Delayed Hemolytic Transfusion Reaction

Delayed hemolytic transfusion reaction is red cell destruction occurring 3 to 14 days (up to 28 days) after a transfusion, from an anamnestic antibody response. Incidence is about 1 in 4000 to 11,000 transfused patients and is higher with repeated transfusion.

A patient immunized by an earlier transfusion or pregnancy has an antibody that has fallen below detectable level, so compatible-appearing blood is given. Re-exposure to the antigen provokes a rapid rise in antibody, which coats transfused cells and removes them.

Antibodies against Kidd (Jk), Rh (E, c), Kell (K) and Duffy (Fy) antigens are the commonest causes. Hemolysis is mostly extravascular (in the spleen and liver), but Kidd antibodies activate complement and can cause intravascular hemolysis.

Patients with sickle cell disease have alloimmunization in 20 to 40% of cases, and delayed reactions occur in 4 to 11% of those chronically transfused.

Hyperhemolysis syndrome is a severe variant, mainly in sickle cell disease and thalassemia. Both donor and the patient's own red cells are destroyed, so hemoglobin falls below the pre-transfusion level, reticulocytes are low and the direct antiglobulin test is often negative. Further transfusion worsens hemolysis.

Complications: severe anemia, acute kidney injury, vaso-occlusive crisis and acute chest syndrome in sickle cell disease, and death in hyperhemolysis.

• Falling hemoglobin or failure of hemoglobin to rise as expected, with mild fever, malaise and jaundice
• Dark urine and pallor
• Usually mild and sometimes discovered only on laboratory review
• Sickle cell disease: severe bone pain, fatigue, dyspnea, dark urine and a pain crisis starting a few days after transfusion
• Red flags: hemoglobin below pre-transfusion level, severe pain, hemoglobinuria, oliguria and chest symptoms

1. Timing and history: a transfusion within the last 3 to 28 days, with previous transfusion or pregnancy.
2. Full blood count with film: falling hemoglobin, spherocytes, polychromasia, reticulocyte count (raised in typical reactions, low in hyperhemolysis).
3. Hemolysis markers: raised LDH and indirect bilirubin, low haptoglobin, urinalysis for hemoglobinuria.
4. Direct antiglobulin test (often positive, with a mixed-field pattern), antibody screen and identification, and an eluate from the red cells.
5. Blood group phenotype of the patient and a comparison of the pre- and post-transfusion samples.
6. Sickle cell disease: hemoglobin S percentage (a fall below the post-transfusion value suggests destruction of the patient's own cells), ferritin (very high in hyperhemolysis) and creatinine.

Differentials: acute hemolytic reaction, autoimmune hemolytic anemia, sickle crisis without hemolysis, hemorrhage, infection with hemolysis, and drug-induced hemolysis.

1. Mild cases: no specific treatment, with folic acid 5 mg orally once daily for 4 weeks and monitoring of hemoglobin every 2 to 3 days.
2. Transfusion only if symptomatic or hemoglobin is critically low: use red cells negative for the identified antigen and crossmatch-compatible by antiglobulin technique.
3. Hydration and renal protection: oral or IV 0.9% saline to maintain urine output above 1 mL/kg/h.
4. Hyperhemolysis in sickle cell disease: avoid further transfusion unless life-threatening (hemoglobin below 40 g/L or hemodynamic compromise). Treat with:
   • Intravenous immunoglobulin 1 g/kg IV daily for 2 days, with methylprednisolone 250 to 500 mg IV daily for 2 days (or prednisolone 1 mg/kg orally daily).
   • Epoetin alfa 150 units/kg SC three times a week or daily by response, with IV iron when ferritin permits, to support erythropoiesis.
   • Rituximab 375 mg/m2 IV weekly for 4 doses to suppress further antibody production in repeated episodes.
   • Eculizumab 900 mg IV weekly for 4 weeks then 1200 mg every 2 weeks in refractory cases, after meningococcal vaccination and with antibiotic prophylaxis (phenoxymethylpenicillin 500 mg orally twice daily).
5. Pain: morphine 0.1 mg/kg IV every 4 hours as needed, with paracetamol 1 g orally every 6 hours.
6. Prevention of recurrence: record the antibody in the patient's permanent blood bank file with a transfusion alert card, and always supply antigen-negative units. In sickle cell disease give red cells matched for Rh (C, E, c, e) and Kell antigens as standard.
7. Reporting to the transfusion laboratory and hemovigilance system.

Follow-up: hemoglobin, reticulocytes and hemolysis markers every 2 to 3 days until stable, then at 4 weeks. Counsel the patient to carry the antibody card and tell every treating team.