Transfusion medicine

Transfusion reactions & complications

Red blood cell alloimmunization

Editorial Board Member: Kyle Annen, D.O.
Deputy Editor-in-Chief: Patricia Tsang, M.D., M.B.A.
Sara Bakhtary, M.D.

Last author update: 31 October 2022
Last staff update: 31 October 2022

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PubMed Search: Red blood cell alloimmunization

Sara Bakhtary, M.D.
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Cite this page: Bakhtary S. Red blood cell alloimmunization. website. Accessed September 21st, 2023.
Definition / general
  • Red blood cell (RBC) alloimmunization is the formation of antibodies to non-self RBC antigens (excluding naturally occurring anti-A and anti-B)
  • Only occurs after exposure through transfusion, pregnancy or transplantation
  • Incidence varies among different patient populations and is estimated to occur in 0.5 - 3% of the general population
Essential features
  • If a patient has an identified RBC alloantibody, an RBC unit negative for the implicated antigen should be selected for transfusion
  • RBC alloimmunization can result in acute hemolytic or, more commonly, delayed hemolytic transfusion reactions, which can be life threatening
  • Red blood cell (RBC)
  • 1 - 1.6% of RBC transfusions are associated with antibody formation; primary alloimmunization occurs days to months after transfusion of antigen positive RBCs (Cohn: Technical Manual, 20th Edition, 2020)
  • RBC alloimmunization involves multiple steps, including RBC antigen recognition and presentation by HLA class II, activation of CD4+ T cells and B cell differentiation into plasma cells (Blood 2012;120:528)
  • Certain individuals seem to be genetically predisposed to RBC alloimmunization (responders) and have a 30% alloimmunization risk (Blood 2008;112:2546)
Clinical features
  • Elevated rates of RBC alloimmunization in patients with sickle cell disease (19 - 43%), thalassemia major (5 - 45%) and myelodysplastic syndromes (15%) due to the high frequency of transfusion (Hematology Am Soc Hematol Educ Program 2016;2016:446, Blood 2018;132:1826)
  • Prophylactic Rh and Kell matching is performed in certain populations, including patients with sickle cell disease or thalassemia major or those with warm autoantibody mediated hemolytic anemia, to reduce alloimmunization (Transfusion 2021;61:3027)
  • RBC alloimmunization poses a unique challenge for people of childbearing potential (Transfus Med Rev 2018;32:213)
  • Clinically significant RBC alloantibodies are associated with hemolytic transfusion reactions, hemolytic disease of the fetus / newborn (HDFN) and decreased survival of transfused RBCs
  • Clinically significant antibodies more commonly cause delayed hemolytic transfusion reactions (via extravascular hemolysis) rather than acute hemolytic reactions
  • Common clinically significant red blood antigen groups include Rh, Kell, Duffy, Kidd and Ss
  • D antigen is the most immunogenic red cell antigen (other than ABO)
  • Presence of RBC alloantibodies can complicate pretransfusion testing and delay blood product availability
  • In non-alloimmunized patients, antigens other than ABO and RhD are not routinely considered in blood product selection for transfusion
  • To prevent alloimmunization, RhD negative recipients (especially individuals of childbearing potential) should receive RhD negative red blood cells
  • Monoclonal antibody therapies such as daratumumab (anti-CD38) interfere with pretransfusion antibody testing by causing panreactivity in indirect antiglobulin test and masking alloantibodies (AABB: Mitigating the Anti-CD38 Interference with Serologic Testing [Accessed 16 December 2021])
Case reports
  • No specific treatment for RBC alloimmunization
  • If a patient has an identified RBC alloantibody or multiple alloantibodies, an RBC unit negative for the implicated antigen(s) should be selected for transfusion
  • Therapeutic plasma exchange has been used to reduce or prevent the red cell alloantibodies, particularly for RHD negative females who have received RH positive transfusions or as a method of antibody reduction for HDFN (J Clin Apher 2019;34:171)
Sample assessment & plan
  • Assessment: Routine antibody testing demonstrated an unexpected antibody in 1/3 of the cells on the antibody screen and a full antibody panel demonstrated positivity in 4/12 cells with a negative auto control. An anti-E was identified while all other common clinically significant alloantibodies were ruled out. Anti-E is part of the Rh blood group system and can cause hemolytic transfusion reactions and hemolytic disease of the fetus and newborn (HDFN).
  • Plan: E negative RBC units will be issued for all future transfusions. Please allow extra time for antihuman globulin (AHG) or Coombs crossmatch testing (1 hour).
Differential diagnosis
  • Alloantibodies must be distinguished from autoantibodies, which develop to self antigens
  • Autoantibodies may mask underlying alloantibodies
Board review style question #1
Which patient scheduled for surgery is most likely to have a red blood cell antibody?

  1. 8 year old child with congenital heart disease
  2. 26 year old woman with fibroids
  3. 60 year old woman who had a previous spinal surgery and has 2 children
  4. 65 year old man with 4 children and coronary artery disease
Board review style answer #1
C. 60 year old woman who had a previous spinal surgery and has 2 children. The patient who has a history of pregnancy and previous surgery with likely transfusion is most likely to have an RBC antibody. RBC alloimmunization occurs after exposure to non-self antigens through pregnancy, transfusion or transplantation.

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Reference: Red blood cell alloimmunization
Board review style question #2
Patients with which disease have the highest red blood cell alloimmunization rates?

  1. Acute leukemia
  2. Iron deficiency anemia
  3. Sickle cell disease
  4. Solid tumor malignancy
Board review style answer #2
C. Sickle cell disease. Patients with sickle cell disease have higher rates of RBC alloimmunization (19 - 43%) compared with 1 - 3% of the general population. Higher rates of RBC alloimmunization are also seen in patients with thalassemia major (5 - 45%) and myeloproliferative syndromes (15 - 59%) as well as patients with warm autoantibody mediated hemolytic anemia.

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Reference: Red blood cell alloimmunization
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