Workup for Microangiopathic Hemolysis
When you suspect microangiopathic hemolysis, immediately obtain: CBC with peripheral smear, LDH, haptoglobin, indirect bilirubin, direct Coombs test, and ADAMTS13 activity level—this core panel must be drawn before any treatment is initiated 1.
Initial Laboratory Confirmation
The syndromic diagnosis of microangiopathic hemolytic anemia (MAHA) requires:
- Hemolysis markers: Elevated LDH, reduced/absent haptoglobin, elevated indirect bilirubin, elevated reticulocyte count
- Negative direct Coombs test (confirms non-immune hemolysis)
- Schistocytes on peripheral smear (>1% supports TMA, but absence does not exclude it due to low sensitivity) 1
- Thrombocytopenia (<150,000/mm³ or 25% reduction from baseline)
Critical pitfall: Do not wait for schistocytes to be present—their absence should not delay diagnosis or treatment, as the test has poor sensitivity 1.
Urgent Differential Diagnosis Testing
Once MAHA is confirmed, the following tests are compulsory to distinguish between life-threatening causes 1:
First-Level (Urgent) Tests:
- ADAMTS13 activity (must be available within hours as urgent test) 1
- <10 IU/dL = TTP (requires immediate plasma exchange)
10 IU/dL = other TMA (aHUS, secondary causes)
- Stool culture for Shiga toxin-producing E. coli (STEC) or verocytotoxin-producing E. coli (VTEC) 1
- Creatinine, urinalysis (hematuria/proteinuria indicates renal involvement)
- Coagulation studies (PT/PTT/fibrinogen to exclude DIC)
Second-Level Tests (for aHUS/complement-mediated TMA):
- Complement levels (C3, C4, CH50, AP50)
- Anti-complement factor H antibodies
- Genetic testing for complement pathway mutations (CFH, CFI, MCP, etc.)
- Consider functional complement assays if available 2
Additional Workup Based on Clinical Context
If neurological symptoms present (10-20% of aHUS cases): Obtain brain MRI with FLAIR sequences looking for bilateral basal ganglia hyperintensities, and EEG 1.
If diarrhea present in children: Timing matters—STEC-HUS typically appears 4-5 days after diarrhea onset. Concurrent diarrhea and HUS or very short prodrome suggests aHUS instead 1.
If age <1 year: Consider non-complement genes (DGKE, WT1 mutations) and metabolic causes (MMACHC/cobalamin deficiency) 1.
If post-renal transplant: Absence of marked thrombocytopenia or significant anemia should not exclude TMA diagnosis 1.
Treatment Decision Algorithm
Before ADAMTS13 results return: If you have confirmed MAHA + thrombocytopenia, initiate plasma exchange within 4-8 hours while awaiting results 3, 4. Delaying treatment for confirmatory testing increases mortality.
After ADAMTS13 results:
- ADAMTS13 <10 IU/dL → Continue plasma exchange + corticosteroids + rituximab for TTP 5
- ADAMTS13 >10 IU/dL + renal involvement + negative STEC → Consider complement inhibition (eculizumab/ravulizumab) for aHUS 6
- Positive STEC → Supportive care (plasma exchange generally not indicated)
Key principle: ADAMTS13 testing is the single most important specific test to classify TMA and guide therapy 6, 7. All other testing helps differentiate non-TTP causes once TTP is excluded.