Guideline for Blood Component and Blood Product Provision during Solid Organ Transplantation

• Summary of Guideline
• Background

1. Introduction
2. Graft Rejection in Incompatible Transplants
3. Haemolytic Reactions
4. Rationale
5. ABO Incompatibility 
   5.1 Major ABO Incompatibility
   5.2 Minor ABO Incompatibility
   5.3 Bidirectional ABO Incompatibility
   5.4 Red Blood Cell
   5.5 Components
   5.6 Management
6. Rhesus D (RhD) Incompatibility
   6.1 Major RhD incompatibility exists where a donor is RhD positive and the recipient is RhD negative
   6.2 Minor Rhesus D incompatibility exists where a donor is RhD negative and the recipient is positive
   6.3 Choice of Rhesus Blood Groups for Transfusion
   6.4 Rhesus Prophylaxis
7. Other RBC blood group systems
8. Special Products

• Glossary of Terms

Summary of Guideline

A key factor in organ selection for solid organ transplantation is ABO compatibility between the donor and the recipient. Currently the number of patients on the transplant waiting list exceeds the number of available organs.  Due to this, selection of ABO incompatible organs are being more readily used for extremely ill patients but this in itself carries risks which must be closely monitored and managed.  These risks include graft rejection and haemolytic complications. This guideline describes the diagnostic tests required to determine if a transplant is under threat of rejection due to haemolytic complications.  This guideline also details scenarios of differing patient and graft blood groups and the recommended transfusion support in each case.

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Background

The ABO histo-blood grouping system belongs to the minor HLA antigens and is the most important transplantation Antigen system in solid organ transplantation¹.  ABO blood group antigens are expressed on the red blood cells, cells of solid tissues and on platelets and lymphocytes².  Pre-existing antibodies in the recipient patient against the ABO antigens of the donor organ have the potential to induce graft rejection.  Ten years ago ABO incompatibility was an absolute barrier for the majority of solid organ transplants.  However recent advances in immunosuppressive treatments and available techniques to reduce anti-A and anti-B alloantibodies in recipient’s serum both pre and post-transplant¹allow transplants across the ABO groups.

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Treatment / Management

1. Introduction

Current practice in transplantation is to match the donor and the recipient by their ABO blood group compatibility.  However due to the increase in the number of patients on the organ transplant wait list exceeding the number of available organs the ability to safely use ABO incompatible organs is becoming more common practice¹.  The provision of the correct blood components and products play a key role in ensuring that ABO incompatible solid organ transplants are successful.  However there are still associated risks.

The ABO histo-blood grouping system belongs to the minor HLA antigens and is the most important transplantation Antigen system in solid organ transplantation¹.  ABO blood group antigens are expressed on the red blood cells, cells of solid tissues and on platelets and lymphocytes².  Pre-existing antibodies in the recipient against the ABO antigens of the donor organ have the potential to induce graft rejection.  Over ten years ago ABO incompatibility was an absolute barrier for the majority of solid organ transplants.  However recent advances in immunosuppressive treatments and available techniques to reduce anti-A and anti-B alloantibodies in the recipient’s serum both pre and post-transplant¹ allow ABO incompatible transplants. 

Therefore, these transplants are high risk for:

• Graft rejection
• Haemolytic complications.

2. Graft Rejection in Incompatible Transplants

Anti-A and Anti-B antibodies directed against the ABO antigens of the donor graft may cause hyper acute, acute and chronic rejection.   The preformed recipient antibodies are responsible for hyper acute and acute rejection whereas the persistence of Anti-A and Anti-B antibodies and the production of new antibodies are responsible for chronic graft rejection.  Currently immunosuppressive drugs ¹¹ can be administered to effectively reduce the formation of antibodies while plasmapheresis or immunoadsorption pre and post-transplant may be useful to reduce the recipient’s titres.

Studies suggest that other Red Blood Cell (RBC) antigenic groups including Duffy and Kidd^3,4 may represent minor histocompatibility antigens therefore antibodies against these systems may shorten the life span of the graft and  result in graft rejection.

3. Haemolytic Reactions

The majority of haemolytic reactions post ABO incompatible transplants are due to “Passenger Lymphocyte Syndrome” (PLS).  PLS is due to the production of antibodies by the donor B lymphocytes, donor derived antibodies (DDAb) ¹².  PLS is a primary or secondary response against the recipient's RBC antigens⁵ and often is referred to as graft versus host reaction.

There are documented cases of PLS in solid organ transplants due to the presence of donor anti-A and anti-B lymphocytes⁵ and reported cases of PLS induced haemolysis involving  other RBC blood group systems including Rhesus¹³.

PLS can develop abruptly and can vary from minor to severe.  Severity is mediated by the quantity of transplanted lymphoid tissue, donor titres of isoagglutinins and a rapid rise in antibody titres in the recipient after transplantation.  Onset of PLS is usually 1-3 weeks post-transplant.  It is a self-limiting process which usually resolves 3 months after the transplant, but may continue for much longer (anecdotally over 2 years for an Rh(D) based one)¹⁶  since the lymphocytes transferred with the organ do not proliferate indefinitely and do not engraft¹⁵.  Patients are supported by RBC transfusions and rarely require RBC exchanges.  As yet it is unknown if the survival of the graft is affected by transfusion therapy.

4. Rationale

The purpose for this document is to provide guidance:

• For clinical staff and Blood Bank Staff as to what RBC and blood components should be requested and issued throughout ABO Incompatible Solid Organ Transplant.
• On any reactions that may be observed during the procedure thought to be caused by blood components or products.
• On Transfusion Management in the event of haemolysis post transplantation.

5. ABO Incompatibility

Three different groups of ABO incompatibility can be distinguished in transplantation: major, minor and bidirectional ABO incompatibility (Table 1).

5.1 Major ABO Incompatibility

Definition:  the presence of anti-A, anti-B or anti-AB antibodies within the recipient’s plasma that is reactive with the donor’s red cell antigens on the graft/donated organ.

The associated risks of Major ABO Incompatibility include graft rejection and limited haemolysis of residual RBC’s in the graft.

5.2 Minor ABO Incompatibility

Definition:  the presence of anti-A, anti-B, or anti-AB antibodies in the donor plasma that are reactive with the recipient’s RBC antigens.

The associated risks of Minor ABO Incompatibility are haemolysis due to PLS.  PLS is most often observed in solid organ transplantation with a Minor ABO incompatibility.

5.3 Bidirectional ABO Incompatibility

Definition: The presence within both the donor and the recipient’s plasma of anti-A or anti-B antibodies which are reactive with recipient and donor red cell antigens respectively.

The associated risks are as for both major and minor incompatibility.

Table 1: Major, Minor and Bi-Directional ABO Incompatibility.

5.4 Red Blood Cell Transfusion

RBC components for transfusion must be ABO-identical or compatible with the recipient’s serum regardless of the organ donor’s blood group⁷ .

5.5 Blood Components (platelets, FFP, cryoprecipitate)

When the donor and the recipient are of different ABO blood groups, special attention must be given to the selection of plasma and platelet preparations.

Major ABO incompatibility
Platelets, FFP and cryoprecipitate should be compatible with the ABO group of the graft to reduce the risk of rejection (Table 2)

Minor ABO incompatibility
Platelets, FFP and cryoprecipitate should be ABO-compatible with both the recipient RBCs and the donor organ tissue cells to avoid transfusing any antibodies that may contribute to RBC haemolysis.  Although platelets exhibit low antigenic expression, substantial quantities of antibodies may be found in platelet preparations².

It is essential that staff within the Blood Transfusion department are made aware of the blood group of the donor organ so that this information can be uploaded onto the Blood Bank IT system therefore any transfusion requirements 4 weeks ¹⁷ post transplantation can be managed accordingly.

5.6 Management

Anticipation of PLS is important.  Unfortunately, the titre of antibody within the donor organ is not reliable as a means of prediction of the occurrence of antibody or haemolysis post transplantation.

Anaemia induced by PLS is usually abrupt in onset and associated with a positive Direct Antiglobulin Test (DAT) as well as the presence of serum antibodies in addition to evidence of haemolysis¹³.  Haemolysis is usually apparent between days 3-24 post- transplant and the timing does not appear to be dependent on antibody specificity.  If the patient develops anaemia post- transplant a haemolysis screen should be requested in the investigation of anaemia.  A haemolysis screen includes tests for DAT and antibody screen (Transfusion Laboratory), Full Blood Count and Reticulocyte (Haematology), Lactate Dehydrogenase and Total Bilirubin (Biochemistry) and Haptoglobin (Immunology). Advice on sample collection can be accessed at www.pathology.leedsth.nhs.uk/Testandtubes

Haemolysis can generally be managed by transfusion of blood group O RBCs (Table 2), avoidance of ABO -incompatible plasma products (platelets, FFP, cryoprecipitate), and maintenance of adequate renal perfusion⁷.  In patients with more severe haemolysis, plasma exchange may be used to decrease the antibody titre.

Table 2:  Platelet, FFP and cryoprecipitate Selection for Recipients of ABO Mismatched Organs^7.17

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6. RhD Incompatibility

6.1 Major RhD incompatibility exists where a donor is RhD positive and the recipient is RhD negative.

In these circumstances the recipient may be at risk of developing alloantibodies against the RhD antigen post-transplant.  There is a paucity of data within the literature that highlights the incidence of immunisation of recipients of solid organ transplants against RBC antigens.    Studies suggest that long term immunosuppression may reduce the rate of alloimmunisation to RBCs antigens; however immunosuppression is less effective against secondary immune responses than primary immune responses.  In a review of 1000 liver transplants 6% formed antibodies against RBC antigens post-transplant, as the majority of these cases developed within 5 weeks it suggests a secondary immune response⁹

A primary immune response was detected in only 0.9% of the cases in the study with antibodies against the RBC antigens not being detected up to 6 months post-transplant.  Studies of liver, heart and lung transplants of RhD positive grafts to RhD negative patients showed a very low incidence of RhD immunisation¹³

It is unknown whether alloantibodies formed by the recipient post-transplant affect the graft survival.

6.2 Minor Rh D incompatibility exists where a donor is RhD negative and the recipient is positive.

The risk in these cases is the occurrence of delayed haemolysis due to donor lymphocyte derived anti-D. The risks are increased if the donor has been previously sensitised to the RhD antigen through pregnancy or transfusions.

6.3 Choice of Rh Blood Groups for Transfusion.

Major RhD incompatibility: RhD Negative Red Cells and Platelets must be given. 

Minor RhD incompatibility: Give RhD positive Red Cells and platelets post- transplantation.  However, if there are any indications of haemolysis due to donor lymphocyte syndrome then RhD negative blood and platelets should be given until haemolysis is no longer detected. 

6.4 Rh Prophylaxis and the use of anti-D injection.

Immunoprophylaxis using anti-D Immunoglobulin should be considered for female patients who are potentially child-bearing to prevent Haemolytic Disease of the Newborn (HDN) in the future.  HDN can be a severe condition causing profound anaemia in the foetus and occasionally severe morbidity and fatalities.

Anti-D immunoglobulin should be considered post solid organ transplant where:

• Female recipient aged 0-50 years of childbearing age potential and
• Donor grouped as RhD positive or RhD weak and
• Recipient grouped RhD negative.
• Graft expecting to contain residual RBC.

An initial dose of 500iu of Anti-D is recommended. Prior to administration of anti-D a sample should also be sent to the Red Cell Immunohaematology (RCI) laboratory for quantification of the volume of circulating RhD positive cells . Further anti D administration should be discussed with Transfusion Lab based on the RCI results.

Patients Informed Consent should be obtained and recorded in the patient’s case notes.  Anti-D must be ordered from the Blood Transfusion Laboratory using the request form found on the Hospital Transfusion Team website:
http://lthweb/sites/hospital-transfusion-team/how-to-order-blood-and-blood-products/Anti-D%20Order%20form%20Apr%2011.pdf

For renal transplant patients, please refer to the Guideline for the Administration of Anti-D to Renal  Transplant Patients http://nww.lhp.leedsth.nhs.uk/common/guidelines/detail.aspx?ID=565

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7. Other RBC blood group systems

If a transplant recipient has other clinically significant red cell alloantibodies at the time of transplantation the donor should be phenotyped for the relevant blood group antigen.  If the recipient and the donor are incompatible methods should be used to reduce antibody titres similar to those for the reduction of anti-A and anti-B antibodies.

Advice should be taken from a red cell Immunohaemotology Consultant if the significance of an alloantibody is uncertain.

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8. Special Transfusion requirements

Hepatitis E Virus (HEV) Negative products-HEV may be acquired in the UK¹⁷ both through the diet and through receiving blood components, tissues and organs from viraemic donors.   The Advisory Committee on the Safety of Blood, Tissues and Organs (SaBTO) has recommended that Solid Organ Transplant patients receive HEV negative screened blood and components.
Solid Organ Transplant patients should receive HEV negative blood and blood components 3 months prior to the elective transplant and remain on HEV negative blood and components for life.

Cytomegalovirus (CMV) Negative products- current guidelines state that children up to 6 months and pregnant women require CMV negative products.

Irradiated – If a transplant patient requires Irradiated components, this and the reason why must be communicated to the Transfusion Laboratory as early as possible so laboratory staff can update the blood bank records on the laboratory IT system to ensure the provision of correct components. For further information on who requires CMV negative and/or irradiated blood components see: the guidelines on the Hospital Transfusion website.

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