What is the treatment approach for Thrombotic Thrombocytopenic Purpura (TTP), Hemolytic Uremic Syndrome (HUS), and Microangiopathic Hemolytic Anemia (MAHA)?

Distinguishing and Managing TTP, HUS, and MAHA

Critical First Step: Immediate ADAMTS13 Testing

The cornerstone of differentiating these thrombotic microangiopathies is urgent ADAMTS13 activity testing—if severely deficient (<10%), you have TTP and must initiate plasma exchange immediately without delay, as mortality increases significantly with treatment postponement. 1

Diagnostic Algorithm

Initial Laboratory Evaluation (Obtain Simultaneously)

• Peripheral blood smear for schistocytes (>1% supports TMA diagnosis, though absence doesn't exclude it) 1, 2
• ADAMTS13 activity level and inhibitor titer (most critical test) 1
• Complete blood count, LDH, haptoglobin, reticulocyte count, indirect bilirubin 3, 2
• Serum creatinine (renal involvement distinguishes HUS) 1
• Direct antiglobulin test (Coombs) to exclude immune hemolysis 1, 3
• Stool studies for Shiga toxin/E. coli O157:H7 if diarrhea present 1
• Complement studies (C3, C4, CH50) for atypical HUS 1, 2

Risk Stratification Tool

For suspected TTP when ADAMTS13 results are pending, use the PLASMIC score (Platelet count, hemolysis variables, absence of active cancer, absence of transplant, MCV, INR, creatinine)—if intermediate-to-high risk in adults, start plasma exchange immediately 1

Pediatric caveat: In children, TTP is rare and plasma exchange carries significant morbidity; acceptable to defer 24-48 hours for ADAMTS13 confirmation 1

Differential Diagnosis Framework

TTP (ADAMTS13 <10%)

• Neurological symptoms predominate (confusion, seizures, focal deficits) 1, 4
• Renal involvement typically mild 4
• No diarrheal prodrome 4
• Requires immediate hematology consultation 1

Typical (STEC) HUS

• Bloody diarrhea prodrome 4-5 days before TMA onset 1
• Predominantly renal failure 1, 4
• Occurs mainly in children 1
• ADAMTS13 activity >10% 5

Atypical HUS

• No diarrhea or very brief diarrhea with simultaneous TMA onset (distinguishes from STEC-HUS) 1
• Progressive renal deterioration with possible neurological involvement 4
• ADAMTS13 activity >10% 5
• Complement dysregulation (abnormal C3, C4, CH50) 1
• Consider DGKE or WT1 mutations if presenting in first year of life 1
• Consider methylmalonic acidemia (MMACHC) with homocystinuria in infants 1

MAHA (Umbrella Term)

MAHA describes the hemolytic process common to all TMAs—schistocytes, elevated LDH, low haptoglobin, thrombocytopenia 3, 2. The specific etiology determines treatment.

Treatment Algorithms by Severity Grade

Grade 1 (Schistocytes Without Clinical Consequences)

TTP:

• Hold immune checkpoint inhibitors if applicable 1
• Discuss resumption risks/benefits (no data supporting restart) 1

HUS:

• Continue monitoring with close laboratory follow-up 1

Grade 2 (Schistocytes + Grade 2 Anemia/Thrombocytopenia)

TTP:

• Prednisone 0.5-1 mg/kg/day 1
• Hematology consultation 1
• Hold immune checkpoint inhibitors, strongly consider permanent discontinuation 1

HUS:

• Supportive care 1
• Continue monitoring 1

Grade 3 (Clinical Consequences: Severe Thrombocytopenia, Anemia, Renal Insufficiency)

TTP:

• Permanently discontinue immune checkpoint inhibitors 1
• Hematology consultation 1
• Prednisone 1-2 mg/kg/day (oral or IV based on symptom severity) 1
• Consider hospital admission 1
• RBC transfusion to Hgb 7-8 g/dL only (minimum necessary units) 1, 3
• Folic acid 1 mg daily 1, 3

Atypical HUS:

• Permanently discontinue immune checkpoint inhibitors 1
• Begin eculizumab 900 mg weekly × 4 doses, then 1200 mg at week 5, then 1200 mg every 2 weeks 1, 3, 6

Grade 4 (Life-Threatening: CNS Hemorrhage/Thrombosis, Renal Failure)

TTP:

• Admit immediately 1
• Urgent hematology consultation 1
• Initiate therapeutic plasma exchange immediately (do not wait for ADAMTS13 results) 1, 3
• Methylprednisolone 1 g IV daily × 3 days (first dose immediately after first plasma exchange) 1
• Offer rituximab to reduce relapse risk 1, 3
• Consider caplacizumab if ADAMTS13 activity severely deficient with inhibitor or elevated anti-ADAMTS13 IgG 1
• Discontinue plasma exchange after initial platelet response 1
• If no exacerbation 3-5 days after stopping plasma exchange: taper steroids over 2-3 weeks, complete rituximab course, discontinue caplacizumab 1

Atypical HUS:

• Admit immediately 1
• Eculizumab therapy (same dosing as Grade 3) 1, 6
• RBC transfusion per guidelines 1

STEC-HUS (Typical):

• Supportive care only 4
• No antibiotics (not beneficial) 4
• Antimotility agents contraindicated 4
• No specific therapies proven effective in children 4

Critical Monitoring Parameters

• Weekly hemoglobin levels during steroid taper, then less frequently 1, 3, 2
• Platelet counts, LDH, haptoglobin to assess treatment response 2
• Immediate evaluation for meningococcal infection signs in patients receiving eculizumab 6

Essential Pitfalls to Avoid

Vaccination requirement: Patients must receive meningococcal vaccines (serogroups A, C, W, Y, and B) at least 2 weeks before eculizumab initiation; if urgent therapy needed, provide antibacterial prophylaxis and vaccinate ASAP 6

Platelet transfusion contraindication: Avoid platelet transfusions in TTP unless life-threatening bleeding, as they may worsen thrombosis 3

Drug-induced TMA: Always obtain detailed medication history—chemotherapy, tacrolimus, cyclosporine, sirolimus, quinine, and antibiotics can cause TMA 1, 7

Plasma-resistant cases: If no response to plasma exchange in TTP, consider alternative immunosuppression (rituximab, IVIG, cyclosporine, infliximab, mycophenolate mofetil, or ATG) 1

Neurological imaging: If neurological symptoms present, obtain brain MRI looking for bilateral symmetric basal ganglia hyperintensities on FLAIR/T2 sequences (suggestive of TMA) 1