How do you differentiate and manage a patient with symptoms suggestive of HUS (Hemolytic Uremic Syndrome) versus TTP (Thrombotic Thrombocytopenic Purpura)?

Differentiating and Managing HUS versus TTP

When a patient presents with thrombocytopenia and microangiopathic hemolytic anemia, immediately order ADAMTS13 activity testing—if severely deficient (<10 IU/dL), the diagnosis is TTP requiring urgent plasma exchange; if ADAMTS13 is normal (>10 IU/dL), proceed with stool testing for Shiga toxin to distinguish STEC-HUS from atypical HUS, which requires eculizumab within 4-8 hours. 1, 2

Initial Laboratory Evaluation

When any patient presents with anemia plus thrombocytopenia, immediately obtain the following tests to confirm thrombotic microangiopathy (TMA): 3, 1, 2

• Complete blood count with platelet count (thrombocytopenia defined as <150,000/mm³ or 25% reduction from baseline) 3, 2
• Peripheral blood smear looking specifically for schistocytes, burr cells, or helmet cells indicating microangiopathic hemolysis 3, 2
• LDH (elevated), haptoglobin (reduced or absent), indirect bilirubin (elevated) to confirm hemolysis 3, 1, 2
• Direct Coombs test (must be negative to confirm non-immune hemolytic anemia) 3, 2
• Serum creatinine and urinalysis for hematuria/proteinuria to assess renal involvement 3, 2

Critical Diagnostic Algorithm

Step 1: Confirm TMA Triad

The diagnosis requires all three components: 3, 1

• Microangiopathic hemolytic anemia (non-immune, confirmed by negative Coombs)
• Thrombocytopenia
• Organ injury (typically renal)

Important caveat: The absence of schistocytes should not exclude early TMA diagnosis due to low sensitivity of this finding. 3 Additionally, 13% of TMA patients may not show significant platelet reduction and 38% may lack significant anemia or thrombocytopenia, particularly post-transplant patients. 3

Step 2: Urgent ADAMTS13 Testing

ADAMTS13 activity must be tested urgently when TMA is confirmed. 3, 1, 2

• ADAMTS13 <10 IU/dL = TTP → Initiate plasma exchange immediately 1, 4
• ADAMTS13 >10 IU/dL → Proceed to distinguish HUS subtypes 1, 5

The distinction is critical because plasma exchange is the treatment of choice for TTP but is much less effective in atypical HUS, which requires eculizumab. 6, 4

Step 3: Distinguish HUS Subtypes (when ADAMTS13 >10%)

A. Test for STEC-HUS (Typical HUS):

• Stool culture AND Shiga toxin/gene testing (both tests required per CDC recommendations) 2
• Clinical history: STEC-HUS typically appears 4-5 days after onset of bloody diarrhea 3, 1, 2
• If diarrhea and HUS appear concomitantly or with very short prodrome, suspect atypical HUS instead 3

B. If STEC testing is negative → Atypical HUS (aHUS):

• Consider complement studies, genetic screening, and anti-factor H antibodies 1
• In children <1 year old, consider mutations in complement-unrelated genes (DGKE, WT1) and cobalamin metabolism defects (MMACHC) 3

Management Based on Diagnosis

TTP Management (ADAMTS13 <10 IU/dL)

• Plasma exchange is the most important acute intervention and must be initiated immediately 6, 7
• Plasma exchange is associated with lower mortality and better outcomes than plasma infusion alone 6
• Historical mortality >90% without treatment; current outcomes dramatically improved with prompt plasma exchange 7

STEC-HUS Management (Shiga toxin positive)

• Supportive care only 2, 6
• IV fluid resuscitation during diarrhea phase to reduce risk of oligoanuric renal failure 2
• Avoid antibiotics—they may worsen outcomes and potentially increase HUS risk 2
• Most cases are self-limiting, though acute kidney injury management often required 6

Atypical HUS Management (ADAMTS13 >10%, STEC negative)

Initiate eculizumab within 4-8 hours of suspected aHUS diagnosis, as delays are associated with worse outcomes and increased morbidity/mortality. 1, 2

Pre-eculizumab requirements: 2, 5

• Administer quadrivalent meningococcal conjugate vaccine (A, C, W, Y) and B meningococcal vaccine
• Initiate long-term antimicrobial prophylaxis with penicillin (or macrolides if penicillin-allergic) for duration of treatment

Efficacy data: 5

• In adults (Study C10-004): 56% achieved complete TMA response, 54% had eGFR improvement ≥15 mL/min/1.73m², and 20 of 24 dialysis-dependent patients discontinued dialysis
• In pediatrics (Study C10-003): 64% achieved complete TMA response, 86% had eGFR improvement ≥15 mL/min/1.73m², and 9 of 11 dialysis-dependent patients discontinued dialysis
• Mean platelet counts increased from baseline to normal range within one week and were maintained through 26 weeks

Historical context: Until recently, plasma exchange was used for aHUS but was mostly ineffective in protecting from subsequent organ damage; eculizumab produces rapid and sustained inhibition of the TMA process with significant improvements in long-term clinical outcomes. 6

Special Populations

Pediatric Considerations

• Age is not a predictor of disease, but higher mortality occurs in children than adults with aHUS 3
• In children, aHUS may be present even if one of the three main parameters (anemia, thrombocytopenia, renal injury) is absent 3
• Serum creatinine ≥1.0 mg/dL in children <13 years indicates acute kidney injury (≥1.5 mg/dL in patients ≥13 years) 3, 2

Neurological Involvement

• Neurological involvement occurs in 10-20% of aHUS patients (less common than in TTP) 3
• If suspected based on neurological symptoms, motor symptoms, generalized weakness, vision changes, seizures, or encephalopathy, obtain neurological consultation, EEG, and brain MRI 3
• Bilateral symmetric hyperintensities of basal ganglia on FLAIR and T2-weighted MRI sequences suggest TMA 3

Common Pitfalls to Avoid

• Do not wait for the classic "pentad" of TTP (thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, renal abnormalities, fever)—sufficient diagnostic criteria are only thrombocytopenia and microangiopathic hemolytic anemia without clinically apparent cause 8
• Do not delay ADAMTS13 testing—it must be performed urgently to guide treatment decisions 3, 1
• Do not assume normal platelet count excludes TMA—if platelet count obtained within 7 days after acute gastrointestinal illness onset is not <150,000/mm³, consider other diagnoses, but recognize that 13% of TMA patients may not show significant thrombocytopenia 3
• Do not use antibiotics in STEC-HUS—they worsen outcomes 2
• Do not delay eculizumab in suspected aHUS—initiate within 4-8 hours as delays worsen outcomes 1, 2