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Serologic changes and transfusion requirements after ABO incompatible stem cell transplant Kimberly W. Sanford, M. D. Associate Medical Director of Transfusion Medicine Virginia Commonwealth University Health System
Objectives
Review basic ABO serology Define the types of incompatible ABO transplants Serologic changes in recipient Discuss transfusion strategies
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Antigen Substance capable of inducing immune response Protein, carbohydrate, lipid Can be cell bound or free floating ANTIGEN
RBC
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Antibody A protein synthesized by B lymphocyte in response to antigen and resides in the plasma
Expected antibody –
Naturally occurring Example
Anti A, Anti-B antibodies
Unexpected antibody
Exposure to donor blood through transfusion Exposure during pregnancy Example:
Anti-D, Anti-Kell antibodies
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ABO System
The antigens present on the surface of RBC are numerous
ABO system
Several hundred antigens present on surface A antigen B antigen AB antigen O lacks both A and B antigen
RBC
Rh system
49 antigens make up the Rh system 5 antigens most important:
D, C,E,c,e Page 5
ABO system Group A
Group AB
Group B
Group O
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ABO antibodies RULES: WE FORM ANTIBODIES TO THE ANTIGENS WE LACK WE DO NOT FORM ANTIBODIES TO OUR OWN ANTIGENS
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Blood Group A
Patient has A antigen on RBC
Patient lacks B antigen
Therefore patient will form Anti-B antibodies, but NOT Anti-A antibodies.
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Blood Group B
Patient has B antigen on RBC
Patient lacks A antigen
Therefore patient forms Anti-A antibodies but NOT Anti-B antibodies
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AB group
Patient have both A and B antigen on RBC
Therefore patient does NOT form any AB antibodies.
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O Blood Group
Patient lacks both A and B antigen
Patient forms both:
Anti-A antibody
Anti-B antibody
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HLA & ABO inherited separately
HLA: Chromosome 6 (6p21.3) contains 200 genes, expressed on WBC
ABO: located on Chromosome 9, expressed on RBC
Patient & donor may be 6/6 HLA match but disparate ABO groups
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HLA system
Human Leukocyte Antigen system expressed on all nucleated cells Mature circulating RBCs do not have nuclei, do not express HLA antigens Look at HLA antigens to determine if donor is a match
Class I: HLA A, B, C Class II: HLA DP, DQ, DR HLA-A, B, DRB1 (Cw) are most important for matching
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HLA and ABO Antigens
HLA compatibility
Strongest predictor for occurrence of severe GVHD
Single most important factor to consider in selecting donor
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ABO mismatch transplant
ABO mismatch does not:
Affect engraftment since stem cells do not have ABO antigens The lack of the ABO antigens allow for homing and engraftment of stem cells regardless of ABO incompatibility Does NOT affect neutrophil, platelet engraftment, graft failure or rejection.
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ABO mismatched transplants
Complications
Require more transfusion
Acute RBC hemolysis
Acute hemolysis of RBC with infusion of HPC product
Delayed RBC hemolysis
Delayed RBC engraftment or RBC aplasia
After engraftment, marrow produces donor RBC incompatible with recipient antibodies. After engraftment, ABO antibodies produced against recipient RBC Patient develops a positive DAT and hemolysis
Can be life threatening Complex transfusion requirements
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Intravascular hemolysis
Antibody binds intravascular to RBC activating complement Complement causes pores in RBC membrane Free hgb escapes, hgb drops, LDH increases, haptoglobin decreases
Complement activation generates
Anaphylatoxins, C3a & C5a
Proinflammatory cytokines activated
Binds NO2 Renal vasoconstriction, ischemia, tubal necrosis, renal failure
IL-1, IL-6, IL-8, TNF Fever, Hypotension, Activate WBC and clotting cascade
Disseminated Intravascular coagulation Death
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Intravascular Hemolysis
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ABO incompatibilities in transplant
Major
Minor
Recipient has ABO antibodies directed against donor RBC
Donor has ABO antibodies directed against recipient RBC
Bidirectional: Major and Minor ABO Incompatibility:
Recipient has ABO antibodies directed against donor red cells AND
Donor has ABO antibodies directed against recipient red cells.
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Major mismatch: O recipient & A donor O recipient: Anti-A, Anti-B antibodies and O RBCs Donor RBCs: A antigen RBC Complications
R
Immediate hemolysis of donor RBC at transplant
R R
R
D
R
R R
D
R
R Page 20
Delayed complications
Delayed hemolysis after RBC engraftment
Persistent recipient anti-A abs
Hemolyze donor A RBC produced from marrow.
Delay RBC engraftment
120-605 days post transplant
20% of patients experience
RBC aplasia (severe)
Reticulocytopenia persists > 60 days RBC precursors not present in marrow aspirate
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Minimize Risk
Apheresis collections can minimize RBC contamination of product to hematocrit < 2-3%.
Remove RBCs from the graft below 10-20 ML during processing of stem cell product
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Minor Mismatch: A recipient & O donor
Recipient A : A RBC and Anti-B abs O donor: infusion of Anti-A abs into recipient Complication
Delayed hemolysis (1-2 wks) after donor lymphocyte engraftment D
R
D
D
D
R
R
R
R
R
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Minimize Risk
Remove donor plasma and antibody from graft to prevent hemolysis at transplant
Biggest risk is 5-14 days after transplant, the donor lymphocytes create antibodies against recipient RBC cells.
Positive DAT and hemolysis of RBC Severe hemolysis can lead to multisystem organ failure Death
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Passenger donor lymphocytes
“Passenger” donor lymphocytes proliferate within the marrow and produce ABO antibodies.
R
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Bidirectional Mismatch: A recipient & B donor
Recipient: A RBC’s with Anti-B antibodies Donor: B RBC’s with Anti-A antibodies R Complication: immediate hemolysis of donor cells, delayed hemolysis after lymphocyte engraftment of recipient RBC and RBC aplasia D R D
D
R D R
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Minimize Risk
Deplete the donor graft of RBC and plasma.
Biggest risk is 5-14 days after transplant, the donor lymphocytes create antibodies against recipient RBC cells.
Delayed RBC engraftment, pure RBC aplasia Positive DAT and hemolysis of RBC Can lead to multisystem organ failure Death
Bidirectional ABO incompatibility have significantly increased risk of mortality over major and minor incompatibilities Page 27
Transfusion support
Difficult to select components
Recipient antibodies can persist for weeks or months after transplant and engraftment Donor lymphocytes produce antibodies against recipient RBC Patients are chimeras
Patient has 2 distinct blood group RBC populations Donor RBC production increases after engraftment, incompatible with persistent recipient antibody
Concerns
Intravascular hemolysis in major and bidirectional mismatches Delayed hemolysis in minor mismatches Select product that will not exacerbate hemolysis Transfusion support can affect overall survival Page 28
ABO/Rh incompatible transplant transfusion
Phase I: Prior to transplant Phase II: Transplant until engraftment
Recipient antibodies are still detectable Chimera: recipient and donor type RBC detectable Front and back types don’t match
Interpret as undetermined type
Phase III: Complete engraftment
Patient RBC type like donor RBCs Patient ABO antibodies are same as donor. Requires confirmed new blood type on 2 separate occasions to switch blood products to donor type
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ABO selection of products
Major Incompatibility: O recipient receives A donor
PRBC
Transfuse with recipient type RBC until recipient antibodies are no longer detectable. Then switch to donor type RBC
Plasma
Continue with donor type plasma
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ABO Selection of PRBC
Major incompatibility: O recipient & A donor
Recipient has Anti-A or Anti B antibody against donor A RBC Transfuse with recipient type, O RBC
R
D
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ABO Selection of Plasma products
Major incompatibility: O recipient & A donor
Recipient has Anti-A or Anti-B antibody against donor A RBC Transfuse with donor type A plasma
R
D
R
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Transfusion for Major Incompatiblity Recipient
Donor
RBC/WBCs
Platelets/FFP
O
A
O
A, AB
O
B
O
B, AB
A
AB
A
AB
B
AB
B
AB
O
AB
O
AB
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ABO selection of products
Minor Incompatibility: A recipient receives O donor
PRBC
Transfuse with donor type RBC until engraftment
Plasma
Continue with recipient type plasma until recipient RBCs are no longer detectable, then switch to donor type
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Minor Mismatch: A recipient & O donor
RBC: provide donor type O RBC start immediately after transplant and continue after engraftment.
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Minor Mismatch: A recipient & O donor
Plasma: provide recipient type A or AB plasma until recipient red blood cells are no longer detected, then switch to donor type plasma.
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Minor ABO Incompatibility Recipient
Donor
RBC/WBCs
Platelets/FFP
A
O
O
A, AB
B
O
O
B, AB
AB
O
O
AB
AB
A
A
AB
AB
B
B
AB Page 37
Bidirectional Mismatch: A recipient & B donor
Bidirectional Incompatibility
PRBC
R
Provide O PRBC
FFP
Provide AB plasma products D R
D
D
R D R
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Bidirectional (Major and Minor) ABO Incompatibility Continue until offending RBC antigens and antibodies are no longer detected.
Recipient
Donor
RBC/WBCs
Platelets/FFP
B
A
O
AB
A
B
O
AB
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RBC Alloantibody incompatibility
Have major and minor incompatibilities of other antigens
Rh system: Anti- D, C, E Anti – Kell or Kidd abs are particularly bad Major: Recipient has antibodies to donor antigens
Minor: Donor has antibodies to recipient RBC antigen
Ex: Kell antigen + donor, recipient with Anti-Kell abs Ex: donor with Anti-E abs, E antigen + recipient
HPC product
Keep low hct during collection Remove plasma from HPC product Provide antigen negative, crossmatch compatible RBC for transfusion. Page 40
Alloimmunization to RBC antigens
Despite immunosuppression, may still see immune response to foreign RBC antigens. Complicates transfusion by now requiring antigen negative blood in addition to ABO transfusion requirements. 2 studies have demonstrated red cell alloimmunization of 2-8% in patients undergoing stem cell transplant.
Perseghin P, Balduzzi A, Galimberti et al. Bone Marrow Transplant 2003;32:231-6. Abou-Elella AA, Camarillo TA, Allen MB et al. Transfusion 1995;35:931-5.
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Rh Negative Transplant patients
Minimize exposure to Rh positive products Rh positive platelets contain about 2 ml of RBC/dose Risk of forming Anti-D is low, 0-22%
22 adult patients, none alloimmunized
35 pediatric patients, none alloimmunized
Cid J, Ortin X, Elies E, et al. Transfusion 2002;42:173-6.patients Molnar R, Johnson R, Sweat LT, Geiger TL. Transfusion 2002;42:177-82.
98 adult patients, received 445 D+ RBC units
22 formed anti-D, 22%
Yazer MH, Triulzi DJ. Transfusion 2007;47:2179-2201.
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Rh Incompatible Transplants Recipient
Donor
Transfusion Protocol
Rh Positive Rh Negative Rh Negative cells
Rh Negative Rh Positive Transfuse Rh Negative red cells; switch to Rh positive cells once the transplanted BM or PBSC begins producing Rh Positive red cells
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Summary
Complex transfusion requirements See acute and delayed hemolysis Lower overall survival in minor and bidirectional mismatched grafts. Delayed RBC engraftment or red blood cell aplasia. ABO doesn’t affect engraftment of stem cell product, lymphocytes or granuloctyes Studies have found ABO incompatibility bigger risk of mortality in certain cases:
based on disease condition reduced intensity conditioning receiving unrelated grafts.
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References
Szczepiorkowski ZM. Transfusion Support for Heamotpoietic Transplant Recipients. In: Roback J. Ed. Technical manual 16th ed. Bethesda MD: American Association of Blood Banks, 2008. 679-96. Tormey CA, Synder EL. Transfusion Support for the Oncology Patient. In: Toby L. Simon et al. Ed. Rossi’s Priniciples of Transfusion Medicine 4th ed. American Association of Blood Banks, 2008. 482-97.
Perseghin P, Balduzzi A, Galimberti et al.Red blood cell support and alloimmunization rate against erythrocyte antigens in patients undergoing hematopoietic stem cell transplantation. Bone Marrow Transplant 2003;32:231-6. Abou-Elella AA, Camarillo TA, Allen MB et al. Low incidence of red cell and HLA antibody formation by bone marrow transplant patients. Transfusion 1995;35:931-5.
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