In a patient with acquired thrombotic thrombocytopenic purpura who has not shown clinical or laboratory improvement after 4–5 days of daily therapeutic plasma exchange at standard volume, what are the recommended next‑step treatments?

Management of Refractory TTP Not Responding to Plasma Exchange

Immediate Escalation Strategy

For acquired TTP patients showing no clinical or laboratory improvement after 4–5 days of daily therapeutic plasma exchange, add caplacizumab immediately if not already initiated, ensure rituximab has been started, and consider intensifying immunosuppression with cyclophosphamide plus vincristine. 1, 2

First-Line Additions for Refractory Disease

Caplacizumab Administration

• Add caplacizumab 11 mg IV bolus immediately, followed by 11 mg subcutaneous daily if not already part of the initial regimen, as it reduces time to platelet normalization and decreases early recurrence risk by 29% compared to placebo 3, 4
• Caplacizumab blocks platelet binding to von Willebrand factor, providing immediate platelet-protective effects independent of immunosuppression 5, 4
• Continue caplacizumab through the plasma exchange period and for 30 days beyond the last exchange, with potential extension up to 28 additional days if ADAMTS13 activity remains suppressed below 10% 3, 1
• Monitor closely for bleeding complications, as caplacizumab increases bleeding-related adverse events from 38% to 54%, though most are mild to moderate 4

Rituximab Verification

• Confirm rituximab has been initiated as part of first-line therapy at 375 mg/m² weekly for 4 weeks or 100 mg weekly, as it should be offered to all acquired TTP patients from treatment onset 1, 6
• Rituximab targets the underlying autoimmune process producing anti-ADAMTS13 antibodies and is associated with improved survival rates exceeding 90% when combined with plasma exchange and corticosteroids 5, 1

Second-Line Immunosuppressive Intensification

Cyclophosphamide Plus Vincristine Regimen

• For patients not responding after 4–5 days of standard therapy, add cyclophosphamide plus vincristine to the existing plasma exchange, corticosteroids, and rituximab regimen 2, 1
• This combination has demonstrated effectiveness in achieving complete remission in refractory and relapsing TTP cases where standard therapy failed 2
• The evidence from a 6-year retrospective analysis showed that all four relapsing patients who received cyclophosphamide plus vincristine achieved complete remission after failing initial therapy 2

Alternative Immunosuppressive Options

• Consider cyclosporine (5 mg/kg/day for 6 days, then 2.5–3 mg/kg/day titrated to blood levels 100–200 ng/mL) with response rates of 50–80% in small series 6
• Mycophenolate mofetil (1000 mg twice daily for at least 3–4 weeks) may be considered, with response rates up to 75% 6
• Anti-thymocyte globulin represents another option for life-threatening refractory cases 1

Emerging Therapy for Refractory Cases

Daratumumab Consideration

• For truly refractory cases failing standard intensification, consider daratumumab (anti-CD38 monoclonal antibody) in combination regimens, as recent evidence shows it can rapidly restore ADAMTS13 activity and eradicate persistent autoantibodies 7
• Case series demonstrate that daratumumab achieved clinical remission in initial diagnosed acquired TTP patients, with successful retreatment in relapsed cases 7
• This represents an emerging option when conventional immunosuppression fails, though evidence remains limited to case series 7

Critical Monitoring During Refractory Phase

Laboratory Assessment

• Check ADAMTS13 activity and inhibitor levels immediately if not already done, as persistent activity below 10% with elevated inhibitors indicates ongoing autoimmune activity requiring more aggressive immunosuppression 1, 5
• Monitor daily platelet count, hemoglobin, LDH, and clinical status during active plasma exchange 1
• Assess for schistocytes on peripheral blood smear to confirm ongoing microangiopathic hemolysis 1

Clinical Vigilance

• Avoid platelet transfusions unless life-threatening hemorrhage occurs, as they may worsen thrombosis 1
• Monitor for neurological deterioration, as 39–80% of patients present with neurologic symptoms including headache, confusion, or seizures 5
• Watch for bleeding complications if caplacizumab is added, particularly epistaxis, gingival bleeding, and more serious hemorrhage 3, 4

Common Pitfalls to Avoid

• Do not delay adding caplacizumab or intensifying immunosuppression while waiting for ADAMTS13 results, as mortality and morbidity from ongoing microthrombosis remain high without prompt escalation 1, 5
• Do not discontinue plasma exchange prematurely even if adding caplacizumab, as the combination provides both immediate platelet protection and removal of autoantibodies 1, 3
• Do not assume treatment failure means the patient would have done worse without therapy—approximately 40% of patients do not improve in the first 4 weeks, but this does not necessarily indicate treatment ineffectiveness 8
• Ensure adequate corticosteroid dosing with methylprednisolone 1 g IV daily for 3 days if not already administered, as inadequate immunosuppression contributes to refractory disease 1