Transfusion reactions

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Blood component transfusions are usually safe and, given extensive screening and pretransfusion testing, serious adverse events are uncommon. When acute reactions occur they are typically mild, with the most common reactions including fever and rash. Rarely, more severe reactions can occur, causing respiratory distress, hemolysis, or shock. As there is significant overlap between the manifestations of mild transfusion reactions and the early stages of severe transfusion reactions, the first step is to stop the blood transfusion while assessment is performed. For minor transfusion reactions, it may be possible to restart the transfusion at a slower rate once more serious diagnoses have been excluded. Patients may also experience delayed transfusion reactions days to weeks after a transfusion. Delayed transfusion reactions typically have a more insidious presentation than acute reactions, and identifying them requires a high degree of clinical suspicion.

See also “Transfusion.”

Immunological transfusion reactions

Nonimmunological transfusion complications

General principles ^[12]

• Acute transfusion reaction refers to an immune or nonimmune-mediated adverse reaction that occurs during or within 24 hours of the transfusion of blood products.
• All patients should undergo a similar initial assessment and management that is focused on stabilization until the underlying diagnosis can be determined.
• Definitive treatment can be provided once the underlying cause has been identified.

Suspect an acute transfusion reaction in any patient who develops a change in vital signs (e.g., fever, hypotension) or any other new symptom during or within 24 hours of blood product transfusion.

Initial management steps for acute transfusion reactions

• All patients
  • Immediately discontinue the transfusion and disconnect the tubing from the patient.
  • Maintain open IV access with IV normal saline.
  • Check patient and blood product IDs for compatibility.
  • Perform an ABCDE survey and determine the severity of the reaction (see “Severity assessment”).
  • Narrow down the underlying cause using a symptom-based diagnostic approach to acute transfusion reactions.
• Severe transfusion reaction
  • Call for help early; consider hematology and ICU consult.
  • Provide respiratory support and immediate hemodynamic support as needed.
  • Notify the blood bank/transfusion services and send them the following:
    • The blood product bag (including the administration set)
    • A posttransfusion patient blood sample
  • Order initial investigations
  • Begin definitive treatment for specific transfusion reaction (e.g., AHTR) once identified.
• Mild transfusion reaction
  • Exclude the possibility of an early manifestation of severe transfusion reactions.
  • Provide symptomatic relief.
  • If symptoms resolve, resume the transfusion.

Do not restart blood component transfusion before a severe transfusion reaction has been ruled out.

Severity assessment

• Mild: the patient is stable with minor symptoms, e.g., isolated fever or cutaneous allergic reaction
• Severe: the patient is unstable or has any of the following features
  • Respiratory distress signs
  • Signs of shock, e.g., chest pain, hypotension
  • Signs of anaphylaxis
  • Signs of hemolysis

If uncertain, treat the reaction as severe.

Initial investigations

• All patients
  • Repeat patient and donor ABO typing and crossmatching.
  • CBC: to assess for anemia, thrombocytopenia
  • Hemolysis workup
  • BMP: to assess for AKI and/or electrolyte imbalances
  • Coagulation panel: to assess for DIC
  • Urinalysis: to assess for hemoglobinuria
• Select patients: depending on the suspected underlying cause
  • DAT to assess for AHTR
  • Blood cultures if sepsis is suspected
  • Chest imaging (e.g., CXR, lung ultrasound, CT chest) to evaluate dyspnea/hypoxemia
  • BNP levels and echocardiography if TACO is suspected

Do not delay stabilization measures pending results of a diagnostic workup in patients with suspected severe transfusion reactions.

Diagnostic approach

Description

Acute hemolytic transfusion reaction (AHTR) is an adverse reaction to blood transfusion that occurs within the first 24 hours after transfusion.

Frequency ^[2]

• ABO-related: 1:200,000 transfusions
• Non-ABO-related: 1:105,000 transfusions

Pathophysiology ^[2]

• ABO incompatibility
  • Immune-mediated destruction of donor RBCs (intravascular hemolysis; ) by recipient anti-A and/or anti-B antibodies (type II hypersensitivity reaction)
  • Immune-mediated destruction of recipient RBCs by donor anti-A or anti-B antibodies
• Non-ABO-related
  • Immune-mediated: the destruction of donor RBCs by recipient alloantibodies to non-ABO RBC antigens
  • Nonimmune-mediated: RBC destruction resulting from mechanical, thermal, or osmolar injuries

Clinical features ^[2]

• Rapid onset during transfusion (because of preformed antibodies) or up to 24 hours after the transfusion
• Clinical presentation ranges from asymptomatic to severe.
• Symptoms include: ^[13]
  • Fever, chills, nausea, flushing
  • Hypotension, tachycardia
  • Flank pain or chest pain
  • Dyspnea, tachypnea
  • Hemoglobinuria (due to intravascular hemolysis)
  • Jaundice (due to intravascular hemolysis)
  • Pruritus, urticaria
  • Burning pain at the IV site
  • Patients in a coma or under general anesthesia may present with oozing from wounds or puncture sites.
• Sequelae include:
  • DIC
  • Shock
  • Renal failure

Diagnosis ^[2][4]

AHTR is mainly a clinical diagnosis.

Confirmatory testing

• Repeat blood typing and crossmatching of patient and donor blood samples.
• Direct Coombs test: usually positive ^[14]
• Visual inspection of recipient plasma for pink discoloration: suggests hemoglobinemia ^[15]

Additional laboratory testing

• CBC
  • Anemia: due to acute hemolysis; check serial hemoglobin to monitor for progressive anemia.
  • Thrombocytopenia: may indicate DIC
• Serum hemolytic indices: ↑ indirect bilirubin, ↑ LDH, ↓ haptoglobin
• BMP: to assess for AKI and electrolyte imbalance (e.g., hyperkalemia resulting from massive hemolysis)
• Coagulation panel: ↑ PTT, ↑ INR, ↓ fibrinogen suggest DIC.
• Urinalysis: hemoglobinuria

Management

AHTR is a medical emergency.

• Stop the transfusion immediately if AHTR is suspected.
• Follow the initial management steps for acute transfusion reactions.
• Initiate fluid resuscitation with normal saline: Maintain urine output > 1 mL/kg/hour. ^[16]
• Contact the transfusion service to undertake a clerical check on both the transfused blood product and the patient information.
• Consider the following:
  • Continuous cardiac monitoring
  • Vasopressors for refractory hypotension
  • Management of hyperkalemia caused by severe hemolysis
  • Transfusion of compatible blood products, e.g.:
    • RBC transfusion for severe anemia (e.g., Hb < 7 g/dL)
    • FFP and platelet transfusion for DIC
• Consult critical care.

Stop the transfusion immediately if AHTR is suspected!

Prognosis ^[17]

• Significant disease progression (e.g., requiring intensive care admission) in approx. 30% of cases.
• Death occurs in 5–10% of cases.

Background

• Frequency: 1 in 900 transfusions (more common in children) ^[2][3]
• Pathophysiology
  • When blood products have been in storage for long periods of time, cytokines may leak from donor WBCs and cause a mild immunologic reaction in the recipient.
  • Preformed recipient antibodies cause lysis of the few remaining leukocytes within donor blood products, resulting in an inflammatory reaction.

Clinical features

• Rapid onset during or within 6 hours of transfusion; (since cytokines are preformed)
• Fever, chills, malaise, flushing, headache
• More common in pediatric patients
• Recurrence is rare.

Diagnosis ^[2][4]

• Clinical diagnosis based on the following findings (both must be present):
  • Temperature increase to ≥ 38°C or an increase of ≥ 1°C from baseline during or shortly after transfusion
  • Exclusion of other potential causes of fever during or following transfusion (e.g., AHTR, TRALI, sepsis)
• Diagnostic evaluation
  • Check patient and blood bag IDs for compatibility and send a patient blood sample for DAT to rule out AHTR.
  • Consider blood cultures to evaluate for sepsis if any of the following are present:
    • A temperature increase of ≥ 2°C
    • Clinical signs of bacterial infection (e.g., ≥ 2 SIRS criteria or qSOFA criteria)
    • Lack of improvement with the cessation of transfusion and antipyretics
  • Consider chest imaging (e.g., CXR) to evaluate for TRALI in patients with hypoxemia or respiratory distress.

Management ^[2][4]

• Treatment
  • Cessation of transfusion until an AHTR has been ruled out
  • Consider antipyretics for fever (e.g., acetaminophen ).
  • Consider meperidine for severe chills/rigors.
  • If other causes of fever have been excluded, restart the transfusion at a slower rate.
• Prevention: Use of leukoreduced blood products

Premedication with antipyretics to prevent FNHTR is not supported by available evidence. ^[2][4]

If a patient receiving a transfusion develops a fever, repeat donor and patient blood typing and crossmatching to rule out ABO incompatibility.

See also “Anaphylaxis.”

• Frequency: 1 in 30,000 transfusions ^[2]
• Pathophysiology
  • Type I hypersensitivity reaction in which preformed IgE antibodies on the surface of mast cells bind to donor plasma proteins (commonly donor IgA in recipients with IgA deficiency), leading to mast cell degranulation
  • Individuals with IgA deficiency should receive IgA-depleted blood products.
• Clinical features: Sudden onset during or up to 3 hours after the transfusion
  • Shock, hypotension, wheezing, respiratory distress
  • Skin reactions (e.g., pruritus, urticaria)
• Diagnosis ^[2]
  • Clinical diagnosis established according to diagnostic criteria for anaphylaxis
  • If the diagnosis is in doubt, consider workup for AHTR, TRALI, and septic transfusion reaction as the presenting features (e.g., hypotension, dyspnea) may be similar.
  • Consider testing the transfusion recipient for serum IgA levels and anti-IgA antibodies.
• Management ^[2]
  • Follow initial management steps for acute transfusion reactions.
  • Treatment is otherwise similar to the management of anaphylaxis from other causes.
    • Administer epinephrine IM
    • into the anterolateral thigh. Repeat every 5–15 minutes as needed.
    • Consider adjunctive therapy with antihistamines, corticosteroids. ^[16]
    • Provide airway management and respiratory support.
    • Provide immediate hemodynamic support to hypotensive patients (e.g., with IV fluid resuscitation and vasopressors as needed).
• Prevention: in patients with a previous history of anaphylactic transfusion reaction ^[2]
  • Use washed blood products (platelets, RBCs) and solvent detergent plasma.
  • Use IgA-deficient blood products for patients with IgA deficiency.
  • The use of prophylactic antihistamines and/or steroids is commonly practiced but lacks supportive evidence. ^[4][17]

• Frequency: 1 in 1200 transfusions (more common in children) ^[2][3]
• Pathophysiology: Preformed recipient antibodies against plasma components in the donor blood cause an allergic reaction.
• Clinical features
  • Onset during or up to 4 hours after transfusion
  • Pruritus, urticaria
• Diagnosis: Clinical diagnosis based on typical presentation with cutaneous symptoms only
• Treatment ^[2][4]
  • Stop transfusion initially.
  • Use H1 antihistamine (e.g., diphenhydramine ) for symptomatic relief.
  • Monitor closely for the development of signs or symptoms that may suggest anaphylaxis (e.g., dyspnea, hypotension).
  • If symptoms have resolved, transfusion may be restarted with the same unit at a slower rate and under observation.
• Prevention: Monitor carefully with subsequent transfusions.

Routine premedication with antihistamines and/or steroids is NOT indicated in patients with a previous history of minor allergic transfusion reactions.

Approach

TRALI and TACO are both characterized by respiratory distress, i.e., dyspnea and hypoxemia, that develops acutely either during or within hours of transfusion.

• Begin initial management steps for acute transfusion reactions for all patients, i.e., stop the transfusion and start acute stabilization.
• Conduct thorough clinical and diagnostic evaluation to differentiate between TRALI and TACO.
• Exclude other conditions with potentially overlapping manifestations: See "Symptom-based diagnostic approach to acute transfusion reactions”.
• Confirm hypoxemia: Typically defined as SpO₂ < 90% on room air or P/F ratio < 300
• Perform chest imaging: e.g., CXR, CT chest, or lung ultrasound
• Consider additional investigations: e.g., BNP, ABG, echocardiogram.
• Consider a trial of diuretic therapy.
• Consult critical care.

Transfusion-related acute lung injury (TRALI)

• Frequency: 1 in 60,000 transfusions ^[2][4]
• Pathophysiology ^[5]
  • Prior to transfusion: sequestration and priming of neutrophils in the pulmonary endothelium due to the recipient's comorbidities ^[18]
  • Following transfusion (most commonly of FFP or platelets): soluble factors (antibodies, certain lipids) in the donor blood lead to activation of the recipient's granulocytes → release of proinflammatory mediators → increase of vascular permeability → plasma transudation into pulmonary interstitium → noncardiogenic pulmonary edema ^[19]
• Differential diagnosis also includes: ARDS, AHTR, septic transfusion reaction, and anaphylactic transfusion reaction
• Management: Provide aggressive supportive care. ^[5][20]
  • Start oxygen therapy.
  • If respiratory failure, begin mechanical ventilation using a lung-protective ventilation strategy. ^[20]
  • Control hemodynamic parameters with judicious use of fluids and vasopressors. ^[20]
• Prognosis
  • Mortality: 10–20% ^[16]
  • With appropriate support, TRALI typically resolves within 1–3 days of ceasing the transfusion. ^[17]

Transfusion-associated circulatory overload (TACO)

• Definition: a transfusion reaction in which patients develop pulmonary edema as a result of volume overload. Typically occurs when a large amount of blood products are transfused rapidly.
• Frequency: 1 in 9000 transfusions ^[2][4]
• Risk factors: underlying cardiovascular or renal disease
• Pathophysiology ^[5]
  • Prior to transfusion: increased susceptibility to volume overload due to heart failure, renal dysfunction, hypoalbuminemia, and/or positive fluid balance
  • Following transfusion
    • Blood product transfusion → expansion of intravascular volume → increased pulmonary venous hydrostatic pressure → (cardiogenic) pulmonary edema
    • Inflammatory cytokines in the transfused product may also play a role.
• Differential diagnosis: heart failure exacerbation, acute MI
• Management: similar to that of acute heart failure ^[5][20]
  • Support oxygenation and ventilation (See also “Respiratory support in acute heart failure”).
  • Correct volume status with diuretics (See also “Diuretic therapy in acute heart failure”).
• Prognosis: mortality ∼ 6.5% ^[21]

Distinguishing TRALI from TACO

Massive transfusion-associated reactions occur following the transfusion of large amounts of RBC units (e.g., > 10 units in 24 hours or ≥ 50% of the patient's blood volume in 4 hours), usually for cases of massive blood loss (e.g., from trauma or surgery). ^[4][22]

• Hypocalcemia ^[4]
  • Resulting from the binding of ionized calcium by citrate (an anticoagulant added to RBC, platelet, FFP, and whole blood transfusion units)
  • Managed with monitoring of ionized calcium and calcium repletion
• Hyperkalemia ^[4]
  • Resulting from the lysis of RBCs in stored blood units; the risk is higher with increased transfusion rate and/or volume and longer storage age.
  • Managed with monitoring of serum potassium and treatment as needed (see “Therapeutic approach to hyperkalemia”)
• Hypothermia ^[4]
  • Triggered by the rapid infusion of cold blood products
  • Can be prevented by using inline blood warming devices
• Coagulopathy ^[9]
  • Thought to be multifactorial, including dilution of platelets and clotting factors, hypothermia, and platelet dysfunction
  • Can be prevented by using a fixed ratio of blood products, e.g., a 1:1:1 of RBCs, FFP, and platelets ^[10]
  • See also “DIC.”

See also “Sepsis.”

• Frequency ^[7]
  • Highest with platelet transfusions (approx. 1 in 10,000–50,000 units) ^[8]
  • Lower with other blood products (e.g., RBC: approx. 1 in 200,000 units)
• Microbiology ^[7][23]
  • Contaminated platelets: most commonly gram-positive organisms (e.g., Staphylococcus aureus, Streptococcus spp.)
  • Contaminated RBC: most commonly gram-negative organisms (e.g., Pseudomonas spp., Yersinia spp., Serratia spp.)
• Clinical features
  • Fever, hypotension, rigors, and other signs of SIRS
  • Usually manifests within 4 hours of transfusion
• Diagnosis ^[4]
  • Obtain bacterial cultures and Gram stains of the patient's blood and any recently transfused (within 4 hours) blood products.
  • Consider workup for AHTR and TRALI, as their presenting features (e.g., fever, hypotension, dyspnea) may be similar.
• Management ^[4]
  • Follow initial management steps for acute transfusion reactions.
  • Support hemodynamics with IV fluid resuscitation and vasopressors as needed.
  • Provide initial broad-spectrum empiric antibiotic therapy for sepsis, including antipseudomonal coverage if RBCs were given.

Initial management steps for acute transfusion reactions

• Stop the transfusion.
• Check patient and blood product IDs for compatibility.
• Maintain open IV access with normal saline.
• Draw blood for a repeat ABO typing and crossmatch.
• Perform a full ABCDE assessment and determine reaction severity.

All patients

• Provide symptomatic relief, e.g., oxygen, antihistamines, antipyretics.
• Identify the underlying cause of the reaction.
• Regularly reassess patients for signs of deterioration.
• Consider initial investigations: e.g., CBC, BMP, coagulation studies, hemolysis workup, urinalysis.
• Consider further investigations based on suspected underlying cause: e.g., Direct Coombs test, chest imaging, echocardiogram, BNP

Severe reactions

• Notify the blood bank and/or transfusion services.
• Consider hematology and ICU consult.
• Provide respiratory support and immediate hemodynamic support as needed.

Mild reactions

• Rule out early presentation of severe reactions.
• If symptoms resolve, consider resumption of blood transfusion at a slower rate.

Delayed transfusion reaction refers to an immune-mediated adverse reaction that occurs > 24 hours after the transfusion of blood products (can be weeks to months later). ^[12]

Delayed hemolytic transfusion reaction (DHTR)

• Frequency: 1 in 22,000 transfusions ^[2]
• Pathophysiology
  • Occurs in patients who were previously sensitized to specific RBC antigens during transfusions, pregnancy, or transplantations
  • Usually caused by alloantibodies that form following exposure to minor blood group antigens (e.g., Kidd or D (Rh) antigens)
  • Reexposure to the RBC antigens → anamnestic response resulting in an increase in anti-RBC alloantibody titers 24 hours to 28 days following transfusion → binding of alloantibodies to donor RBCs causing extravascular hemolysis
• Clinical features ^[4]
  • Onset days or weeks after transfusion (due to the delay in the anamnestic response)
  • Most commonly asymptomatic
  • May cause:
    • Mild fever
    • Jaundice
    • Anemia
    • Chest, abdomen, or back pain
  • May be mistaken for vasoocclusive crises in patients with sickle cell disease (SCD)
• Diagnosis ^[2][4]
  • Positive DAT
  • CBC: to evaluate for anemia
  • Laboratory evidence of hemolysis
• Treatment ^[2][4]
  • Most cases are self-limited; and thus no acute therapy is usually required.
  • Additional RBC transfusions are preferably delayed (unless severe anemia) until the culprit alloantibodies are identified.
• Prevention ^[4]
  • Primary prevention in individuals requiring chronic transfusions (e.g., thalassemia, SCD): use of antigen-matched RBC units whenever feasible
  • Secondary prevention in individuals with identified alloantibodies: use of antigen-negative RBC units in future transfusions
  • See “Extended RBC phenotype matching.”

Posttransfusion purpura

• Frequency ^[6]
  • 1 in 57,000 transfusions ^[2]
  • Occurs primarily in women with a history of multiple pregnancies or multiple transfusions
• Pathophysiology ^[6]
  • Occurs in patients who had previously been sensitized to platelet antigens through pregnancy or transfusion.
  • Reexposure to platelet antigens → anamnestic response resulting in an increase in anti-platelet alloantibodies → binding of antibodies to both donor and patient platelets causing platelet destruction by the reticuloendothelial system
• Clinical features: Onset in 5–10 days after transfusion
  • Petechiae
  • Purpura
  • Other clinical features of thrombocytopenia
• Diagnosis ^[6]
  • CBC: typically shows severe thrombocytopenia
  • Blood smear: to rule out pseudothrombocytopenia and assess for other differential diagnoses of platelet disorders
  • Coagulation studies: usually normal
  • PF4 antibody immunoassay: to rule out HIT or VITT in exposed patients
  • Confirmatory testing for platelet-specific alloantibodies
• Treatment: As it may take time to obtain results from confirmatory testing, treatment is initiated presumptively in patients who develop severe unexplained thrombocytopenia 5–10 days after transfusion. ^[6]
  • Preferred treatment: intravenous immunoglobulin (IVIG)
  • High-dose steroids (e.g., dexamethasone ) are often used but have unproven efficacy.
• Prevention: Use washed, antigen-negative, or autologous blood products for all subsequent transfusions. ^[4][6]

Platelet transfusions may be administered to patients with life-threatening bleeding but are usually ineffective in increasing platelet counts in patients with posttransfusion purpura.

Transfusion-associated graft-versus-host disease ^[4]

• An extremely rare complication seen in severely immunocompromised patients
• Manifests with maculopapular rash, fever, diarrhea, and marrow failure 5–10 days after transfusion
• Almost always fatal