Transfusion in Transplantation

The importance of organ transplantation as a clinical activity has increased in recent years. Kidney transplantation still accounts for the vast majority of transplant operations, besides autologous and allogeneic bone marrow and peripheral blood stem cells transplantation are now well established procedures in the treatment of certain hematologic malignancies. In addition, transplantation of liver is now done with growing success and that of other solid organs including, heart, lung and pancreas is carried out, at least on experimental basis.


The blood bank plays a vital role in transplantation programs in transfusion of blood and blood products in transplantation.


BONE MARROW TRANSPLANTATION


Bone marrow transplantation is used to treat patients with various hematologic disorders like :


•           Various leukemias


•           Aplastic anemia


•           Hemoglobulinopathies like thalassemia major


•           Immunodeficiency syndrome


•           Malignant diseases


Bone marrow transplant recipients present different type of problems than solid organs transplant recipients :


•      The bone marrow transplant recipient is totally ablated before receiving an allogeneic marrow, due to it the recipient is at risk of opportunistic infections.


•      Allogeneic bone marrow graft has immunologically potent lymphocytes, and the donor lymphocytes can recognize and respond to the HLA antigens in the recipient, resulting in graft-versus-host disease (GVHD). Graft rejection and GVHD are more severe with mismatched HLA antigens. HLA-A, HLA-B, HLA-C and HLA-DR matching of donor and recipient is important.


•     Another difference is that the ABO antigens do not serve as a transplant barrier for marrow recipients. The donor-recipient ABO incompatibility does not increase the incidence of graft rejection or GVHD. The data shows that ABO antigens are not present on stem cells

Red Blood Cells Transfusion in BMT


•     Major ABO-compatible transplant recipients require few RBCs transfusion than in ABO- incompatible transplant. ABO antibodies can cause delay in donors RBC production, necessitating more RBC transfusion. The median time for incompatible antibody disappearance in ABO - incompatible transplant is about 38.5 days (range 0 -116 days).


•     During the transplant, the recipient's bone marrow hematopoietic stem cells and immune system are ablated and reconstituted with the donor's cells. This causes problems in blood bank related to transfusion support and the selection of blood during engraftment. It becomes difficult to decide whether to use blood components of donor's or recipient's ABO blood group.


•      For major ABO-incompatible marrow recipients, recipient type RBCs are provided until there are no detectable incompatible plasma antibodies and the DCT test is negative. Any plasma containing products should be donor type, to prevent passive transfer of incompatible A and B antibodies.


For example, in group O patient who received group A bone marrow transplant, the patient continues to produce anti-A and anti-B. In this situation group O red cells transfusion is given until anti-A is no longer detected. Components containing significant amount of plasma, such as platelets and FFP must be compatible with the donors blood groups. In this case group A platelets or FFP should be used.


•      For minor ABO-incompatible marrow transplants, (recipient A/B blood group and donor O group marrow) RBCs should be donors type, and plasma products should be recipient type until recipient RBCs are no longer detected.


•      For transplant that are both major and minor ABO-incompatible, RBCs should be group O and plasma products should be of AB group.


For example, in case B group marrow is transplanted in A group recipient or reverse, then group O red cells and AB group plasma or platelets are used.


Granulocytes Transfusions in BMT


Granulocytes transfusions are beneficial in granulocytopenic patients (< 0.2x 109 granulocytes/ L) who have infection unresponsive to antibiotics. However, certain problems are associated with granulocytes transfusions like:


•     Insufficient granulocytes collection for effective transfusion dose.


•     Short intravascular survival time of granulocytes (about 6 hours), suggesting daily administration of granulocytes is too frequent.


•    Antibodies from prior RBCs transfusions may limit effective granulocytes transfusions of even HLA matched or partial HLA-matched donors.


•      Increase incidence of CMV infection after granulocytes transfusions. Granulocytes transfusions should be continued till the count of granulocytes is more than 0.2 x 109 /L. However more rapid WBC engraftment rates with the use of GM-CSF and G-CSF reduce the period of granulocytopenia; granulocytes transfusions have limited use.


Platelets Transfusions in BMT

Indications of platelets transfusions are:


•     When platelets count falls to < 15 to 20 x l09/litre (spontaneous bleeding usually does not occur until platelet counts are < 5 to 10 x 109/litre).


•     When platelets count > 20 x l09/litre with bleeding or associated with GVHD or viral infection.


The adult dose of platelets is 2.4-3x1011 platelets. This can be provided by infusing platelets separated from 5 to 6 units of whole blood (450 ml) or obtained from one donor by plateletpheresis. Alloimmunization is delayed and/or decreased by the use of single-dolor platelets. Leukocyte - poor blood products can decrease the incidence of alloimmunization and refractoriness to platelet transfusion.


Complications and their management:


•     BMT patients are often immnuosuppressed and may be at the risk of graft-versus host disease (GVHD), which is a potentially fatal complication by transfused lymphocytes. Treatment of red cells and platelets by gamma irradiation under controlled conditions inactivates the lymphocytes and reduces the risk of GVHD.


•     Some immunosuppressed patients are at the risk of cytomegalous virus (CMV) infection transmitted by blood transfusion. This can be avoided or reduced by transfusing blood that is tested and contains no CMV antibodies or by the use of leukocytes-depleted blood components.


Conclusions

Transfusions Prior to BMT


•           Transfusion of blood or components before BMT diminishes the success of long term engraftment.


•           Transfusion from blood relative, specially relative who serve as marrow donor, is likely to immunize the recipient.


•           Lower risk of immunization with random donor blood.


To eliminate immunization give:


•           Leukocytes-depleted cellular components (red cells / platelets)


•           Single donor component (e.g. platelets prepared from apheresis)


•           Gamma irradiated blood cellular components


•           HLA-matched blood cellular components


Autologous Blood for Marrow Recipient


•           Autologous pre-donation for blood replacement after marrow harvest is very useful and safe procedure and significantly reduces blood transmitted diseases and immunization.


•           Bone marrow aspirate and blood loss is 300-1,800 ml (average 1,000 ml). Bone marrow donor suffers a loss of 20 - 30% blood volume.


•           Hemoglobin after donation should be 12.5 g/dl. Iron is given if needed.


Scheme of Autologous Pre-deposit for Morrow Donor

    


                                         Pre-dohation                                                Days prior to                                                                                                

Donation                          Hb.g/dl                                                       Surgery                                    Vol. of Donation                                                             

First                                    >13                                                                14 (9-27)                             300(200-350)                                                                                                                                                                                                                                       

Second                             >12                                                                  8 (4-20)                               300(200-450)                                                                                                                            


Transfusions after BMT


■     Red cells transfusion support is required until


•              Engraftment occurs


•              Blood cells production is adequate


•              To maintain Hb 9-10 g/dl


■     To prevent GVHD:


Blood cellular components (except autologous blood) must be irradiated.


■     To prevent CMV:


If the recipient is negative for CMV


•             Use components from CMV sero-negative donor


•             Or use highly efficient leukocyte reduction filters


Platelets Transfusion :


•           Platelets are given every 2-3 days to maintain platelet count of >10,000/ul


•           If patient becomes refractory to random donors platelets, HLA matched platelets, prepared from apheresis, are given.


Granulocytes Transfusion:


•           Prophylactic granulocytes transfusion is not given.


•          Therapeutic granulocytes are rarely needed.


TRANSFUSION IN SOLID ORGANS TRANPLANTATION


Solid organ transplantation is the ideal therapy for organ system failure in certain diseases.

Allogeneic transplantation of foreign tissue can induce a cellular and humoral response that often leads to graft rejection. The severity of rejection often can be reduced by selecting HLA-matched organ for the recipient


The ABO system antigens are also a barrier to organ selection for transplantation. All normal individuals possess isoagglutinins to those antigens that they lack. Therefore, the same rules that govern the selection of blood for transfusion apply to the selection of most renal and heart transplant.


In addition to laboratory testing, graft rejection can be minimized with immunosuppressive therapy. Steroids decrease the humoral response and the cellular response can be inhibited with cyclosporine and azathioprine.


The third mechanism that influence is based upon the induction of tolerance to donor-specific antigens. The transfusion of blood from a potential donor promote graft acceptance through tolerance induction if the patient is not sensitized after donor-specific transfusions.


BLOOD TRANSFUSION IN LIVER TRANSPLANTATION


Liver transplantation is a lengthy, complex operation. It is done in patients who are generally in the end-stage of liver failure and frequently have coagulation deficiencies and thrombocytopenia.


The transfusion needs of these patients are more than any other transplantation due to:


•           Risk of excessive bleeding due to the presence of pre-existing hemorrhagic disorders such as esophageal varices.


•           Technical factors associated with the lengthy and complicated surgery.


•           Disease associated hemostatic dysfunctions (multiple coagulation defficiency and thrombocytopenia).


•           Removal of liver during surgery leave the patient ahepatic for some time, which further complicates the coagulation. This phase is associated with:


Decrease in Factors VIII and V


Decrease in fibrinogen

Increase in fibrinolysis


This period continues until approximately 30-60 minutes after donor liver revascularization and during this period it is very difficult to maintain hemostasis.


•      The post operative period is often associated with hypercoagulable state, perhaps due to slow recovery of normal levels of anticoagulant proteins such as antithrombin III and protein C and S after surgery.


Requirement of blood and blood products:


•      On average liver transplant patients require 15 to 30 units of whole blood or red cells, 20 to 30 units of fresh frozen plasma (FFP), 10 to 20 units of random-donor platelets (or equivalent by plateletpheresis) and 8 to 10 units of cryoprecipitate during the operation and in the immediate post operative period.


•      Intraoperative salvage may reduce the need of units of blood during operation.


•      In early phase of operation the use of whole blood may be optimum strategy because it provide necessary volume support, oxygen-carrying capacity and stable coagulation factors.


•      During ahepatic phase as there is cessation of the production of coagulation factors and enhanced fibrinolysis. FFP and cryoprecipitate(factor VIII) along with red cells are required.


•      Pediatric liver transplant may require on average 4 units of red cells (0.6 units of RBCs /Kg body weight), 7 to 8 units of FFP, 3 to 4 units of platelets, and 1 to 2 units of cryoprecipitate.


Monitoring of coagulation :


•      Coagulation is monitored hourly with rapidly assayed prothrombin time, partial thromboplastin time, fibrinogen level, platelet count and other key coagulation factors (e.g. V and VII) if indicated.


•     Aprotinin is bovine serine protease inhibitor, which reduces fibrinolysis and protects platelet function during surgery. However, its dosage regime has not been standardized,


anaphylactic reactions and thrombosis have been reported during liver transplant.


Considerations of ABO and Rh:


Except in emergencies, donors livers should be ABO-compatible with the recipient and ABO- idcntical red blood cells and fresh forzen plasma is used. In case of massive transfusion group A/ B recipients can be sitched to group O RBCs and group AB recipients can be switched to group  RBCs. If the supply of AB FFP is insufficient, early use of A group RBCs followed by a switch to group A FFP is appropriate. A gneral rule for massive transfusion is to switch red cells first, then switch plasma, and reverse the order when returning to the patient's original blood type.


Transfusion support of RH(D)-negative patients not immunizd to the D antigen is not standardized. Mostly it is preferred to provide D-negative blood to D-negative premenopausal females, if needs are excepted to be moderate. If massive blood loss occurs, the patient could then be switched intra-operatively to D-positive blood, if necessary. Production of anti-D occurs less frequently in D-negative liver transplant patients. D-negative males and post-menopausal D-negative females without anti-D in their blood can be transfused with D-positive blood.


Coagulation Considerations:


During surgery, hemodilution, platelet consumption, disordered thrombin regulation, and fibrinolysis derange the hemostatic process. The coagulopathy is specially severe during the anhepatic and early reperfusion stage. Hematocrit guides the use of RBCs, colloid and crystalloids; the platelet count guides transfusion of platelets; the prothrombin time and activated partial thromboplastin time guide use of FFP; fibrinogen determinations guide the use of cryoprecipitated AHF and atifibrinolytic agents.


Serologic problems in liver transplantation:


•            Positive DAT and alloantibodies prior to surgery, as many patients for liver transplant may have already received many blood transfusions, may cause problem in pretransfusion serological evaluation.


•            Donor lympocytes transplanted with the organ may continue to survive and function in the recipients. Transplanted B lymphocytes may continue to produce antibody(ies) that they may produce in the donor.


The production of donor-derived red cells antibody(ies) occur more frequently in the recipient who receive ABO incompatible liver. In such cases donor-derived antibody(ies) develop in 1 to 2 weeks and can persists for 6 months.


Donor-derived antibody(ies) can result in DAT positive. During this period blood selected for transfusion should be compatible with both the recipient and donor-derived antibody(ies).


•            Large quantity of blood transfusion may cause irnmunosuppression in the patient.


•            Patients who receive large volume of blood may have higher rate of bacterial infection and transmission of CMV.


Blood Transfusion in Kidney Transplantation


The renal transplantation is simpler and faster surgical procedure than other solid-organ transplants. The best graft survival rates are obtained when kidneys are obtained from HLA-identical, ABO- compatible siblings but such donors are available for few cases only. Three general strategies are considered by transplantation surgeons and immunologists before transplant to minimize graft rejection ;


(1)       The use of immunosuppressive agents like azathioprine, prednisone and cyclosporine.


(2)         The matching of donor and recipient antigens to minimize graft 'foreignness'. Antigen disparities that effect graft rejection include the ABO blood group antigens and HLA antigens. It is not clear what combination of HLA gene products matching promotes optimal graft survival. HLA-DR is the most critical for good graft survival. In highly sensitized recipients, it is necessary to match for HLA-A and HLA-B because of the presence of class 1 antibodies. In highly sensitized recipients, identification of HLA serum antibodies is also important.


(3) The induction of tolerance to donor-specific antigens : Several studies have shown that donor-specific blood transfusion and transplants from living related individuals have potential benefits.


The effects of blood transfusion on the success of renal transplantation are complex and paradoxic. The transfusion of blood may lead to HLA antibody immunization. Yet graft survival rates are improved with pre-transplant blood which does not result in forming HLA antibodies. It has been observed that the transfusion effect is lost with the newer immunosuppressive agents. Preferably transfusion of leukocyte-reduced red cells with leukocyte-deplated filters should be given to reduce the chances of immunization.


The data for re-combinant Epo, G-CSF, and GM-CSF led its routine use in patients with renal failure. Therapeutically effective levels are maintained after single intravenous or subcutaneous injection for 24 hours. An increase in reticulocytes counts occur with in 10 days if EPO is given daily. Epo avoids viral exposure and reduces HLA sensitization associated with blood transfusion.


Perioperative Transfusion


With overall change in intraoperative surgical practice, lower hematocrit levels (30%) are accepted without transfusion. Some workers have found a higher incidence of delayed graft function when patient's Hct level is more than 30%. This has been attributed to sludging of blood in microcirculation. Minimum amounts of red cells are used during kidney transplant, and other components are seldom required. Mostly two cross-matched units are kept for the kidney transplant.

Many institution simply use type-and-screen procedure.


TRANSFUSION IN HEART TRANSPLANTATION:


Heart transplantation is done to treat cardiomyopathies and end stage of ischemic heart disease. As heart has extremely short total ischemic time (3 hours for heart, compared with 72 hours for kidneys) HLA matching is not feasible. Total ischemic time is the duration during which there is no blood flow through organ. The single most important HLA test performed pretransplant is the HLA antibodies screening. Recipients with no HLA antibodies receive transplants without HLA - matching. Those with HLA antibodies require pretransplant cross-matches for class 1 and 11 HLA match to determine recipient-donor compatibility.


Heart transplants need on average 5 to 6 units of RBCs, 4 units of FFP and Ito 2 units of platelets.


TRANSFUSION IN LUNG TRANSPLANTATION:


Majority of cases with emphysema and cystic fibrosis need double-lung transplants. The indications for single-lung transplant are pulmonary fibrosis and emphysema. In addition, more patients now undergoing single-lung transplant for primary hypertension, previously treated by heart-lung transplantation.


Short ischemic time like heart, HLA matching is not possible. However, the HLA matching between recipient and donor play important role in live-donor transplant in graft survival rate.


The requirement of blood and its components is similar to that of heart transplant.


TRANSFUSION IN PANCREAS TRANSPLANTATION:


The primary indication of pancreas transplant is diabetes. The majority of pancreas transplants are simultaneous pancreas/kidney transplants, equal numbers of pancreas transplants following kidney transplant and few pancreas transplants alone. Increased long survival rates of transplant have been reported with HLA-DR matching. Pancreas transplants alone need about 2 units of RBCs and pancreas-kidney transplants recipients need on average 3-4 units of RBCs.


Because of risks of cardiac complications with pancreas transplantation, islet cell transplantation has been actively pursued.

 


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