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Transfusion reactions and adverse events associated with transfusion
Abstract
Transfusion reactions remain a major issue particularly for patients with chronic transfusion requirements. The majority of reactions are mild, but some are severe and rarely fatal. In 2017, 44 fatal transfusion reactions occurred in the United States. Transfusion reactions and adverse events from transfusion can be divided between events that occur during or within several hours of the transfusion (acute) or events that occur over 24 hours after the end of the transfusion (delayed). While patients do not always meet the standard definition of a particular transfusion reaction, it is essential to categorize reactions to accurately track, manage, and prevent future reactions. This chapter will focus on the presentation, physiology, management, and prevention strategies of the major types of transfusion reactions.
Classification and tracking transfusion reactions
The first known human blood transfusions were associated with high rates of fatality likely due to incompatible transfusions. , Following Karl Landsteiner’s discovery of the ABO blood group system, blood transfusions have become an increasingly safe cornerstone of medical therapy. While the rates of transfusions are declining in the United States, millions of transfusions are still given each year. Hemovigilance systems have been implemented throughout the world to monitor and improve the safety of blood transfusions. In the United States, the Centers for Disease Control (CDC) started a voluntary hemovigilance database in 2010 called the National Healthcare Safety Network (NHSN) Hemovigilance Module (HM). , The NHSN HM provides valuable safety data for transfusions in the United States; however, the voluntary, passive reporting system likely leads to underreporting. Adverse events are tracked across the entire transfusion process from donor collection to transfusions to patients. To standardize reporting, the NHSN HM uses a classification system for different transfusion reactions ( Tables 93.1 and 93.2 ).
TABLE 93.1
Summary of Acute Transfusion Reactions
| ACUTE TRANSFUSION REACTIONS | |||
|---|---|---|---|
| Reaction | Diagnosis | Management | |
|
|
Key symptoms Back/flank pain; chills/rigors; DIC; epistaxis; fever; hematuria; hypotension; oliguria/anuria; pain and/or oozing at IV site; renal failure Hemolysis labs Fibrinogen; haptoglobin; bilirubin; LDH; hemoglobinemia; hemoglobinuria; plasma discoloration c/w hemolysis; spherocytes on smear |
Stop transfusion and avoid additional incompatible transfusions; Supportive care. Consider exchange transfusion with antigen-negative blood depending on clinical severity. IVIG may be useful particularly for patients with sickle cell anemia and AHTR |
| Febrile nonhemolytic transfusion reaction (FNHTR) | Occurs during or ≤4 h with either fever (≥38 °C and ≥1 °C change from pretransfusion value) OR chills/rigors with no other clear cause of fever | Stop transfusion and rule out hemolytic transfusion reaction; Consider giving antipyretic and restarting transfusion depending on severity of reaction. Consider culturing blood product unit and patient. | |
| Allergic | ≥2 allergic symptoms during or ≤4 h post-transfusion | Allergic symptoms Conjunctival edema; edema of lips, tongue or uvula; erythema/edema or periorbital area; Flushing; hypotension; localized angioedema; maculopapular rash; pruritus; respiratory distress/bronchospasm; urticaria |
Stop transfusion and administer an antihistamine. Consider restarting transfusion at slower rate when symptoms improve (depending on severity). |
| Anaphylactic/Severe Allergic | Severe presentation of allergic transfusion reaction. May involve circulatory shock and/or airway obstruction (upper or lower) | Stop transfusion and administer epinephrine, antihistamine. Consider hydrocortisone if prolonged or severe symptoms | |
|
|
Supportive care. Glucocorticoids unlikely to be helpful. | |
| Transfusion-associated circulatory overload (TACO) | New or exacerbation of ≥3 TACO symptoms within 6 h post-transfusion | TACO symptoms Acute respiratory distress; BNP; CVP; left heart failure; positive fluid balance; Imaging evidence of pulmonary edema |
Stop transfusion; Supportive care with focus on diuresis and respiratory support. |
| Septic | Laboratory evidence of pathogen in transfusion recipient with evidence of pathogen in transfusion component and/or donor and/or same pathogen in different recipient of component from same donor | Stop transfusion; supportive care and anti-microbial coverage | |
| Hypotensive | Hypotension within 1 hr after transfusion and no other known cause | Stop transfusion (usually rapid improvement within 10 min; if not, evaluate for other causes); Supportive care | |
CDC. National Healthcare Safety Network biovigilance component hemovigilance module surveillance protocol [monograph on the internet]. Available from: https://www.cdc.gov/nhsn/pdfs/biovigilance/bv-hv-protocol-current.pdf .
TABLE 93.2
Summary of Delayed Transfusion Reactions
| DELAYED TRANSFUSION REACTIONS | |||
|---|---|---|---|
| Reaction | Diagnosis | Management | |
|
|
|
|
|
|
Avoid future incompatible blood transfusions. | |
|
|
TA-GVHD symptoms Rash (erythematous, maculopapular eruption spread centrally to extremities; can progress to erythroderma and hemorrhagic bullous); diarrhea; fever; hepatomegaly; liver dysfunction; marrow aplasia; pancytopenia |
Immunosuppression; consider stem cell transplantation |
|
|
IVIG; consider glucocorticoids (unclear efficacy); Depending on clinical severity, consider whole blood exchange or plasma exchange; Transfuse antigen-negative platelets if patient has active bleeding | |
| Iron overload | Evidence of iron overload based on iron stores. Confirm iron overload with T2*MRI and/or tissue biopsy. | Consider evaluating for hereditary hemochromatosis depending on patient’s risk factors for transfusion related iron overload; Phlebotomy and/or iron chelation. | |
CDC. National Healthcare Safety Network biovigilance component hemovigilance module surveillance protocol [monograph on the internet]. Available from: https://www.cdc.gov/nhsn/pdfs/biovigilance/bv-hv-protocol-current.pdf .
Acute transfusion reactions
Acute reactions occur during or within several hours of a blood transfusion. Allergic transfusion reactions accounted for almost half (46.8%) of adverse transfusion reactions reported to the NHSN HM between 2010 and 2012. The majority of acute reactions are mild and occur more frequently with platelet transfusions (421.7/100,000) compared to other blood products. ,
Acute hemolytic transfusion reaction
Physiology
An acute hemolytic transfusion reaction (AHTR) occurs when the recipient’s immune system hemolyzes or rapidly clears the donor’s red blood cells. This typically occurs in cases of major incompatible transfusions, when the recipient has pre-formed preformed antibodies against antigens expressed on donor red blood cells. Whether a recipient develops intravascular or extravascular hemolysis depends on the capacity of the recipient’s alloantibody to activate complement. The onset of symptoms is likely due to the titer and capacities of the alloantibody, as well as the density of the donor’s antigen, with immediate reactions occurring with high titer alloantibodies that have high affinity for a donor antigen present at higher levels on donor red blood cells. , The most severe AHTRs are associated with ABO incompatibility due to the presence of circulating naturally occurring isoagglutinins. Recipient isoagglutinins directed against the A and B antigens are IgM and can bind the donor’s red blood cells leading to complement activation and rapid intravascular hemolysis. The most common cause of major ABO incompatible transfusions are clerical errors (patient identification at the time of sample collection or at the time of blood administration). Non-ABO antigen incompatible hemolytic reactions are more frequent but less severe. Extravascular hemolysis can typically occur with non-ABO red blood cell antigens, is IgG mediated, and donor cells are removed from circulation by the recipient’s reticuloendothelial system.
Minor ABO incompatible hemolytic reactions occur when donor isoagglutinins react against the recipient’s red blood cells. This can occur from products with high content of donor plasma such as plasma units and platelets. There are a number of cases reported in the literature describing hemolytic transfusion reactions associated with passive transfer of anti-A or anti-B isoagglutinins through platelet transfusions. Isoagglutinin titers may determine the risk for hemolysis, but whether there is a critical titer is still controversial. Isoagglutinin titers can be reduced in platelet products with plasma additive solutions, which replace ∼70% of the plasma content.
Incidence
AHTRs are an uncommon event. The rate of a hemolytic transfusion reaction is 1 in 367,393 red blood cell units per year, based on the SHOT hemovigilance database from the United Kingdom. In 2017, only seven fatal hemolytic transfusion reactions were reported to the FDA; the majority (six of seven) were from non-ABO incompatible transfusions.
Presentation and differential diagnosis
The classic description of an AHTR with intravascular hemolysis consists of fever, flank pain, and red urine from hemoglobinuria. However, symptoms are often subtle and nonspecific. Of the symptoms seen in other forms of transfusion reactions, only hives has not been described in an AHTR. A high index of suspicion is necessary particularly for patients who are not interactive such as during anesthesia. In these cases, the only sign of an AHTR may be disseminated intravascular coagulopathy (DIC). If unrecognized, patients may continue to receive incompatible transfusions. In one series of 35 patients who developed an AHTR during anesthesia, 25% received up to 6 additional units due to ongoing bleeding.
Alternative etiologies of hemolysis should be considered such as autoimmune hemolytic anemia, artificial heart valve dysfunction, drug-induced hemolysis, microangiopathic hemolytic anemias, and infections associated with hemolysis such as malaria.
NHSN hemovigilance diagnostic criteria
- 1.
Any key symptom during or <24 hours post-transfusion
- a.
Back/flank pain; chills/rigors; DIC; epistaxis; fever; hematuria; hypotension; oliguria/anuria; pain and/or oozing at IV site; renal failure
- a.
- 2.
Greater than two laboratory findings consistent with hemolysis:
- a.
Decreased fibrinogen; decreased haptoglobin; increased bilirubin; increased LDH; hemoglobinemia; hemoglobinuria; plasma discoloration consistent with hemolysis; spherocytes on smear
- i.
Note that hemolysis may be intravascular, extravascular, or both.
- a.
- 3.
Positive direct antiglobulin test (DAT) and positive elution (immune-mediated hemolysis) or negative serologic testing and confirmed physical cause (non–immune-mediated hemolysis)
Management.
If an AHTR is suspected during a transfusion, the transfusion should be immediately stopped and work up should be done to confirm hemolysis with visual examination and DAT. It is critical to avoid additional incompatible transfusions and to provide supportive care including intravenous hydration to prevent renal damage. If the patient needs to continue transfusion support during the transfusion reaction investigation, transfusing with group O red blood cell units minimizes the risk of ABO incompatibility. Depending on timing and clinical severity, an exchange transfusion with antigen negative blood can be considered. For non-ABO and IgG-mediated acute hemolytic reactions, intravenous immunoglobulin (IVIG) may be useful, particularly for patients with sickle cell anemia. ,
Prevention.
Prevention of AHTRs should focus on reducing the risk of an incompatible transfusion. This means providing appropriate ABO compatible transfusions, but also focusing on antigen appropriate units for patients with alloantibodies. Notably, the majority of fatalities from hemolytic transfusion reactions in the US in 2017 were from non-ABO antigen incompatible transfusions. To prevent incompatible transfusions, clinical providers and transfusion services must focus on limiting the rate of “wrong blood in tube” (WBIT) events, or mislabeled pretransfusion samples, as well as reducing the rate of providing incorrect products to patients.
Febrile nonhemolytic transfusion reaction
Physiology
The pathophysiology of febrile nonhemolytic transfusion reactions (FNHTRs) is not fully defined. Some correlative studies suggest that donor derived antibodies directed against the recipient’s HLA or granulocyte antigens drives the recipient’s inflammatory response. Another hypothesis is that donor cytokines accumulated during storage are the main cause of febrile reactions.
Incidence
FNHTRs are the second most common adverse transfusion reaction after allergic reactions. FNHTRs accounted for 36.1% of adverse reactions reported to the NHSN HM between 2010 and 2012. Any blood product can cause a FNHTR, and children appear to be more likely to develop FNHTRs than adults.
Presentation and differential diagnosis
FNHTR is a diagnosis of exclusion. The classic presentation is a new fever and/or chills during or within 4 hours of the transfusion. These clinical signs are indistinguishable from numerous causes of fever and/or chills including AHTR, septic transfusion reaction, or another underlying cause of fever such as a preexisting infection.
NHSN hemovigilance diagnostic criteria
- 1.
Occurs during or <4 hours after transfusion
- 2.
Fever (>38 °C and ≥1 °C change from pretransfusion value) OR chills/rigors with no other clear cause of fever
Management.
If the patient develops signs of a FNHTR during the transfusion, the transfusion should be immediately stopped. Given the signs and symptoms are indistinguishable from an AHTR, hemolysis should be ruled out before classifying the reaction as a FNHTR. Additionally, a septic transfusion reaction must also be considered; however, practices differ on which clinical situations warrant further culturing of the blood product. Depending on the severity of the reaction, antipyretics may be beneficial.
Prevention.
Patient specific factors.
Approximately 40% of recipients with a history of a FNHTR will experience another FNHTR. , Many providers prescribe premedication with acetaminophen and/or an antihistamine for patients with a history of FNHTR. Patients should not receive premedication if they have never had a FNHTR, as this practice does not reduce the rate of FNHTR in patients with no prior history of transfusion reactions. A single center prospective study found that premedication reduces the rate of fever, but does not mitigate other symptoms such as chills. Notably, premedication can mask a fever potentially preventing early recognition of an AHTR or another cause of fever. This is particularly important in patient populations at higher risk of infection such as patients with severe neutropenia.
Product specific factors
The incidence of FNHTRs has decreased since the implementation of prestorage leukoreduction supporting the contributing role of donor leukocytes in FNHTRs. Platelet products have higher rates of FNHTRs compared to red blood cells, which may be due to the higher concentration of donor plasma in conventional platelet products. Platelet products appear to have similar rates of FNHTR regardless of whether the product is an apheresis unit or derived from pooled whole blood donation. , Reducing donor plasma with platelet additive solutions (PAS) reduces the incidence of FNHTRs compared to conventional platelets. Prestorage leukoreduction may also decrease the incidence of FNHTR with platelet products compared to leukoreduction after storage.
Allergic and anaphylactic transfusion reactions
Physiology
The underlying physiology of allergic transfusion reactions is unknown but appears to be a combination of recipient and product factors. Platelet products, followed by plasma products, have the highest rates of allergic transfusion reactions. This combined with the fact that reducing donor plasma in products reduces the incidence of allergic transfusion reactions, suggests that something in donor plasma contributes to an allergic reaction. However, donor plasma alone does not explain the majority of reactions as recipients of split apheresis platelets from the same donor rarely have similar rates of allergic reactions. Recipient factors also contribute to allergic reactions. Recipients with higher levels of IgE and atopic predisposition have an increased risk of allergic reactions. ,
In rare cases, allergic transfusion reactions are due to antibodies in individuals with protein deficiencies, such as IgA, haptoglobin, and C4, but the pathophysiologic role of these antibodies remains uncertain. Some allergic reactions may be from passive transfer of donor antibodies to food antigens such as peanuts. However, these particular scenarios are too rare to account for the majority of allergic reactions.
Incidence
Allergic transfusion reactions occur in 1 to 4% of transfusions. Anaphylaxis, a severe form of an allergic reaction, is rare, occurring in less than 10% of all allergic transfusion reactions. Fatalities are exceedingly uncommon; in 2017, three probable fatal allergic transfusion reactions were reported to the FDA.
Presentation and differential diagnosis
Pruritus and urticaria are the most common symptoms in allergic transfusion reactions; however, multiple organ systems can be involved. Other etiologies of an allergic reaction should be considered particularly if the onset of the allergic reaction correlates more with exposure to another therapy.
NHSN hemovigilance diagnostic criteria
- 1.
≥2 allergic symptoms during or ≤4 hours after transfusion.
- a.
Allergic symptoms: conjunctival edema; edema of lips, tongue, or uvula; erythema/edema or periorbital area; flushing; hypotension; localized angioedema; maculopapular rash; pruritus; respiratory distress/bronchospasm; urticaria
- a.
An anaphylactic or severe allergic reaction is a more severe presentation that may involve circulatory shock and/or airway obstruction.
Management.
If a patient develops allergic symptoms during a transfusion, the transfusion should be immediately stopped and the patient should be treated supportively based on symptoms. H1 receptor antagonists, such as diphenhydramine, can relieve symptoms. The transfusion may be restarted depending on the severity of the reaction and the recipient should be reassured that additional allergic transfusion reactions are unlikely with subsequent transfusions. Common practice includes transfusing at a slower rate; however, both transfusion volume and rate do not appear to influence the incidence of allergic reactions.
If the recipient has signs of anaphylaxis, the transfusion should be immediately stopped and epinephrine should be given. If possible, epinephrine should be administered intramuscularly; subcutaneous administration results in slower onset of effect due to vasoconstriction. Intravenous epinephrine should be avoided unless no other route is feasible to limit the inotropic and chronotropic side effects. Glucocorticoids have been used for prolonged allergic symptoms for patients with severe anaphylaxis but lack randomized data and have not been studied in the transfusion setting.
Prevention.
Patient-specific factors.
Premedication with acetaminophen and/or antihistamines does not reduce the incidence of allergic transfusion reactions and should not be used to prevent allergic reactions in patients who have not had recurrent allergic transfusion reactions. The majority of recipients who experience an allergic transfusion reaction will not have recurrent reactions; subsequent transfusions may instead desensitize recipients and prevent future allergic reactions.
For patients with recurrent allergic reactions and/or anaphylaxis, the indication and need for the transfusion should be evaluated. If transfusion is required, premedication can be offered. The majority of providers prefer H1 antihistamines for premedication; however, nonsedating H2 histamine receptor blockers can also be considered. However, neither H1 nor H2 antihistamines have high-quality evidence for the treatment of anaphylaxis.
Product specific factors
Platelets.
Reducing the amount of donor plasma in platelet products reduces the incidence of allergic transfusion reactions. This can be done through volume reduction or washing, both of which will reduce the function of the platelet unit and thus should be reserved only for recipients with persistent allergic reactions despite premedication. , Platelets can be stored in platelet additive solutions (PAS), which replaces two thirds of the plasma content of the unit. PAS decreases the incidence of allergic transfusion reactions. Although some reports demonstrate conflicting data, a meta-analysis suggests there is no difference in allergic transfusion reactions with pooled versus apheresis platelets. Similarly, ABO-matched and ABO-mismatched apheresis platelets have equivalent rates of allergic transfusion reactions.
Plasma.
Plasma products are the second most likely product to cause allergic transfusion reactions. Solvent detergent treated plasma products may reduce the risk of allergic reactions.
Red blood cells.
Allergic reactions rarely occur with red blood cell transfusions. However, if a recipient has severe allergic reactions to red blood cells, washing could be considered as it also decreases the rate of allergic transfusion reactions from red blood cells.
IgA deficiency.
IgA-deficient blood products may be required for patients with IgA deficiency who have proven anti-IgA antibodies and a history of an allergic or anaphylactic transfusion reaction; however, there is conflicting data to suggest IgA is implicated in allergic transfusion reactions. Additionally, blood products from donors with IgA deficiency do not increase the rate of allergic transfusion reactions, despite the fact that some of these donors have anti-IgA in their plasma.
Donor-specific factors.
A minority of allergic reactions are due to products from a particular donor. This may be due to donor antibodies, but additional investigation is required before screening tests can be implemented to identify which donors are most likely to cause an allergic reaction in most recipients.
Transfusion-related acute lung injury
Physiology
Transfusion-related acute lung injury (TRALI) is hypothesized to be a two-hit phenomenon. First, the recipient’s neutrophils are primed and sequester in the lung microenvironment as a response to an underlying risk factor or endothelial injury. Second, the transfused blood product activates the recipient’s primed neutrophils resulting in lung damage from inflammation and capillary leak. Antibodies directed against white blood cells (human leukocyte antigens class I and II, as well as anti-neutrophil antibodies) in the donor plasma are thought to be a primary activator of recipient neutrophils.
Incidence
Historically, TRALI occurred in 1 in 5 to 10,000 of plasma containing products. After implementation of policies to avoid plasma products from female donors, the incidence of TRALI has decreased and fatalities from TRALI now are less common than from transfusion related circulatory overload (TACO). In 2017, five possible and likely fatalities due to TRALI were reported to the FDA. In 2009, TRALI occurred in 0.81 per 10,000 units at two academic centers. The true incidence of TRALI is likely underestimated both due to underreporting and the difficulty to delineate TRALI from other common forms of respiratory distress in hospitalized patients. This is particularly notable as TRALI is more likely in critically ill patients.
Presentation and differential diagnosis
Patients with TRALI usually develop acute respiratory distress during or immediately after transfusion, but by definition, it can occur up to 6 hours afterward. All patients must have hypoxemia and pulmonary infiltrates. Other signs and symptoms may include fever (33% of cases), hypotension (32% of cases), and cyanosis (25% cases). Alternative etiologies of acute respiratory distress such as acute respiratory distress syndrome (ARDS) should be considered.
NHSN hemovigilance diagnostic criteria
- 1.
No evidence of acute lung injury before transfusion
- 2.
Acute lung injury ≤6 hours post-transfusion
- 3.
Hypoxemia
- 4.
Bilateral infiltrates on imaging
- 5.
No left atrial hypertension (i.e., circulatory overload)
Notably, an international expert panel in 2019 proposed two updated TRALI definitions and recommended removing the term “possible TRALI.” TRALI type I occurs when patients develop TRALI without any risk factors for ARDS, which is consistent with the NHSN HM criteria listed above. TRALI type II is the term suggested for patients with preexisting mild ARDS prior to the transfusion event and/or risk factors for ARDS.
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