What is the treatment approach for distinguishing and managing Thrombotic Thrombocytopenic Purpura (TTP) versus Atypical Hemolytic Uremic Syndrome (aHUS)?

Distinguishing and Managing TTP versus Atypical HUS

Immediately measure ADAMTS13 activity level before initiating treatment, but do not delay therapeutic plasma exchange if TTP is clinically suspected, as ADAMTS13 <10% confirms TTP while >10% suggests aHUS—this distinction is critical because TTP requires plasma exchange while aHUS requires complement blockade with eculizumab. 1, 2

Diagnostic Approach: The Critical First Steps

Immediate Laboratory Testing

Order these tests urgently and simultaneously:

• ADAMTS13 activity level and inhibitor titer - this is the single most important distinguishing test 3, 1
• Peripheral blood smear - schistocytes are critical for diagnosis, though low sensitivity means their absence doesn't exclude TMA 1
• Complete blood count with platelet count 1
• Hemolysis markers: LDH, haptoglobin, indirect bilirubin, reticulocyte count 3, 2
• Direct antiglobulin test (DAT) - must be negative to confirm non-immune hemolysis 2
• Renal function: creatinine, urinalysis for hematuria/proteinuria 3, 1
• Coagulation studies: PT, aPTT, fibrinogen to exclude DIC 3
• Complement testing: C3, C4, CH50 if aHUS suspected 3

The Diagnostic Triad

All three must be present to diagnose TMA: 1, 2

• Non-immune microangiopathic hemolytic anemia (schistocytes, elevated LDH, low haptoglobin, negative DAT)
• Thrombocytopenia (often severe and precipitous)
• Organ involvement (typically renal, but neurologic in TTP)

The ADAMTS13-Based Algorithm

ADAMTS13 <10%: This is TTP

Clinical features that support TTP: 4

• Neurological symptoms (confusion, seizures, focal deficits, coma)
• Cardiac involvement possible
• Renal involvement less prominent than in aHUS
• May have fever

Immediate TTP management - do not wait for ADAMTS13 results if clinical suspicion is high: 3, 1, 2

1. Initiate therapeutic plasma exchange (TPE) immediately - 1-1.5 times plasma volume daily using fresh frozen plasma 2
2. Administer methylprednisolone 1g IV daily for 3 days, starting immediately after first TPE 3, 2
3. Continue with prednisone 1-2 mg/kg/day after initial methylprednisolone 2
4. Continue daily TPE until: platelet count >150,000/mm³ AND LDH normalizes, then taper slowly 2
5. Consider adding caplacizumab for acquired TTP in combination with TPE and immunosuppression 2

For refractory TTP (no improvement after 4-5 days of TPE): 2, 5

• Add rituximab 375 mg/m² weekly for 3-4 weeks

ADAMTS13 >10%: Consider Atypical HUS

Clinical features that support aHUS: 3, 6

• Renal involvement predominates (elevated creatinine, hematuria, proteinuria)
• May have bloody diarrhea, decreased urination
• Abdominal pain, vomiting
• Hypertension, edema
• Less prominent neurological features than TTP

Critical distinction in children: 2

• If diarrhea occurred 4-5 days before HUS onset → likely STEC-HUS (Shiga toxin)
• If diarrhea and HUS are concurrent → suggests atypical HUS

Atypical HUS management: 3, 1, 6

1. Initiate eculizumab therapy for complement-mediated aHUS 3, 1
2. Administer meningococcal vaccination and long-term penicillin prophylaxis (required with eculizumab) 1
3. Aggressive blood pressure control if malignant hypertension present 6
4. Supportive care: fluid/electrolyte management, renal replacement therapy if needed 2

For STEC-HUS specifically: 2

• Avoid antibiotics and antimotility agents - these worsen outcomes
• Supportive care only

Transfusion Guidelines: Critical Pitfalls to Avoid

Red Blood Cell Transfusion

Transfuse conservatively - only to relieve symptoms or achieve hemoglobin 7-8 g/dL in stable, non-cardiac patients. 3, 1, 2

• Do not transfuse more than the minimum necessary 3
• Discuss with blood bank that a patient with possible TMA is in-house before transfusions 3

Platelet Transfusion

Platelet transfusion is contraindicated in TTP unless life-threatening bleeding is present. 2

This is a critical pitfall - platelet transfusion may worsen microvascular thrombosis 2

Graded Management Approach

Grade 1-2 (Mild): Evidence of hemolysis without severe clinical consequences

• Hold any causative medications 1
• Hematology consultation 3, 1
• Prednisone 0.5-1 mg/kg/day 3, 1
• Monitor hemoglobin weekly during steroid taper 1, 2
• Folic acid 1 mg daily supplementation 3, 2

Grade 3 (Severe): Significant thrombocytopenia, anemia, or renal insufficiency

• Consider hospital admission 3
• Hematology consultation immediately 3
• Prednisone 1-2 mg/kg/day (oral or IV) 3
• RBC transfusion per guidelines if symptomatic 3

Grade 4 (Life-threatening): CNS hemorrhage, thrombosis, or renal failure

• Admit patient immediately 3
• Urgent hematology consultation 3
• Initiate TPE immediately for TTP 3, 2
• IV methylprednisolone 1g daily for 3 days 3
• Consider rituximab, IVIG, cyclosporine, or mycophenolate for refractory cases 3

Monitoring During Acute Phase

Daily monitoring should include: 1, 2

• CBC with differential
• Platelet count
• LDH
• Haptoglobin
• Creatinine

Weekly monitoring during steroid taper: 1, 2

• Hemoglobin levels

Critical Pitfalls and How to Avoid Them

Pitfall #1: Waiting for ADAMTS13 Results

Do not delay plasma exchange while awaiting ADAMTS13 results if TTP is strongly suspected clinically - mortality increases dramatically with delayed treatment. 1, 2

The clinical diagnosis of TTP based on thrombocytopenia, microangiopathic hemolysis, and neurologic symptoms is sufficient to start TPE 3, 1

Pitfall #2: Dismissing Low Schistocyte Counts

Do not exclude TMA based on "rare" schistocytes alone - low schistocyte counts can occur in early or evolving TMA due to low test sensitivity. 1

Even schistocytes >1% can be significant in the right clinical context 1

Pitfall #3: Over-Transfusing

Avoid aggressive transfusion - target hemoglobin 7-8 g/dL only, as excessive transfusion may worsen fluid overload and outcomes. 3, 1, 7

Fluid overload is a significant complication, particularly with plasma infusion 7

Pitfall #4: Using Antibiotics in STEC-HUS

Never use antibiotics or antimotility agents in suspected STEC-HUS - these worsen outcomes. 2

Secondary Causes to Consider

Always evaluate for: 3, 2

• Drug exposure (chemotherapy, sirolimus, tacrolimus, quinine, ticlopidine)
• HIV, HCV, H. pylori infection
• Malignancy
• Stem cell transplantation
• Pregnancy/postpartum state
• Antiphospholipid syndrome (check aPLA if suspected) 3, 6

For antiphospholipid syndrome-associated TMA: 3

• Long-term anticoagulation with warfarin (not DOACs)
• Plasma exchange for catastrophic APS
• Consider eculizumab for refractory cases