What is the approach to a hemolysis (breakdown of red blood cells) workup and treatment?

Hemolysis Workup and Management

Initial Diagnostic Approach

Begin with a comprehensive laboratory panel including CBC with indices, reticulocyte count, peripheral blood smear, LDH, haptoglobin, direct and indirect bilirubin, and direct antiglobulin test (Coombs test) to confirm hemolysis and guide further evaluation. 1, 2

Essential Laboratory Tests

• CBC with indices to assess degree of anemia and red cell parameters 1, 2
• Peripheral blood smear is critical to identify schistocytes (suggesting microangiopathic hemolysis), spherocytes (suggesting hereditary spherocytosis or autoimmune hemolysis), or other abnormal morphologies 1, 3
• Reticulocyte count should be elevated in hemolysis, indicating adequate bone marrow response; a low reticulocyte count despite hemolysis suggests concurrent bone marrow suppression, nutritional deficiency, or autoimmune reaction against marrow precursors 1, 3, 4
• LDH is elevated in hemolysis, particularly intravascular hemolysis 1, 4
• Haptoglobin is decreased in hemolysis as it binds free hemoglobin 1, 4
• Direct and indirect bilirubin with indirect (unconjugated) bilirubin elevated in hemolysis 1
• Direct antiglobulin test (DAT/Coombs test) differentiates immune-mediated from non-immune causes 1, 3

Critical History and Physical Examination Elements

• Drug exposure history: specifically ask about ribavirin, rifampin, dapsone, interferon, cephalosporins, penicillins, NSAIDs, quinine/quinidine, fludarabine, ciprofloxacin, lorazepam, diclofenac, tacrolimus, cyclosporine, and sirolimus 1
• Recent insect, spider, or snake bites as potential triggers 1
• Symptoms: weakness, pallor, jaundice, dark-colored urine, fever, inability to perform physical activity 1
• New onset hypertension or cardiac symptoms if considering thrombotic microangiopathy 1

Algorithmic Approach Based on Initial Results

If DAT (Coombs Test) is Positive: Immune-Mediated Hemolysis

• Proceed with antibody identification and cold agglutinin testing 3
• Evaluate for autoimmune hemolytic anemia with autoimmune serology 1
• Screen for paroxysmal nocturnal hemoglobinuria (PNH) with flow cytometry for GPI-anchored proteins 1
• Consider drug-induced hemolytic anemia based on medication history 1

If DAT is Negative: Non-Immune Causes

• Evaluate for hereditary causes: G6PD deficiency, hereditary spherocytosis, other enzymopathies or membranopathies 1, 3
• Assess for mechanical hemolysis: prosthetic heart valves, microangiopathic processes 3
• Consider infectious causes: screen for EBV, CMV, HHV6, mycoplasma, shiga toxin, E. coli O157 1

If Schistocytes Present on Smear: Thrombotic Microangiopathy

• Immediately check ADAMTS13 activity to rule out thrombotic thrombocytopenic purpura (TTP) 1, 3
• Evaluate for hemolytic uremic syndrome (HUS): check serum creatinine, assess for bloody diarrhea, evaluate for shiga toxin 1
• Complement testing: C3, C4, CH50 for atypical HUS 1
• Homocysteine and methylmalonic acid levels 1

Additional Workup for Refractory or Unclear Cases

• Bone marrow biopsy and aspirate if no obvious cause or concern for myelodysplastic syndrome 1
• Protein electrophoresis and cryoglobulin analysis 1
• Nutritional assessments: B12, folate, iron, copper, ceruloplasmin, vitamin D 1
• Viral studies: parvovirus, which can cause pure red cell aplasia 1
• DIC panel including PT/INR if concerned for disseminated intravascular coagulation 1
• Free hemoglobin and hemosiderinuria for intravascular hemolysis 1
• Methemoglobinemia assessment if clinically indicated 1

Management Based on Severity Grading

Grade 1 (Hemoglobin <LLN to 10.0 g/dL)

• Continue close clinical monitoring with regular laboratory evaluation 1, 2
• Identify and address underlying cause 2
• Supportive care only 1

Grade 2 (Hemoglobin <10.0 to 8.0 g/dL)

• Consider hematology consultation 2
• Initiate prednisone 0.5-1 mg/kg/day if immune-mediated 1, 2
• Strongly consider permanent discontinuation of causative agent (if immune checkpoint inhibitor-related) 1

Grade 3 (Hemoglobin <8.0 g/dL, transfusion indicated)

• Hematology consultation is mandatory 1, 2
• Administer prednisone 1-2 mg/kg/day (oral or IV depending on symptoms/speed of development) 1, 2
• Permanently discontinue causative agent if drug-induced 1
• Consider RBC transfusion per existing guidelines: transfuse only the minimum number of units necessary to relieve symptoms or return patient to safe hemoglobin range (7-8 g/dL in stable, non-cardiac inpatients) 1
• Offer folic acid 1 mg once daily supplementation 1
• Use clinical judgment to consider hospital admission 1

Grade 4 (Life-threatening consequences, urgent intervention indicated)

• Immediate hospital admission required 1, 2
• Urgent hematology consultation 1, 2
• IV corticosteroids: methylprednisolone or prednisone 1-2 mg/kg/day 1, 2
• If no improvement or worsening on corticosteroids, initiate additional immunosuppressive therapy: rituximab, IVIG, cyclosporine A, or mycophenolate mofetil 1
• RBC transfusion per existing guidelines; discuss with blood bank team prior to transfusions 1

Special Management Considerations

For Thrombotic Microangiopathies (TTP/HUS)

Grade 3-4 disease requires immediate plasma exchange (PEX) in conjunction with hematology consultation 1, 2

• Administer methylprednisolone 1 g IV daily for 3 days, with first dose immediately after first PEX 1
• May offer rituximab for refractory cases 1
• For atypical HUS (Grade 3): begin eculizumab therapy 900 mg weekly for four doses, 1,200 mg week 5, then 1,200 mg every 2 weeks 1

For Immune-Mediated Hemolysis

• Corticosteroids are first-line therapy 2
• Consider rituximab or other immunosuppressants for refractory cases 1, 2
• Discuss with blood bank that patient may have antibodies complicating crossmatch 1

Common Pitfalls to Avoid

• Do not over-transfuse: transfuse only to relieve symptoms or achieve safe hemoglobin (7-8 g/dL), not to "normalize" hemoglobin, as this can suppress reticulocyte response 1
• Low reticulocyte count with hemolysis is a poor prognostic factor: suggests concurrent bone marrow involvement and requires more aggressive workup including bone marrow biopsy 3, 4
• Schistocytes on smear mandate urgent ADAMTS13 testing: delay in diagnosing TTP can be fatal, and plasma exchange should not be delayed while awaiting results 1, 3
• Always review medication list carefully: drug-induced hemolysis is common and reversible if identified early 1
• In immune checkpoint inhibitor-related hemolysis, permanent discontinuation is required for Grade 3-4 disease: do not attempt to rechallenge 1

Ongoing Monitoring

• Regular CBC, reticulocyte count, and hemolysis markers (LDH, haptoglobin, bilirubin) to assess response to treatment 2
• Adjust therapy based on clinical response and laboratory trends 2
• For patients on immunosuppression, monitor for infectious complications and consider antimicrobial prophylaxis 1