Initial Treatment Approach for Hemolytic Anemia
The initial treatment of hemolytic anemia depends critically on distinguishing immune from non-immune causes using the direct antiglobulin test (DAT), with corticosteroids (1 mg/kg prednisone or methylprednisolone daily) as first-line therapy for warm autoimmune hemolytic anemia, while cold agglutinin disease requires rituximab-based therapy, and non-immune causes demand etiology-specific interventions. 1, 2, 3
Immediate Diagnostic Workup Before Treatment
Before initiating any therapy, confirm hemolysis with laboratory markers including elevated reticulocyte count, elevated lactate dehydrogenase (LDH), decreased or absent haptoglobin, elevated indirect (unconjugated) bilirubin, and peripheral blood smear evaluation 1. Perform the direct antiglobulin test (DAT) before starting treatment to differentiate immune from non-immune hemolysis 1. The indirect antiglobulin test detects free autoantibodies in serum 1.
When anemia plus thrombocytopenia presents in the emergency setting, immediately measure haptoglobin, indirect bilirubin, and LDH levels 4. If the triad of non-immune hemolytic anemia, thrombocytopenia, and renal involvement is present, urgently determine ADAMTS13 activity (severely deficient at <10 IU/dL in TTP) and test for verocytotoxin-producing Escherichia coli (VTEC) in stool 4.
Treatment Algorithm Based on DAT Results
DAT-Positive (Immune-Mediated) Hemolytic Anemia
For warm antibody autoimmune hemolytic anemia, initiate corticosteroids at 1-1.5 mg/kg/day prednisone orally as first-line therapy 2, 3, 5. Alternatively, use 1-2 mg/kg/day intravenous methylprednisolone for severe cases 6. This remains the standard initial approach despite the lack of licensed treatments for AIHA 3.
Add rituximab early in severe cases or if no prompt response to steroids is achieved within the first weeks 3. The First International Consensus Group recommends considering rituximab addition early rather than waiting for steroid failure in severe presentations 3.
For cold agglutinin disease, use rituximab with or without bendamustine as first-line therapy, as this condition is resistant to steroids and splenectomy 3, 5. All patients with cold agglutinin syndrome should avoid cold exposure 2.
Evaluate for secondary causes including lymphoproliferative disorders, autoimmune diseases, infections, and drug-induced hemolysis through careful history, physical examination, autoantibody screening, immunoglobulin levels, and imaging/bone marrow evaluation in selected cases 1, 7. Secondary AIHA may be treated similarly to primary AIHA, with additional therapy directed at the underlying disorder 2.
DAT-Negative (Non-Immune) Hemolytic Anemia
When DAT is negative, consider hereditary causes systematically 1:
Membranopathies (hereditary spherocytosis, hereditary elliptocytosis): Diagnose using osmotic fragility testing or eosin-5-maleimide (EMA) binding test 1
Enzymopathies: Measure pyruvate kinase (PK) activity by spectrophotometry and G6PD enzyme activity 1. Critical caveat: falsely normal PK levels occur with markedly elevated reticulocyte count, recent blood transfusions, incomplete platelet/leukocyte removal, or kinetically abnormal mutant enzymes 1. Confirm PK deficiency with PKLR gene sequencing when enzyme assays are equivocal 1.
Paroxysmal nocturnal hemoglobinuria (PNH): Perform flow cytometry screening with 90% sensitivity and 95% specificity 1. For confirmed PNH, complement inhibitors (eculizumab, ravulizumab) are the recommended treatment 1, 8.
Thrombotic microangiopathy: If microangiopathic hemolytic anemia with schistocytes, thrombocytopenia, and renal involvement is present, urgent plasma exchange is recommended for TTP 1. For atypical hemolytic uremic syndrome (aHUS), eculizumab is indicated to inhibit complement-mediated thrombotic microangiopathy 8.
Next-generation sequencing (NGS) gene panel analyzing 68+ hemolytic anemia-related genes is the gold standard for hereditary hemolytic anemias when initial testing is inconclusive 1.
Etiology-Specific Treatment Considerations
For drug-induced hemolysis, discontinue the offending agent immediately 1.
For hemolysis in Waldenström macroglobulinemia unresponsive to corticosteroids, use standard doses of rituximab alone without maintenance therapy 4. If hyperviscosity symptoms are present, perform plasmapheresis first (a 3-4 liter plasma exchange lowers plasma IgM by 60-75%) 4.
For cancer-related hemolysis from autoimmune processes (chronic lymphocytic leukemia) or erythrophagocytosis in histiocytic tumors, address the underlying malignancy while managing hemolysis 4.
Supportive Care and Monitoring
Administer RBC transfusions to maintain hemoglobin at safe levels while avoiding overtransfusion 6. Discuss with the blood bank before transfusions as cross-matching may be difficult in immune-mediated cases 6.
Monitor iron status regularly, especially with repeated transfusions, and consider iron chelation therapy according to guidelines for chronic transfusions 1, 6.
Exclude nutritional deficiencies (folate, vitamin B12, iron) in the initial workup, though folate deficiency is rare (<1%) in the general population due to food fortification 4. Reserve testing for high clinical suspicion cases with macrocytosis or neurological symptoms 4.
Critical Pitfalls to Avoid
Do not dismiss thrombotic microangiopathy due to absence of schistocytes, as this test has low sensitivity 4, 1. The absence of schistocytes should not exclude an earlier diagnosis of TMA 4.
Do not interpret PK activity without considering confounders: reticulocytosis, recent transfusions, or leukocyte contamination can falsely normalize results 1.
For DAT-negative AIHA, diagnose after excluding other causes of hemolysis and support with response to steroids 7. These cases are often severe and may require multiple treatments 7.
In pregnancy-associated AIHA, steroids and intravenous immunoglobulin are usually effective, though refractory cases occur 7.