What are the diagnostic criteria and treatment options for thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura (TTP) and atypical hemolytic uremic syndrome (aHUS)?

Diagnosis of Thrombotic Microangiopathy

Diagnostic Criteria

The diagnosis of TMA requires the triad of microangiopathic hemolytic anemia (MAHA), thrombocytopenia, and organ injury (typically renal), with immediate laboratory evaluation to distinguish between TTP and aHUS subtypes. 1, 2

Core Laboratory Findings

• MAHA confirmation requires a negative direct Coombs test, elevated LDH, reduced or unmeasurable haptoglobin, with or without schistocytes on peripheral blood smear 1, 2, 3
• Thrombocytopenia is defined as platelet count <150,000/mm³ or a 25% reduction from baseline 1
• Renal involvement manifests as elevated creatinine, hematuria, and/or proteinuria 1, 2

Critical Diagnostic Pitfall

The absence of schistocytes should NOT exclude early TMA diagnosis due to low sensitivity of this finding 1. When clinical suspicion exists with thrombocytopenia and anemia, immediately check haptoglobin, indirect bilirubin, and LDH levels 2.

Immediate Diagnostic Workup

First-Line Testing

• ADAMTS13 activity level must be obtained urgently (before initiating treatment if possible) to distinguish TTP from other TMAs 1, 2, 3

  • Severely deficient ADAMTS13 (<10 IU/dL) confirms TTP 1
  • Normal ADAMTS13 (>10%) suggests aHUS or secondary TMA 1

• Stool testing for Shiga toxin-producing E. coli (STEC) is mandatory to exclude STEC-HUS 1

Additional Laboratory Evaluation

• Complete blood count, reticulocyte count, LDH, haptoglobin, indirect bilirubin 2, 3
• Renal function tests (creatinine, urinalysis) 2
• Coagulation parameters (PT, aPTT, fibrinogen) to exclude DIC 2
• Screening for secondary causes: HIV, HCV, H. pylori 2

Differential Diagnosis Algorithm

Step 1: ADAMTS13 Activity

• <10% → TTP (proceed to TTP treatment immediately)
• >10% → Proceed to Step 2

Step 2: Stool STEC Testing

• Positive → STEC-HUS (supportive care only, avoid antibiotics)
• Negative → Proceed to Step 3

Step 3: Clinical Context

• Diarrhea 4-5 days before HUS onset in children → Likely STEC-HUS 2
• Concurrent diarrhea and HUS → Suggests aHUS 2
• Pregnancy/postpartum, malignancy, drugs, autoimmune disease → Secondary TMA or aHUS 1

Special Diagnostic Considerations

Pediatric Patients

• aHUS may be present even if one of the three main parameters (MAHA, thrombocytopenia, renal injury) is absent 1
• In children <1 year old, consider non-complement gene mutations (DGKE, WT1) 1

Neurological Involvement

• Neurological symptoms occur in a significant proportion of TTP patients (confusion, seizures, coma, focal deficits) 2
• Neurological involvement is uncommon in aHUS (10-20% of patients), but when suspected, obtain neurology consultation, EEG, and brain MRI 1

Pregnancy-Associated TMA

• Distinguish from HELLP syndrome and preeclampsia 4
• May represent aHUS triggered by pregnancy 1, 4

Treatment Initiation Based on Diagnosis

TTP (ADAMTS13 <10%)

Immediately initiate therapeutic plasma exchange (TPE) upon diagnosis, as delay increases mortality 2, 3

• TPE at 1-1.5 times plasma volume daily using fresh frozen plasma 2
• Continue daily until platelet count >150,000/mm³ and LDH normalizes, then taper slowly 2
• Methylprednisolone 1g IV daily for 3 days, followed by prednisone 1-2 mg/kg/day 2, 3
• Consider adding caplacizumab for acquired TTP in combination with TPE and immunosuppression 2
• For refractory cases, add rituximab 375 mg/m² weekly for 3-4 weeks 2, 3

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

Complement inhibitors (eculizumab or ravulizumab) are the standard treatment for aHUS 1, 5, 6

• Eculizumab dosing: 900 mg IV weekly for 4 weeks, then 1200 mg at week 5, then 1200 mg every 2 weeks 5
• Ravulizumab dosing: Weight-based loading dose followed by maintenance dosing every 4-8 weeks 6
• Mandatory meningococcal vaccination (serogroups A, C, W, Y, and B) at least 2 weeks before treatment, or provide antibiotic prophylaxis if urgent therapy needed 1, 5, 6
• Pregnancy-associated aHUS also responds to complement inhibition 1

STEC-HUS

• Supportive care only: fluid and electrolyte management, blood pressure control 2
• Avoid antibiotics and antimotility agents 2
• RBC transfusion only when necessary, renal replacement therapy if needed 2

Supportive Care Measures (All TMAs)

• Transfuse RBCs conservatively, targeting hemoglobin 7-8 g/dL in stable patients 2
• Avoid platelet transfusions unless life-threatening bleeding present 2
• Folic acid 1 mg daily supplementation 2
• Monitor hemoglobin weekly during corticosteroid taper 2
• Continuous cardiac monitoring if concurrent myocarditis suspected 2