As summarized in Table 25-2, hemolysis due to the administration of antigenically incompatible red cells can be either immediate or delayed. Immediate hemolytic reactions are nearly always due to ABO incompatibility. For example, if an individual with type B blood receives a unit of type A blood by mistake, the recipient's preexisting IgM anti-A antibodies will cause complement fixation and intravascular lysis of the transfused red cells. The patient's clinical presentation depends on how much blood was infused before the error was suspected and the transfusion stopped. Patients generally develop fever and chills, often accompanied by dyspnea, tachycardia, hemoglobinuria, and severe pain, usually in the lower back. Transfusion of a large volume of ABO-incompatible blood often produces hypotensive shock, oliguria, and disseminated intravascular coagulation. Note that all of these findings except for hypotension are likely to be missed if the patient is in the operating room under general anesthesia. At the first signal that incompatible blood may have been administered, the infusion must be stopped and serologic testing repeated on the donor and recipient blood. During this time it is critical to maintain intravenous access and careful monitoring of blood pressure and urine output. Fortunately, contemporary blood banking has a series of safeguards in place that make this complication very rare. In New York State, 9,000,000 units of blood were transfused over the decade 1990 through 1999. A total of 462 patients (about 1 per 20,000 units given) suffered adverse consequences from administration of ABO-incompatible blood.
TABLE 25-2Hemolytic Transfusion Reactions ||Download (.pdf) TABLE 25-2 Hemolytic Transfusion Reactions
| ||Acute ||Delayed |
|Timing ||Immediate ||3-10 days after transfusion |
|Mechanism ||Preformed antibody ||Anamnestic antibody response |
|Antibody ||IgM or complement-fixing IgG(eg, anti-A or anti-B) ||IgG, no complement fixation(eg, anti-Rh) |
|Site of hemolysis ||Usually intravascular ||Usually extravascular |
|Clinical sequelae ||Severe cases: shock, disseminated intravascular coagulation, acute renal failure ||Usually none |
Delayed hemolytic transfusion reactions are more commonly encountered and seldom caused by error. As mentioned earlier, patients develop alloantibodies to protein antigens only after pregnancy or transfusions. The Rh D antigen is highly immunogenic and will trigger detectable levels of anti-D after a single exposure. In contrast, antigens such as Rh C, c, E, and e as well as Kell and Duffy (Fig. 25-5) and others, shown in Figure 25-2, are less immunogenic, but in some cases nevertheless trigger a primary immune response in an antigen-negative recipient. This primary response may not cause the development of a sufficiently high antibody titer to be detectable by the screening procedure described in Figure 25-5. However, if at a later point in time the recipient is transfused with a second unit containing this antigen, within 3 to 10 days an anamnestic immunologic response will raise the titer of antibody to sufficient levels to cause clinically significant hemolysis. As mentioned at the beginning of this chapter, anti-Rh antibody is an IgG and does not fix complement. Accordingly, the hemolysis is extravascular and not nearly as severe as that encountered in immediate hemolytic reactions due to ABO incompatibility. Figure 25-7 depicts a typical delayed transfusion reaction. This complication should be suspected in any patient who develops an unexplained drop in hemoglobin or hematocrit within a week of receiving transfused red cells. Often the patient has no symptoms or signs but occasionally may develop fever, chills, and jaundice, and rarely hemoglobinuria. The diagnosis is established either by documenting the presence of antibody-coated red cells in the patient's blood by the direct antiglobulin test (Chapter 11, Fig. 11-3A) or by the indirect antiglobulin test (Chapter 11, Fig. 11-3B), in which the patient's serum is tested against a panel of red cells with characterized antigens as well as against the donor red cells that were recently infused. Often the direct antiglobulin test is negative because the antibody-coated red cells have been rapidly cleared by resident macrophages. Delayed hemolytic transfusion reactions usually do not require therapy. However, the patient's hemoglobin and hematocrit levels should be closely monitored, and care must be given to ensure that future red cell transfusions are antigen negative.
Time course of a typical delayed hemolytic transfusion reaction due to the anamnestic induction of anti-c antibodies. On day 0, the patient was transfused with Rh c+ red cells, resulting in the desired increment in hematocrit level. By day 5, a rise in the serum bilirubin level suggested the possibility of hemolysis. At this time, the direct antiglobulin test result was positive. As the antibody-coated donor red cells were rapidly cleared from the circulation, the serum bilirubin level rose further, and the hematocrit level fell rapidly. DAT, direct antiglobulin test.
Hemolytic disease of the fetus and newborn (HDFN) involves an immunologic response following the "transfusion" of red cells from the fetus into the maternal circulation. By far the most common cause of HDFN is maternal Rh D alloimmunization. The pathogenesis is similar to that of a delayed hemolytic transfusion reaction; a typical scenario is as follows. An Rh-negative mother is carrying a fetus that has inherited the D antigen from its father. During the first pregnancy, leakage of fetal red cells across the placenta results in the mother becoming immunized against the D antigen. However the amount of anti-D antibody that crosses the placenta into the fetal circulation is too low to cause hemolysis. With subsequent pregnancies, the mother mounts an anamnestic immunologic response to D+ fetal red cells, putting the fetus and newborn at high risk of developing alloimmune hemolysis. The baby develops severe anemia and generalized edema (hydrops) owing to tissue hypoxia. In addition, the high levels of nonconjugated bilirubin in fetal and neonatal plasma can cross the blood-brain barrier and accumulate in the brain, particularly in the basal ganglia, causing irreversible neurologic damage (kernicterus). If signs of fetal distress during the third trimester trigger a hematologic investigation leading to the diagnosis of HDFN, intrauterine transfusion will prevent the development of hydrops and kernicterus. Fortunately, HDFN is rarely encountered today thanks to the discovery 50 years ago that the administration of anti-D immunoglobulin (RhoGAM, Ortho Clinical Diagnostics, Rochester, NY) to Rh-negative mothers after their first delivery safely and effectively suppresses sensitization to Rh D and prevents the development of HDFN in subsequent pregnancies.
TRANSFUSION-RELATED LUNG INJURY
Approximately one in 3000 patients develops acute interstitial pneumonitis within 6 hours of transfusion, accompanied by dyspnea, tachycardia, hypoxemia, fever, and hypotension. Figure 25-8 shows the rapid development of bilateral pulmonary infiltrates in a patient whose lungs were normal prior to transfusion. This acute process is often difficult to distinguish from pulmonary edema, pulmonary embolus, bacterial pneumonia, pulmonary hemorrhage, or acute respiratory distress syndrome. It is likely that transfusion-related acute lung injury (TRALI) is a form of acute respiratory distress syndrome caused by donor antibodies that bind to and activate either recipient neutrophils or pulmonary endothelial cells. In many cases, the causative antibodies appear to be against HLA antigens. Other cases are associated with pathogenic antibodies against a polymorphic antigen expressed on neutrophils, called choline transporter-like protein 2 (CLT2); these antibodies are particularly prone to cause severe and often fatal TRALI. TRALI is the most commonly encountered serious complication of transfusion therapy. The treatment of TRALI is primarily supportive. All patients require oxygen and most need ventilator assistance. These episodes usually resolve over 48 to 96 hours, but the mortality is 5% to 25%. The risk of TRALI can be reduced by the use of plasma from male donors, because women may become HLA-alloimmunized during pregnancy. Cases of suspected TRALI are investigated by the blood bank. Donors of blood products believed to have caused TRALI are permanently banned from donating blood.
Development of transfusion-related acute lung injury (TRALI) following blood transfusion. A. Pre transfusion; B. Post-transfusion showing rapid emergence of bilateral pulmonary infiltrates. (Modified with permission from Bux J. Transfusion-related acute lung injury (TRALI): a serious adverse event of blood transfusion. Vox Sang 2005;89:1-10.)
TRANSMISSION OF INFECTIOUS PATHOGENS
A variety of bacterial, viral, and parasitic infections can be transmitted by transfusion of blood or blood products. Current transfusion practice mandates routine screening for the pathogens listed in Table 25-3. Bacterial contamination is particularly problematic in platelet concentrates that are stored at room temperature. Occasional cases of malaria in the United States have arisen through transfusion of blood from a donor who has recently returned from a tropical area. The viral pathogens of most concern are human immunodeficiency virus (HIV), hepatitis C, and hepatitis B. However, thanks to highly sensitive and specific immunologic and genetic methods for detection, the risk of transmission of these viruses via blood products has fallen several orders of magnitude over the last 25 years. As Figure 25-9 shows, there is only a short (10 day) window of time between exposure to HIV infection and its detection by testing for HIV RNA in the blood. Despite these advances, the lay public continues to harbor fears that HIV and hepatitis are the most likely serious complications of transfusion therapy. In fact, as Table 25-4 shows, TRALI and administration of incompatible blood pose much higher risks than viral pathogens.
The human immunodeficiency virus (HIV) "window period" or time intervals between exposure to HIV and the detection of HIV ribonucleic acid (RNA) and HIV antibody.
TABLE 25-3Infectious Disease Screening ||Download (.pdf) TABLE 25-3 Infectious Disease Screening
Human immunodeficiency viruses 1 and 2 (HIV1 and HIV2)
Hepatitis B virus
Hepatitis C virus
Human T-cell lymphotropic viruses 1 and 2 (HTLV1 and HTLV2)
West Nile virus
Trypanosomiasis (Chagas disease)
TABLE 25-4Risks of Blood Transfusion ||Download (.pdf) TABLE 25-4 Risks of Blood Transfusion
| ||Per-Unit Risk |
|Transfusion-related acute lung injury ||1/3000 |
|Incompatible blood ||1/14,000 |
|Pathogen || |
| Bacteria (platelets) ||1/75,000 |
| Hepatitis B virus ||1/200,000 |
| Hepatitis C virus ||1/2,000,000 |
| Human immunodeficiency virus ||1/2,000,000 |