What is the most likely diagnosis for a patient with severe anemia, elevated leukocyte count, and a positive direct antiglobulin test after a recent blood transfusion?

Delayed Hemolytic Transfusion Reaction (DHTR)

The most likely diagnosis is a delayed hemolytic transfusion reaction (DHTR), characterized by hemolysis occurring 2-10 days after transfusion with a positive direct antiglobulin test, hemoglobinuria (dark urine), fever, and a drop in hemoglobin below pre-transfusion levels despite recent transfusion. 1, 2, 3

Clinical Presentation Supporting DHTR

The patient's presentation 10 days post-transfusion with the following features is classic for DHTR:

• Hemoglobin dropped from 7.8 g/dL to 5.8 g/dL despite receiving 2 units of packed RBCs 10 days prior, indicating destruction of both transfused and native red cells 2, 4
• Dark urine representing hemoglobinuria from intravascular hemolysis 1, 3
• Positive direct antiglobulin test (DAT) confirming antibody-coated red blood cells 1, 2, 3
• Elevated indirect bilirubin (3.6 mg/dL of the 4.0 total) indicating hemolysis 3
• Markedly elevated LDH (720) consistent with red cell destruction 3
• Low-grade fever (100.4°F) typical of transfusion reactions 1
• Scleral icterus from hyperbilirubinemia 3

Mechanism and Pathophysiology

DHTR occurs when a patient develops or has an anamnestic response to red cell alloantibodies following transfusion. 1, 2 The patient's history of two pregnancies places her at risk for alloimmunization to red cell antigens (Rh, Kell, Kidd, Duffy systems). 1, 5 The antibody was likely undetectable at the time of transfusion 10 days ago but rapidly increased after re-exposure to the antigen, causing destruction of transfused cells and potentially her own cells through bystander hemolysis. 2, 5

Key Distinguishing Features from Other Diagnoses

This is not simply worsening iron deficiency anemia because:

• Iron deficiency does not cause hemoglobinuria, positive DAT, or elevated indirect bilirubin 3
• The hemoglobin decreased despite recent transfusion 4
• Fever and elevated LDH point to active hemolysis 3

This is not autoimmune hemolytic anemia (AIHA) because:

• AIHA typically presents with gradual onset, not acute deterioration 10 days post-transfusion 3
• The temporal relationship to transfusion is pathognomonic for DHTR 1, 2
• While both have positive DAT, the clinical context differs significantly 3, 5

Immediate Management Priorities

Transfusion Considerations

If transfusion is absolutely necessary for life-threatening anemia, proceed with extreme caution using phenotypically matched blood after extensive compatibility testing. 6, 1

• Avoid transfusion if clinically possible as additional transfusions may worsen hemolysis 6, 2, 4
• If hemoglobin remains >5.5-6.0 g/dL and patient is hemodynamically stable, supportive care alone may be preferable 7, 8, 4
• Communicate immediately with blood bank to perform adsorption studies to detect underlying alloantibodies 1, 5
• Request extended phenotype matching (C/c, E/e, K, Jka/Jkb, Fya/Fyb, S/s) if transfusion is unavoidable 6, 1
• Transfuse slowly and in small volumes (single units with reassessment) to monitor for worsening hemolysis 1, 2

Immunosuppressive Therapy

Consider immunosuppressive therapy with IVIg, high-dose corticosteroids, or rituximab if hemolysis is severe or progressive. 6

• IVIg 0.4-1 g/kg/day for 3-5 days (up to total 2 g/kg) 6
• Methylprednisolone 1-2 mg/kg/day IV or oral equivalent 6
• Rituximab 375 mg/m² repeated after 2 weeks primarily to prevent additional alloantibody formation 6
• These interventions have very low certainty evidence but are reasonable in life-threatening situations 6

Supportive Care

• Maintain adequate hydration to prevent acute tubular necrosis from hemoglobinuria 3
• Folic acid 1 mg daily supplementation 6
• Erythropoietin with or without IV iron to stimulate endogenous red cell production 6
• Monitor hemoglobin, bilirubin, LDH, and haptoglobin closely 3

Critical Pitfalls to Avoid

• Do not transfuse routinely without blood bank consultation - this may precipitate catastrophic hemolysis 6, 2, 5
• Do not assume all blood is incompatible - proper adsorption studies can identify safe units 1, 5
• Do not delay immunosuppression if hemolysis is progressive and hemoglobin continues to fall 6
• Do not use liberal transfusion triggers - restrictive strategies (Hb 7-8 g/dL) are safer in hemolytic conditions 6, 4

Long-term Management

• Complete alloantibody identification through adsorption studies before any future transfusions 1, 5
• Maintain extended phenotype records for this patient permanently 6
• Counsel regarding future transfusion risks and pregnancy implications 1
• Address underlying iron deficiency with IV iron once acute hemolysis resolves 7