What is the diagnosis for a patient with elevated serum lactate dehydrogenase (LDH), positive direct antiglobulin test (DAT), hyperbilirubinemia, and anemia following blood transfusion?

Delayed Hemolytic Transfusion Reaction (DHTR)

The clinical presentation of elevated LDH, positive direct antiglobulin test (DAT), hyperbilirubinemia, and anemia following blood transfusion is diagnostic of a delayed hemolytic transfusion reaction (DHTR). This represents antibody-mediated destruction of transfused red blood cells, typically occurring 3-21 days post-transfusion 1, 2.

Diagnostic Criteria

A DHTR is defined by a significant hemoglobin drop within 21 days post-transfusion associated with one or more of the following findings 1:

• New red cell alloantibody detection (though antibody may not be immediately identifiable) 1
• Positive direct antiglobulin test indicating antibody coating of red cells 1, 2
• Elevated lactate dehydrogenase from red cell lysis 3, 2, 4
• Elevated indirect (unconjugated) bilirubin from increased heme catabolism 3, 4, 5
• Decreased or undetectable haptoglobin as it binds free hemoglobin 3, 2
• Accelerated HbS% increase with concomitant fall in HbA post-transfusion (in sickle cell patients) 1
• Reticulocytopenia or reticulocytosis from baseline 1
• Hemoglobinuria in severe cases 6

Laboratory Workup

Immediately obtain the following tests to confirm DHTR and exclude alternative diagnoses 7, 3:

• Complete blood count with differential and reticulocyte count 3
• Peripheral blood smear to assess for schistocytes (if present, consider thrombotic microangiopathy) 7
• Repeat antibody screen and direct antiglobulin test 1, 2
• LDH, haptoglobin, total and indirect bilirubin 3, 4, 5
• Urinalysis for hemoglobinuria 3, 6
• ADAMTS13 activity if thrombocytopenia or schistocytes present (to exclude TTP) 7, 3

Serial antibody screening within 3 months of the DHTR is recommended, as antibody specificity may become apparent weeks to months after the event 1.

Common Antibody Specificities

While any alloantibody can cause DHTR, the following have been documented in case reports:

• Anti-Fya (Duffy system) 2
• Anti-Jk3 (Kidd system null phenotype) 6
• Anti-At(a) 4
• Anti-Yta 5
• Anti-Tc(a) (Cromer system) 8

Management Algorithm

Immediate Actions

Stop all further transfusions immediately unless life-threatening anemia with ongoing hemolysis is present 1. Additional transfusions may worsen hemolysis and potentially induce multiorgan failure and death 1.

Supportive Care (All Patients)

Initiate supportive measures including 1:

• Erythropoietin with or without IV iron 1
• Serial monitoring of hemoglobin, hematocrit, HbA/HbS fractions (if applicable), reticulocyte count, bilirubin, LDH, and urinalysis 1
• Adequate hydration to prevent acute kidney injury from hemoglobinuria 6

Immunosuppressive Therapy for Hyperhemolysis

If hyperhemolysis is present (hemoglobin drops below pretransfusion level with rapid decline of posttransfusion HbA), initiate immunosuppressive therapy promptly 1:

First-line agents 1:

• IVIg: 0.4-1 g/kg/day for 3-5 days (up to total dose of 2 g/kg) 1
• High-dose corticosteroids: Methylprednisolone or prednisone 1-4 mg/kg/day 1

Second-line agent 1:

• Eculizumab: For patients with clinical deterioration despite first-line agents 1
  • Adult dosing (>40 kg): 900-1200 mg weekly 1
  • Requires meningococcal vaccination and ciprofloxacin prophylaxis 1

Rituximab 1:

• Primarily indicated for prevention of additional alloantibody formation in patients requiring future transfusion 1
• Dosing: 375 mg/m² repeated after 2 weeks 1

Transfusion in Life-Threatening Anemia

If transfusion is absolutely necessary for life-threatening anemia 1:

• Use extended antigen-matched red cells (C/c, E/e, K, Jka/Jkb, Fya/Fyb, S/s) 1
• Transfuse only to relieve symptoms or achieve hemoglobin 7-8 g/dL 7
• Do not transfuse more than the minimum necessary 7

Critical Pitfalls to Avoid

Do not assume autoimmune hemolytic anemia based solely on positive DAT 4. The temporal relationship to transfusion and presence of alloantibodies distinguish DHTR from autoimmune processes 2, 4.

Do not continue transfusing incompatible blood in the setting of ongoing hemolysis, as this can precipitate hyperhemolysis syndrome with multiorgan failure 1.

Do not delay immunosuppression in patients with hyperhemolysis (hemoglobin below pretransfusion baseline), as mortality risk increases with delayed treatment 1.

Recognize that hyperhemolysis can occur with negative DAT and no identifiable antibody, particularly in sickle cell disease patients 1. Clinical recognition based on laboratory markers and temporal relationship to transfusion is critical 1.

Special Considerations for Sickle Cell Disease

In patients with sickle cell disease, DHTRs carry particular risk for hyperhemolysis syndrome 1. The American Society of Hematology guidelines specifically address this population, recommending aggressive immunosuppression and avoidance of further transfusion unless absolutely necessary 1.