Serologic changes and transfusion requirements after ABO incompatible stem cell transplant

Serologic changes and transfusion requirements after ABO incompatible stem cell transplant

Kimberly W. Sanford, M. D.Associate Medical Director of Transfusion MedicineVirginia Commonwealth University Health System

Objectives

Review basic ABO serology Define the types of incompatible ABO

transplants Serologic changes in recipient Discuss transfusion strategies

AntigenSubstance capable of inducing immune

response Protein, carbohydrate, lipid Can be cell bound or free floating

RBC

ANTIGEN

AntibodyA 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

ABO System The antigens present on the

surface of RBC are numerous Several hundred antigens

present on surface ABO system

A antigen B antigen AB antigen O lacks both A and B

antigen Rh system

49 antigens make up the Rh system

5 antigens most important: D, C,E,c,e

RBC

ABO systemGroup A Group

B

Group AB Group O

ABO antibodies

RULES:

WE FORM ANTIBODIES TO THE ANTIGENS WE LACK

WE DO NOT FORM ANTIBODIES TO OUR OWN ANTIGENS

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.

Blood Group B

Patient has B antigen on RBC

Patient lacks A antigen

Therefore patient forms Anti-A antibodies but NOT Anti-B antibodies

AB group

Patient have both A and B antigen on RBC

Therefore patient does NOT form any AB antibodies.

O Blood Group Patient lacks both A and

B antigen

Patient forms both:

Anti-A antibody

Anti-B antibody

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

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

HLA and ABO Antigens

HLA compatibility

Strongest predictor for occurrence of severe GVHD

Single most important factor to consider in selecting donor

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.

ABO mismatched transplants Complications

Require more transfusion Delayed RBC engraftment or RBC aplasia

Acute RBC hemolysis Acute hemolysis of RBC with infusion of HPC product

Delayed RBC hemolysis 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

Intravascular hemolysis Antibody binds intravascular to RBC activating

complement Complement causes pores in RBC membrane Free hgb escapes, hgb drops, LDH increases, haptoglobin

decreases Binds NO2 Renal vasoconstriction, ischemia, tubal necrosis, renal failure

Complement activation generates Anaphylatoxins, C3a & C5a

Proinflammatory cytokines activated IL-1, IL-6, IL-8, TNF Fever, Hypotension, Activate WBC and clotting cascade

Disseminated Intravascular coagulation Death

Intravascular Hemolysis

ABO incompatibilities in transplant Major

Recipient has ABO antibodies directed against donor RBC

Minor 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.

Major mismatch: O recipient & A donor O recipient: Anti-A, Anti-B antibodies and O RBCs

Donor RBCs: A antigen RBC Complications

Immediate hemolysis of donor RBC at transplant

R

RR

RR R R

R

DD R

Delayed complications Delayed hemolysis after RBC engraftment

Persistent recipient anti-A abs 120-605 days post transplant

Hemolyze donor A RBC produced from marrow. Delay RBC engraftment

20% of patients experience RBC aplasia (severe)

Reticulocytopenia persists > 60 days RBC precursors not present in marrow aspirate

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

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

R

R

RR

R

R

DD

DD

Minimize Risk Remove donor plasma and antibody from

graft to preventhemolysis 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

Passenger donor lymphocytes “Passenger” donor lymphocytes proliferate

within the marrow and produce ABO antibodies.

R

Bidirectional Mismatch: A recipient & B donor Recipient: A RBC’s with Anti-B antibodies Donor: B RBC’s with Anti-A antibodies Complication: immediate hemolysis of donor cells,

delayed hemolysis after lymphocyte engraftment of recipient RBC and RBC aplasia

R

R

R

R

D

D

D

D

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

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

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

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

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

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

DR

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

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

Minor Mismatch: A recipient & O donor RBC: provide donor type O RBC start immediately

after transplant and continue after engraftment.

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.


A O O A, AB

B O O B, AB

AB O O AB

AB A A AB

AB B B AB

Minor ABO Incompatibility

Bidirectional Mismatch: A recipient & B donor Bidirectional Incompatibility

PRBC Provide O PRBC

FFP Provide AB plasma products

R

R

R

R

D

D

D

D


B A O AB

A B O AB

Bidirectional (Major and Minor) ABO Incompatibility Continue until offending RBC antigens and antibodies are no longer detected.

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

Ex: Kell antigen + donor, recipient with Anti-Kell abs Minor: Donor has antibodies to recipient RBC antigen

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.

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.

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 Cid J, Ortin X, Elies E, et al. Transfusion 2002;42:173-

6.patients 35 pediatric patients, none alloimmunized

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.

Rh Incompatible TransplantsRecipient 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

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.

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.

Serologic changes and transfusion requirements after ABO incompatible stem cell transplant

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