Blood Types, Transfusion, and Tissue and Organ Transplantation PDF

CHAPTER 36 Blood Types; Transfusion; and Tissue and UN...

CHAPTER 36 Blood Types; Transfusion; and Tissue and UNIT VI Organ Transplantation ANTIGENICITY CAUSES IMMUNE blood types, as shown in Table 36-1, depending on the REACTIONS OF BLOOD presence or absence of the two agglutinogens, the A and B agglutinogens. When neither A nor B aggluti- When blood transfusions from one person to another nogen is present, the blood is type O. When only type were first attempted, immediate or delayed agglutina- A agglutinogen is present, the blood is type A. When tion and hemolysis of the red blood cells (RBCs) often only type B agglutinogen is present, the blood is type occurred, resulting in typical transfusion reactions B. When both A and B agglutinogens are present, the that frequently led to death. Soon it was discovered blood is type AB.! that the blood types of different people have different antigenic and immune properties so that antibodies in Genetic Determination of the Agglutinogens. The ABO the plasma of one blood type will react with antigens blood group genetic locus has three alleles, which means on the surfaces of the RBCs of another blood type. If three different forms of the same gene. These three al- proper precautions are taken, one can determine ahead leles—IA, IB, and IO—determine the three blood types. of time whether the antibodies and antigens present in We typically call these alleles A, B, and O, but geneticists the donor and recipient blood will cause a transfusion often represent alleles of a gene by variations of the same reaction. symbol. In this case, the common symbol is the letter “I,” which stands for immunoglobulin. Multiplicity of Antigens in the Blood Cells The type O allele is functionless or almost function- At least 30 commonly occurring antigens and hundreds less, so it causes no significant type O agglutinogen on of other rare antigens, each of which can at times cause the cells. Conversely, the type A and type B alleles do antigen-antibody reactions, have been found on the sur- cause strong agglutinogens on the cells. Thus, the O faces of the cell membranes of human blood cells. Most allele is recessive to both the A and B alleles, which show of the antigens are weak and therefore are of importance co-dominance. principally for studying the inheritance of genes to estab- Because each person has only two sets of chromosomes, lish parentage. only one of these alleles is present on each of the two chro- Two particular types of antigens are much more likely mosomes in any individual. However, the presence of three than the others to cause blood transfusion reactions. They different alleles means that there are six possible combina- are the O-A-B system of antigens and the Rh system.! tions of alleles, as shown in Table 36-1: OO, OA, OB, AA, BB, and AB. These combinations of alleles are known as the genotypes, and each person is one of the six genotypes. O-A-B BLOOD TYPES One can also observe from Table 36-1 that a person with genotype OO produces no agglutinogens, and there- A AND B ANTIGENS—AGGLUTINOGENS fore the blood type is O. A person with genotype OA or Two antigens—type A and type B—occur on the sur- AA produces type A agglutinogens and therefore has faces of the RBCs in a large proportion of people. It is blood type A. Genotypes OB and BB give type B blood, these antigens (also called agglutinogens because they and genotype AB gives type AB blood.! often cause RBC agglutination) that cause most blood Relative Frequencies of Different Blood Types. The transfusion reactions. Because of how these agglutino- prevalence of the different blood types among one group gens are inherited, people may have neither of them on of persons studied was approximately as follows: their cells, they may have one, or they may have both simultaneously.! O: 47% A: 41% Major O-A-B Blood Types. In transfusing blood from one person to another, the blood of donors and re- B: 9% cipients is normally classified into four major O-A-B AB: 3% 471 UNIT VI Blood Cells, Immunity, and Blood Coagulation Table 36-1 Blood Types With Their Genotypes and 400 Anti-A agglutinins in Average titer of agglutinins Constituent Agglutinogens and Agglutinins groups B and O blood Genotypes Blood Types Agglutinogens Agglutinins 300 OO O – Anti-A and Anti-B 200 Anti-B agglutinins OA or AA A A Anti-B in groups A and O blood OB or BB B B Anti-A 100 AB AB A and B – 0 0 10 20 30 40 50 60 70 80 90 100 Age of person (years) It is obvious from these percentages that the O and A genes occur frequently, whereas the B gene occurs Figure 36-1. Average titers of anti-A and anti-B agglutinins in the plasma of people with different blood types. infrequently.! AGGLUTININS AGGLUTINATION PROCESS IN When type A agglutinogen is not present in a person’s TRANSFUSION REACTIONS RBCs, antibodies known as anti-A agglutinins develop in When bloods are mismatched so that anti-A or anti-B the plasma. Also, when type B agglutinogen is not pres- plasma agglutinins are mixed with RBCs that contain A ent in the RBCs, antibodies known as anti-B agglutinins or B agglutinogens, respectively, the RBCs agglutinate develop in the plasma. as a result of the agglutinins attaching themselves to the Referring once again to Table 36-1, note that type O RBCs. Because the agglutinins have two binding sites (IgG blood, although containing no agglutinogens, does con- type) or ten binding sites (IgM type), a single agglutinin tain both anti-A and anti-B agglutinins. Type A blood can attach to two or more RBCs at the same time, thereby contains type A agglutinogens and anti-B agglutinins, and causing the cells to be bound together by the agglutinin. type B blood contains type B agglutinogens and anti-A This binding causes the cells to clump, which is the pro- agglutinins. Finally, type AB blood contains both A and B cess of agglutination. Then these clumps plug small blood agglutinogens but no agglutinins. vessels throughout the circulatory system. During the Titer of Agglutinins at Different Ages. Immediately ensuing hours to days, physical distortion of the cells or after birth, the quantity of agglutinins in the plasma is al- attack by phagocytic white blood cells destroys the mem- most zero. At 2 to 8 months after birth, an infant begins branes of the agglutinated cells, releasing hemoglobin into to produce agglutinins—anti-A agglutinins when type A the plasma, called hemolysis of the RBCs. agglutinogens are not present in the cells, and anti-B ag- Acute Hemolysis Occurs in Some Transfusion Reac- glutinins when type B agglutinogens are not in the cells. tions. Sometimes, when recipient and donor bloods are Figure 36-1 shows the changing titers of the anti-A and mismatched, immediate hemolysis of RBCs occurs in the anti-B agglutinins at different ages. A maximum titer is circulating blood. In this case, the antibodies cause lysis usually reached at 8 to 10 years of age, and this titer grad- of the RBCs by activating the complement system and ually declines throughout the remaining years of life.! forming a membrane attack complex (also called cytol- Origin of Agglutinins in Plasma. The agglutinins are ytic complex) that inserts itself into the lipid bilayer of the gamma globulins, as are almost all antibodies, and they cell membranes; this insertion creates membrane pores are produced by the same bone marrow and lymph gland that are permeable to ions and causes osmotic lysis of the cells that produce antibodies to any other antigens. Most cells, as described in Chapter 35. Immediate intravascu- of them are IgM and IgG immunoglobulin molecules. lar hemolysis is far less common than agglutination fol- But why are these agglutinins produced in people who lowed by delayed hemolysis, because not only does there do not have the respective agglutinogens in their RBCs? have to be a high titer of antibodies for lysis to occur, but A possible answer to this question is that small amounts also a different type of antibody seems to be required, of type A and B antigens enter the body in food, bacteria, mainly the IgM antibodies; these antibodies are called and other ways, and these substances initiate the develop- hemolysins.! ment of the anti-A and anti-B agglutinins. BLOOD TYPING For example, infusion of group A antigen into a recipi- ent having a non-A blood type causes a typical immune Before giving a transfusion to a person, it is necessary to response, with formation of more anti-A agglutinins determine the blood type of the recipient and donor blood than ever. Also, the neonate has few, if any, agglutinins, so that the bloods can be appropriately matched. This pro- showing that agglutinin formation occurs almost entirely cess is called blood typing and blood matching, and these after birth.! procedures are performed in the following way. The RBCs 472  Chapter 36 Blood Types; Transfusion; and Tissue and Organ Transplantation Table 36-2 Blood Typing: Agglutination of Cells of noted that even in Rh-negative people, some of the other Different Blood Types With Anti-A or Anti-B Agglutinins Rh antigens can still cause transfusion reactions, although in the Sera the reactions are usually much milder. Sera About 85% of all whites are Rh positive, and 15% are Red Blood Cell Types Anti-A Anti-B Rh negative. In American blacks, the percentage of Rh- UNIT VI positives is about 95%, whereas in African blacks, it is O − − nearly 100%. Over 95% of Native Americans and Asians A + − living in China, Japan, and Korea are also Rh positive, B − + and it is estimated that the worldwide frequencies of Rh- AB + + positive and Rh-negative blood types are 95% and 6%, respectively.! are first separated from the plasma and diluted with saline Rh IMMUNE RESPONSE solution. One portion is then mixed with anti-A aggluti- Formation of Anti-Rh Agglutinins. When RBCs con- nin and another portion is mixed with anti-B agglutinin. taining Rh factor are injected into a person whose blood After several minutes, the mixtures are observed under does not contain the Rh factor—that is, into an Rh- a microscope. If the RBCs have become clumped—that negative person—anti-Rh agglutinins develop slowly, is, agglutinated—then an antibody-antigen reaction has reaching a maximum concentration of agglutinins about resulted. 2 to 4 months later. This immune response occurs to a Table 36-2 lists the presence (+) or absence (−) of much greater extent in some people than in others. With agglutination of the four types of RBCs. Type O RBCs multiple exposures to the Rh factor, an Rh-negative per- have no agglutinogens and therefore do not react with the son eventually becomes strongly sensitized to Rh factor.! anti-A or anti-B agglutinins. Type A blood has A agglu- tinogens and therefore agglutinates with anti-A aggluti- Characteristics of Rh Transfusion Reactions. If an Rh- nins. Type B blood has B agglutinogens and agglutinates negative person has never been exposed to Rh-positive with anti-B agglutinins. Type AB blood has both A and blood, transfusion of Rh-positive blood into that person B agglutinogens and agglutinates with both types of will likely cause no immediate reaction. However, anti-Rh agglutinins.! antibodies can develop in sufficient quantities during the next 2 to 4 weeks to cause agglutination of the transfused cells that are still circulating in the blood. These cells are Rh BLOOD TYPES then hemolyzed by the tissue macrophage system. Thus, Along with the O-A-B blood type system, the Rh blood a delayed transfusion reaction occurs, although it is usu- type system is also important when transfusing blood. ally mild. On subsequent transfusion of Rh-positive blood The major difference between the O-A-B system and Rh into the same person, who is now already immunized system is the following. In the O-A-B system, the plasma against the Rh factor, the transfusion reaction is greatly agglutinins responsible for causing transfusion reactions enhanced and can be immediate and as severe as a trans- develop spontaneously, whereas in the Rh system, sponta- fusion reaction caused by mismatched type A or B blood.! neous agglutinins almost never occur. Instead, the person must first be massively exposed to an Rh antigen—such Erythroblastosis Fetalis (Hemolytic as by transfusion of blood containing the Rh antigen— Disease of the Newborn) before enough agglutinins to cause a significant transfu- Erythroblastosis fetalis is a disease of the fetus and new- sion reaction will develop. born child characterized by agglutination and phagocyto- sis of the fetus’s RBCs. In most cases of erythroblastosis Rh Antigens—Rh-Positive and Rh-Negative. There are fetalis, the mother is Rh negative and the father is Rh six common types of Rh antigens, each of which is called positive. The baby has inherited the Rh-positive antigen an Rh factor. These types are designated C, D, E, c, d, and from the father, and the mother develops anti-Rh aggluti- e. A person who has a C antigen does not have the c anti- nins from exposure to the fetus’s Rh antigen. In turn, the gen, but the person missing the C antigen always has the mother’s agglutinins diffuse through the placenta into the c antigen. The same is true for the D-d and E-e antigens. fetus and cause RBC agglutination. Also, because of the manner of inheritance of these fac- tors, each person has one of each of the three pairs of an- Incidence of Erythroblastosis Fetalis. An Rh-negative tigens. mother having her first Rh-positive child usually does not The type D antigen is widely prevalent in the popula- develop sufficient anti-Rh agglutinins to cause any harm. tion and is considerably more antigenic than the other Rh However, about 3% of second Rh-positive babies exhibit antigens. Anyone who has this type of antigen is said to some signs of erythroblastosis fetalis, about 10% of third be Rh positive, whereas a person who does not have type babies exhibit the disease, and the incidence rises pro- D antigen is said to be Rh negative. However, it must be gressively with subsequent pregnancies.! 473 UNIT VI Blood Cells, Immunity, and Blood Coagulation Effect of Mother’s Antibodies on the Fetus. After anti- The mechanism whereby Rh immunoglobulin globin Rh antibodies have formed in the mother, they diffuse prevents sensitization of the D antigen is not completely slowly through the placental membrane into the fetus’s understood, but one effect of the anti-D antibody is to blood. There they cause agglutination of the fetus’s blood. inhibit antigen-induced, B lymphocyte antibody produc- The agglutinated RBCs subsequently hemolyze, releasing tion in the expectant mother. The administered anti-D hemoglobin into the blood. The fetus’s macrophages then antibody also attaches to D antigen sites on Rh-positive convert the hemoglobin into bilirubin, which causes the fetal RBCs that may cross the placenta and enter the cir- baby’s skin to become yellow (jaundiced). The antibodies culation of the expectant mother, thereby interfering with can also attack and damage other cells of the body.! the immune response to the D antigen.! Clinical Picture of Erythroblastosis. The jaundiced, erythroblastotic newborn baby is usually anemic at birth, TRANSFUSION REACTIONS RESULTING and the anti-Rh agglutinins from the mother usually cir- FROM MISMATCHED BLOOD TYPES culate in the infant’s blood for another 1 to 2 months after If donor blood of one blood type is transfused into a birth, destroying more and more RBCs. recipient who has another blood type, a transfusion reac- The hematopoietic tissues of the infant attempt tion is likely to occur in which the RBCs of the donor blood to replace the hemolyzed RBCs. The liver and spleen are agglutinated. It is rare that the transfused blood causes become greatly enlarged and produce RBCs in the same agglutination of the recipient’s cells, for the following rea- manner that they normally do during the middle of gesta- son. The plasma portion of the donor blood immediately tion. Because of the rapid production of RBCs, many early becomes diluted by all the plasma of the recipient, thereby forms of RBCs, including many nucleated blastic forms, decreasing the titer of the infused agglutinins to a level are passed from the baby’s bone marrow into the circu- usually too low to cause agglutination. However, the small latory system, and it is because of the presence of these amount of infused blood does not significantly dilute the nucleated blastic RBCs that the disease is called erythro- agglutinins in the recipient’s plasma. Therefore, the recip- blastosis fetalis. ient’s agglutinins can still agglutinate the mismatched Although the severe anemia of erythroblastosis fetalis is donor cells. usually the cause of death, many children who barely sur- As explained earlier, all transfusion reactions eventu- vive the anemia exhibit permanent mental impairment or ally cause immediate hemolysis resulting from hemoly- damage to motor areas of the brain because of precipita- sins or later hemolysis resulting from phagocytosis of tion of bilirubin in the neuronal cells, causing the destruc- agglutinated cells. Hemoglobin released from the RBCs is tion of many of these cells, a condition called kernicterus.! then converted by the phagocytes into bilirubin and later Treatment of Neonates With Erythroblastosis Fetalis. excreted in the bile by the liver, as discussed in Chapter One treatment for erythroblastosis fetalis is to replace the 71. The concentration of bilirubin in the body fluids often neonate’s blood with Rh-negative blood. The Rh-negative rises high enough to cause jaundice—that is, the person’s blood is infused over a period of 1.5 or more hours while internal tissues and skin become colored with yellow bile the neonate’s own Rh-positive blood is being removed. pigment. However, if liver function is normal, the bile pig- This procedure may be repeated several times during the ment will be excreted into the intestines by way of the first few weeks of life, mainly to keep the bilirubin level liver bile, so jaundice usually does not appear in an adult low and thereby prevent kernicterus. By the time these unless more than 400 milliliters of blood are hemolyzed transfused Rh-negative cells are replaced with the infant’s in less than a day. own Rh-positive cells, a process that requires 6 weeks or Acute Kidney Failure After Transfusion Reactions. more, the anti-Rh agglutinins that had come from the One of the most lethal effects of transfusion reactions is mother will have been destroyed.! kidney failure, which can begin within a few minutes to Prevention of Erythroblastosis Fetalis. The D antigen a few hours and continue until the person dies of acute of the Rh blood group system is the primary culprit in renal failure. causing immunization of an Rh-negative mother to an The kidney shutdown seems to have three causes: Rh-positive fetus. In the 1970s, a dramatic reduction in 1. The antigen-antibody reaction of the transfusion re- the incidence of erythroblastosis fetalis was achieved with action releases toxic substances from the hemolyz- the development of Rh immunoglobulin globin, an anti- ing blood that cause powerful renal vasoconstric- D antibody that is administered to the expectant mother tion. starting at 28 to 30 weeks of gestation. The anti-D anti- 2. Loss of circulating RBCs in the recipient, along body is also administered to Rh-negative women who with production of toxic substances from the deliver Rh-positive babies to prevent sensitization of the hemolyzed cells and the immune reaction, often mothers to the D antigen. This step greatly reduces the cause circulatory shock. The arterial blood pressure risk of developing large amounts of D antibodies during falls very low, and renal blood flow and urine output the second pregnancy. decrease. 474  Chapter 36 Blood Types; Transfusion; and Tissue and Organ Transplantation 3. If the total amount of free hemoglobin released into ATTEMPTS TO OVERCOME IMMUNE the circulating blood is greater than the quantity REACTIONS IN TRANSPLANTED TISSUE that can bind with haptoglobin (a plasma protein Because of the extreme potential importance of trans- that binds small amounts of hemoglobin), much of planting certain tissues and organs, serious attempts the excess leaks through the glomerular membranes have been made to prevent antigen-antibody reactions UNIT VI into the kidney tubules. associated with transplantation. The following specific If this amount is still slight, it can be reabsorbed procedures have met with some degrees of clinical or through the tubular epithelium into the blood and will experimental success. cause no harm; if large, then only a small percentage is reabsorbed. Yet, water continues to be reabsorbed, Tissue Typing—Human Leukocyte Antigen Com- causing the tubular hemoglobin concentration to rise plex of Antigens. The most important antigens for so high that the hemoglobin precipitates and blocks causing graft rejection are a complex called human many of the kidney tubules. Thus, renal vasoconstric- leukocyte antigen (HLA) antigens. Six of these antigens tion, circulatory shock, and renal tubular blockage are present on the tissue cell membranes of each per- together cause acute renal shutdown. If the shutdown son, but there are about 150 different HLA antigens to is complete and fails to resolve, the patient dies within choose from, representing more than 1 trillion possible 7 to 12 days, as explained in Chapter 32, unless treated combinations. Consequently, it is virtually impossible with an artificial kidney.! for two persons, except in the case of identical twins, to have the same six HLA antigens. Development of significant immunity against any of these antigens can TRANSPLANTATION OF TISSUES AND cause graft rejection. ORGANS The HLA antigens are on the white blood cells, as Most of the different antigens of RBCs that cause trans- well as on the tissue cells. Therefore, tissue typing for fusion reactions are also widely present in other cells of these antigens is done on the membranes of lympho- the body, and each bodily tissue has its own additional cytes that have been separated from the person’s blood. complement of antigens. Consequently, foreign cells The lymphocytes are mixed with appropriate antisera transplanted anywhere into the body of a recipient can and complement; after incubation, the cells are tested produce an immune reaction. In other words, most recip- for membrane damage, usually by determining the rate ients are just as able to resist invasion by foreign tissue of transmembrane uptake by the lymphocytic cells of a cells as to resist invasion by foreign bacteria or RBCs. special dye. Some of the HLA antigens are not severely antigenic. Autografts, Isografts, Allografts, and Xenografts. A Therefore, a precise match of some antigens between transplant of a tissue or whole organ from one part of the donor and recipient is not always essential to allow same animal to another part is called an autograft; from allograft acceptance. By using a more advanced method one identical twin to another, an isograft; from one person of genetic testing and obtaining the best possible match to another or from an animal to another animal of the between donor and recipient, the grafting procedure has same species, an allograft; and from a nonhuman animal become far less hazardous. The best success has been to a human or from an animal of one species to one of with tissue type matches between siblings and between another species, a xenograft.! parent and child. The match in identical twins is exact, Transplantation of Cellular Tissues. In the case of auto- so transplants between identical twins are almost never grafts and isografts, cells in the transplant contain virtually rejected because of an immune reaction.! the same types of antigens as in the tissues of the recipi- ent and will almost always continue to live normally and Prevention of Graft Rejection by indefinitely if an adequate blood supply is provided. At the Suppressing the Immune System other extreme, immune reactions almost always occur in If the immune system were completely suppressed, graft xenografts, causing death of the cells in the graft within 1 rejection would not occur. In fact, in a person who has day to 5 weeks after transplantation unless some specific serious depression of the immune system, grafts can be therapy is used to prevent the immune reactions. successful without the use of significant therapy to pre- Some of the different cellular tissues and organs that vent rejection. However, in the person with a healthy have been transplanted from one person to another as immune system, even with the best possible tissue typing, allografts, either experimentally or for therapeutic pur- allografts seldom resist rejection for more than a few days poses, are skin, kidney, heart, liver, glandular tissue, or weeks without the use of specific therapy to suppress bone marrow, and lung. With proper matching of tissues the immune system. Furthermore, because the T cells between persons, many kidney allografts have been suc- are mainly the portion of the immune system important cessful for at least 5 to 15 years and allograft liver and for killing grafted cells, their suppression is much more heart transplants for 1 to 15 years.! important than suppression of plasma antibodies. Some 475 UNIT VI Blood Cells, Immunity, and Blood Coagulation of the therapeutic agents that have been used for this pur- therapy attempts to balance acceptable rates of rejection pose include the following: with moderation of the adverse effects of immunosup- 1. Glucocorticoid hormones from adrenal cortex pressive drugs. glands (or drugs with glucocorticoid-like activity). These drugs inhibit genes that code for several cy- tokines, especially interleukin-2 (IL-2). IL-2 is an Bibliography essential factor that induces T-cell proliferation and Branch DR: Anti-A and anti-B: what are they and where do they come antibody formation. from? Transfusion 55 Suppl 2:S74, 2015. 2. Various drugs that have a toxic effect on the lym- Burton NM, Anstee DJ: Structure, function and significance of Rh pro- phoid system and therefore block formation of an- teins in red cells. Curr Opin Hematol 15:625, 2008. Dierickx D, Habermann TM: Post-transplantation lymphoproliferative tibodies and T cells, especially the drug azathio- disorders in adults. N Engl J Med 378:549, 2018.. prine. Ezekian B, Schroder PM, Freischlag K, et al: Contemporary strate- 3. Cyclosporine and tacrolimus, which inhibit forma- gies and barriers to transplantation tolerance. Transplantation tion of T-helper cells and, therefore, are especially 102:1213, 2018. efficacious in blocking the T-cell rejection reac- Flegel WA: Pathogenesis and mechanisms of antibody-mediated he- molysis. Transfusion 55 Suppl 2:S47, 2015. tion. These agents have proven to be highly valuable Kramer CSM, Israeli M, Mulder A, et al: The long and winding road drugs because they do not depress some other por- towards epitope matching in clinical transplantation. Transpl Int tions of the immune system. 32:16, 2019. 4. Immunosuppressive antibody therapy. including spe- Loupy A, Lefaucheur C: Antibody-mediated rejection of solid-organ cific antilymphocyte or IL-2 receptor antibodies. allografts. N Engl J Med 379:1150, 2018. MacDonald KP, Blazar BR, Hill GR: Cytokine mediators of chronic Use of these agents often leaves the person unpro- graft-versus-host disease. J Clin Invest 127:2452, 2017. tected from infectious disease; therefore, sometimes Montgomery RA, Tatapudi VS, Leffell MS, Zachary AA: HLA in trans- bacterial and viral infections become rampant. In addi- plantation. Nat Rev Nephrol 14:558, 2018. tion, the incidence of cancer is several times greater in Watchko JF, Tiribelli C: Bilirubin-induced neurologic damage—mech- an immunosuppressed person, presumably because the anisms and management approaches. N Engl J Med 369:2021, 2013. immune system is important in destroying many early Webb J, Delaney M: Red blood cell alloimmunization in the pregnant cancer cells before they can begin to proliferate. patient. Transfus Med Rev 32:213, 2018. Transplantation of living tissues in people has been Westhoff CM: Blood group genotyping. Blood. 133:1814, 2019 successful mainly because of the development of drugs Westhoff CM: The structure and function of the Rh antigen complex. that suppress the responses of the immune system. With Semin Hematol 44:42, 2007. Yazer MH, Seheult J, Kleinman S, Sloan SR, Spinella PC: Who’s afraid the introduction of improved immunosuppressive agents, of incompatible plasma? A balanced approach to the safe trans- successful organ transplantation has become much more fusion of blood products containing ABO-incompatible plasma. common. The current approach to immunosuppressive Transfusion 58:532, 2018. 476