What is the approach to managing a patient with hemolytic anemia?

Approach to Managing Hemolytic Anemia

Begin with laboratory confirmation of hemolysis through reticulocytosis, elevated LDH, elevated unconjugated bilirubin, decreased haptoglobin, and peripheral blood smear examination for schistocytes and red cell morphology abnormalities, followed by direct antiglobulin test (DAT) to differentiate immune from non-immune causes. 1, 2

Initial Diagnostic Workup

Confirm Hemolysis

• Complete blood count with reticulocyte count: Reticulocytosis confirms active hemolysis and adequate bone marrow compensation 1, 2
• Lactate dehydrogenase (LDH): Elevated levels indicate red cell destruction 3, 1
• Haptoglobin: Decreased or absent levels confirm intravascular hemolysis 3, 1
• Bilirubin: Elevated unconjugated (indirect) bilirubin reflects hemoglobin breakdown 3, 1
• Peripheral blood smear: Essential to identify schistocytes (microangiopathic hemolysis), spherocytes (hereditary spherocytosis or autoimmune), sickle cells, target cells, or other morphologic abnormalities 1, 2

Critical Branching Point: Direct Antiglobulin Test (DAT/Coombs)

• Perform DAT immediately to distinguish immune-mediated from non-immune hemolysis 1, 4
• Monospecific DAT is mandatory: Tests separately for IgG and C3d to classify warm vs. cold antibody-mediated disease 5

DAT-Positive (Immune-Mediated) Hemolytic Anemia

Warm Autoimmune Hemolytic Anemia (wAIHA)

• IgG-positive DAT indicates warm antibodies reacting at body temperature (60-70% of AIHA cases) 5, 6
• Identify secondary causes: Screen for lymphoproliferative disorders, systemic autoimmune diseases (SLE, rheumatoid arthritis), infections, drugs (immune checkpoint inhibitors, cephalosporins, penicillins, NSAIDs), and immunodeficiencies 3, 6

First-Line Treatment:

• Corticosteroids: Prednisone 1 mg/kg/day orally for moderate cases (Grade 2) 3, 6
• Severe cases (Grade 3-4): Methylprednisolone 1-2 mg/kg/day IV immediately 3, 7
• Add rituximab early in severe cases or if no prompt response to steroids within 1-2 weeks 5, 6
• Folic acid supplementation for all patients due to increased red cell turnover 7
• Prophylactic anticoagulation for severe hemolysis due to thrombotic risk 6
• Recombinant erythropoietin when reticulocytopenia or inadequate bone marrow compensation is present 6

Second-Line Treatment:

• Rituximab is now preferred over splenectomy for relapsed/refractory disease 5, 6
• Splenectomy reserved for later lines when rituximab fails 6

Cold Agglutinin Disease (CAD)

• C3d-positive DAT with IgM antibodies reacting at temperatures <20°C (20-25% of AIHA cases) 5, 6
• First-line treatment: Rituximab with or without bendamustine for patients requiring therapy 5
• Avoid cold exposure as clinical management strategy 5

Drug-Induced Hemolytic Anemia

• Discontinue offending medication immediately: Common culprits include immune checkpoint inhibitors, cephalosporins, penicillins, NSAIDs, quinine/quinidine, fludarabine, ribavirin, rifampin, dapsone 3
• Grade 2 (Hgb 8.0-10.0 g/dL): Hold immune checkpoint inhibitor and strongly consider permanent discontinuation; administer prednisone 0.5-1 mg/kg/day 3
• Grade 3 (Hgb <8.0 g/dL): Permanently discontinue immune checkpoint inhibitor; admit patient; hematology consultation; prednisone 1-2 mg/kg/day 3

DAT-Negative (Non-Immune) Hemolytic Anemia

Thrombotic Microangiopathy (TMA) Evaluation

This is a critical emergency requiring immediate differentiation:

• ADAMTS13 activity must be tested urgently when TMA is confirmed (anemia + thrombocytopenia + schistocytes) 3, 8
• ADAMTS13 <10% indicates thrombotic thrombocytopenic purpura (TTP) requiring immediate plasmapheresis 3, 8
• ADAMTS13 normal with renal involvement suggests hemolytic uremic syndrome (HUS) 3, 8

Atypical HUS (aHUS) Workup

• Diagnostic triad: Microangiopathic hemolytic anemia (negative Coombs, elevated LDH, reduced haptoglobin, schistocytes) + thrombocytopenia (<150,000/mm³ or 25% reduction) + acute renal injury (hematuria, proteinuria, elevated creatinine) 3, 8
• Note: Up to 50% of aHUS cases may not have all three signs clearly present at onset 3, 8

Immediate Testing:

• Complement levels: C3, C4, CH50 (classical pathway), AP50 (alternative pathway) 3, 8
• Stool culture and Shiga toxin testing to exclude STEC-HUS 8
• Genetic testing: Next-generation sequencing of complement genes (CFH, CFHR1-5, C3, CD46, CFI, THBD, DGKE, CFB) for all suspected aHUS cases 3, 8
• Important: 40-50% of aHUS patients have no identifiable mutation but can still be diagnosed based on clinical criteria 3, 8

Treatment:

• Eculizumab or ravulizumab (C5 inhibitors) are indicated for aHUS to inhibit complement-mediated thrombotic microangiopathy 9
• Meningococcal vaccination required at least 2 weeks before first dose, unless delay poses greater risk than infection; then give prophylactic antibiotics until 2 weeks post-vaccination 9
• Dosing for adults: Eculizumab 900 mg IV weekly x4 weeks, then 1200 mg at week 5, then 1200 mg every 2 weeks 9

Hereditary Hemolytic Anemias

When to suspect:

• Family history of anemia, splenectomy, or gallstones at young age 7, 2
• Chronic compensated hemolysis with reticulocytosis 7, 2
• Specific red cell morphology on smear 1, 2

Membranopathies:

• Hereditary spherocytosis: Spherocytes on smear, positive osmotic fragility test, family history 7
• Splenectomy for severe cases with transfusion dependence 7

Enzymopathies:

• Glucose-6-phosphate dehydrogenase (G6PD) deficiency: Screen with G6PD enzyme assay; avoid oxidant drugs (dapsone, primaquine, sulfonamides, nitrofurantoin); treat triggering infections 3, 7
• Pyruvate kinase (PK) deficiency: Most common glycolytic enzyme defect; measure PK enzymatic activity; monitor iron status; consider iron chelation with chronic transfusions 3, 7

Hemoglobinopathies:

• Exclude thalassemias and hemoglobinopathies with hemoglobin electrophoresis or HPLC 3
• Next-generation sequencing is gold standard for complex hereditary cases when conventional testing is non-diagnostic 7, 2

Paroxysmal Nocturnal Hemoglobinuria (PNH)

• Flow cytometry for CD55 and CD59 deficiency on red cells, granulocytes, and monocytes 9
• Eculizumab reduces hemolysis in PNH patients: 600 mg IV weekly x4 weeks, then 900 mg at week 5, then 900 mg every 2 weeks 9

Supportive Management Across All Types

Transfusion Strategy

• Transfuse for symptomatic anemia or hemoglobin <7-8 g/dL depending on clinical status and comorbidities 3, 7
• Avoid overtransfusion to prevent iron overload 7
• Warm blood products to 37°C in cold agglutinin disease 5

Iron Overload Monitoring

• Monitor ferritin and transferrin saturation in patients with chronic transfusion requirements 3, 7
• Initiate iron chelation therapy (deferoxamine or deferasirox) when systemic iron overload develops 3, 7

Additional Considerations

• Folic acid 1-5 mg daily for all patients with chronic hemolysis due to increased red cell turnover 7, 6
• Avoid splenectomy in children <5 years due to infection risk; if performed, ensure pneumococcal, meningococcal, and Haemophilus influenzae vaccinations 7
• Genetic counseling and family screening for hereditary forms 3, 7

Common Pitfalls to Avoid

• Do not rely on single CBC: Serial monitoring is essential as hemoglobin may appear near-normal due to dehydration 8
• Do not exclude hemolysis based on absent schistocytes: Sensitivity is low in early disease 8
• Do not delay ADAMTS13 testing: TTP requires immediate plasmapheresis, not steroids alone 3, 8
• Do not start eculizumab without meningococcal vaccination unless life-threatening emergency; then give prophylactic antibiotics 9
• Do not reduce ribavirin dose in hepatitis C treatment-related anemia without considering epoetin, as dose reduction does not compromise SVR in triple therapy 3