Residency · Residency · Pathology

Transfusion Reactions: Recognition and Investigation

Introduction

Transfusion reactions encompass a spectrum of adverse events occurring during or after blood product administration. Timely recognition, appropriate investigation, and systematic reporting are essential responsibilities of the transfusion medicine service and directly impact patient safety.

Classification of Transfusion Reactions

Acute Reactions (Within 24 Hours)

Acute hemolytic transfusion reaction (AHTR) results from ABO-incompatible transfusion causing intravascular hemolysis. Febrile non-hemolytic transfusion reaction (FNHTR) is caused by cytokines in stored products or recipient antibodies to donor leukocytes. Allergic/urticarial reactions are IgE-mediated with mild cutaneous symptoms. Anaphylactic reactions are severe and associated with IgA deficiency and anti-IgA antibodies. Transfusion-related acute lung injury (TRALI) results from donor antibodies to recipient HLA or neutrophil antigens. Transfusion-associated circulatory overload (TACO) is volume overload, especially in patients with cardiac or renal compromise. Septic transfusion reaction arises from bacterial contamination of blood products, particularly platelets.

Delayed Reactions (>24 Hours)

Delayed hemolytic transfusion reaction (DHTR) results from an anamnestic antibody response causing extravascular hemolysis 3-14 days post-transfusion. Delayed serologic transfusion reaction (DSTR) involves detection of a new antibody without clinical hemolysis. Transfusion-associated graft-versus-host disease (TA-GVHD) occurs when donor T-lymphocytes engraft in an immunocompromised recipient and is usually fatal. Post-transfusion purpura (PTP) causes thrombocytopenia 5-10 days post-transfusion from anti-HPA antibodies. Transfusion-transmitted infections are rare with current testing and include HIV, HBV, HCV, bacteria, and parasites.

Acute Hemolytic Transfusion Reaction

Pathophysiology

AHTR is most commonly caused by ABO incompatibility due to clerical or identification errors. Recipient naturally occurring IgM anti-A or anti-B activates complement on transfused RBCs, resulting in intravascular hemolysis with hemoglobinemia, hemoglobinuria, DIC, renal failure, and shock. The mortality rate of ABO-incompatible transfusion is approximately 10-40%.

Clinical Signs

Clinical signs include fever, chills, flank pain, chest tightness, hypotension, and dark urine. In anesthetized patients, the reaction may manifest as unexplained hypotension, hemoglobinuria, DIC, and diffuse oozing from surgical sites. Symptoms may begin after only 10-50 mL of incompatible blood.

Immediate Management

The transfusion must be stopped immediately while maintaining IV access with normal saline. Patient and unit identification should be verified at the bedside through a clerical check. Post-reaction blood samples and the remaining blood product are sent to the blood bank. Supportive care includes aggressive hydration, vasopressors, and monitoring of renal function and coagulation.

Investigation Workup

Blood Bank Investigation Steps

The investigation proceeds in a structured sequence: (1) clerical check to verify patient identity, blood type, and unit compatibility records; (2) visual inspection of the post-reaction sample for hemolysis (pink or red plasma) compared with the pre-transfusion sample; (3) direct antiglobulin test (DAT) which is positive in immune-mediated hemolysis, detecting IgG and/or C3 on patient RBCs; (4) repeat ABO/Rh typing on pre- and post-transfusion samples and the donor unit segment; (5) antibody screen and crossmatch repeated on the post-transfusion sample; (6) urinalysis for hemoglobinuria; and (7) LDH, bilirubin, and haptoglobin as markers of hemolysis (elevated LDH and bilirubin with decreased haptoglobin).

Interpreting DAT Results

An IgG positive DAT suggests alloantibody or autoantibody-mediated hemolysis. C3 positive indicates complement activation, seen in ABO incompatibility and cold antibodies. IgG and C3 positive may indicate an alloantibody with complement activation. A negative DAT does not completely exclude hemolysis, as it may occur if incompatible cells are completely destroyed.

TRALI and TACO

TRALI

TRALI presents as acute respiratory distress within 6 hours of transfusion with bilateral pulmonary infiltrates, hypoxemia, and no evidence of circulatory overload. The pathogenesis involves donor HLA or HNA antibodies that activate recipient neutrophils in the pulmonary vasculature. Mitigation strategies include a male-predominant plasma policy and testing female donors for HLA antibodies. Management is supportive, with mortality approximately 5-10%.

TACO

TACO is volume overload presenting with dyspnea, hypertension, tachycardia, and pulmonary edema. Risk factors include advanced age, cardiac disease, renal insufficiency, and rapid transfusion rate. BNP/NT-proBNP levels are elevated and help distinguish TACO from TRALI. Prevention includes slow transfusion rate, diuretics, and volume-reduced products.

Allergic and Anaphylactic Reactions

Allergic (Urticarial)

Allergic reactions manifest as hives, pruritus, and localized erythema and occur in 1-3% of transfusions. The transfusion can often be resumed after antihistamine administration if symptoms resolve. Pre-medication with diphenhydramine is of limited proven benefit.

Anaphylaxis

Anaphylaxis presents with hypotension, bronchospasm, angioedema, and cardiovascular collapse. It is associated with IgA deficiency and anti-IgA antibodies, which occur with a prevalence of approximately 1 in 700. Treatment requires epinephrine, airway management, and hemodynamic support. Future products should be washed cellular components or IgA-deficient donor products.

Bacterial Contamination

The highest risk is with platelet concentrates due to their storage at 20-24 degrees C. Common organisms include gram-positive skin flora (S. epidermidis, S. aureus) and gram-negative rods (Yersinia and Serratia in RBCs). Pathogen reduction technology such as Intercept and Mirasol reduces but does not eliminate the risk. Investigation includes Gram stain and culture of the residual product and patient blood.

Reporting and Prevention

All transfusion reactions must be documented and reported to the transfusion medicine service. Serious reactions are reported to institutional quality and safety committees and, where applicable, to the FDA (for fatalities) and hemovigilance systems. Root cause analysis for AHTR most commonly reveals patient identification or labeling errors. Prevention strategies include two-person verification, electronic patient identification with barcoding, and bedside identity checks.

Clinical Pearls

The most common cause of fatal acute hemolytic transfusion reactions is clerical error leading to ABO-incompatible transfusion, making patient identification at the bedside the critical safety check. A positive DAT with hemolysis markers confirms immune-mediated hemolysis but does not identify the specific mechanism without further serologic workup. Distinguishing TRALI from TACO has direct therapeutic implications: TRALI is managed supportively while TACO requires diuresis. Bacterial contamination risk is highest with platelet products due to room temperature storage conditions.

References

1. Delaney M, et al. Transfusion reactions: prevention, diagnosis, and treatment. Lancet. 2016;388(10061):2825-2836.
2. Vlaar APJ, et al. A consensus redefinition of transfusion-related acute lung injury. Transfusion. 2019;59(7):2465-2476.
3. Fung MK, et al., eds. AABB Technical Manual. 20th ed. AABB Press; 2020.
4. Bolton-Maggs PHB, et al. Serious Hazards of Transfusion (SHOT) Annual Report. 2022.

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