Transfusion Reactions

Updated: Mar 15, 2023
  • Author: S Gerald Sandler, MD, FCAP, FACP; Chief Editor: Emmanuel C Besa, MD  more...
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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, 5]

Rapid test to distinguish hematuria from hemoglobi Rapid test to distinguish hematuria from hemoglobinuria. The onset of red urine during or shortly after a blood transfusion may represent hemoglobinuria (indicating an acute hemolytic reaction) or hematuria (indicating bleeding in the lower urinary tract). If freshly collected urine from a patient with hematuria is centrifuged, red blood cells settle at the bottom of the tube, leaving a clear yellow urine supernatant. If the red color is due to hemoglobinuria, the urine sample remains clear red after centrifugation.

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. [6, 7]

For patient education information, see the Blood Transfusions Directory.



Acute transfusion reactions are typically classified into the following entities [8] :

  • 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. [9, 10] 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). [11] 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. [12] 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. [13]

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. [14, 15]

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. [16]

Acute hemolytic transfusion reactions due to immune hemolysis may occur in patients who have no antibodies detectable by routine laboratory procedures. [17] 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. [18, 19]

Nonimmune hemolytic transfusion reactions occur when red blood cells (RBCs) are damaged before transfusion, resulting in hemoglobinemia and hemoglobinuria without significant clinical symptoms. [20]

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. [21] However, while anaphylactic reactions do occur, uncommonly, the link to anti-IgA is not regarded as evidence based. [22]

Patients with congenital haptoglobin deficiency, typically of Northeast Asian origin, may experience anaphylactic nonhemolytic transfusion reactions when transfused with conventional blood components. [23, 24] Patients with hereditary C1-inhibitor deficiency may have recurrent attacks of angioedema when transfused with standard plasma-containing blood components. [25]

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.



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 antibodies and whose transfused product contains donor plasma with a normal content of IgA. [26] 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. [27]  When the American Red Cross converted to predominantly male-donated plasma, the number of cases of TRALI decreased very significantly from 2006 to 2008. [27]

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. [28]




United States

In 2019, approximately 10.8 million units of whole blood or red blood cells (RBCs), 2.2 million platelet units, and 2.1 million plasma units were transfused in the United States. [29]  Blood transfusions have been declining in the United States since 2008, most likely due to growing adoption of blood management processes. From 2015 to 2017, transfusions of RBCs and whole blood declined 6.1%, a slower decline compared with declines during 2013–2015 but similar to declines during 2008–2013. [30]

Adverse transfusion reactions were reported to hospital transfusion services in 282 per 100,000 units transfused. [31] 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 [32, 33, 34, 35, 36, 37, 38]

  • Circulatory (volume) overload: Varies with concurrent illness; overall risk approximately 1 in 100 [37]

  • 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. [39] The frequency of sepsis associated with bacterially contaminated RBCs is estimated to be one in 250,000. [40] The frequency of contaminated RBCs based on culturing was one in 38,465 or 2.6/100,000 units. [41, 42]

  • 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. [43]

  • Allergic: One case per 333 population

  • Anaphylactic: The estimated frequency is one in 20,000 to 47,000 blood components transfused [44]


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. [45, 46]

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%. [47]


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.


Acute transfusion reactions may occur at any age. However, 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. [48] The presence of any transplacentally transferred maternal IgG anti-A, B, or AB is unlikely to cause a clinically significant reaction.

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 the incidence of reactions was the same in both sexes in adults, in pediatric patients, reactions were more common in males than in females (7.9/1000 versus 4.3/1000, respectively). [49]

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. [50]




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. [51]  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. [52]  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. [53]  The mortality rate for anaphylaxis is estimated to be approximately 1 per year. [21]

Although uncommon, TRALI was the second most frequent cause of acute transfusion fatality reported to the US Food and Drug Administration (FDA), accounting for 21% of deaths in fiscal years 2016-2020. [29]  Early and intensive pulmonary support reduces the risk of a fatal outcome. No long-term morbidity has been described in survivors.

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. [38]  

Transfusion associated circulatory overload (TACO) was the most frequent cause of acute transfusion fatality reported to the US Food and Drug Administration (FDA) from 2016-2020, accounting for 34% of deaths in that period. [29]  In Switzerland, TACO was the leading cause of morbidity ad mortality related to blood transfusion, with 88 reported cases of which 27 were life-threatening or fatal (31%). [54]  

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. [40, 55]

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. [56]

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. [57]  Alloimmunization to RBC blood group antigens may also delay solid-organ transplantation if a significant number of serologically compatible RBCs are required. [58]