How do you distinguish Thrombotic Thrombocytopenic Purpura (TTP) from Hemolytic Uremic Syndrome (HUS)?

Distinguishing TTP from HUS

Immediately measure ADAMTS13 activity when thrombotic microangiopathy (TMA) is suspected—ADAMTS13 activity <10 IU/dL confirms TTP, while normal or mildly reduced levels (with negative stool testing for Shiga toxin-producing E. coli) indicate atypical HUS. 1, 2

Initial Emergency Workup

When any patient presents with anemia plus thrombocytopenia, immediately order the following tests to distinguish between TTP and HUS 1, 2:

• Complete blood count with peripheral blood smear (looking for schistocytes, though >1% favors TMA, their absence does NOT exclude diagnosis due to low sensitivity) 1, 2
• Haptoglobin (reduced in both conditions) 1
• LDH and indirect bilirubin (elevated in both) 1, 2
• Direct Coombs test (negative in both, confirming non-immune hemolysis) 1, 2
• ADAMTS13 activity (urgent—this is the key discriminator) 1, 2
• Stool testing for verocytotoxin-producing E. coli (VTEC/STEC) 1, 2
• Creatinine and urinalysis (for hematuria/proteinuria) 2

The Critical Discriminator: ADAMTS13 Activity

ADAMTS13 activity <10 IU/dL = TTP 1, 2

ADAMTS13 activity normal or mildly reduced = HUS (if STEC negative) or other TMA 1

This single test is the most reliable way to distinguish TTP from HUS, as TTP results from severe ADAMTS13 deficiency while HUS does not 1, 3.

Clinical Features That Help Distinguish

Favoring TTP over HUS:

• More prominent neurological involvement (confusion, seizures, focal deficits) 1
• Fever 1
• More gradual onset 1
• Less severe renal involvement (though can occur) 1
• More severe thrombocytopenia and more abundant schistocytes 1

Favoring HUS over TTP:

• Prominent acute renal injury (hematuria, proteinuria, elevated creatinine) 1, 2
• Preceding diarrheal illness (especially bloody diarrhea 4-5 days before HUS symptoms suggests STEC-HUS) 1, 4, 2
• Less severe thrombocytopenia (moderate) and fewer schistocytes 1
• Neurological involvement less common (only 10-20% of atypical HUS cases) 1, 2

Timing Considerations for Diarrheal History

STEC-HUS: Diarrhea onset typically 4-5 days BEFORE HUS symptoms develop 2

Atypical HUS: Short diarrhea period OR simultaneous onset of diarrhea and HUS symptoms 4, 2

If platelet count obtained within 7 days after gastrointestinal illness onset is not <150,000/mm³, consider alternative diagnoses 1, 4.

Hypertension-Associated TMA

When severe hypertension coexists with TMA and advanced retinopathy, this usually indicates malignant hypertension-induced TMA rather than primary TTP or HUS 1:

• ADAMTS13 activity is normal or only slightly reduced (not severely deficient as in TTP) 1
• Thrombocytopenia is moderate with few schistocytes 1
• Blood pressure lowering improves TMA within 24-48 hours 1

Treatment Implications

Do not delay treatment while awaiting ADAMTS13 results—atypical HUS is a medical emergency requiring immediate complement inhibitor therapy, while TTP requires plasma exchange 2. However, the ADAMTS13 result will guide definitive management and prevent inappropriate prolonged plasma exchange when it is unlikely to be successful 5.

Common Pitfalls

• Do not exclude TMA based on absence of schistocytes—sensitivity is low, especially early in disease 1, 2
• Do not assume all post-diarrheal cases are STEC-HUS—timing matters; simultaneous onset suggests atypical HUS 4, 2
• In pediatric patients <1 year, up to 50% may not have all three classic TMA features at presentation—maintain high suspicion 2
• The term "TTP/HUS" should be avoided as it obscures important pathogenic and therapeutic differences 3