What labs and management are recommended for suspected hemolysis (breakdown of red blood cells)?

Diagnostic Approach and Management of Hemolysis

For suspected hemolysis, a comprehensive laboratory workup should include complete blood count with indices, reticulocyte count, peripheral blood smear, LDH, haptoglobin, bilirubin levels, and direct antiglobulin test (DAT) to establish the diagnosis and determine the underlying cause. 1, 2

Initial Diagnostic Workup

• Confirm hemolysis with laboratory tests including complete blood count, reticulocyte count, peripheral blood smear, lactate dehydrogenase (LDH), haptoglobin, and bilirubin levels 2
• Assess for reticulocytosis, which indicates adequate bone marrow response to hemolysis; normal or low reticulocyte count with evidence of hemolysis suggests concurrent bone marrow suppression 2
• Examine peripheral blood smear for abnormal red cell morphology that may suggest specific causes of hemolysis (e.g., schistocytes in microangiopathic hemolytic anemia, spherocytes in hereditary spherocytosis) 1, 2
• Measure LDH (increased), unconjugated bilirubin (increased), and haptoglobin (decreased) to confirm hemolysis 1, 2
• Perform direct antiglobulin test (DAT) to differentiate immune from non-immune causes 1, 2

Additional Testing Based on Initial Results

If DAT is positive (immune-mediated hemolysis):

• Perform antibody identification, cold agglutinin testing, or drug-induced antibody testing 1, 2
• Evaluate autoimmune serology 1
• Consider paroxysmal nocturnal hemoglobinuria (PNH) screening 1
• Assess for malignancies, autoimmune disorders, or drug reactions 1

If DAT is negative (non-immune hemolysis):

• If schistocytes are present, evaluate for thrombotic microangiopathies with ADAMTS13 activity and inhibitor titer 1
• Check for glucose-6-phosphate dehydrogenase deficiency if oxidative stress is suspected 1
• Evaluate for common drug causes of hemolysis (ribavirin, rifampin, dapsone, interferon, cephalosporins, penicillins, NSAIDs, etc.) 1
• Consider hereditary causes such as membrane disorders or enzymopathies 1, 2

Additional specialized testing:

• Hemoglobin electrophoresis to rule out hemoglobinopathies 1
• Evaluation for infectious causes (viral/bacterial including mycoplasma) 1
• Protein electrophoresis and cryoglobulin analysis 1
• Assessment for methemoglobinemia if suspected 1

Management Based on Severity and Cause

Grade 1 Hemolysis (Hgb < LLN to 10.0 g/dL):

• Close clinical follow-up and laboratory evaluation 1
• Supportive care 1
• Folic acid supplementation (1 mg daily) 1

Grade 2 Hemolysis (Hgb < 10.0 to 8.0 g/dL):

• Consider prednisone 0.5-1 mg/kg/day if immune-mediated 1
• Identify and discontinue causative medications 1
• Supportive care with close clinical laboratory evaluations 1

Grade 3 Hemolysis (Hgb < 8.0 g/dL, transfusion indicated):

• Hematology consultation 1
• Prednisone 1-2 mg/kg/day (oral or IV depending on symptoms/speed of development) if immune-mediated 1
• Consider RBC transfusion per existing guidelines; transfuse minimum units necessary to relieve symptoms or return to safe Hgb range (7-8 g/dL in stable, non-cardiac patients) 1
• For thrombotic microangiopathies, consider eculizumab therapy (900 mg weekly for four doses, 1,200 mg week 5, then 1,200 mg every 2 weeks) 1

Grade 4 Hemolysis (Life-threatening consequences):

• Immediate hospital admission 1
• Urgent hematology consultation 1
• IV prednisone 1-2 mg/kg/day 1
• For severe immune-mediated hemolysis not responding to corticosteroids, consider rituximab, IVIG, cyclosporin A, or mycophenolate mofetil 1
• For thrombotic microangiopathies, initiate therapeutic plasma exchange according to existing guidelines 1
• RBC transfusion as needed (discuss with blood bank team prior to transfusion) 1

Special Considerations

• For hyperhemolysis in sickle cell disease, consider high-dose steroids and IVIG as first-line treatment, followed by eculizumab for patients who continue to deteriorate 1
• In patients with suspected pyruvate kinase deficiency, specific enzyme activity measurement and genetic testing should be performed 1
• For hemolysis related to immune checkpoint inhibitor therapy, management includes holding or permanently discontinuing the immunotherapy based on severity 1

Common Pitfalls to Avoid

• Failure to distinguish between intravascular and extravascular hemolysis, which have different etiologies and management approaches 2, 3
• Missing in vivo hemolysis by assuming all hemolyzed samples are due to collection errors 4
• Inadequate evaluation of drug-induced hemolysis, which can occur through multiple mechanisms 1
• Overlooking nutritional deficiencies (B12, folate, iron) that can complicate hemolytic anemia 1
• Delaying treatment of life-threatening hemolysis while awaiting complete diagnostic workup 1