What is the appropriate treatment for Thrombotic Microangiopathy (TMA)?

Treatment of Thrombotic Microangiopathy (TMA)

The appropriate treatment for TMA depends critically on rapid etiological diagnosis, with immediate plasma exchange plus glucocorticoids initiated empirically in adults with suspected TTP while awaiting ADAMTS13 results, followed by etiology-specific therapy once the underlying cause is identified. 1

Immediate Diagnostic and Empiric Treatment Approach

Initial Risk Stratification

• Calculate the PLASMIC score immediately upon TMA suspicion to assess TTP probability—scores >5 points indicate intermediate-to-high risk requiring urgent intervention. 1
• Obtain blood samples for ADAMTS13 activity/antibodies and antiphospholipid antibodies before initiating any treatment, as these tests guide definitive therapy. 1, 2
• In adults with intermediate-to-high PLASMIC scores, initiate plasma exchange and glucocorticoids immediately without waiting for confirmatory testing, as delayed treatment significantly increases mortality. 1, 3

Critical pediatric caveat: In children, TTP is uncommon and plasma exchange carries substantial morbidity—it is acceptable to defer plasma exchange for 24-48 hours until ADAMTS13 results confirm the diagnosis. 1

Supportive Laboratory Monitoring

• Monitor platelet count, LDH, haptoglobin, and renal function regularly throughout treatment to assess response. 2, 4
• Check peripheral blood smear for schistocytes, though their absence does not exclude early TMA. 4, 5

Etiology-Specific Definitive Treatment

TTP (ADAMTS13 Activity <10%)

For confirmed TTP, implement plasma exchange plus high-dose glucocorticoids plus rituximab, with or without caplacizumab. 1, 2

• Plasma exchange removes anti-ADAMTS13 antibodies and replaces deficient enzyme. 1, 6
• Methylprednisolone 1 g IV daily for 3 days, with first dose given after the first plasma exchange. 4
• Add rituximab early in the treatment course to reduce relapse risk. 1, 4
• Caplacizumab (von Willebrand factor inhibitor) can be added to accelerate platelet recovery. 1

Complement-Mediated TMA (Including Atypical HUS)

For complement-mediated TMA, initiate eculizumab or ravulizumab as first-line therapy. 2, 4, 7, 8

• Eculizumab has demonstrated mean eGFR improvement from 17 to 47 mL/min/1.73m² by 26 weeks in complement-mediated TMA. 4
• Ravulizumab is FDA-approved for atypical HUS to inhibit complement-mediated TMA in patients ≥1 month of age. 7
• Mandatory meningococcal vaccination (serogroups A, C, W, Y, and B) at least 2 weeks before initiating complement inhibitors, or provide antibacterial prophylaxis if urgent treatment cannot be delayed. 7, 8
• Both drugs are available only through REMS programs due to serious meningococcal infection risk. 7, 8

Antiphospholipid Syndrome-Associated TMA

Treat APS nephropathy with long-term anticoagulation using warfarin, not direct oral anticoagulants. 1

• Anticoagulated patients showed higher complete response rates (59.5% vs. 30.8%) compared to those without anticoagulation. 1
• Direct oral anticoagulants are inferior to warfarin for preventing thromboembolic events in APS. 1
• Plasma exchange may be added in severe cases or catastrophic APS. 1, 2, 4

Catastrophic APS

For catastrophic APS with multi-organ thrombosis, combine glucocorticoids, plasma exchange, and consider rituximab or eculizumab. 1

• Plasma exchange has been associated with improved patient survival in retrospective studies. 1
• Eculizumab shows emerging efficacy as complement activation is involved in aPLA-induced tissue injury. 1

Drug-Induced TMA (Including CNI-Induced)

Immediately discontinue the offending agent—for CNI-induced TMA, convert to belatacept or alternative immunosuppression. 2, 4

• CNI withdrawal or conversion is essential for recovery in CNI-induced post-transplant TMA. 2, 4

Supportive Care Measures

Transfusion Management

• Transfuse RBCs only to minimum necessary to relieve symptoms or achieve hemoglobin 7-8 g/dL in stable patients. 4
• Avoid platelet transfusions unless life-threatening bleeding occurs, as they may worsen thrombotic complications. 4
• Provide folic acid supplementation 1 mg daily. 4

Post-Treatment Monitoring and Discontinuation Considerations

After TMA Resolution

• Continue monitoring until clinical and laboratory parameters normalize. 2, 4
• For patients discontinuing complement inhibitors: monitor for at least 12 weeks for TMA recurrence signs (mental status changes, seizures, angina, dyspnea, thrombosis). 8
• Watch for laboratory indicators of TMA recurrence: ≥25% decrease in platelets, ≥25% increase in creatinine, or ≥25% increase in LDH from treatment nadir. 8

Common Pitfalls to Avoid

• Never delay plasma exchange in adults with suspected TTP while awaiting ADAMTS13 results—mortality increases significantly with treatment delays. 1, 3
• Do not assume schistocyte absence excludes TMA—sensitivity is low in early disease. 4, 5
• Do not use direct oral anticoagulants for APS-associated TMA—warfarin is superior. 1
• Do not initiate complement inhibitors without ensuring meningococcal vaccination or prophylactic antibiotics are in place. 7, 8
• In approximately 50% of TMA cases at onset, not all three classic findings (hemolytic anemia, thrombocytopenia, renal involvement) are clearly present—maintain high clinical suspicion. 5