Distinguishing HUS from TTP: Diagnostic and Treatment Approach
When a patient presents with microangiopathic hemolytic anemia and thrombocytopenia, immediately order ADAMTS13 activity and stool testing for Shiga toxin-producing E. coli (STEC)—ADAMTS13 <10 IU/dL confirms TTP requiring urgent plasma exchange, while positive STEC with diarrhea 4-5 days before symptoms indicates typical HUS requiring supportive care only, but if diarrhea and symptoms appear simultaneously or STEC is negative, suspect atypical HUS requiring complement inhibitor therapy. 1, 2
Immediate Diagnostic Algorithm
Step 1: Confirm Thrombotic Microangiopathy (TMA)
When any patient presents with anemia plus thrombocytopenia in the emergency setting, immediately obtain: 1, 2
- Complete blood count with peripheral blood smear for schistocytes
- LDH, haptoglobin, indirect bilirubin (elevated LDH and reduced haptoglobin confirm hemolysis)
- Direct Coombs test (must be negative to confirm non-immune hemolysis)
- Creatinine and urinalysis for hematuria/proteinuria (confirms renal involvement)
- Platelet count <150,000/mm³ or 25% reduction from baseline 1, 2
Critical caveat: Schistocytes >1% favor TMA diagnosis, but their absence should NOT exclude early TMA diagnosis due to low test sensitivity—do not delay treatment while waiting for schistocytes. 2, 3
Step 2: Differentiate TTP from HUS Immediately
Order these tests urgently and simultaneously: 1, 2
ADAMTS13 activity (results needed within hours, not days):
- <10 IU/dL = TTP confirmed → Start plasma exchange immediately 1, 4
- ≥10 IU/dL = Proceed to HUS differentiation 1, 2
Stool testing for STEC/verocytotoxin-producing E. coli:
- Test for both STEC O157 culture AND Shiga toxin/genes 5, 3
- Consider distinguishing Shiga toxin 1 vs 2 (stx2 more potent, higher HUS risk) 5
Distinguishing Typical (STEC) HUS from Atypical HUS
Typical STEC-HUS Indicators:
- Diarrhea onset 4-5 days BEFORE HUS symptoms (this timing is pathognomonic) 1, 5
- Positive stool STEC testing 1, 2
- Bloody diarrhea in ~60% of cases 5
- Predominantly affects children <5 years 5, 3
Atypical HUS (aHUS) Indicators:
- Short diarrhea period OR simultaneous onset of diarrhea and HUS (not the typical 4-5 day gap) 1, 2
- Negative STEC testing 1, 2
- Can occur at any age 1
- May present without all three classic findings (up to 50% of cases lack one component at onset) 1, 3
Pediatric-specific consideration: In children <1 year old with aHUS, test for complement-unrelated genes (DGKE, WT1) and consider methylmalonic acidemia with homocystinuria (MMACHC) causing cobalamin deficiency. 1, 2, 5
Treatment Pathways Based on Diagnosis
For TTP (ADAMTS13 <10 IU/dL):
Start plasma exchange immediately—this is a medical emergency with high mortality without treatment. 4, 6
- Plasma exchange using fresh frozen plasma reduces failure of remission (RR 2.87) and mortality (RR 1.91) compared to plasma infusion alone 6
- Add caplacizumab 11 mg IV bolus at least 15 minutes before first plasma exchange, then 11 mg subcutaneous daily 4
- Continue immunosuppressive therapy 4
- Warning: Caplacizumab increases bleeding risk—withhold 7 days before elective procedures 4
For Typical STEC-HUS:
Supportive care ONLY—do NOT use plasma exchange, antibiotics, or antimotility agents. 5, 7, 6
- Administer IV fluids aggressively during diarrhea phase (reduces oligoanuric renal failure risk) 5
- Dehydration at admission increases dialysis need 5
- Antibiotics may worsen outcomes and increase HUS risk—avoid them 5
- Antimotility agents are contraindicated 7
- No specific therapies have proven effective in children with typical HUS 7, 6
- Monitor daily: hemoglobin, platelets, electrolytes, BUN, creatinine during days 1-14 3
- Typical HUS usually recovers spontaneously with good prognosis 7, 8
For Atypical HUS (aHUS):
Initiate complement inhibitor therapy (eculizumab or ravulizumab) immediately—delays increase morbidity and mortality. 1, 7
- aHUS has >50% progression to chronic renal dysfunction and 10% mortality without treatment 5, 9
- Plasma exchange may be used as bridge therapy while awaiting complement inhibitor 7, 9
- Mandatory meningococcal vaccination (quadrivalent A,C,W,Y conjugate + B vaccine) plus long-term penicillin prophylaxis due to complement inhibition 1
- Obtain genetic testing for complement pathway mutations (CFH, CFHR1-5, C3, CD46, CFI, THBD, DGKE, CFB) for prognosis 1, 3
- Gene variants found in 60% of aHUS cases; absence doesn't exclude diagnosis 1
Neurological Involvement Assessment
Neurological symptoms occur in 10-20% of aHUS patients and are the first cause of death—monitor closely. 1, 5
If neurological symptoms present (motor symptoms, weakness, vision changes, seizures, encephalopathy): 1, 2
- Obtain neurology consultation immediately
- Perform EEG and brain MRI with FLAIR and T2-weighted sequences
- Look for bilateral symmetric hyperintensities in basal ganglia (suggestive of TMA) 1, 2
Neurological involvement is MORE common in TTP than HUS—this clinical feature helps differentiate when laboratory results are pending. 9
Critical Pitfalls to Avoid
Do NOT wait for ADAMTS13 results to start plasma exchange if TTP is suspected—mortality is too high without immediate treatment 4, 9
Do NOT give antibiotics for suspected STEC infection—they may increase HUS risk and worsen outcomes 5, 7
Do NOT assume absence of all three classic findings excludes HUS—up to 50% of aHUS cases lack one component at onset, especially in newborns 1, 3
Do NOT use plasma exchange for typical STEC-HUS in children—no benefit shown and supportive care alone is appropriate 7, 6
Do NOT miss the 4-5 day diarrhea-to-HUS timing—this distinguishes typical from atypical HUS and completely changes management 1, 5
In post-transplant patients, do NOT exclude TMA based on normal platelets or hemoglobin—13% lack thrombocytopenia and 38% lack significant anemia/thrombocytopenia 1