require regular transfusions as they age [9]. Interestingly, individuals who are homozygote for α142 STOP→Gln; TAA→CAAα (Hb Constant Spring), α PA1(AATAAG)α (Poly A), or Hb Taybe can present with hydrops during pregnancy and severe anaemia requiring transfusion during first few months of life, which will resolve by age 1 [3, 9]. These patients will remain non-transfusion dependent thereafter.

Regular transfusion is the cornerstone of treatment in long-term survivors of haemoglobin Bart’s hydrops foetalis (α-thalassaemia major). Intrauterine transfusion is associated with improved prenatal outcomes in patients with haemoglobin Bart’s hydrops foetalis, although their effect on the long-term outcomes is not entirely clear [5].

It is important to identify any other modifiable cause of anaemia (e.g., folate deficiency, vitamin B12 deficiency, or G6PD enzyme deficiency) prior to embarking on a chronic transfusion programme.

When to start regular transfusions?

In individuals with HbH disease, deciding to start regular transfusions and defining transfusion targets is complex and requires experience and clinical judgment. This complexity arises from several factors. First, there is little data available to systematically study and compare the long-term outcomes of regular transfusions versus other treatment approaches (e.g., continuing on-demand transfusions or splenectomy), and recommendations in this setting are based on expert opinions. Second, there is considerable heterogeneity in clinical presentation and underlying disease process in HbH disease, especially in those with non-deletional types. Patients can have predominantly a haemolytic disease (majority of patients), while some genotypes can lead to a significant apoptosis of early erythroid cells leading to ineffective erythropoiesis similar to β-thalassaemia [1]. Third, in patients with HbH disease, the need for regular transfusions is a dynamic process, and occasionally, patients who require transfusions may no longer be transfusion-dependent and vice versa. Fourth, there is a heterogeneity of the proportion of circulating HbH in different subtypes of HbH disease [4, 9]. As HbH is a non-functional haemoglobin due to its extremely high oxygen affinity, the total haemoglobin may not be a true representation of tissue oxygen delivery in those patients who have a high level of circulating HbH (> 20%) [12]. Finally, a regular transfusion programme should be decided per individual case as this requires significant resources and is associated with considerable burden on both patients and health care systems.

In general, if a disease modifying therapy is required, regular transfusion is the intervention of choice for young children, and early splenectomy is not recommended. This is because of the higher risk of overwhelming sepsis in young children. Furthermore, some of these children may no longer require transfusion later in life even without splenectomy.

For patients with genotypes that are associated with severe anaemia (effective Hb < 70 g/L) and considerable ineffective erythropoiesis, a transfusion approach similar to those with β-thalassaemia is desired [1, 13] and splenectomy is not generally recommended (please see Chapter 10 Splenomegaly and Splenectomy). In contrast, patients with a predominantly haemolytic disease, those with effective Hb >70 g/L, or those with symptomatic splenomegaly or hypersplenism may be considered for splenectomy if the resources are scarce or if a regular transfusion programme is associated with significant burden on patients’ quality of life. In this setting, long-term complications of splenectomy (e.g., risk of thrombotic events, pulmonary hypertension) should be carefully reviewed [14, 15].

In patients who are being considered for transfusion, lower pre-transfusion haemoglobin targets as compared to β-thalassaemia may be acceptable (80-90 g/L) as generally there is less degree of ineffective erythropoiesis in HbH disease in comparison to β-thalassaemia [16, 17]. However, those with a high proportion of circulating HbH or those with genotypes associated with significant ineffective erythropoiesis may require higher pre-transfusion haemoglobin targets to adjust for the non-functional HbH [18, 19] or to suppress ineffective erythropoiesis. The decision to start regular transfusion should be made through a patient-centred approach. A severity scoring system to predict the need for regular transfusions in children has been recently developed and validated [13].

Recommendations

  • The criteria to start regular transfusion in individuals with HbH disease are not well defined and are generally based on expert opinion.
  • It is recommended that “effective” haemoglobin be measured at a steady state. Effective haemoglobin can be calculated as total Hb x (1- [HbH % + Hb Bart’s %] / 100). Please note that the current technology of Hb analysis by automatic high-performance liquid chromatography (HPLC) such as Variant (Bio Rad) could not accurately quantitate the percentage of HbH and Hb Bart’s. The percentage of HbH and Hb Bart’s can be more accurately measured by capillary electrophoresis system; however, caution should be exercised that this is not done during an acute haemolytic event.
  • Initiations of regular transfusion should be individualized and be offered through a patient-centred approach.
  • Regular transfusions should be considered in the following settings:
    -

    Patients with Hb Bart’s hydrops foetalis (α-thalassaemia major).

    -

    Patients with baseline “effective” haemoglobin < 70 g/L (or < 80 g/L if effective haemoglobin cannot be calculated).

    -

    Declining haemoglobin concentration or development of symptomatic anaemia in those who have not been on regular transfusions.

    -

    To prevent or reduce the long-term sequelae of chronic haemolytic anaemia or to suppress ineffective erythropoiesis.

    -

    Frequent acute haemolytic events requiring on-demand transfusions

    -

    Children and adolescents with growth failure, poor academic performance, diminished exercise tolerance, or delayed puberty.

    -

    Poor quality of life due to anaemia.

  • When regular transfusion is being considered, alternative therapeutic interventions, such as splenectomy, should also be reviewed.
  • Careful monitoring and treatment of iron overload is paramount, although, as compared to β-thalassaemia, ferritin may underestimate the degree of tissue iron due to the difference in the pathophysiology of α- vs. β-thalassaemia.
  • In low-resource settings, or if a regular transfusion programme and iron chelation are challenging or not feasible, splenectomy can be considered in those who are older than 5 years of age with a predominantly haemolytic HbH disease. Pre-splenectomy vaccination for encapsulated organisms is highly recommended. Patients with severe anaemia requiring transfusion from early childhood or those with significant ineffective erythropoiesis should be treated similar to β-thalassaemia and in general, splenectomy is not recommended.
  • A pre-transfusion haemoglobin target of 80-90 g/L is acceptable in most patients. However, those with high proportion of circulating HbH and those with ineffective erythropoiesis may require higher pre-transfusion haemoglobin targets.
  • Patients with Hb Bart’s hydrops foetalis (α-thalassaemia major) require an aggressive transfusion approach to suppress significant erythropoiesis and improve oxygenation through increasing functional (non-HbH) haemoglobin. In these patients, “functional” haemoglobin should be calculated for a pre-transfusion functional Hb target of 90-100 g/L.
  • The need for ongoing regular transfusion should be regularly evaluated, as some patients may become transfusion independent.

Haemovigilance and blood conservation

According to the World Health Organization, “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” [20].

In general, principals of haemovigilance for blood transfusion in α-thalassaemia is similar to β-thalassaemia and readers are referred to Thalassaemia International Federation Guidelines for the Management of Transfusion Dependent Thalassaemia for further review [7].

One of the important aspects of transfusion in thalassaemia is the risk of alloimmunization, which is the development of specific red cell antibodies following frequent exposure to blood products [21]. The development of antibodies to red cell antigens is a significant event and has major implications for the transfusion therapy [22]. Here, we would like to highlight that the data related to prevalence of alloimmunization and its risk factors in α-thalassaemia are quite scarce, and limited studies have included transfusion dependent thalassaemia patients as a single group [21–24]. In the absence of further specific data, it is reasonable to follow similar recommendations for β-thalassaemia. Risk of alloimmunization is likely higher during pregnancy, in splenectomized patients, and in those who have had minimal transfusion exposure [7]. Patients with α-thalassaemia should have extended red cell antigen typing that includes at least A, B, O, C, c, D, E, e, and Kell antigens and preferably a full red cell phenotype/genotype panel, and all patients should be transfused using A, B, O, C, c, D, E, e, and Kell compatible blood [7].

Recommendations

Recommendations

  • Use a product that is collected, tested, selected, issued, and administered in adherence to established quality and safety regulations and guidance.
  • Blood transfusion should be administered by staff trained in blood transfusion.
  • Involve informed patient consent.
  • The transfusion should be performed in a system with a good haemovigilance structure.
  • If possible, do not waste valuable donated blood.
  • Blood storage for <2 weeks, conditioning to achieve mean 24-hour post-transfusion RBC survival ≥75%.
  • Leucoreduced packed red blood cells (≤1 x 106 leucocytes/unit) with haemoglobin content ≥40 g (pre-storage filtration preferred).
  • Patients with α-thalassaemia should have extended red cell antigen typing that include at least A, B, O, C, c, D, E, e, and Kell antigens and preferably a full red cell phenotype/genotype penal should be done prior to first transfusion.
  • All patients should be transfused with A, B, O, C, c, D, E, e, and Kell compatible blood.
  • Patients are advised to have appropriate vaccinations against transfusion-transmitted infections.

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