What is the treatment for Thrombotic Thrombocytopenic Purpura (TTP) and Hemolytic Uremic Syndrome (HUS)?

TTP and HUS: Diagnosis, Clinical Features, and Treatment

Immediate Recognition and Diagnostic Approach

For any patient presenting with thrombocytopenia plus anemia, immediately check haptoglobin, indirect bilirubin, and LDH levels to evaluate for thrombotic microangiopathy 1. The diagnosis of TTP/HUS requires the combination of:

• Thrombocytopenia (platelets <150,000/mm³ or 25% reduction from baseline) 1
• Microangiopathic hemolytic anemia with negative direct Coombs test, elevated LDH, reduced haptoglobin, and schistocytes on peripheral smear 1
• Renal involvement (elevated creatinine, hematuria, and/or proteinuria) 1

Critical pitfall: The absence of schistocytes should NOT exclude TMA diagnosis due to low test sensitivity 1. Schistocytes >1% strongly favor TMA, but their absence doesn't rule it out 1.

Essential Immediate Testing

When the triad is present, urgently obtain ADAMTS13 activity level (within hours) to distinguish TTP from other causes 1, 2. ADAMTS13 activity <10% confirms TTP 1.

Additional first-line tests include 1:

• Peripheral blood smear for schistocytes
• PT, aPTT, fibrinogen (typically normal, distinguishing from DIC)
• Blood type, direct antiglobulin test
• Stool testing for Shiga toxin-producing E. coli (STEC)
• Creatinine and urinalysis

Second-line investigations 1:

• Complement levels (C3, C4, CH50, AP50) for atypical HUS
• HIV, HCV, CMV serology
• Consider brain MRI if neurological symptoms present

Clinical Features

TTP Presentation

Neurological symptoms occur in 73% of patients and can range from mild confusion to severe seizures, coma, or focal deficits 3. Fever occurs in 46-89% of cases 4, 3. The classic "pentad" (thrombocytopenia, hemolytic anemia, neurological symptoms, renal dysfunction, fever) is present in only 6% of patients at presentation 4.

HUS Presentation

In children, distinguish STEC-HUS from atypical HUS by timing: STEC-HUS typically appears 4-5 days after diarrhea onset, while concurrent diarrhea and HUS suggests atypical HUS 1.

Atypical HUS features include 1:

• Bloody diarrhea (but shorter duration than STEC-HUS)
• Decreased urination or hematuria
• Abdominal pain, vomiting
• Pallor, unexplained bruising
• Hypertension and edema
• Confusion or seizures (10-20% of cases)

In infants <1 year old with HUS, consider mutations in complement-unrelated genes (DGKE, WT1) and metabolic causes like MMACHC 1.

Treatment

TTP Treatment Protocol

Immediately initiate therapeutic plasma exchange (TPE) upon diagnosis—delay increases mortality 1, 2, 5. Do not wait for ADAMTS13 results if clinical suspicion is high 1.

Grade 4 (Life-threatening) TTP Management 1, 2:

1. Admit patient and obtain immediate hematology consultation 1

2. Initiate TPE at 1-1.5 times plasma volume daily using fresh frozen plasma as replacement fluid 2, 5, 4. Continue daily until:

   • Platelet count >150,000/mm³ 2, 4
   • LDH normalizes 2, 4
   • Then taper slowly 4

3. Administer methylprednisolone 1g IV daily for 3 days, with first dose given immediately after first TPE 1, 2. Follow with prednisone 1-2 mg/kg/day 1, 2, 6.

4. Consider adding caplacizumab (CABLIVI): FDA-approved for acquired TTP in combination with TPE and immunosuppression 7. Dosing:

   • 11 mg IV bolus before first TPE
   • Then 11 mg subcutaneous daily after each TPE session
   • Continue for 30 days after stopping TPE 7
   • Reduces TTP recurrence from 38% to 4% and shortens time to platelet recovery 7

5. For refractory cases not responding to TPE and steroids, add rituximab 375 mg/m² weekly for 3-4 weeks 1, 2.

Grade 2-3 TTP Management 1:

• Hematology consultation 1
• Prednisone 0.5-1 mg/kg/day for Grade 2 1
• Hold immune checkpoint inhibitors if applicable 1

HUS Treatment Approach

For atypical HUS, supportive care is primary with consideration of complement blockade therapy 1. The evidence does not provide specific FDA-approved complement inhibitor protocols in these guidelines, but eculizumab is the standard of care based on general medical knowledge.

For STEC-HUS, avoid antibiotics and antimotility agents as they may worsen outcomes (general medical knowledge). Provide supportive care with:

• Fluid and electrolyte management 1
• Blood pressure control 1
• RBC transfusion only when necessary (Hgb 7-8 g/dL target in stable patients) 1
• Renal replacement therapy if needed 1

Monitoring and Supportive Care

• Monitor hemoglobin weekly during corticosteroid taper 1
• Provide folic acid 1 mg daily supplementation 1
• Transfuse RBCs conservatively (minimum units necessary, target Hgb 7-8 g/dL in stable patients) 1
• Avoid platelet transfusions unless life-threatening bleeding (general medical knowledge—may worsen thrombosis)
• Continuous cardiac monitoring for arrhythmias if concurrent myocarditis suspected 1

Prognostic Factors

Advanced age and severe renal impairment (creatinine >2 mg/dL) predict treatment failure and poor outcome 3. Complete response to TPE typically occurs after median 13-15 exchanges 4. Relapse occurs in 13-21% of patients, most commonly within first 2 years, and responds promptly to repeat TPE 7, 3.

Special Populations

In pregnancy, TPE remains first-line treatment with concurrent corticosteroids 2. The median treatment duration is 35 days 7.