Approach
Although the large majority of transfusions are completed without incident, it is important to note that every recipient is at risk for transfusion reaction. From a diagnostic standpoint, it is helpful to divide immune-mediated transfusion reactions into acute and delayed types. Nonimmune-mediated reactions are uncommon and will not be specifically discussed.
Acute reactions: history
Important historical factors that increase risk of a transfusion reaction should be noted. These factors include ABO incompatibility (unusual, and typically resulting from clerical error), pregnancy or previous transfusion (associated with sensitization to antigens predisposing to future reactions), transplantation and immunocompromised status (associated with graft-versus-host disease), IgA deficiency (associated with anaphylactoid reaction), and prior history of transfusion reaction.[3][9]
Acute reactions: clinical presentation
Signs and symptoms of an acute hemolytic reaction typically evolve during or immediately following transfusion. They overlap for various immune-mediated reaction etiologies. Symptoms include chills and fever, headache, nausea and vomiting, or anxiety.[3] Pallor may be seen with severe anemia. Pain along the infused extremity is a more specific symptom for acute hemolytic transfusion reaction. Abdominal, chest, or back pain may also accompany generalized symptoms. Hemoglobinuria, manifested as red urine, is often present. In severe acute hemolytic transfusion reaction, the patient may progress toward hypotension, renal failure, and disseminated intravascular coagulation (DIC).[3] The severity of the reaction is proportional to the amount of incompatible blood transfused.[3]
Typical symptoms of an allergic reaction include pruritus, flushing, and dyspnea. Symptoms often occur within minutes of the initiation of transfusion. Urticaria typically evolves, and angioedema develops less commonly. Anaphylaxis - a serious, potentially life-threatening, systemic allergic reaction - may follow.[5] Anaphylaxis is generally rapid in onset, with variable signs and symptoms, and typically affects two or more body systems (e.g., cutaneous, respiratory, cardiovascular).[5] However, atypical presentations may only appear to affect a single system (e.g., isolated hypotension).[5] There may be features of respiratory compromise (e.g., dyspnea, wheezing, stridor, hypoxemia, reduced peak expiratory flow) and/or cardiovascular compromise or associated end-organ dysfunction (e.g., hypotension, hypotonia/collapse, syncope, incontinence).[5] Gastrointestinal symptoms may also be present (e.g., cramping abdominal pain, vomiting, diarrhea).[5] It should be noted that typical cutaneous features of anaphylaxis (e.g., urticaria, flushing, pruritus, angioedema) are not always present.[5] Be aware that infants and young children may display other age-specific symptoms of anaphylaxis, some of which may be hard to distinguish from normal behaviors, such as crying, irritability, clinging, withdrawal, fingers in ears and pulling, or scratching at skin.[5] Further, retrospective studies have found that, when compared to older children, infants with anaphylaxis experience cutaneous symptoms more frequently but respiratory symptoms less frequently.[5] Severity of an anaphylactic reaction can be variable, and hypotension and hypoxemia are suggestive of more severe anaphylaxis.[5] Severe anaphylaxis is associated with older age and preexisting cardio-pulmonary disease, and those taking beta-blockers and/or angiotensin-converting enzyme (ACE) inhibitors may experience increased severity of reaction (possibly directly related to the effects of these drugs on the body’s ability to compensate during anaphylaxis and to respond to treatment with epinephrine and/or due to the presence of the underlying cardiovascular disorders that these drugs are often used to treat).[5]
Febrile nonhemolytic transfusion reactions present with fever. More specifically, the fever is defined as a rise in temperature of at least 1.8°F (1°C) above 98.6°F (37°C) for which no other cause is identifiable. Most episodes are benign, but initially may be indistinguishable from the onset of an acute hemolytic transfusion reaction.
Transfusion-related acute lung injury (TRALI) is characterized by the sudden onset of dyspnea and tachypnea, often accompanied by fever and tachycardia.[6] Rales may be noted on exam. Hypotension may also be observed. Onset is typically within 1 to 2 hours following the transfusion of any blood product (most commonly RBC, platelet, or FFP), but onset has been observed from as early as during transfusion to as long as 6 hours after transfusion, and by definition occurs within 6 hours of transfusion.[6][7][8]
Acute reactions: investigations
In any acute reaction, transfusion should be immediately stopped but venous access should be maintained.[1] When an acute hemolytic reaction is suspected, differentiation by laboratory investigation includes the following steps:
The transfusion should be stopped, with the component bag and tubing disconnected from the patient.
A clerical check should be performed to confirm that the recipient matches the unit being transfused.[1] This is paramount because a patient-component mismatch implies that an additional patient in the hospital is at risk for the same mismatch and being transfused with the wrong blood.
Post-transfusion blood samples should be obtained from the recipient and sent to the blood bank, along with the blood bag and tubing.
Repeat ABO testing on the post-transfusion sample should be performed on the patient's blood and the remainder of the transfused unit.
The direct antiglobulin test should be performed to identify whether hemolysis has occurred, indicating the presence of an acute hemolytic transfusion reaction.[1]
The plasma specimen should also be visually inspected for color change (indicating the presence of free hemoglobin due to hemolysis). Visual inspection 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 direct antiglobulin test.
Hemolysis may be supported by presence of free hemoglobin in urine and low serum haptoglobin. Post-transfusion urine samples should be obtained.[1]
D-dimer, PT, and PTT may be elevated due to DIC.
Febrile nonhemolytic transfusion reaction is a diagnosis of exclusion. The diagnosis may be made when the observed clinical response is consistent and the laboratory investigation excludes the presence of hemolysis.
Gram stain and culture of component and post-transfusion recipient samples may also be considered when suspicion of transfusion-associated sepsis is a possibility.[4]
The diagnosis of anaphylaxis is clinical, based on the clinical history and the signs and symptoms present during the event.[5] When diagnostic tests are performed it is important that these do not delay emergency management of the suspected acute anaphylactic episode.[5][32] In cases where anaphylaxis is observed, the patient should be tested for antibodies to IgA, and quantitative IgA levels should be assessed. Taking tryptase levels can also aid with postacute confirmation of the diagnosis.[5][32] In the UK, the National Institute for Health and Care Excellence (NICE) recommends taking two acute mast cell tryptase levels: the first should be obtained as soon as possible after emergency treatment has started; the second should be taken ideally within 1-2 hours (but no later than 4 hours) from symptom-onset.[32] NICE advises that a third sample may be required when the patient is followed up in the specialist allergy service to establish their baseline mast cell tryptase level.[32] Similarly, a 2023 anaphylaxis practice parameter update commissioned by the Joint Task Force on Practice Parameters (JTFPP) suggests (based on moderate-certainty evidence) that an acute serum tryptase level should be measured as soon as possible (ideally within 2 hours of the onset of symptoms) and that this should be followed by a second serum tryptase measurement at a later time to establish the patient’s baseline level.[5] An acute tryptase level that is elevated above the upper limit of normal (e.g., >11.4 ng/mL in many laboratories) is supportive of a diagnosis of anaphylaxis, as is an acute level that shows significant elevation from the patient’s baseline tryptase level (even where the acute level is still within the normal range, i.e., an acute tryptase level in the normal range does not rule out anaphylaxis).[5]
When transfusion-related acute lung injury (TRALI) is suspected, a chest x-ray should be obtained.[1] Evidence of bilateral patchy alveolar infiltrates supports the diagnosis. TRALI is clinically defined as the onset of acute lung injury in temporal relation to transfusion. Criteria for acute lung injury include acute onset of symptoms, absence of circulatory overload, bilateral pulmonary infiltrates on chest x-ray, and hypoxemia as demonstrated by PaO2/FIO2 <300 mmHg. A CBC with differential may demonstrate eosinophilia and/or an acute decrease in neutrophil count, but these associated findings do not necessarily rule in or disprove the diagnosis of TRALI.
Serum electrolytes and creatinine are also advisable for acute immune-mediated transfusion reactions. Hemolysis can lead to renal toxicity, and release of intracellular cations can precipitate serious electrolyte disorders.
Delayed reactions: history
Prior exposure to foreign red-cell antigen following pregnancy, previous transfusion, or organ transplantation is associated with delayed hemolytic transfusion reaction.[3] Immunocompromised patients such as those with leukemia, lymphoma, or congenital immune deficiencies are at risk for graft-versus-host disease. Prior transfusion or pregnancy may sensitize patients to human platelet antigen 1a, thus predisposing patients to thrombocytopenia and resulting post-transfusion purpura.
Delayed reactions: clinical presentation
Delayed hemolytic transfusion reactions may present with fever or anemia, occurring days to weeks following transfusion.[3] Pallor may be present on exam. Jaundice develops in some patients. Hemoglobinuria may be observed as red urine due to hemolysis that is primarily extravascular. Rarely, acute renal failure and DIC occur. Delayed hemolysis may occur in the absence of symptoms. The diagnosis may be made when a new positive direct antiglobulin test and/or positive antibody screen is identified during the preparation of a subsequent transfusion.
Transfusion-associated graft-versus-host disease occurs rarely, and typically in immunocompromised patients. Symptoms usually begin 8 to 10 days following transfusion, and include maculopapular rash, fever, and diarrhea.[9] It tends to lead to marrow aplasia with rapid progress toward death. Evidence of toxic epidermal necrolysis (TEN) may be present.
Post-transfusion purpura is uncommon. Patients typically present with disseminated purpura, and bleeding from mucous membranes, GI tract, and urinary tract may result from the associated thrombocytopenia.
Delayed reactions: investigations
Differentiation by laboratory test of delayed hemolytic transfusion reactions is most often done by blood bank testing, which reveals a positive alloantibody screen, or a new alloantibody in a recently-transfused patient.[3]
When attempting to evaluate the etiology of anemia in a patient with a recent history of transfusion, the direct antiglobulin test should be positive, suggesting the diagnosis of delayed hemolytic transfusion reaction. Elevated LDH and bilirubin, presence of free hemoglobin in urine, and low serum haptoglobin support the diagnosis of hemolysis. D-dimer, PT, and PTT may be elevated, particularly with DIC. Electrolytes, chest x-ray, and blood gases are advisable as these reactions can lead to renal failure, electrolyte disorders, and pulmonary infiltrates.
Transfusion-associated graft-versus-host disease may be identified by skin biopsy of the affected area, or of biopsy of the gut or liver.[9] HLA typing of the recipient and donor should also be performed.
When post-transfusion purpura is suspected, platelet antibody screening will confirm the diagnosis.
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