How to manage thrombotic thrombocytopenic purpura (TTP) caused by drugs such as mitomycin and cisplatin?

Management of Drug-Induced Thrombotic Thrombocytopenic Purpura (TTP) from Mitomycin and Cisplatin

Immediate discontinuation of the offending drug (mitomycin or cisplatin) is the first critical step in managing drug-induced TTP, followed by prompt initiation of therapeutic plasma exchange (PEX) according to existing guidelines. 1

Diagnosis and Initial Evaluation

• Check for clinical pentad of TTP:

  • Thrombocytopenia
  • Microangiopathic hemolytic anemia
  • Neurological abnormalities
  • Renal dysfunction
  • Fever

• Essential laboratory workup:

  • Complete blood count with peripheral smear to check for schistocytes
  • ADAMTS13 activity level and inhibitor titer
  • LDH, haptoglobin, reticulocyte count, bilirubin
  • Prothrombin time, activated partial thromboplastin time, and fibrinogen
  • Blood group and antibody screen, direct antiglobulin test
  • Urinalysis

Management Algorithm

Step 1: Initial Management

• Immediately discontinue mitomycin or cisplatin 2, 3
• Obtain immediate hematology consultation 1
• Admit patient to hospital 1

Step 2: Initiate Therapeutic Plasma Exchange (PEX)

• Begin PEX according to existing guidelines 1
• First PEX should be performed as soon as possible after diagnosis
• Continue daily PEX until clinical improvement and platelet count normalization
• Further PEX dependent on clinical progress 1

Step 3: Corticosteroid Administration

• Administer methylprednisolone 1g IV daily for 3 days with first dose immediately after first PEX 1
• Then transition to prednisone 1-2 mg/kg/day 1

Step 4: Consider Additional Therapies

• For patients not responding to PEX and steroids:
  • Add rituximab (375 mg/m² weekly for 4 weeks) 1
  • Consider caplacizumab if ADAMTS13 activity level is normal with an inhibitor or elevated anti-ADAMTS13 IgG 1
  • Other immunosuppressive options include cyclophosphamide, cyclosporine, or mycophenolate mofetil 1

Step 5: Monitoring and Tapering Therapy

• Monitor platelet count, hemoglobin, LDH, and clinical symptoms daily
• If no exacerbation within 3-5 days after stopping PEX:
  • Taper steroids over 2-3 weeks
  • Complete course of rituximab (if receiving)
  • Discontinue caplacizumab (if receiving) 1

Special Considerations

Mechanism-Based Approach

Drug-induced TTP occurs through two principal mechanisms:

1. Dose-related toxicity (common with mitomycin and cisplatin) - direct endothelial damage 2, 3
2. Immune-mediated reaction - development of autoantibodies against ADAMTS13 2

Mitomycin-Specific Considerations

• TTP typically occurs after cumulative doses exceed 40 mg/m² 3
• Higher risk with combination chemotherapy regimens
• May have delayed onset (weeks to months after exposure)

Cisplatin-Specific Considerations

• Often occurs during or shortly after administration 4
• May be part of combination regimens (like TIP: paclitaxel, ifosfamide, cisplatin)
• Renal dysfunction is often prominent

Pitfalls and Caveats

• Avoid re-exposure to the offending drug - critical to prevent recurrence 2
• Do not delay PEX while waiting for ADAMTS13 results - mortality increases with treatment delay
• Avoid platelet transfusions unless life-threatening bleeding is present
• Monitor for PEX complications (catheter-related infections, electrolyte abnormalities)
• Drug-induced TTP may have a different response pattern compared to idiopathic TTP
• Consider underlying malignancy's contribution to the clinical picture

Prognosis

The prognosis of drug-induced TTP depends on:

• Prompt recognition and discontinuation of the offending drug
• Early initiation of PEX
• Underlying health status of the patient
• Specific drug involved (mitomycin-induced TTP typically has worse outcomes than other drug-induced forms)

With appropriate management, mortality has decreased from nearly 90% to 10-20% in drug-induced TTP cases 5.