Prophylactic red blood cell matching in patients with sickle cell disease (SCD) and transfusion-dependent thalassemia (TDT) 

The January 2025 issue of the British Journal of Haematology (BJHAEM) published an updated evidence-based guideline for red blood cell antigen matching in patients with hemoglobinopathies.¹  Alloimmunization to red blood cell antigens has been linked to patient morbidity and mortality in patients with sickle cell disease (SCD) and transfusion-dependent thalassemia (TDT).  The practice of transfusing prophylactically antigen-matched red blood cells is a common practice in the United States used to prevent alloimmunization in select patient populations; however, the evidence supporting this common practice is somewhat limited.  This guideline by the International Collaboration for Transfusion Medicine Guidelines (ICTMG) updated six recommendations in its 2018 guideline.  Additionally, the BJHAEM published a commentary providing additional thoughts and comments on prophylactic antigen matching in the lifelong care of these complex patient populations. 

The Recommendations Reviewed 

Six new observational studies underwent qualitative review. In these studies, the overall rate of alloimmunization was lower using extended matching (0%-24%) than when using limited matching (0%-50%). However, the studies’ overall risk of bias ranged from moderate to critical; and a Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) assessment found that the certainty of evidence to recommend an extended matching strategy was very low. The first two recommendations from the 2018 ICTMG guideline remain unchanged after the literature review. These recommendations are that patients with SCD and TDT receive red blood cells that are RhD, RhCcEe, and K prophylactically matched as well as negative for antigens to which the patients have any identified clinically significant antibodies.  These recommendations apply to SCD and TDT patients even in the absence of any identified alloantibodies.  Of the remaining 4 recommendations, the most important changes were regarding providing extended antigen matching prophylactically.   The 2018 guideline indicated that patients with SCD or TDT “with one or more clinically significant alloantibodies should probably be transfused with CcEe K Fya Fyb Jka Jkb S and s matched RBCs.”  The guideline panel could not make recommendations as to whether these patients should be transfused with more extensively antigen-matched RBCs.  Facilities commonly provide extensively matched RBCs to SCD and TDT patients prophylactically to minimize alloimmunization; however, the panel felt the potential benefits of this approach might be outweighed by its uncertain impact on cost, resources, and provision of blood for patients who are already alloimmunized. 

Transfusion Medicine Approach  

SCD and TDT are distinct clinical diseases united by a high frequency for developing alloantibodies.  The occurrence of alloimmunization can lead to several negative consequences including fatal transfusion reactions and complications in pregnancy.  Providing extensively matched antigen-negative red blood cells has emerged as a best practice to attempt to prevent alloimmunization and the associated downstream effects.   Genotyping only needs to be performed once and may be helpful in determining the presence of variant or rare antigens, potentially decreasing the risk of patient alloimmunization.  The cost of genotyping should be balanced against the cost of a possibly complex serologic workup.   Balancing the desire to provide extensively matched antigen-negative units against the availability and cost of such units has led to a variety of approaches across institutions.²  The guideline and commentary emphasize that this patient population is distinct and complex with their transfusion needs.  High value should be placed on avoiding the adverse effects of alloimmunization while not compromising the timely supply of blood. Patient-specific care options may improve patient outcomes, suggesting that a one-size-fits-all policy approach may not be the best option for this patient population.  While a very conservative approach (prophylactic extensive matching) may reduce alloimmunization, it could also restrict patients from the blood they need and delay surgeries, while a less conservative approach might make more units available but increase the risk of alloimmunization.  The timing of these two articles is of note, given the recent emergence of gene therapies for SCD and TDT, which could decrease red blood cell use over patients’ lifetimes, but a global withdrawal of a major disease-modifying drug (voxelotor)² that no longer holds that promise. These challenges stress the need for clinical flexibility on extensive phenotype matching with a case-by-case approach to achieve optimal patient outcomes balanced with the knowledge that the certainty of evidence to recommend an extensive matching strategy is low.  

1. Wolf J, Blais-Normandin I, Bathla A, Keshavarz H, Chou ST, Al-Riyami AZ, Josephson CD, Massey E, Hume HA, Pendergrast J, Denomme G, Grubovic Rastvorceva RM, Trompeter S, Stanworth SJ; International Collaboration for Transfusion Medicine Guidelines (ICTMG). Red cell specifications for blood group matching in patients with haemoglobinopathies: An updated systemic review and clinical practice guideline from the International Collaboration for Transfusion Medicine Guidelines.  Br J Haematol. 2025;206(1):94-108. 

2. Gehrie EA, Booth GS. Contextualizing prophylactic red blood cell antigen matching in the lifelong care of sickle cell disease and thalassaemia patients. Br J Haematol. 2025;206(1):382-384.