What every physician should know about transfusion reactions ============================================================ * Suzanne Bakdash, MD MPH * Mark H. Yazer MD * © 2007 Canadian Medical Association Blood transfusions can be life-saving in the appropriate setting. The vast majority of transfusions are completed without incident, but every transfusion recipient is at risk of a variety of adverse events (termed transfusion reactions) that can occur during, shortly after or long after the transfusion. Most transfusion reactions are diagnosed by exclusion; thus, any significant change in a patient's condition during transfusion should prompt an investigation. Successful investigation of a transfusion reaction depends on detailed observation, documentation and reporting of the patient's vital signs, before and after the transfusion, and the signs and symptoms that prompted the investigation. In this article, we review some of the most common transfusion reactions using a case-based approach. ## Case 1 A 56-year-old woman with leukemia, neutropenia and thrombocytopenia required a platelet transfusion after chemotherapy. Midway through the transfusion, the patient developed chills and rigors, her temperature rose from 37.2°C to 38.4°C and her heart rate increased slightly. Her other vital signs remained stable. The transfusion was stopped and samples were sent to the blood bank for investigation. The results of a direct anti-globulin test were negative, and no free hemoglobin was observed on visual inspection of the plasma. The initial clinical management and investigation at the blood bank of a transfusion reaction are shown in Figure 1. ![Figure1](http://www.cmaj.ca/https://www.cmaj.ca/content/cmaj/177/2/141/F1.medium.gif) [Figure1](http://www.cmaj.ca/content/177/2/141/F1) **Figure 1:** Management and blood bank investigation of a suspected transfusion reaction. Specific therapeutic interventions should be based on the recipient's signs, symptoms and underlying medical condition. *Transfusion can only be started after the recipient's identity is verified and matches the information on the blood unit. If a transfusion reaction is suspected, the clinical staff should repeat this verification. The blood bank will also compare the identifiers on the returned unit with that on the accompanying documentation to verify that the correct patient received the unit. †Identifies whether hemolysis, mediated by IgG or complement, has occurred. In most blood banks, this test is performed on the post-reaction specimen and, if positive, is also performed on a pre-transfusion sample for comparison. ‡Visual inspection for colour change is a sensitive test that can detect small amounts of free hemoglobin in the plasma. This test complements the direct antiglobulin test and may be the only indicator of hemolysis if the antibody or complement-coated red blood cells were rapidly cleared from the patient's circulation (resulting in a negative result of a direct antigen test despite the presence of immune-mediated hemolysis). §Although post-transfusion urine samples may be difficult to obtain, the presence of free hemoglobin in the urine indicates the presence of a large amount of free hemoglobin in the plasma, which exceeds the binding capacity of circulating haptoglobin. The findings in this case are characteristic of a febrile nonhemolytic transfusion reaction. This diagnosis is usually defined by an otherwise unexplained rise in temperature of at least 1°C during or shortly after transfusion. It can be difficult to diagnose with certainty if the patient is already at risk for developing a fever; however, an increase of 1°C that is temporally related to transfusion should always prompt an investigation (other causes of transfusion-related fever are shown in Table 1). Antipyretic premedications may obscure a fever, but they do not usually prevent chills and rigors, which are manifestations of a cytokine-mediated systemic inflammatory response. View this table: [Table1](http://www.cmaj.ca/content/177/2/141/T1) Table 1. Platelets, more often than red blood cells, are the cause of febrile nonhemolytic transfusion reaction because they are stored at room temperature, which is conducive to leukocyte activation and cytokine accumulation. When caused by red blood cells, febrile nonhemolytic transfusion reactions are usually mediated by recipient antibodies against donor leukocytes; therefore, removing leukocytes from blood products before transfusion can reduce this type of reaction. This is one of the reasons that the Canadian Blood Services adopted universal leukoreduction of blood products in 1999. Treatment of febrile nonhemolytic transfusion reactions is symptomatic (Figure 1). Medication with antipyretics before any subsequent transfusions and the use of leukoreduced components can help to reduce the frequency and severity of these reactions. ## Case 2 A 46-year-old man required urgent reversal of warfarin anticoagulation before a surgical procedure. Twenty minutes after starting transfusion of a unit of fresh-frozen plasma, the patient developed an itchy rash on his face, chest and arms, and he remarked that his throat felt a little “tight.” His blood pressure and temperature remained unchanged. The transfusion was immediately stopped and an antihistamine was administered. The patient's symptoms resolved 45 minutes later. The blood-bank investigation for hemolysis was negative. An allergic reaction is a common reaction to a transfusion and is mediated by recognition of antigens in the donor plasma by preformed recipient IgE antibodies. In the case of a simple allergic reaction (a mild rash that resolves with antihistamine administration, accompanied by stable blood pressure and no dyspnea), some institutions allow the same unit to be restarted after the symptoms resolve. Other institutions require a new unit of blood product be provided if the transfusion remains necessary. More severe allergic reactions are associated with hypotension and airway edema, and sometimes require administration of epinephrine and emergent intubation. People who are IgA deficient and have anti-IgA antibodies may experience severe allergic reactions to blood products and require plasma products from IgA-deficient donors for future transfusions. These patients may receive red blood cells and platelets from donors who are not IgA deficient if the plasma component is removed by repeated washing. Consultation with the blood bank is advised if a severe allergic reaction is suspected. Any medications or other substances administered around the time of transfusion should be considered before attributing an allergic reaction to the blood product. Prophylactic measures for future transfusions depend on the severity of the reaction. Premedication with antihistamines before transfusion is usually sufficient for patients who have had a previous simple allergic reaction. Additional prophylaxis with corticosteroids may be beneficial to those with a history of moderate to severe allergic reactions. ## Case 3 A 78-year-old woman with anemia and congestive heart failure received 200 mL of red blood cells over a 30-minute period before tachypnea developed and she began complaining of dyspnea and mild chest pain. The transfusion was immediately stopped. The patient did not have fever or chills. Rales and crackles were heard in both lung fields, jugular venous distention was apparent and hypertension was noted. A chest radiograph showed cardiogenic pulmonary edema. The results of a blood-bank investigation for hemolysis were negative. Her symptoms were relieved when a diuretic was administered and 1 L fluid was voided. This clinical scenario is typical of transfusion-associated circulatory overload, which is underreported and should be suspected when a patient at risk of volume overload (e.g., heart, lung or kidney failure) complains of dyspnea or demonstrates signs of respiratory distress. The treatment of transfusion-associated circulatory overload includes supplemental oxygen and diuretics. Although much less common than transfusion-associated circulatory overload, transfusion-related acute lung injury (TRALI) may present in a similar manner. Transfusion-related acute lung injury can be differentiated by the typical chest radiograph findings of noncardiogenic pulmonary edema and by the absence of jugular venous distension and normal right-atrial pressure. Brain (b-type) natriuretic peptide is normally used to help diagnose the presence and severity of heart failure. However, in a transfusion setting, elevated post transfusion levels are suggestive of transfusion-associated circulatory overload and maintenance of pre-transfusion levels is suggestive of transfusion-related acute lung injury. This test may be used as a marker to help to distinguish between these 2 types of reactions, although this test is not yet available at all hospitals. ## Case 4 A 67-year-old man presented with an upper gastrointestinal bleed secondary to a perforated ulcer. The patient received a total of 6 units of red blood cells over a 2-day period. The pre-transfusion results of a direct anti-globulin test and an antibody screen were negative. Two weeks later, the patient presented to his primary care physician with complaints of fatigue. On examination, the patient appeared mildly jaundiced, and the results of laboratory tests showed a 28 g/L decrease in his hemoglobin level, as well as decreased haptoglobin and increased lactate dehydrogenase and bilirubin levels. The results of a new direct anti-globulin test and an antibody screen were positive, and red-cell alloantibodies were identified. This case highlights some of the findings of delayed extravascular immune-mediated hemolysis. The antibody titre in patients who form alloantibodies against red blood cells following a pregnancy or transfusion can sometimes drop over time until it falls below the limit of detection of an antibody screening test. If the transfusion service does not have a record of this antibody, no special measures would be taken to avoid transfusing the patient with red blood cells that carry the corresponding antigen. Transfusion of such a product may trigger an anamnestic immune response leading to increased antibody production and immune-mediated hemolysis of the donor red blood cells (i.e., a delayed hemolytic transfusion reaction), and the “new” antibodies would be detected upon subsequent screening. Less frequently, delayed hemolytic transfusion reactions may be caused by the formation of new alloantibodies against recently transfused red blood cells. This type of transfusion reaction can occur any time from 3 days to 2 weeks post transfusion, and it may be observed before or after the patient is discharged from hospital. Delayed hemolytic transfusion reactions may be asymptomatic and might only be detected by abnormal results of follow-up testing. If a delayed hemolytic transfusion reaction is suspected, tests for laboratory markers of hemolysis should be ordered (e.g., haptoglobin, lactate dehydrogenase, bilirubin), and a direct anti-globulin test and an antibody screen should be performed. Management of delayed hemolytic transfusion reactions is supportive and may include additional transfusions with antigen-negative units. In contrast, acute hemolytic transfusion reactions are associated with immune-mediated intravascular hemolysis, and the mortality rate is 1 in 30. The presentation can vary (Table 1); therefore, every time a transfusion reaction is suspected, acute hemolysis must be ruled out by a clerical check, direct anti-globulin testing and visual inspection of the recipient's post-transfusion plasma for the presence of free hemoglobin. Post-transfusion urine can also be analyzed for presence of free hemoglobin. ABO incompatibility because of clerical error or patient misidentification remains the most frequent cause of acute hemolytic transfusion reactions. ABO incompatibility, transfusion-related acute lung injury and transfusion-associated sepsis are 3 of the most common causes of transfusion-associated fatalities. Transfusion-associated graft-versus-host disease, although rare, is another complication associated with a high mortality rate. ## Comments Approaches to the differential diagnosis and management of some of the more common manifestations of transfusion reactions are outlined in Table 1 and Figure 1, and the timeline of occurrence and the estimated risk are shown in Table 2. Other less common, but clinically important, transfusion sequelae include the transmission of viral infections. Table 3 describes a number of infectious agents and their current estimated risk of transmittance via transfusion of blood products. A recent paper provides a graph of the risk of acquiring several transfusion-transmitted viruses over time,4 as well as a discussion of interventions that might further enhance the safety of the blood supply and of the emerging pathogen, human herpesvirus. View this table: [Table2](http://www.cmaj.ca/content/177/2/141/T2) Table 2. View this table: [Table3](http://www.cmaj.ca/content/177/2/141/T3) Table 3. Appendix 1 presents a brief patient-oriented discussion of some of the more common questions and concerns that a patient may have about transfusions. Another source of information about transfusion reactions is the *Bloody Easy* handbook.5 In summary, a blood transfusion can be a vital medical intervention. Physicians and nurses who provide care to transfusion recipients need to remain alert for the signs and symptoms of transfusion reactions, particularly during and shortly after the transfusion; however, some adverse consequences of the transfusion may not become apparent until days, weeks or even years later. Complete documentation, reporting of suspected reactions and consultation with a transfusion-medicine physician provide the basis for successful investigation of transfusion reactions and the ability to implement interventions that may help protect the patient during subsequent transfusions. @ See related article page [149](http://www.cmaj.ca/lookup/volpage/177/149?iss=2) ## Appendix 1 View this table: [Table4](http://www.cmaj.ca/content/177/2/141/T4) Appendix 1. ## Footnotes * This article has been peer reviewed. **Acknowledgements:** We thank Dr. Darrell Triulzi for his critical review and thoughtful discussion of the manuscript. **Competing interests:** None declared. ## REFERENCES 1. 1. Brecher ME, ed. *AABB technical manual*. 15th ed. Bethesda (MD): American Association of Blood Banks Press; 2005. 2. 2. Perrotta PL, Snyder EL. Non-infectious complications of transfusion therapy. Blood Rev 2001;15:69-83. 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