Robertson D. Davenport, associate professor of pathology and medical director of the Blood Bank and Transfusion Service at the University of Michigan, explains.

There are several important differences between blood transfusions and organ transplants. Transfused red cells are expected to last for no more than three months, while transplants will hopefully function for many years. Transfusions are given intravascularly, and transplants are, of course, implanted. Immune responses to foreign antigens that are given intravascularly tend to be less pronounced than responses to antigens introduced through other routes. Transplanted organs contain some immune cells from the donor that can stimulate the recipient, whereas most immune cells that might be in a transfusion are filtered out before administration.

Blood transfusions may be rejected by the recipient, resulting in a transfusion reaction, but such cases are relatively rare. In order to comprehend how this can happen, it is necessary to understand some basic immunology. There are two basic types of immune responses: humoral, or antibody-mediated, and cellular. Humoral immune responses result in the production of antibodies that are specific to a foreign antigen. When these antibodies attach to the antigen--on bacteria, for example--immune complexes are formed. The body's macrophages, mainly in the liver and spleen, then remove and destroy the immune complexes. Once attached to antigens, antibodies can also activate what is known as the complement pathway. As an end result, complement activation can punch holes in the membranes of bacteria or cells that are coated with antibodies. When red blood cells are the target of antibodies and complement, a condition called hemolysis results. Immune responses evoked by blood transfusion, when they occur, are usually humoral in nature. Organ and bone marrow transplants, in contrast, usually evoke cellular immune responses, which lead to the production of specific cytotoxic lymphocytes.

The most important blood cell antigens in transfusion are in the ABO system. Blood types can be A (having A but not B antigens on red cells), B (having B but not A antigens), AB (having both A and B antigens), or O (having neither). Virtually everyone over the age of six months has antibodies to the A or B antigens that they don't produce. For example, a group A individual has A antigen on his red cells and anti-B in his plasma. If blood is transfused to a patient who already has antibodies to the transfused cells (giving this individual group B blood, for example) then a serious reaction can occur. Because antibodies to A and B antigens are good at activating complement, transfusion of ABO incompatible red cells can cause breakdown of the cells in circulation and a strong inflammatory response. The end result can be kidney failure and even death. Fortunately, this type of immediate rejection of transfused red cells is rare.

A more common type of rejection of transfused red cells is a delayed hemolytic reaction. In this case, the patient does not have preexisting antibodies to the transfused red cells. Rather, an immune response occurs days to weeks after the transfusion. The antibodies produced in such reactions tend not to activate complement, so the transfused red cells in circulation do not usually break down. Instead, the cells are removed by the spleen and a milder inflammatory response may occur. Delayed hemolytic reactions occur in about one out of every 5,000 transfusions. The antibodies involved can be directed against one or more of hundreds of known blood group antigens. Delayed hemolytic transfusion reactions usually are not very severe, but sometimes do cause renal failure. Patients with sickle cell anemia are at greater risk of having delayed hemolytic reactions because they often receive many transfusions. These reactions can be more severe than in other patients because the loss of normal hemoglobin containing red cells and the inflammation caused by the reaction can trigger a sickle crisis.

Blood banks perform pretransfusion compatibility testing to avoid hemolytic reactions. Routine pretransfusion testing consists of analyzing the patients red cells for A and B antigens, testing for the presence of anti-A and anti-B in the plasma, testing for the Rh(D) antigen on red cells and screening for other red cell antibodies in the plasma. Because ABO incompatibility can be so serious, doctors need to be sure that a patients ABO type is correct. That is why hospitals test for both the antigens and the antibodies and require agreement between the tests in order to conclude the blood type. Out of hundreds of other blood group antigens (including dozens in the Rh system), testing is routinely performed for only one other: the Rh(D) antigen, which is the most likely to cause an immune response. If it is present, the patient is Rh-positive. There is about an 85 percent chance that an Rh-negative person will make antibodies if transfused with Rh-positive blood, whereas other blood group antigens are not such strong immune stimulators. The screening test for unexpected (not A or B) antibodies covers about 25 that patients are most likely to make and can detect red cell antibodies that were generated in response to previous transfusions or pregnancies. If the screen is positive, further testing is performed to identify the specificity of the antibody and select blood from a donor that lacks the corresponding antigen. More commonly, the antibody screen is negative and we can safely transfuse ABO compatible red cells despite other blood group differences between the donor and recipient that may be present.

The situation is a little different for transfusions of platelets rather than red cells, which occur with patients undergoing chemotherapy. Because A and B antigens are weakly expressed on platelets, they are less important in this case. Although there are antigens that are specific to platelets, it is rare for people to make antibodies against them even after repeated transfusions. But HLA antigens, which are critically important in transplantation, are strongly expressed on platelets (but only very weakly expressed on red cells). It is common for patients to make antibodies to HLA antigens in response to transfusions or pregnancy. When platelets are transfused to a patient with corresponding HLA antibodies they are very rapidly cleared from circulation, which is essentially immediate rejection of the transfusion. Usually there is not a clinically evident reaction, as in case of incompatible red cell transfusion, but the platelet transfusion is ineffective. Such a patient can become refractory to platelet transfusion (meaning that the platelet count does not rise and the patient experiences no benefit) and may be at risk for serious bleeding. Refractoriness to platelet transfusion is a serious problem in cancer chemotherapy and bone marrow transplantation. Unfortunately, it is much more difficult to test for HLA and platelet antibodies than it is to test for red cell antibodies. Platelet compatibility testing is done for patients who do not have a successful response after several platelet transfusions.

Things get even more complicated when white cells (such as lymphocytes) are transfused. Normally, there are very small numbers of viable white cells in most units of blood transfused today. People with normal immune systems can reject transfused donor lymphocytes, which is a good thing. If transfused lymphocytes are not rejected there can be problems. Very sensitive tests for donor white cells have shown that they may persist in the recipients blood for one or two weeks after transfusion before they are rejected. It is possible for transfused lymphocytes to survive and proliferate, however. Small numbers of donor lymphocytes have been found in some patients months or years after transfusion. This results in a state of microchimerism, in which a little of the patients immune system is genetically foreign. We do not know the full implications of microchimerism, but it most likely causes some abnormalities in immune responses. In the most severe case, transfused lymphocytes can not only survive, but also react against the patients tissues. This causes graft-versus-host disease, which is usually fatal. Patients with markedly impaired cellular immunity are at risk of transfusion-associated graft-versus-host disease. Blood for such patients is routinely gamma irradiated to prevent this rare but very serious reaction.