What are the key differences in diagnosis and treatment between Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS)?

TTP vs HUS: Key Diagnostic and Treatment Differences

The critical first step is urgent ADAMTS13 activity testing: if <10%, diagnose and treat as TTP with immediate plasma exchange; if >10%, diagnose as HUS and determine the subtype (STEC-HUS vs aHUS) to guide complement inhibitor therapy. 1, 2, 3

Diagnostic Differentiation

Essential Laboratory Testing

When confronted with the triad of microangiopathic hemolytic anemia, thrombocytopenia, and organ involvement, you must immediately order:

• ADAMTS13 activity level - this is the definitive test distinguishing TTP from HUS 1, 3
• Stool testing for verocytotoxin-producing E. coli (VTEC/Shiga toxin) - to identify STEC-HUS 1, 2
• Complete blood count with peripheral smear - schistocytes >1% support TMA diagnosis, though their absence does not exclude it due to low test sensitivity 1, 2, 3
• LDH, haptoglobin, indirect bilirubin - to confirm hemolysis 1
• Creatinine and urinalysis - to assess renal involvement 1
• Direct Coombs test - must be negative to confirm non-immune hemolysis 1

Key Diagnostic Distinctions

TTP is defined by:

• ADAMTS13 activity <10% 1, 3
• More prominent neurological involvement (though this can occur in both) 1
• Less severe renal involvement compared to HUS 1, 4
• Can have more gradual onset 1

HUS is defined by:

• ADAMTS13 activity >10% 1, 3
• Prominent renal injury (hematuria, proteinuria, elevated creatinine) 1
• Typically follows acute gastrointestinal illness in STEC-HUS (diarrhea appears 4-5 days before HUS onset) 1
• Neurological involvement occurs in only 10-20% of aHUS cases 1

HUS Subtype Classification

Once HUS is diagnosed (ADAMTS13 >10%), distinguish between:

STEC-HUS (typical HUS):

• Positive stool test for Shiga toxin/VTEC 1, 2
• History of bloody diarrhea 4-5 days before HUS onset 1
• More common in children 1

Atypical HUS (aHUS):

• Negative VTEC testing 1, 2
• Complement-mediated pathophysiology 1
• May have genetic mutations in complement regulatory proteins (CFH, CFI, CD46, C3, CFB, THBD, DGKE) in 50-60% of cases 1, 2
• Can occur at any age 1

Treatment Algorithms

For TTP (ADAMTS13 <10%)

Immediate management - do not delay:

• Initiate therapeutic plasma exchange (PEX) immediately - mortality increases with delayed treatment; do not wait for ADAMTS13 results if TTP is strongly suspected clinically 3, 5, 6
• Administer methylprednisolone 1g IV daily for 3 days 2, 3
• Avoid platelet transfusions unless life-threatening bleeding occurs, as they may worsen thrombosis 2, 3
• RBC transfusion only to relieve symptoms or achieve hemoglobin 7-8 g/dL in stable patients 2, 3

For refractory cases:

• Consider rituximab, IVIG, cyclosporine A, or mycophenolate mofetil 3

Monitoring:

• Daily CBC with differential, LDH, haptoglobin, and creatinine during acute phase 3
• Assess platelet count normalization (target >150,000/mm³) 2

For STEC-HUS

Supportive care only:

• No intervention has proven superior to supportive therapy alone in postdiarrheal HUS 5
• Avoid antibiotics, as they may increase Shiga toxin release 2
• Provide renal support as needed (may require dialysis) 1, 2
• Monitor for complications 2

For Atypical HUS (aHUS)

This is a medical emergency requiring immediate action:

• Initiate complement inhibitor therapy (eculizumab or ravulizumab) immediately - do not delay while awaiting genetic testing results, as mutations are found in only 50-60% of cases 2, 3
• Eculizumab dosing: 900 mg weekly for 4 doses, then 1,200 mg at week 5, followed by 1,200 mg every 2 weeks 2, 3
• Mandatory meningococcal vaccination (serogroups A, C, W, Y, and B) before or concurrent with therapy 2, 3
• Long-term penicillin prophylaxis due to increased meningococcal infection risk 2, 3

Critical warning:

• Discontinuing complement inhibitors carries 10-20% risk of disease recurrence and renal failure 2, 3

Common Pitfalls to Avoid

• Do not delay plasma exchange in suspected TTP while awaiting ADAMTS13 results - mortality increases with treatment delay 3, 6
• Do not exclude TMA based on absent or rare schistocytes - the test has low sensitivity, especially early in disease 1, 2, 3
• Do not give antibiotics in suspected STEC-HUS - they may worsen outcomes by increasing toxin release 2
• Do not transfuse platelets in TTP/HUS except for life-threatening bleeding - they worsen microvascular thrombosis 2, 3
• Do not assume absence of marked thrombocytopenia excludes TMA - particularly in post-transplant patients, 13% lack significant platelet reduction 1
• Do not stop complement inhibitors prematurely in aHUS without thorough risk assessment - relapse risk is substantial 2, 3

Special Clinical Contexts

Pregnancy-triggered aHUS:

• C5 inhibitors (eculizumab/ravulizumab) should be initiated immediately and have been instrumental in resolving TMA 2

Renal transplant recipients:

• aHUS may recur or present de novo in the graft 1, 2
• Diagnosis is complicated; absence of thrombocytopenia or anemia should not exclude TMA 1

Pediatric considerations:

• In newborns, HUS may present without all three classic parameters (thrombocytopenia, anemia, elevated creatinine) 2
• When aHUS presents in the first year of life, consider mutations in DGKE or WT1 genes 1
• Evaluate creatinine relative to age-appropriate norms 2

Genetic counseling:

• Offer to all patients with confirmed aHUS diagnosis due to possible genetic transmission 1, 2