Sickle cell disease (SCD) and thalassemia are complex hemoglobinopathies. Although they are grouped here together, their clinical manifestations and treatment modalities are different. Red blood cell (RBC) transfusion is a cornerstone for the management of patients with SCD and thalassemia. Transfusion in SCD patients can be for acute indications where transfusion can be life-saving, or for regular long-term therapy. These indications range from those in which transfusion is strongly recommended to those where it is unproven or controversial, and therefore requiring individualized decision. There are insufficient randomized clinical trials (RCT) to direct the clinicians on when to transfuse SCD patients. Transfusion for indications where evidence is limited should be based on a case-by-case assessment.

Homozygeous ß Thalassemia can be broadly clinically categorized as:
  • “transfusion-dependent thalassemia, TDT” who require regular transfusion from infancy to sustain life and suppress ineffective erythropoiesis, and
  • “non-transfusion dependent thalassemia, NTDT” who have moderate hemolytic anemia but maintaining a hemoglobin (Hb) level that is sufficient for growth and development without transfusion support. (1)

However, these patients may have worsening anemia particularly upon exposure to physiological stressor or other triggers which necessitates transfusion support. (2)

This guideline summarizes the evidence in transfusing patients with SCD and thalassemia. This may not be appropriate for all clinical scenarios and clinical decisions must be based on individual patient consideration. This guideline serves only as a guide and should not replace clinical judgment in each individual clinical situation. Consultation with a hematologist with expertise in managing SCD and thalassemia patients is advised as required. 

General Comments
  • An extended RBC phenotype should be performed for all patients with SCD and thalassemia using a pre-transfusion specimen. This ideally should be performed in the first year of life before the start of a regular transfusion program.(3, 4)
  • If the patient has been recently transfused, DNA-based methods can be used to determine the predicted phenotype.(5)
  • A full cross-match and antibody screen of new antibodies should be performed before each transfusion. In centers that meet regulatory requirements, an electronic cross match can be performed.
  • Every patient should have a complete record of antigen typing, antibodies, and transfusion reactions.
  • Components provided need to be phenotype matched based on existing guidelines and recommendations. (3, 4, 6-11)
  • If allo-antibodie(s) are identified, RBCs used for transfusion should be negative for the corresponding antigen(s) and cross match compatible.
  • RBC units for patients with SCD should be sickle test negative. (12)
  • It is recommended to provide fresh units (less than 7-14 days old) if possible for SCD and thalassemia patients, as fresher units may reduce frequency of transfusion. (3, 12)
  • Before first transfusion, a course of hepatitis B vaccination should be started and completed if possible. (3) Serologic testing for hepatitis A, B, C and HIV should be performed as baseline measures, and all patients who do not have serologic immunity to hepatitis B virus should start a vaccination program and show evidence of immunity before the start of the transfusion. (4, 8, 12)
  • Cytomegalovirus negative components are recommended for potential candidates for stem cell transplantation. (1)
  • Chronic transfusion is associated with the risk of iron overload and related complications including cardiac, hepatic and endocrine. This necessitate monitoring of iron overload and appropriate chelation therapy initiated. (13)

 

Transfusion indications in Sickle Cell Disease

Indications for acute Transfusion

Acute ischemic stroke: Transfusion has been shown to be beneficial in the management of ischemic stroke. Urgent transfusion is also required in patients with acute neurological symptoms aiming to achieve a HbS below 30% (12, 14). This will often require an exchange transfusion, but an initial top-up transfusion many be needed depending on the patient’s Hb (12). It is important to avoid hypervolemia during the procedure and to keep the post transfusion Hb at 10 g/dl, as a high hematocrit (Hct) may worsen the neurological insult. (12, 14) 

Acute anemia: Top-up transfusions may be necessary especially if the acute anemia is accompanied with reticulo-cytopenia suggestive of parvovirus B19 infection, or in symptomatic patients, or in those who show signs of imminent or established cardiovascular compromise. The threshold Hb level for the transfusion depends on the patient’s baseline Hb and clinical status, while the target is the patient’s Hb steady-state level.(12) Exchange transfusion is indicated in the unwell patient with exacerbation of the anemia due to acute multi-organ failure and mesenteric syndrome.(14, 15) 

Splenic and hepatic sequestration: In patients with splenic and hepatic sequestration, transfusion follows fluid resuscitation but should be managed cautiously with small volumes to avoid hyper-viscosity due to the return of the sequestered RBC to the circulation.  Over-transfusion to Hb > 80 g/dl should be avoided. Patients with recurrent episodes of splenic sequestration (two or more) should be considered for splenectomy.(14) 

Acute chest syndrome (ACS): If there is suspicion of ACS, it is advisable to ensure availability of blood for exchange transfusion ahead of time, as acute respiratory failure can intervene rapidly and blood transfusion can be life-saving. Transfusion may be given by simple or exchange depending on the clinical severity. (14) Exchange transfusion is recommended in patients with features of severe ACS, those who fail to response to initial simple transfusion, or patients with a higher Hb level (> 90 g/dl) at time of presentation. (14, 16) Early top-up transfusion may avoid the need for exchange transfusion in these patients. (12) A target HbS of < 30-40% is often used, but should be guided by the clinical response. (16) 

Severe SCD crisis: Transfusion is beneficial in selected patients with severe complicated SCD crisis if substantial drop in the  Hb from baseline, hemodynamic compromise or concern of impending critical organ complications. (14) 

Acute Priapism: The benefit of transfusion to relieve established acute priapism has not been evaluated in RCTs. (14) Patients may require a transfusion if in preparation for a shunt or drainage procedure under general anesthesia and may also benefit from an exchange transfusion if no response to these procedures. (14, 17) 

Severe sepsis: An exchange transfusion or simple transfusion may be useful in cases with severe sepsis. (14, 18) 

 

There are no data at present to support transfusion in the acute management of hemorrhagic stroke. There is insufficient evidence for the benefit of blood transfusion for managing leg ulcers, pulmonary hypertension, end-stage liver disease and progressive sickle cell retinopathy. A full risk assessment is recommended with consultation with an experienced hematologist. (14)

 

Indications for chronic Transfusion

Primary stroke prevention and silent cerebral infarcts: The best data to support chronic transfusion in SCD patients are for primary infarctive stroke prevention (19, 20) and secondary prevention of silent cerebral infarcts in pediatric patients. (21)

  • Annual Transcranial Doppler (TCD) ultrasound assessment in SCD children from the age of 2 years is recommended.
  • Children with raised cerebral blood flow-velocities ≥ 200 cm/s benefit from a chronic transfusion program aiming to maintain HbS to below 30%.(12, 14, 19)
  • Regular transfusion should be continued throughout childhood (up to the age 16 years), as a significant number of children revert to high TCD velocities or develop overt stroke after discontinuation.(14, 20)
  • Hydroxyurea is efficacious and non-inferior to blood transfusion, and should be considered for primary stroke prevention in children with SCD and high TCD velocities with no severe Magnetic Resonance Angiography (MRA)-defined cerebral vasculopathy or prior transient ischemic attacks after a minimum of one year of initial transfusion.(14, 22) It is recommended to determine the duration of the initial period of transfusion prior to the switch-over to hydroxyurea on a case-by-case basis, after a minimum of one year of transfusion support. (14)
  • Blood transfusion was found to reduce the incidence of infarct recurrence in children with SCD and silent cerebral infarcts.(21) Transfusion should be offered to children who are identified as being at the greatest risk. (14)
  • TCD has not been validated in adults SCD patients and there are no studies performed to evaluate the efficacy of transfusion for primary stroke prevention in this group of patients, nor in patients who have been on long-term transfusions for primary stroke prevention since childhood.(14) Management of these patients should be decided individually.

Secondary stroke prevention: 

  • Transfusion plus chelation is superior to hydroxyurea for secondary stroke prevention in children with SCD. (23) Long-term transfusion is recommended to maintain HbS <30%. Transfusion for secondary stroke prevention my need to be continued indefinitely, but should also be tailored to the needs of the patients and get reviewed regularly with the patient &/or parents.(14)
  • Data on transfusion for secondary stroke prevention in adult SCD patients is limited. Long-term transfusion to maintain HbS <30% is however recommended for the prevention of recurrent stroke. (14)

Other indications: Other indications for long-term transfusion support in SCD are recurrent acute chest syndrome not prevented by hydroxyurea, or for whom it is contraindicated, recurrent vaso-occlusive crisis and progressive organ failure.(12, 14) Long-term transfusions may also benefit patients with recurrent painful crises, where hydroxyrea is ineffective or contraindicated.(14)

 

Special indications

Preoperative settings: There is no consensus as to which SCD patients need preoperative transfusion. (12)

  • Preoperative transfusion (simple transfusion to Hb 10 g/dl if Hb < 9 g/dl or exchange if Hb ≥ 9 g/dl) is recommended for SCD patients undergoing elective medium-risk (e.g abdominal, tonsillectomy, orthopedic) and major-risk (e.g cardiovascular) surgeries.(14) There is only one RCT which showed that conservative transfusion raising Hb level of 10g/dl was as effective in preventing pre-operative complications as aggressive exchange reducing HbS to < 30%. (24)
  • All other patients undergoing elective surgeries should be individually assessed, taking into account previous history, urgency and complexity of the surgery.
  • For patients requiring emergency surgeries, the urgency and complexity of the surgery should be taken into account in the timing of the perioperative transfusion. Provided transfusion will not result in undue delay to surgery, simple transfusion should be given preoperatively to target a Hb of 10 g/dl.(14)

Pregnancy: 

  • Prophylactic transfusion should be considered in patients with previous or current medical, obstetric or fetal complications related to SCD, patients previously on hydroxyurea because of severe disease and in patients with multiple pregnancies.(14)
  • Transfusion should be considered in women with worsening anemia or those with acute SCD complications (e.g acute chest syndrome, stroke).
  • Routine prophylaxis is not routinely required and not recommended in uncomplicated pregnancies. (14, 25)
  • Women on long term transfusion for other indications should continue regular transfusion throughout pregnancy.

 

Transfusion Indications in homozygeous ß Thalassemia

Transfusion-dependent thalassemia (TDT)
  • The decision of regular transfusion in infants with ß thalassemia usually occur in the first two years of life.(9) Where possible, this decision should not be delayed until after the 3rd year of age, as the risk of alloimmunization increases with subsequent difficulty in finding suitable RBC units. (3)
  • Once an infant with ß thalassemia is diagnosed, close monitoring from the age of 3 months is required for clinical signs indicative of the initiation of regular transfusion. The Hb level should be checked at least monthly.
  • Indication for initiation of regular transfusion in infants with ß thalassemia include severe anemia below 7 g/dl on two occasions 1-2 weeks apart, accompanied by inappropriate fatigue, poor feeding, development delay or regression or symptoms of heart failure and after excluding contributing causes such as infections. (3, 8, 9) Reassessment after first transfusion for anemia is important to decide if regular transfusions is required or not. If the Hb falls again promptly, it is reasonable to assume longer term dependency necessitating the start of a regular transfusion program.(1, 3)
  • Other causes of the initiation of the transfusion irrespective of the Hb level include failure to thrive, increasing splenomegaly, fractures, evidence of extramedullary hematopoiesis such as bony expansions and changing appearance of facial bones.(3, 9)
  • In children, regular transfusion should aim for a trough pre-transfusion Hb level of 9-10.5 g/dl.(3, 26) Occasional patients with cardiac disease, extramedullary hematopoiesis &/or inadequate bone marrow suppression benefit from higher transfusion thresholds of 11-12 g/dl, although the limited evidence in this. (3) Volume to transfuse is measured based on particular formula.(9, 27, 28)
  • Once commenced, regular transfusions are usually given regularly every 2-4 weeks.(3) With aging patients, a transfusion every two weeks may be necessary. (8) Transfusion requirements are likely to increase in pregnant patients.
  • It is recommended to maintain a record of transfusion including the volume or weight of administered units, the Hb/Hct of the units, the patient’s weight, transfusion reactions and red cell antibodies formed.(4, 9)
  • In patients undergoing elective surgeries, a preoperative assessment should include transfusion history and baseline Hb levels to plan pre-and peri-operative transfusion regimen, and to allow surgeries to be undertaken with optimal Hb level. (10-12 g/dl) Post transfusion Hb should not be higher than 14-15 g/dl to avoid risk of hyper-viscosity and stroke.(9)
  • Splenectomy is sometimes indicated for hypersplenism and for those with splenectomy and high transfusion requirements.(29)

 

 

Non-Transfusion-dependent thalassemia (NTDT)

  • It is important to monitor the patients once the diagnosis has been established to assess the transfusion requirements. Decision for transfusions depends on several factors rather than the Hb level alone. (30) Increased risk of transfusion-induced iron overload, endocrinopathies and alloimmunization should be taken into account when deciding when to transfuse these patients. (31)
  • Regular transfusion is not required in this group of patients during childhood, unless if evidence of fall in height velocity or bony changes. Therefore, during the first 3-5 years of life, children should be monitored carefully for evidence of thalassemic features resulting from ineffective erythropoiesis. Children can be commenced on regular transfusions till maximum height is achieved, and bones are fused before attempting to wean off then stop regular transfusions.(3) It is important to maintain the child in good health and normal growth and development with avoiding unnecessary transfusions in those with minor clinical features.
  • Older children, adolescents and adults should continue to be monitored regularly for any indications that may arise. Some adolescents will require
  • transfusion because of poor growth, delayed/absent puberty, or complications due to bone expansions.
  • During adulthood, episodic transfusion may be indicated during acute episodes of anemia, pregnancy, surgery and infections.(2, 10, 32) Transfusion should be considered in the management, primary prevention (in high-risk populations) or secondary prevention in some settings. These include the development of thrombotic or cerebrovascular disease, pulmonary hypertension with or without secondary heart failure, extramedullary hematopoietic pseudo-tumors, leg ulcers, silent brain infarcts and thrombotic events.(10) Once transfusion is initiated, the patient will require closer monitoring and therapy should be individually tailored to meet patient’s needs.(10)
  • The decision for regular transfusion should be made with consultation with a specialist in managing these patients. Indications include symptomatic anemia, delayed growth, bone deformities or fractures, pulmonary hypertension, chronic ankle ulceration ,cerebrovascular accidents and silent ischemic lesions, and symptomatic extramedullary hematopoiesis. (3, 11)

 

 

References

  1. How I treat thalassemiaEliezer A, Patricia J.Blood. 2011;118:3479-88.
  2. When to consider transfusion therapy for patients with non‐transfusion‐dependent thalassaemia.Taher A, Radwan A, Viprakasit V.Vox sanguinis. 2015;108(1):1-10.
  3. Standards for the Clinical Care of Children and Adults with Thalassaemia in the UKAnne Yardumian PT, Farrukh Shah, Kate Ryan,Matthew W Darlison, Elaine Miller, George Constantinou3rd ed. London, UK: Thalassaemia Society; 2016.
  4. Guidelines for the clinical care of patients with thalassemia in Canada. Anemia Institute for Research and Education & Thalassemia Foundation of Canada. Sayani F, Warner M, Wu J, Wong-Rieger D, Humphreys K, Odame I. Canadian Pediatric Society, 2009
  5. Blood group genotyping: from patient to high-throughput donor screeningVeldhuisen B, van der Schoot CE, de Haas MVox sanguinis. 2009;97(3):198-206.
  6. Challenges of alloimmunization in patients with haemoglobinopathiesChou ST, Liem RI, Thompson AABritish journal of haematology. 2012;159(4):394-404.
  7. Immune regulation in chronically transfused allo-antibody responder and nonresponder patients with sickle cell disease and beta-thalassemia major.Bao W, Zhong H, Li X, Lee MT, Schwartz J, Sheth S, et al. American journal of hematology. 2011;86(12):1001-6.
  8. Standards of care guidelines for thalassemia.Vichinsky E, Levine L, Bhatia S, Bojanowski J, Coates T, Foote D, et al.Children’s Hospital & Research Center Oakland, USA. 2008.
  9. Guidelines for the management of transfusion dependent thalassaemia (TDT).Cappellini M-D, Cohen A, Porter J, Taher A, Viprakasit V.TIF publication. 2014(20).
  10. Guidelines for the management of non transfusion dependent thalassaemia (NTDT): Thalassaemia Taher A, Vichinsky E, Musallam K, Cappellini M-D, Viprakasit V.International Federation, Nicosia, Cyprus; 2013.
  11. Guidelines for diagnosis and management of Beta-thalassemia intermedia.Karimi M, Cohan N, De Sanctis V, Mallat NS, Taher A.Pediatric hematology and oncology. 2014;31(7):583-96.
  12. Sickle cell disease in childhood: standards and guidelines for clinical care: NHS Sickle Cell and Thalassaemia Screening ProgrammeDick M. NHS 2010
  13. Standards for the clinical care of adults with sickle cell disease in the UKOlujohungbe A, Bennett L, Chapman C, Davis B, Howard J, Ryan K, et al.Sickle Cell Society, London, UK. 2008.
  14. Guidelines on red cell transfusion in sickle cell disease Part II: indications for transfusion. Davis BA, Allard S, Qureshi A, Porter JB, Pancham S, Win N, et al. British journal of haematology. 2016.
  15. Acute multiorgan failure syndrome: a potentially catastrophic complication of severe sickle cell pain episodes. Hassell KL, Eckman JR, Lane PA. The American journal of medicine. 1994;96(2):155-62.
  16. Guideline on the management of acute chest syndrome in sickle cell disease. Howard J, Hart N, Roberts‐Harewood M, Cummins M, Awogbade M, Davis B. British journal of haematology. 2015;169(4):492-505.
  17. The Transfusion Alternatives Preoperatively in Sickle Cell Disease (TAPS) study: a randomised, controlled, multicentre clinical trial. Howard J, Malfroy M, Llewelyn C, Choo L, Hodge R, Johnson T, et al. The Lancet. 2013;381(9870):930-8.
  18. Indications for red cell transfusion in sickle cell disease. Ohene-Frempong K, Seminars in hematology; 2001: Elsevier.
  19. Prevention of a first stroke by transfusions in children with sickle cell anemia and abnormal results on transcranial Doppler ultrasonography. Adams RJ, McKie VC, Hsu L, Files B, Vichinsky E, Pegelow C, et al. The New England journal of medicine. 1998;339(1):5-11.
  20. Discontinuing prophylactic transfusions used to prevent stroke in sickle cell disease.Adams RJ, Brambilla D. The New England journal of medicine. 2005;353(26):2769-78.
  21. Controlled trial of transfusions for silent cerebral infarcts in sickle cell anemia.DeBaun MR, Gordon M, McKinstry RC, Noetzel MJ, White DA, Sarnaik SA, et al. New England Journal of Medicine. 2014;371(8):699-710.
  22. Hydroxycarbamide versus chronic transfusion for maintenance of transcranial doppler flow velocities in children with sickle cell anaemia—TCD With Transfusions Changing to Hydroxyurea (TWiTCH): a multicentre, open-label, phase 3, non-inferiority trial. Ware RE, Davis BR, Schultz WH, Brown RC, Aygun B, Sarnaik S, et al. The Lancet. 2016;387(10019):661-70.
  23. Stroke with transfusions changing to hydroxyurea (SWiTCH). Ware RE, Helms RW. Blood. 2012:blood-2011-11-392340.
  24. A comparison of conservative and aggressive transfusion regimens in the perioperative management of sickle cell disease. Vichinsky EP, Haberkern CM, Neumayr L, Earles AN, Black D, Koshy M, et al. New England Journal of Medicine. 1995;333(4):206-14.
  25. Pregnancy and sickle cell disease: A review of the current literature. Boga C, Ozdogu H. Critical reviews in oncology/hematology. 2016;98:364-74.
  26. A moderate transfusion regimen may reduce iron loading in beta-thalassemia major without producing excessive expansion of erythropoiesis. Cazzola M, Borgna-Pignatti C, Locatelli F, Ponchio L, Beguin Y, De Stefano P. Transfusion. 1997;37(2):135-40.
  27. Guidelines on transfusion for fetuses, neonates and older children. New HV, Berryman J, Bolton‐Maggs PH, Cantwell C, Chalmers EA, Davies T, et al. British journal of haematology. 2016;175(5):784-828.
  28. Calculating the required transfusion volume in children. Davies P, Robertson S, Hegde S, Greenwood R, Massey E, Davis P. Transfusion. 2007;47(2):212-6.
  29. Transfusion requirements and effects in patients with thalassaemia major. Rebulla P, Modell B. The Lancet. 1991;337(8736):277-80.
  30. Optimal management of β thalassaemia intermedia. Taher AT, Musallam KM, Cappellini MD, Weatherall DJ.British journal of haematology. 2011;152(5):512-23.
  31. Overview on practices in thalassemia intermedia management aiming for lowering complication rates across a region of endemicity: the OPTIMAL CARE study. Taher AT, Musallam KM, Karimi M, El-Beshlawy A, Belhoul K, Daar S, et al. Blood. 2010;115(10):1886-92.
  32. Paraspinal extramedullary hematopoiesis in patients with thalassemia intermedia. Haidar R, Mhaidli H, Taher AT.European Spine Journal. 2010;19(6):871-8.

 

The author

Arwa Al Riyami

Arwa Al Riyami

Clinical Transfusion Working Party Chair, Senior Consultant Hematopathologist, Sultan Qaboos University Hospital, Muscat, Oman