Transfusion medicine

Stem cell transplant

ABO incompatible HSCT


Editorial Board Member: Kyle Annen, D.O.
Deputy Editor-in-Chief: Patricia Tsang, M.D., M.B.A.
Tiffany Chambers, M.D.
Mrigender Singh Virk, M.D.

Last author update: 11 July 2022
Last staff update: 11 July 2022

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PubMed Search: ABO incompatible hematopoietic stem cell transplantation

Tiffany Chambers, M.D.
Mrigender Singh Virk, M.D.
Page views in 2022: 215
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Cite this page: Chambers T, Virk M. ABO incompatible HSCT. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/transfusionmedABOincompatibleHSCT.html. Accessed February 3rd, 2023.
Definition / general
  • ABO blood group matching is not a barrier to successful hematopoietic stem cell transplantation (HSCT)
  • ABO blood group incompatibility has important implications for transfusion medicine support
  • Reference: Hematology Am Soc Hematol Educ Program 2015;2015:378
Essential features
  • ABO incompatible transplants are classified as major, minor or bidirectional
  • In a major ABO incompatible transplant, the recipient has isohemagglutinins directed against the donor red cells
  • In a minor ABO incompatible transplant, the donor graft has isohemagglutinins directed against the recipient red cells
  • In a bidirectional ABO incompatible transplant, there are both major and minor ABO incompatibilities
  • ABO incompatible transplants are associated with acute hemolysis immediately after infusion as well as delayed complications that may include pure red cell aplasia in major ABO incompatible transplants and passenger lymphocyte syndrome in minor ABO incompatible transplants
Terminology
  • ABO mismatched HSCT
Pathophysiology
  • ABO incompatible HSCT is possible because ABO blood group antigens are not expressed on pluripotent or early committed hematopoietic progenitor cells
  • Complications associated with ABO incompatible HSCT are due to naturally occurring (anti-A or anti-B) antibodies present within the recipient or the donor graft
  • Reference: Biol Blood Marrow Transplant 2013;19:1152
Diagrams / tables

Major / minor / bidirectional incompatibility
Donor
O A B AB


Recipient
O Compatible Major Major Major
A Minor Compatible Bidirectional Major
B Minor Bidirectional Compatible Major
AB Minor Minor Minor Compatible
Clinical features
  • 40 - 50% of all HSCTs are ABO incompatible (Vox Sang 2010;98:455)
  • ABO incompatible transplants are classified as major, minor or bidirectional
  • All are associated with both immediate and delayed complications
  • Major ABO incompatibility is the presence of naturally occurring ABO antibodies in the recipient directed against the donor's red cell antigens
    • Acute hemolysis of infused donor red cells can occur immediately during graft infusion
    • Acute hemolysis may be prevented via graft manipulation to reduce donor red cells
    • Delayed red cell engraftment and pure red cell aplasia (PRCA) are both delayed complications that arise due to the continued production of antidonor ABO antibodies by the residual B cells and plasma cells in the recipient
    • Delayed red cell engraftment and PRCA occur more frequently in reduced intensity conditioning (RIC) transplantation that uses less chemotherapy and radiation than the standard myeloablative regimen
  • Minor ABO incompatibility is the presence of naturally occurring ABO antibodies in the donor graft directed against the recipient's red cell antigens
    • Acute hemolysis of recipient red cells can occur immediately during graft infusion but is typically mild and self limited
    • Acute hemolysis may be prevented via graft manipulation to reduce donor plasma
    • Passenger lymphocyte syndrome (PLS) is a delayed complication that occurs 5 - 15 days after transplantation due to the production of ABO isohemagglutinins by donor lymphocytes
  • Bidirectional incompatibility is the presence of both major and minor incompatibility and is associated with the complications of both
  • Reference: Transfusion 2011;51:1143
Symptoms
  • Acute hemolysis classically presents with fever, flank pain and red urine; however, the presentation depends on the type of incompatibility and the volume infused
  • Delayed red cell engraftment and pure red cell aplasia may both present with the symptoms of anemia, such as pallor and exercise intolerance
  • Passenger lymphocyte syndrome presents with the symptoms of delayed hemolytic anemia, such as pallor, tachycardia, tachypnea and hypotension (Transfus Med Rev 2020;34:178)
Blood donor screening
Blood donor testing
Donor deferral
Laboratory
  • Acute hemolysis:
    • Positive direct antiglobulin test (DAT)
    • Low haptoglobin
    • Elevated bilirubin
    • Elevated lactate dehydrogenase (LDH)
    • Decreased hemoglobin
  • Passenger lymphocyte syndrome:
    • ABO antibody directed against recipient ABO group antigen on reverse type or antibody titers
    • Positive direct antiglobulin test (DAT)
    • Low haptoglobin
    • Elevated bilirubin
    • Elevated LDH
    • Decreased hemoglobin
  • Delayed red cell engraftment and pure red cell aplasia:
    • Low reticulocyte count
    • ABO antibody directed against donor ABO group antigen on reverse type or antibody titers
    • ABO forward type shows no conversion to donor blood type
    • Chimerism study may show full engraftment of all cell lines except red blood cells
  • Reference: Hematology Am Soc Hematol Educ Program 2015;2015:378
Case reports
Treatment
  • Acute hemolysis is treated with hydration and transfusion
  • Passenger lymphocyte syndrome is generally self limited; may require transfusion support and red blood cell exchange
  • Pure red cell aplasia may be treated with erythropoietin, immunosuppression taper, donor lymphocyte infusion, rituximab and plasma exchange (American Society for Apheresis [ASFA] category III)
  • References: J Clin Apher 2016;31:149, Hematology Am Soc Hematol Educ Program 2015;2015:378
Sample assessment & plan
  • A 50 year old man with a history of myelodysplastic syndrome underwent a bidirectional ABO incompatible hematopoietic stem cell transplant (group B recipient, group A donor) 6 weeks prior and demonstrates 100% donor chimerism; however, the patient has yet to convert to the donor blood type. He remains transfusion dependent with a reticulocyte count of 0.4% and a hemoglobin of 6.9 g/dL. The findings may represent delayed red cell engraftment in the setting of ABO incompatible HSCT; however, disease relapse and parvovirus B19 should be excluded.
Differential diagnosis
  • Transplant associated or drug induced thrombotic microangiopathic hemolytic anemia (TA-TMA, DIHA):
  • Autoimmune hemolytic anemia:
    • Spherocytes on peripheral blood smear
    • Positive direct antiglobulin test (DAT) with eluate demonstrating a panagglutinin (an agglutinin that agglutinates the red cells of all blood groups)
  • Infection (e.g., parvovirus B19):
    • Clinical signs of infection (fever, rash, fatigue, etc.)
    • Positive serology or PCR test
  • Graft failure:
    • Loss of donor cell chimerism
  • Disease relapse:
    • Histologic or flow cytometry immunophenotypic evidence of recurrent disease
Board review style question #1

A 65 year old, A positive woman experiences a mild drop in hemoglobin following a bidirectional ABO incompatible hematopoietic stem cell transplant with a B positive donor. Her direct antiglobulin test is positive. Additional testing is performed shown in the image above. What is the most likely cause of these results?

  1. Acute hemolytic transfusion reaction
  2. Autoimmune hemolytic anemia
  3. Graft failure
  4. Passenger lymphocyte syndrome
  5. Pure red cell aplasia
Board review style answer #1
D. Passenger lymphocyte syndrome is due to the production of ABO isohemagglutinins by donor lymphocytes directed against recipient red cell antigens. The recipient is group A while the donor is group B and therefore produces anti-A isohemagglutinins against recipient red blood cells.

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Reference: ABO incompatible HSCT
Board review style question #2
Major ABO incompatible hematopoietic stem cell transplantation is associated with a delayed engraftment of which of the following?

  1. Granulocytes
  2. Lymphocytes
  3. Platelets
  4. Red cells
Board review style answer #2
D. Red cells. A major ABO incompatible transplant is associated with a delayed red cell engraftment beyond the expected recovery period of 2 - 3 weeks due to recipient isohemagglutinins directed against engrafted red cell progenitors.

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Reference: ABO incompatible HSCT
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