Transfusion Reactions

Practice Essentials

Acute transfusion reactions present as adverse signs or symptoms during or within 24 hours of a blood transfusion.^[1]  The most frequent reactions are fever, chills, pruritus, or urticaria, which typically resolve promptly without specific treatment or complications. Other signs occurring in temporal relationship with a blood transfusion, such as severe shortness of breath, red urine (see image below), high fever, or loss of consciousness may be the first indication of a more severe potentially fatal reaction.^{[2, 3, 4]}

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Rapid test to distinguish hematuria from hemoglobinuria. The onset of red urine during or shortly after a blood transfusion may represent hemoglobinur....

Transfusion reactions require immediate recognition, laboratory investigation, and clinical management. If a transfusion reaction is suspected during blood administration, the safest practice is to stop the transfusion and keep the intravenous line open with 0.9% sodium chloride (normal saline). A clerical check of the information on the blood unit label and the patient's identification should be performed to ensure that the "right" blood unit was administered to the "right" patient. In most cases, the residual contents of the blood component container should be returned the blood bank, together with a freshly collected blood sample from the patient, and a transfusion reaction investigation should be initiated.

Acute transfusion reactions may present in complex clinical situations when the diagnosis requires distinguishing between a reaction to the transfused blood product and a coincidental complication of the illness being treated that occurs during or immediately after a blood transfusion.

Delayed hemolytic transfusion reactions (DHTRs) occur in patients who have received transfusions in the past. These patients may have very low antibody titers that are undetectable on pretransfusion testing, so that seemingly compatible units of red blood cells (RBCs) are transfused. Exposure to antigen-positive RBCs then provokes an anamnestic response and increased synthesis of the corresponding antibody. After several days, the antibody titer becomes high enough to hemolyze transfused RBCs. The frequency of DHTRs is estimated to be approximately 1 case per 5400 red cell units transfused.

DHTRs are a potentially life-threatening complication of sickle-cell disease (SCD) treatment. In SCD, DHTRs appear to be an immune process that develop because of differences in erythrocyte antigens between blood donors of European descent and patients of African descent. Hemolysis in DHTR can be severe, because both the transfused and autologous red blood cells may be destroyed (so-called bystander hemolysis); DHTR can evolve into hyperhemolysis syndrome Most episodes lead to insufficient reticulocytosis or even profound reticulopenia.^{[5, 6]}

For patient education information, see the Blood Transfusions Directory and Blood in the Urine.

• References

Pathophysiology

Acute transfusion reactions are typically classified into the following entities^[7] :

• Transfusion-related acute lung injury (TRALI)
• Circulatory (volume) overload
• Bacterial contamination and endotoxemia
• Acute hemolytic reactions
• Nonhemolytic febrile reactions
• Allergic reactions

Transfusion-related acute lung injury

TRALI has two proposed pathophysiologic mechanisms: the antibody hypothesis and the neutrophil priming hypothesis.^{[8, 9]} Both mechanisms lead to pulmonary edema in the absence of circulatory overload.

The antibody hypothesis states that a human leukocyte antigen (HLA class I, HLA class II) or human neutrophil antigen (HNA) antibody in the transfused component reacts with neutrophil antigens in the recipient (ie, when antileukocyte antibodies are transfused passively in a plasma-containing blood component).^[10] The recipient's neutrophils lodge in the pulmonary capillaries and release mediators that cause pulmonary capillary leakage. As a consequence, many patients with TRALI will develop transient leukopenia.^[11] However, transfusions of blood components containing neutrophil antibodies may cause a wide range of reactions, including leukopenia, that do not meet the definition of TRALI.^[12]

The neutrophil priming hypothesis does not require antigen-antibody interactions and occurs in patients with clinical conditions that predispose to neutrophil priming and endothelial activation such as infection, surgery, or inflammation. Bioactive substances in the transfused component activate the primed, sequestered neutrophils, and pulmonary endothelial damage occurs.

Circulatory overload

Circulatory (volume) overload occurs when the volume of the transfused blood components and that of any coincidental infusions cause acute hypervolemia. Typically, this causes acute pulmonary edema.^{[13, 14]}

Bacterial contamination

Bacterial contamination and endotoxemia may result from any of the following:

• Inadequate sterile preparation of the phlebotomy site
• Opening the blood container in a nonsterile environment
• The presence of bacteria in the donor's circulation at the time of blood collection

Acute hemolytic reactions

Acute hemolytic transfusion reactions may be either immune-mediated or nonimmune-mediated. Immune-mediated hemolytic transfusion reactions caused by immunoglobulin M (IgM) anti-A, anti-B, or anti-A,B typically result in severe, potentially fatal complement-mediated intravascular hemolysis. Immune-mediated hemolytic reactions caused by IgG, Rh, Kell, Duffy, or other non-ABO antibodies typically result in extravascular sequestration, shortened survival of transfused red cells, and relatively mild clinical reactions.^[15]

Acute hemolytic transfusion reactions due to immune hemolysis may occur in patients who have no antibodies detectable by routine laboratory procedures.^[16] Experimental evidence supports a central role for cytokines in the pathophysiology of hemolytic transfusion reactions. Tumor necrosis factor appears to be the most commonly identified mediator of intravascular coagulation and end-organ injury but other cytokines have also been implicated, including interleukin (IL)-8, monocyte chemoattractant protein, and IL-1 receptor antagonist.^{[17, 18]}

Nonimmune hemolytic transfusion reactions occur when red blood cells (RBCs) are damaged before transfusion, resulting in hemoglobinemia and hemoglobinuria without significant clinical symptoms.^[19]

Nonhemolytic febrile reactions

Nonhemolytic febrile transfusion reactions are usually caused by cytokines from leukocytes in transfused red cell or platelet components, causing fever, chills, or rigors. In the transfusion setting, a fever is defined as a temperature elevation of 1º C or 2º F. A nonhemolytic transfusion reaction is a diagnosis of exclusion, because hemolytic and septic reactions can present similarly.

Allergic reactions

Allergic reactions typically present as rash, urticaria, or pruritus and are indistinguishable on examination from most food or drug allergies. Allergic reactions are IgE mediated. These reactions are usually attributed to hypersensitivity to allogeneic proteins in plasma, on leukocytes or platelets or, uncommonly, soluble allergens found in the transfused blood component. Anaphylactic reactions have been reported to be associated with anti-IgA in recipients who are IgA deficient.^[20] However, while anaphylactic reactions do occur, uncommonly, the link to anti-IgA is not regarded as evidence based.^[21]

Patients with congenital haptoglobin deficiency, typically of Northeast Asian origin, may experience anaphylactic nonhemolytic transfusion reactions when transfused with conventional blood components.^{[22, 23]} Patients with hereditary C1-inhibitor deficiency may have recurrent attacks of angioedema when transfused with standard plasma-containing blood components.^[24]

Delayed hemolytic reactions

Approximately 3 months is required for a patient to produce detectable levels of antibody after first exposure to a foreign red blood cell (RBC) antigen through transfusion or pregnancy. If no additional RBC antigen stimulus occurs, the antibody can become undetectable in 50% of patients within 5 years. Following renewed exposure to the same antigen, a more rapid antibody response can occur from 3 to 21 days later. Peak antibody production usually occurs between 7 and 10 days after exposure. Transfused RBCs containing the antigen undergo extravascular hemolysis by the reticuloendothelial system of the spleen and liver over a period of several hours to days.

• References

Epidemiology

Frequency

United States

Approximately 20.9 million units of blood components, including approximately 13.8 million units of whole blood or red blood cells, were transfused in 2011 in the United States; this was a decrease of 11.6% from 2008, and most likely reflects growing adoption of blood management processes. Adverse transfusion reactions were reported to hospital transfusion services for 0.24% of transfused components.^{[25, 13]}

The frequency of specific types of reactions is as follows:

• TRALI: Estimated to occur in 0.014-0.08% of blood component transfusions or in 0.04-0.16% of patients transfused^{[26, 27, 28, 29, 30, 31, 32]}
• Circulatory (volume) overload: Varies with concurrent illness; overall risk approximately 1 in 100^[31]
• Bacterial contamination/endotoxemia: The incidence of septic reactions may be as high as one case per 700 pooled random donor platelet concentrates and one case per 4000 single-donor (apheresis) platelet products. In a study of 1,004,206 apheresis platelet collections, 186 (1:5399) had confirmed-positive bacterial cultures.^[33] The frequency of sepsis associated with bacterially contaminated RBCs is estimated to be one in 250,000.^[34] The frequency of contaminated RBCs based on culturing was one in 38,465 or 2.6/100,000 units.^{[35, 36]}
• Acute hemolytic, immune mediated (fatal): One case per 250,000-600,000 population
• Acute hemolytic, immune mediated (nonfatal): One case per 6000-33,000 population
• Acute hemolytic, nonimmune: Infrequent
• Febrile, nonhemolytic: The frequency of febrile nonhemolytic transfusion reactions increases directly with the number of previous transfusions or pregnancies in the recipient, as well as the presence of leukocytes and/or plasma in the transfused component. Of nearly 100,000 units of whole blood and RBCs transfused, less than 1% resulted in a febrile reaction, and only 15% experienced a second reaction when subsequently transfused.^[37]
• Allergic: One case per 333 population
• Anaphylactic: The estimated frequency is one in 20,000 to 47,000 blood components transfused^[38]

Age

In a single-institution review of 133,671 transfusions, Oakley et al reported an incidence of 6.2 reactions per 1000 transfusions in pediatric patients (age < 21 years) versus 2.4 reactions per 1000 transfusions in adults. While incidence of reactions was the same between sexes in adults, in pediatric patients, reactions were more common in males than in females (7.9/1000 versus 4.3/1000, respectively).^[39]

Mortality/Morbidity

Complications include the following:

• TRALI: Although uncommon, TRALI was the most frequent cause of acute transfusion fatality reported to the US Food and Drug Administration (FDA) from fiscal years 2008 through 2012, accounting for 37% of deaths.^[40] Early and intensive pulmonary support reduces the risk of a fatal outcome. No long-term morbidity has been described in survivors.
• Circulatory (volume) overload: Outcome varies with the overall clinical status of the patient. No long-term sequelae occur.
• In a meta-analysis of health care–associated infection after RBC transfusion, the risk of serious infections was 11.8% with restrictive transfusion thresholds (ie, hemoglobin of < 7.0 g/dL) and 16.9% when liberal thresholds were used. Such infections included pneumonia, mediastinitis, wound infection, and sepsis.^[41]
• Bacterial contamination/endotoxemia is potentially fatal and may be caused by gram-positive or gram-negative bacteria. Early diagnosis, initiation of broad-spectrum antibiotics, and other intensive supportive measures may reverse the outcome of an otherwise fatal complication of transfusion. Based on the frequency of sepsis and positive cultures of platelet units, the mortality rate is estimated to be approximately 1 in 50,000 platelet units.^{[34, 42]}
• Acute hemolytic reactions (antibody mediated): Most severe and fatal reactions result from inadvertent transfusion of group AB or group A red cells to a group O recipient. Renal failure and disseminated intravascular coagulation (DIC) are potential complications for patients who survive the initial acute reaction. Mortality increases directly with the volume of incompatible blood that was transfused.
• Acute hemolytic reactions (non–antibody-mediated) are typically benign; these include mechanical hemolysis of serologically compatible RBCs due to freezing, pressure infusion pumps, and osmotic hemolysis.^[43] Transfusion of serologically compatible but hemolyzed red cells results in acute hemoglobinemia and hemoglobinuria. Rarely, short- or long-term complications occur.
• Nonhemolytic febrile reactions are discomforting but typically benign. Occasionally, patients may have rigors, nausea, vomiting, and considerable distress. Patients who develop fever associated with a blood transfusion must be monitored carefully until the possibility of bacterial contamination of the blood product is excluded.
• Allergic reactions are typically benign but bothersome to recipients. Occasionally, allergic reactions may progress from pruritus and hives to bronchospasm and a generalized reaction, but such events are uncommon.
• Anaphylactic reactions are potentially, but rarely, fatal. The only fatal case of anti–IgA-related anaphylaxis identified in the medical literature by the authors involved a patient with an anti–IgA/IgA reaction who died of a myocardial infarction.^[44] Patients experiencing an acute attack of angioedema due to C1-inhibitor deficiency may have severe abdominal or subcutaneous attacks or laryngeal edema requiring emergency treatment.^[45] The mortality rate for anaphylaxis is estimated to be approximately 1 per year.^[20]
• Alloimmunization to RBC blood group antigens may be considered a complication of RBC transfusions, because such patients may be at risk of delays in the future if they require urgent transfusion of compatible RBCs.^[46] Alloimmunization to RBC blood group antigens may also delay solid-organ transplantation if a significant number of serologically compatible RBCs are required.^[47]

Race

In the United States, sickle cell anemia is found predominantly in the black population. Patients with sickle cell anemia require repeated red cell transfusions and, as a result, may form multiple alloantibodies to common Rh, Kell, Kidd, or other blood group antigens. The presence of such alloantibodies may increase the time required for a transfusion service to supply serologically compatible red cells. If undetected, these red cell alloantibodies may cause shortened survival of transfused red cells and extravascular hemolysis, but severe acute hemolytic reactions are uncommon.^{[48, 49]}

In addition, patients with sickle cell anemia may experience delayed hemolytic transfusion reactions. The first clinical signs of these delayed reactions, which include dark urine/hemoglobinuria, appear a median of 9.4 days after the triggering transfusion. In one study, overall mortality was 6%.^[50]

Sex

Multiparous women may form alloantibodies to leukocyte, red cell, or platelet antigens as the result of an overt or inapparent fetal-maternal hemorrhage. Women who form leukocyte antibodies following pregnancy are more likely to have febrile, nonhemolytic transfusion reactions if subsequently transfused with leukocyte-containing blood components.

Multiparous women who form IgG red cell alloantibodies may experience delays while serologically compatible red cells are located for future transfusions. Undetected weak IgG alloantibodies are unlikely to cause acute hemolytic reactions, but they may cause shortened survival of the transfused incompatible red cells.

Age

Acute transfusion reactions may occur at any age. Age-related variations are as follows:

• Because newborns do not form antibodies to ABO blood group antigens (anti-A, B, or AB) during the first few months of life (ie, infants do not form anti-A or anti-B until 3-4 months after birth), acute ABO-related transfusion reactions are not observed in this age group.^[51] The presence of any transplacentally transferred maternal IgG anti-A, B, or AB is unlikely to cause a clinically significant reaction.
• Most blood transfusions are administered to persons aged 60 years and older; therefore, most acute transfusion reactions also occur in this age group.
• A decline in the titers of ABO antibodies after the sixth decade of life reduces the likelihood that the inadvertent transfusion of ABO-incompatible red cells will cause a severe fatal reaction.^[52]

• References

History

A history of previous blood transfusions or pregnancy is often present but is not essential for the diagnosis of a febrile nonhemolytic transfusion. Acute transfusion reactions caused by ABO antibodies, transfusion-related acute lung injury (TRALI; from donor's antibodies), allergy, IgA/anti-IgA anaphylaxis, or sepsis may occur during the first transfusion or subsequent transfusions.

Persons known to have formed red cell alloantibodies as the result of previous transfusions or pregnancy should be informed and provided with a written report listing the antibodies to be presented to the transfusion service if additional transfusions are required at another hospital.

Red cell antibodies may decrease in titer and, although remaining clinically important, may not be detected by routine compatibility testing before future red cell transfusions. Ask patients scheduled for red cell transfusions about any history of previous transfusions and if they are aware of any complications or blood bank antibody problems. Obtain details of any previous transfusions during the medical history or when obtaining the patient's informed consent for a transfusion.

In individuals with sickle cell disease, clinical manifestations of delayed hemolytic transfusion reactions (DHTRs) usually appear 5–15 days after the triggering transfusion, and include hemoglobinuria, jaundice, and pallor due to acute hemolysis. In addition, patients may have signs and symptoms that mimic severe vaso-occlusive crisis (ie, pain, fever, and acute chest syndrome), as well as profound anemia, often with reticulocytopenia. If DHTR is misdiagnosed as vaso-occluisive crisis and the patient is treated with an additional transfusion, this may further exacerbate hemolysis and clinical symptoms and cause life-threatening multiorgan failure.^{[5, 6]}

• References

Physical

Acute hemolytic reactions manifest as follows:

• Early signs may include fever, hypotension, flushing, wheezing, anxiety, and/or red-colored urine
• Late signs may include a generalized bleeding tendency (DIC) and/or hypotension

Nonhemolytic febrile reactions typically involve only fever. However, some patients also have severe rigors, shaking, chills, hypotension, and vomiting.

Allergic reactions typically comprise maculopapular rash and/or urticaria without fever or hypotension. Anaphylactic reactions manifest as follows:

• Dyspnea
• Wheezing
• Anxiety
• Hypotension without fever
• Bronchospasm in severe cases

Transfusion-related acute lung injury (TRALI) manifests as rapid onset of shortness of breath, hypoxemia, and rales, without signs of acute cardiogenic pulmonary edema and fever.

Circulatory (volume) overload manifests as follows:

• Shortness of breath
• Rales
• Orthopnea
• Tachycardia
• Distended jugular veins
• Other evidence of cardiac decompensation

Continuous monitoring of vital signs during general anesthesia may prevent acute circulatory (volume) overload, but it may not detect early signs of other reactions (eg, acute hemolytic transfusion reactions). However, the onset of abnormal bleeding/generalized oozing during surgery in a transfused patient should raise the question of a hemolytic transfusion reaction with disseminated intravsacular coagulation (DIC).

Bacterial contamination manifests as high fever, shock, tachycardia, and weak pulse, without a clear focus of infection. Examination of the contents of the container of blood being transfused may reveal clots, discoloration, or a difference in color between the contents of the bag (hemolyzed by contaminating bacteria) and the contents of the segmented tubing attached to the bag (not hemolyzed, no bacteria). In a review of septic transfusion reactions resulting from bacterially contaminated platelets, Hong et al reported that the reactions developed 9 to 24 hours posttransfusion, and occurred only in neutropenic patients.^[53]

• References

Causes

Acute hemolytic reactions (ABO incompatibility)

Accidental transfusion of RBCs of a different ABO type than the patient's typically occurs for one of two reasons, as follows:

• Misidentification of either the patient or the blood component when the blood sample was collected for compatibility testing
• Failure to recognize that two patients have the same or similar names but different ABO blood types

Most transfusions of incorrect RBCs to the incorrect patient due to misidentification are clinically benign. More than 60% of random units of RBCs in a blood bank are serologically compatible with random recipients because approximately 40% are type O (ie, universal donor) and 20% are the same blood type as the patient or are otherwise ABO-compatible.

Febrile nonhemolytic reactions

Cytokines and other normal constituents of leukocytes, platelets, or plasma accumulate in blood components during storage. When blood components are transfused, some recipients react with varying generalized symptoms, of which fever is the most common symptom.

Allergic reactions

The clinical presentation of rash, pruritus, and/or urticaria during a transfusion suggests that the recipient was exposed to a foreign substance in the blood product to which the recipient is sensitized. Usually, a specific allergen is not identified. Studies in the medical literature suggest that causes of allergic reactions include polymorphic proteins in the donors' plasma, food (eg, nuts, tomatoes), or medications (eg, penicillin) that the donor ingested immediately before collection of the implicated blood product.

Anaphylactic reactions

Most cases of anaphylaxis are reported in recipients with IgA deficiency who developed anti-IgA and whose transfused product contains donor plasma with a normal content of IgA. Not all IgA-deficient persons who have anti-IgA have a history of transfusions or pregnancy. Similar reactions in ahaptoglobinemia have been reported.

Transfusion-related acute lung injury

Neutrophils are the effector cells that adhere to the pulmonary endothelium to increase permeability and cause pulmonary edema. Elements leading to activation of the neutrophils include transfused human leukocyte or neutrophil antigen (HLA or HNA) antibodies and transfused bioactive substances such as lipids or cytokines. Patients with certain clinical conditions (eg, infection, inflammation, surgery) have primed neutrophils that are susceptible to activation by transfused bioactive substances.

Because pregnancy is a common cause of alloimmunization to HLAs and HNAs, most cases of TRALI have been traced to plasma-containing blood components collected from female blood donors.^[54] When the American Red Cross converted to predominantly male-donated plasma, the number of cases of TRALI decreased very significantly from 2006 to 2008.^[54]

Circulatory (volume) overload

Increased fluid volume in susceptible patients, including those with cardiovascular compromise, elderly patients, and small children, may result in pulmonary edema. A usual transfusion rate is 2-2.5 mL/kg per hour. In at-risk patients, blood products can be transfused at a slower rate.

Bacterial contamination (sepsis)

Bacteria may enter the blood product container if it is opened at any time from collection from the donor until transfusion to the recipient. Bacteria on the donor's skin may enter the container if the needle entry site on the donor's skin is sterilized incompletely.

Some donors implicated in septic reactions have low concentrations of bacteria (eg, Yersinia enterocolitica) in their blood (eg, bacteremia) but do not have a fever or other signs at the time of collection. If such contaminated blood is stored for a few days at room temperature (eg, platelets) or for a few weeks at refrigerated temperature (eg, red cells), bacteria may grow and elaborate endotoxin, which is a major adverse factor in such reactions.^[55]

• References

Laboratory Studies

In acute hemolytic reactions,^[43] the workup includes the following:

• Visual inspection of the recipient's plasma and urine
• Retyping of donor and recipient red blood cells (RBCs)
• Direct antiglobulin (Coombs) testing

Plasma in a sample of centrifuged anticoagulated venous blood is clear and pink-red if significant intravascular hemolysis (eg, hemoglobinemia) has occurred within the previous few hours. If serum from a nonanticoagulated sample (eg, clotted blood) is examined, a risk exists of traumatic hemolysis in the laboratory when the clot is separated, resulting in a false-positive interpretation. The red discoloration (eg, hemoglobinemia) may be present immediately after transfusion of only several milliliters of incompatible red cells and may persist for hours until the hemoglobin is metabolized to bilirubin. At that time, depending on the volume of incompatible RBCs that were transfused, the plasma may be deep red-brown or yellow.

Within minutes of an ABO blood group–incompatible transfusion, the recipient's urine may become red. To distinguish between hematuria (red cells from the lower urinary tract) and hemoglobinuria (hemoglobin monomers and dimers cleared from the plasma by the kidney), centrifuge the urine. As illustrated below, centrifuged urine from a patient with hematuria is clear yellow with red cells sedimented at the bottom of the tube. Urine from a patient with hemoglobinuria remains clear red and unchanged in color.

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Rapid test to distinguish hematuria from hemoglobinuria. The onset of red urine during or shortly after a blood transfusion may represent hemoglobinur....

Repeat ABO typing of the donor's unit should be performed, using a sample from the blood container's segmented tubing. Repeat ABO typing of the recipient is done using a blood sample collected after the transfusion reaction. A discrepancy between the original ABO type and the repeat ABO typings should raise the urgent question of whether a mix-up of blood samples could place another patient at risk of a similar mismatched transfusion.

On direct antiglobulin (Coombs) testing, ABO-related acute transfusion reactions usually cause a positive direct antiglobulin reaction, reflecting the presence of complement (C3d) on circulating red cells, as well as the recipient's anti-A, anti-B, or anti-A,B. In certain situations, donor-derived IgG anti-A, anti-B, or anti-A,B may be detected on circulating red cells.

In febrile nonhemolytic reactions,^[56] the recipient's plasma has a normal appearance on visual inspection. Red discoloration indicating hemolysis excludes this diagnosis. The recipient's urine also has a normal appearance. Red discoloration indicating hemolysis excludes this diagnosis. On retyping of donor and recipient red cells for ABO/Rh(D), the results are concordant; no discrepancy should be detected. A direct antiglobulin (Coombs) test yields a negative result.

In allergic reactions, the presence of red plasma or urine, discordant pretransfusion and posttransfusion ABO blood types, or a positive antiglobulin (Coombs) test indicates other diagnoses in addition to an allergic reaction. Allergic transfusion reactions usually do not cause an increased number of eosinophils in subsequent white blood cell (WBC) differential counts.

Anaphylactic reactions are excluded by the presence of red plasma or urine, discordant pretransfusion and posttransfusion ABO blood types, or a positive direct antiglobulin (Coombs) test result. Demonstration of anti-IgA in a pretransfusion sample of the recipient's serum or plasma establishes the diagnosis. Testing for anti-IgA is difficult to perform and is available only in a few reference laboratories; therefore, screening for IgA deficiency should be the initial laboratory study. The presence of IgA in the recipient's pretransfusion sample excludes the diagnosis of a class-specific IgA/anti-IgA reaction.

In transfusion-related acute lung injury (TRALI),^[14] plasma levels of brain natriuretic peptide (BNP) may be useful in distinguishing the cardiogenic pulmonary edema present in circulatory overload from the noncardiogenic pulmonary edema present in TRALI.^[11] A hemolytic or septic reaction may present with similar symptoms as TRALI and should be excluded. In circulatory overload: Plasma levels of BNP may supplement clinical and radiologic findings.

In bacterial contamination, culture of the implicated unit and the patient's blood is necessary to establish the diagnosis. A hemolytic reaction may present similarly and should be excluded.

In delayed hemolytic transfusion reactions (DHTRs), accelerated hemolysis is indicated by increased serum bilirubin and lactate dehydrogenase concentrations and a decline in total hemoglobin compared with the early post-transfusion value. Mekontso Dessap et al reported that a sharp decline in the hemoglobin A concentration is characteristic of DHTRs, and proposed a diagnostic nomogram for DHTR based on hemoglobin A concentration as a biologic marker of the survival of transfused red blood cells.^[57]

• References

Medical Care

Management  of transfusion reactions varies according to the type of reaction.^[58] Acute hemolytic reactions (antibody mediated) are managed as follows:

• Immediately discontinue the transfusion while maintaining venous access for emergency management.
• Anticipate hypotension, renal failure, and DIC.
• Prophylactic measures to reduce the risk of renal failure may include low-dose dopamine (1-5 mcg/kg/min), vigorous hydration with crystalloid solutions (3000 mL/m²/24 h), and osmotic diuresis with 20% mannitol (100 mL/m²/bolus, followed by 30 mL/m²/h for 12 h).
• If DIC is documented and bleeding requires treatment, transfusions of frozen plasma, pooled cryoprecipitates for fibrinogen, and/or platelet concentrates may be indicated.

Acute hemolytic reactions (nonantibody mediated) are managed as follows:

• The transfusion of serologically compatible, although damaged, red blood cells (RBCs) usually does not require rigorous management.
• Diuresis induced by an infusion of 500 mL of 0.9% sodium chloride per hour, or as tolerated by the patient, until the intense red color of hemoglobinuria ceases is usually adequate treatment.

In febrile, nonhemolytic reactions, fever usually resolves in 15-30 minutes without specific treatment. If fever causes discomfort, oral acetaminophen (325-500 mg) may be administered. Avoid aspirin because of its prolonged adverse effect on platelet function.

In allergic reactions, diphenhydramine is usually effective for relieving pruritus that is associated with hives or a rash. The route (oral or intravenous) and the dose (25-100 mg) depend on the severity of the reaction and the weight of the patient.

In anaphylactic reactions, a subcutaneous injection of epinephrine (0.3-0.5 mL of a 1:1000 aqueous solution) is standard treatment. If the patient is sufficiently hypotensive to raise the question of the efficacy of the subcutaneous route, epinephrine (0.5 mL of a 1:10,000 aqueous solution) may be administered intravenously. Although no documented evidence exists that intravenous corticosteroids are beneficial for the management of acute anaphylactic transfusion reactions, theoretical considerations cause most clinicians to include an infusion of hydrocortisone or prednisolone if an immediate response to epinephrine does not occur.

Transfusion-related acute lung injury (TRALI) is managed as follows:

• Immediately discontinue the transfusion while preserving venous access.
• Patients with mild episodes should respond to oxygen administered by nasal catheter or mask. If shortness of breath persists after oxygen administration, transfer the patient to an intensive care setting where mechanical ventilation can be employed.
• In the absence of signs of acute volume overload or cardiogenic pulmonary edema, diuretics are not indicated.
• No evidence exists that corticosteroids or antihistamines are beneficial.
• Treat complications with specific supportive measures.

Circulatory (volume) overload is managed as follows:

• Move the patient into a sitting position and administer oxygen to facilitate breathing.
• The most specific treatment is discontinuing the transfusion and removing the excessive fluid.
• If practical, the unit of blood component being transfused may be lowered to reverse the flow and to decrease intravascular volume by a controlled phlebotomy.
• Less urgent situations may be managed by a parenteral or oral diuretic (eg, furosemide).
• If the patient has symptomatic anemia requiring additional transfusions of RBCs, select concentrated (ie, CPDA-1-anticoagulated) red cells (hematocrit = 80-85%). Avoid red cell components diluted with saline additives (ie, AS-1).

Bacterial contamination (sepsis) is managed as follows:

• Immediately discontinue the transfusion, including all tubing, filters, and administration sets, and save the transfusion materials for cultures, while preserving venous access.
• After appropriate blood cultures have been obtained, initiate treatment with intravenous broad-spectrum antibiotics. If a microbiologic stain or a culture of the contents of the transfused product identifies an organism, the initial broad-spectrum antibacterial approach may be modified accordingly.

Randomized controlled studies of delayed hemolytic transfusion reactions have yet to be performed, so no validated treatment approaches or therapy guidelines exist. Off-label treatments described in the literature include the following, used alone or in combination^{[5, 6]} :

• Intravenous immunoglobulin (IVIg)
• Recombinant erythropoietin (EPO)
• Corticosteroids
• Rituximab – For patients who have developed alloimmunization after DHTR, to prevent further alloimmunization
• Eculizumab - For some life-threatening episodes

An observational study by Noizat-Pirenne et al demonstrated that pre-transfusion administration of rituximab may have a preventive benefit in SCD patients with a history of severe DHTR. Five of the eight study patients did not develop DHTR, while the remaining three experienced only mild DHTR. No newly formed antibodies were detected in any patient. Because rituximab can have serious adverse effects, these authors suggest that this treatment be considered cautiously, and only when transfusion is absolutely necessary in such patients.^[59]

• References

Consultations

The possibility of an acute transfusion reaction should trigger an immediate consultation with the medical director of the hospital's blood bank or a designee (eg, a clinical pathology resident, transfusion medicine fellow). Depending on the findings, the blood bank consultant may arrange for microbiologic stains and cultures of the residual contents of the blood product container, clerical checks for patient and product identification in the laboratory, repeat compatibility testing using a freshly collected blood sample from the recipient, or other pertinent diagnostic studies.

The diagnosis of an acute hemolytic transfusion reaction should trigger consultation with a nephrologist to ensure optimal prophylactic measures to prevent renal damage.^[60]

A hematology consultation is appropriate if a hemolytic transfusion reaction or bacterial contamination precipitates DIC.

A clinical diagnosis of bacterial contamination of a transfused blood product should trigger an infectious diseases consultation.

• References

Guidelines Summary

In 2012, the British Committee for Standards in Haematology Blood Transfusion Task Force issued a guideline for investigating and managing acute transfusion reactions. This guideline provides a flow diagram for recognition and initial management of suspected acute transfusion reactions.^[61]

In 2013, the Canadian Blood Services updated its clinical guide to transfusion medicine. The guide contains management algorithms for adverse reactions.^[62]

• References

Medication Summary

Use an antihistamine to ameliorate allergic reactions to plasma. These agents serve as adjuncts to epinephrine and other standard measures for therapy of anaphylaxis related to transfusions of plasma-containing blood products.

Analgesics and antipyretics reduce fever that is associated with nonhemolytic transfusion reactions. An osmotic diuretic promotes urinary excretion of hemoglobin that results from an acute hemolytic transfusion reaction.

• References

Diphenhydramine hydrochloride (Benadryl, Diphen)

• Dosing, Interactions, etc.

Clinical Context:  Antihistamine with anticholinergic effects that competes with histamine for receptor sites on effector cells. Among other indications, used to treat urticaria, pruritus, and other histamine-mediated manifestations of allergic reactions to blood products.

• References

Class Summary

Antihistamines prevent histamine response in sensory nerve endings and blood vessels. These agents are more effective in preventing histamine response than in reversing it.

• References

Acetaminophen (Tylenol, Panadol)

• Dosing, Interactions, etc.

Clinical Context:  Nonopiate, nonsalicylate analgesic and antipyretic. Reduces fever by acting directly on hypothalamic heat-regulating centers, which increase dissipation of body-heat via vasodilation and sweating.

• References

Class Summary

Analgesics and antipyretics improve patient comfort and reduce fever.

• References

Mannitol injection 20% USP (Osmitrol)

• Dosing, Interactions, etc.

Clinical Context:  An obligatory osmotic diuretic only slightly metabolized and excreted by the kidney. Induces diuresis by increasing the osmolarity of the glomerular filtrate, thereby hindering tubular reabsorption of water. Excretion of sodium and chloride is also enhanced.

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Class Summary

Osmotic agents increase the osmolarity of the glomerular filtrate and induce diuresis. This, in turn, hinders the tubular reabsorption of water, also causing sodium and chloride excretion to increase.

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Epinephrine (Epi-Pen, Adrenaline)

• Dosing, Interactions, etc.

Clinical Context:  A sympathomimetic that activates both alpha receptors and beta receptors. Causes bronchial smooth muscle relaxation and cardiac stimulation.

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Dopamine (Intropin)

• Dosing, Interactions, etc.

Clinical Context:  An immediate precursor to epinephrine, dopamine stimulates dopaminergic, beta-adrenergic, and alpha-adrenergic receptors.

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Class Summary

Vasopressors are used to reverse the hemodynamic compromise that is associated with anaphylaxis or allergic reaction.

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Furosemide (Lasix)

• Dosing, Interactions, etc.

Clinical Context:  Acts by inhibiting sodium and chloride resorption in the ascending loop of Henle, promoting excretion of sodium, water, chloride, and potassium.

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Class Summary

Diuretics may be used to alleviate volume overload that is caused by transfusion of blood products.

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Deterrence/Prevention

Persons known to have formed red cell alloantibodies as the result of previous transfusions or pregnancy should be informed and provided with a written report that lists the antibodies to be presented to the transfusion service if additional transfusions are required at another hospital.

Ask patients scheduled for red cell transfusions about any history of previous transfusions and if they are aware of any complications or blood bank antibody problems.

Obtain details of any previous transfusions during the medical history or when obtaining the patient's informed consent for a transfusion.

In cases of transfusion reaction, retype the donor and recipient RBCs. A discrepancy between the original ABO type and the repeat ABO typings should raise the urgent question of whether a mix-up of blood samples could place another patient at risk of a similar mismatched transfusion.

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Complications

Acute hemolytic reactions (antibody mediated): Renal failure and DIC are potential complications for patients who survive the initial acute reaction.

Acute hemolytic reactions (non–antibody mediated): Transfusion of serologically compatible but hemolyzed red cells results in acute hemoglobinemia and hemoglobinuria. Rarely, short- or long-term complications occur.

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Prognosis

Acute hemolytic reactions (antibody mediated): Most severe and fatal reactions result from inadvertent transfusion of group AB or group A red cells to a group O recipient.

Acute hemolytic reactions (non–antibody mediated) are typically benign.

Nonhemolytic febrile reactions are discomforting but typically benign.

Allergic reactions are benign but bothersome to recipients.

Anaphylactic reactions are potentially, but rarely, fatal.

TRALI: In one study, 78% of patients with TRALI required initiation of mechanical ventilation, 25% required initiation of vasopressors, and 17% died; however, the researcher concluded that underlying risk factors for acute lung injury may have had the principal influence on clinical outcomes.^[32] Early and intensive pulmonary support reduces the risk of a fatal outcome.

Circulatory (volume) overload: The outcome varies with the overall clinical status of the patient.

Bacterial contamination/endotoxemia is potentially fatal and may be caused by gram-positive or gram-negative bacteria. Early diagnosis, initiation of broad-spectrum antibiotics, and other intensive supportive measures may reverse the outcome of an otherwise fatal complication of transfusion.

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