15.1 Immunologic Transfusion Reactions

15.1 Immunologic Transfusion Reactions

Transfusion reactions are classified by mechanism (immunologic vs. nonimmunologic) and timing (acute, within 24 hours, vs. delayed, days to weeks later). Immunologic reactions occur when a recipient's immune system responds to antigens on transfused cells or to proteins in donor plasma, or when donor antibodies react against recipient antigens. Recognizing the classic presentation of each reaction and running the correct workup is a core SBB competency.

Acute Hemolytic Transfusion Reaction (AHTR)

AHTR is caused almost always by ABO incompatibility, most commonly from a clerical error: a mislabeled pretransfusion sample, a misidentified patient at the bedside, or the wrong unit issued to the wrong patient. Preformed recipient anti-A and/or anti-B bind antigen on transfused RBCs and fix complement through the classical pathway to completion (C5b-9, the membrane attack complex), producing rapid intravascular hemolysis.

Classic signs and symptoms include fever, chills, flank or back pain, hypotension, tachycardia, hemoglobinemia and hemoglobinuria (red or pink plasma/urine), and, in severe cases, disseminated intravascular coagulation (DIC) and acute renal failure from free hemoglobin precipitating in the renal tubules. Reported incidence is roughly 1 in 38,000 to 1 in 70,000 transfused units, and severity correlates with the volume of incompatible blood infused, so stopping the transfusion at the first sign of a reaction is critical.

Workup algorithm (in order):

1. Stop the transfusion immediately; keep the IV line open with normal saline.
2. Notify the patient's physician and the blood bank; return the unit, tubing, and attached bag to the blood bank.
3. Clerical check — recheck the patient identification on the wristband, requisition, and unit tag against the blood bank record. Because ABO-incompatible AHTR is overwhelmingly a clerical error, this step alone frequently identifies the cause (wrong patient sampled or wrong unit issued).
4. Visually compare a post-transfusion plasma sample to the pretransfusion sample for hemoglobinemia.
5. Repeat ABO/Rh typing on both the pretransfusion and post-transfusion samples and on the implicated unit.
6. Perform a direct antiglobulin test (DAT) on the post-transfusion sample; a positive DAT (often mixed-field, since only the transfused cells are coated) confirms in vivo antibody and/or complement coating of donor cells.
7. Repeat the antibody screen and crossmatch.
8. Gram stain and culture the residual unit to rule out bacterial contamination as a coexisting or alternative cause.
9. Obtain haptoglobin, LDH, indirect bilirubin, plasma/urine hemoglobin, and monitor renal function and coagulation studies.
10. Treat supportively: IV fluids to maintain renal perfusion, diuretics, vasopressors for hypotension, and management of DIC if present.

Febrile Nonhemolytic Transfusion Reactions (FNHTR)

FNHTR is defined as a temperature rise of 1°C or more associated with transfusion, with or without chills/rigors, and no other explanation. It is the most common reaction historically reported with platelet transfusion. Two mechanisms contribute: accumulation of pyrogenic cytokines (IL-1beta, IL-6, TNF-alpha) released by donor leukocytes during storage, and recipient antibodies directed against donor leukocyte HLA or granulocyte antigens. Universal prestorage leukoreduction has substantially reduced FNHTR rates by removing leukocytes before cytokines accumulate.

FNHTR is a diagnosis of exclusion — because fever can also signal AHTR or bacterial contamination, the same first steps apply: stop the transfusion, perform the clerical check, and rule out hemolysis (DAT, visual check, repeat typing) and sepsis (Gram stain/culture) before attributing fever to FNHTR alone. Treatment is antipyretics (acetaminophen is preferred; aspirin is avoided in thrombocytopenic patients). Patients with recurrent FNHTR may be premedicated or switched to leukoreduced components if not already receiving them.

Allergic and Anaphylactic Reactions

Allergic reactions present as urticaria, pruritus, and localized erythema, caused by recipient IgE reacting with soluble proteins in donor plasma. Mild, isolated urticaria without other systemic signs may be managed with antihistamines (diphenhydramine) and, per institutional policy, the transfusion may sometimes continue after symptoms resolve.

Anaphylactic reactions are severe and rapid — occurring within seconds to minutes — with hypotension, bronchospasm, laryngeal edema, and gastrointestinal symptoms, but typically without fever. The classic cause tested on SBB exams is a recipient with severe IgA deficiency who has formed anti-IgA antibodies from prior transfusion or pregnancy exposure; even trace IgA in donor plasma triggers reaction. IgA deficiency is present in roughly 1 in 700 to 1 in 1,200 individuals, though severe/complete deficiency with anti-IgA is far rarer. Workup includes a quantitative serum IgA level and testing for anti-IgA antibodies; management requires immediate cessation of transfusion, epinephrine, and, for future transfusions, IgA-deficient blood products or extensively washed cellular components to remove residual plasma.

Transfusion-Related Acute Lung Injury (TRALI)

TRALI is noncardiogenic pulmonary edema developing within 6 hours of transfusion, presenting with acute hypoxemia, bilateral pulmonary infiltrates on chest imaging, fever, and hypotension, without evidence of volume overload. The leading model is a two-hit hypothesis: the recipient's underlying illness primes neutrophils sequestered in the pulmonary microvasculature (hit one), and donor antibodies against recipient HLA class I/II or human neutrophil antigens (HNA), transfused in the plasma component, activate the primed neutrophils (hit two), triggering capillary leak. Donors implicated are disproportionately multiparous women, alloimmunized to HLA/HNA antigens through prior pregnancies, which led blood centers to adopt predominantly male donor or HLA-antibody-tested female donor plasma policies. TRALI has historically been a leading cause of transfusion-related fatality; management is supportive (oxygen, ventilatory support), and most cases resolve within 48 to 96 hours.

Delayed Serologic and Hemolytic Transfusion Reactions

A delayed serologic transfusion reaction (DSTR) is a positive antibody screen and/or DAT that develops days to weeks after transfusion without clinical evidence of hemolysis. A delayed hemolytic transfusion reaction (DHTR) adds clinical/laboratory hemolysis — falling hemoglobin, rising bilirubin and LDH, jaundice, and reticulocytosis — typically 3 to 14 days post-transfusion. Both result from an anamnestic (secondary) immune response: the recipient was previously sensitized to a non-ABO antigen (through prior transfusion or pregnancy) but the antibody had fallen below the detection threshold of routine pretransfusion testing. Re-exposure to the antigen triggers rapid antibody production; IgG-coated donor cells are then cleared extravascularly by splenic macrophages rather than by intravascular complement lysis. The Kidd system (Jka/Jkb) is the classic teaching example because Kidd antibodies are notoriously evanescent, but Rh, Duffy, and Kell antibodies also commonly cause DHTR.

Transfusion-Associated Graft-Versus-Host Disease (TA-GVHD)

TA-GVHD occurs when viable, immunocompetent donor lymphocytes in a transfused cellular component engraft and proliferate in a recipient who cannot reject them, then attack host tissue. This happens in severely immunocompromised recipients, or in immunocompetent recipients who share one HLA haplotype with the donor (as in directed donations from blood relatives or HLA-matched platelet donors) — the donor is homozygous for the shared haplotype, so the host's immune system does not recognize the donor cells as foreign, but the donor's lymphocytes recognize the recipient's other haplotype as foreign. Onset is 4 to 30 days after transfusion, with erythematous rash progressing to erythroderma, fever, watery/bloody diarrhea, liver dysfunction, and — the finding that distinguishes it from other forms of GVHD — bone marrow aplasia/pancytopenia. Mortality approaches 90 to 100 percent. Gamma or X-ray irradiation of cellular components (minimum 2,500 cGy) is the only reliable prevention; leukoreduction does not prevent TA-GVHD. At-risk groups requiring irradiated components include patients with congenital cellular immunodeficiency, hematopoietic progenitor cell transplant recipients, intrauterine and neonatal exchange transfusion recipients, recipients of HLA-matched or crossmatch-compatible platelets, and recipients of directed donations from blood relatives.

Posttransfusion Purpura (PTP)

PTP is a rare but severe thrombocytopenia occurring 5 to 12 days after transfusion, almost exclusively in multiparous women (or previously transfused patients) who are negative for the platelet-specific antigen HPA-1a and have been alloimmunized against it. Paradoxically, the resulting antibody destroys not only the transfused HPA-1a-positive platelets but also the patient's own HPA-1a-negative platelets, through mechanisms proposed to involve immune complex formation or transient acquisition of soluble HPA-1a antigen by autologous platelets. Platelet counts can fall to critically low levels with major bleeding risk. Platelet transfusion, even HPA-matched, is often ineffective because the destructive process affects autologous platelets too; IVIG is first-line treatment, with plasma exchange reserved for refractory cases.