What is the diagnosis and treatment for a patient with elevated Lactate Dehydrogenase (LDH), hyperbilirubinemia (specifically high indirect bilirubin), and hypohemoglobinemia (low hemoglobin)?

Hemolytic Anemia: Diagnosis and Management

Primary Diagnosis

The triad of elevated LDH, elevated indirect bilirubin, and low hemoglobin indicates hemolysis until proven otherwise, requiring immediate confirmation with reticulocyte count, haptoglobin, peripheral blood smear, and direct Coombs test. 1, 2

Immediate Diagnostic Workup

Essential Laboratory Tests

• Reticulocyte count (should be elevated in hemolysis) 3, 1
• Haptoglobin (decreased in hemolysis; the combination of elevated LDH and decreased haptoglobin is specific for hemolysis) 1, 2
• Direct Coombs test (Direct Antiglobulin Test) to differentiate immune from non-immune causes 3, 1, 2
• Peripheral blood smear to identify schistocytes (suggesting thrombotic microangiopathy), spherocytes (hereditary spherocytosis or autoimmune hemolytic anemia), or other abnormal morphologies 3, 1, 2
• Complete blood count with differential to assess for thrombocytopenia (which would suggest TMA) 4, 5

Critical Caveat

Note that 25% of autoimmune hemolytic anemia cases may present with normal LDH levels, so do not exclude hemolysis based solely on LDH 6. The combination of low hemoglobin, low haptoglobin, elevated indirect bilirubin, and positive direct Coombs test establishes the diagnosis even with normal LDH 6.

Differential Diagnosis Algorithm

If Thrombocytopenia is Present (Platelet Count Low)

This combination demands urgent evaluation for thrombotic microangiopathy (TMA), which includes life-threatening conditions like TTP and aHUS. 4, 5

• Immediately order ADAMTS13 activity level and inhibitor titer (do not wait for results to initiate treatment if clinical suspicion is high) 4
• Check creatinine and urinalysis for renal involvement 4
• Obtain PT, aPTT, fibrinogen to exclude DIC 4
• If ADAMTS13 <10%: Diagnosis is TTP—immediately initiate therapeutic plasma exchange and methylprednisolone 1g IV daily for 3 days 4
• Do NOT transfuse platelets unless life-threatening bleeding (platelet transfusion may worsen thrombosis in TTP) 4
• If ADAMTS13 >10% with TMA triad: Consider aHUS and begin eculizumab therapy (900 mg weekly × 4 doses) with meningococcal vaccination and penicillin prophylaxis 4

If Thrombocytopenia is Absent (Platelet Count Normal)

Positive Direct Coombs Test = Autoimmune Hemolytic Anemia (AIHA)

Initiate corticosteroids immediately as first-line therapy. 3, 1, 4

• Prednisone 1-2 mg/kg/day orally (or IV if unable to take oral medications) 3, 1
• Grade severity by hemoglobin level: 3
  • Grade 1 (Hgb <LLN to 10.0 g/dL): Continue monitoring with close follow-up
  • Grade 2 (Hgb <10.0 to 8.0 g/dL): Administer prednisone 0.5-1 mg/kg/day
  • Grade 3 (Hgb <8.0 g/dL): Prednisone 1-2 mg/kg/day, consider hematology consultation and hospital admission
  • Grade 4 (Life-threatening): Admit patient, IV corticosteroids 1-2 mg/kg/day, consider IVIG, rituximab, cyclosporin A, or mycophenolate mofetil if no improvement
• Transfuse RBCs only if symptomatic or Hgb <7-8 g/dL in stable patients; transfuse minimum units necessary 3
• Provide folic acid 1 mg daily supplementation 3

Negative Direct Coombs Test = Non-Immune Hemolysis

Evaluate for hereditary causes, drug-induced hemolysis, infections, and mechanical causes. 3, 1, 2

• Review medication history for drugs causing hemolysis (ribavirin, rifampin, dapsone, interferon, cephalosporins, penicillins, NSAIDs, quinine/quinidine, fludarabine, ciprofloxacin) 3
• Check glucose-6-phosphate dehydrogenase (G6PD) levels for enzymopathy 3
• Evaluate for hereditary spherocytosis if spherocytes on smear with family history 2, 7
• Consider pyruvate kinase deficiency if chronic hemolysis with normal RBC morphology; confirm with PK enzyme activity assay and PKLR gene sequencing 3
• Assess for paroxysmal nocturnal hemoglobinuria (PNH) with flow cytometry screening 3
• Evaluate for infectious causes: malaria, babesiosis (especially if fever, thrombocytopenia, and endemic area exposure), mycoplasma 3
• Check for mechanical hemolysis: history of mechanical heart valves, march hemoglobinuria 1

Special Considerations

Wilson Disease

If patient is young (<40 years) with hemolysis and very high bilirubin (>20 mg/dL), calculate alkaline phosphatase to bilirubin ratio. 3

• Ratio ≥2.0 suggests Wilson disease 3
• Check serum ceruloplasmin (typically low but may be normal in 15% of cases), serum and urinary copper levels 3
• Examine for Kayser-Fleischer rings (present in ~50% of acute presentations) 3
• Wilson disease with acute liver failure requires immediate liver transplant evaluation as recovery without transplantation is rare 3
• Do NOT initiate penicillamine in acute presentation; use albumin dialysis, continuous hemofiltration, or plasmapheresis for acute copper lowering 3

Babesiosis in Endemic Areas

Evidence of hemolysis with elevated indirect bilirubin, anemia, and elevated LDH is particularly suggestive of babesiosis in patients from endemic regions. 3

• Evaluate for coinfection with Lyme disease if tick exposure history 3
• Check for thrombocytopenia, leukopenia, neutropenia which are characteristic 3

Hepatitis-Associated Hemolysis

Acute hepatitis A (and other viral hepatitides) can cause acute hemolysis with marked indirect hyperbilirubinemia. 8

• Consider viral hepatitis serology if elevated transaminases present 8
• Hemolysis may occur even with negative Coombs test 8

Monitoring During Treatment

• Daily CBC with differential, LDH, haptoglobin, indirect bilirubin, and reticulocyte count during acute phase 4
• Weekly hemoglobin monitoring during corticosteroid tapering if AIHA 4
• Assess for iron overload with ferritin in chronic hemolysis cases 3, 1

Common Pitfalls to Avoid

• Do not exclude hemolysis based on normal LDH alone—25% of AIHA cases have normal LDH 6
• Do not delay plasma exchange in suspected TTP while waiting for ADAMTS13 results—mortality is high without immediate treatment 4
• Do not transfuse platelets in TTP unless life-threatening bleeding 4
• Do not perform PK enzyme assay within 50 days of transfusion due to donor RBC contamination 3
• Haptoglobin can be decreased in mechanical heart valves without clinically significant hemolysis 1
• Schistocytes may be absent in early TMA 1