Drug-Associated Thrombotic Thrombocytopenic Purpura-Hemolytic Uremic Syndrome (TTP-HUS): Frequency, Presenting Features, and Clinical Outcomes.
Authors: Saste Vaishali V. , Terrell Deirdra R. , Vesely Sara K. , George James N. 
Published: October 2019

The Oklahoma TTP-HUS Registry enrolled 360 consecutive patients, 1989–2006, who had a clinical or renal biopsy diagnosis of an initial episode of TTP-HUS and a request for plasma exchange treatment (PEX). 47 (13%) appeared to have a drug-associated etiology determined by the use of a drug previously reported to be associated with TTP or HUS.

Patient Characteristics Quinine (n=23) Ticlopidine (n=2) Clopidogrel (n=1) Calcineurin inhibitors (n=5) Chemotherapy (n=16) *median; ‡seizure, stroke, coma, focal abnormalities anytime during the course; †most abnormal values at diagnosis ± 7 days, median; **defined by ↑ Cr ≥0.5 mg/dL x 2 days or Cr ≥4.0 and dialysis; §only for patients who received PEX Age* (years) 61 68 17 52 57 Female (%) 96% 50% 100% 60% 69% Race (% white) 96% 50% 100% 100% 94% Time from last dose* 3 days 3 days 0 days 1 day 105 days Severe neurologic abnormalities (%)‡ 30% 50% 0% 40% 6% Platelet count†(/μL ) 26 6 81 35 38 Hematocrit†(%) 23 23 13 21 22 LDH†(U/L) 2143 2120 581 1346 805 Creatinine†(mg/dL) 7.0 4.0 1.6 7.0 4.5 Acute renal failure (%)** 91% 0% 0% 40% 38% Response to PEX§ 95% (21/22) NA 100% (1/1) 25% (1/4) 47% (7/15) Death (30 days) 13% 50% 0% 20% 13% Death (1 year) 13% 50% 0% 20% 69%

Calcineurin inhibitors were cyclosporine (3) and tacrolimus (2); chemotherapy agents were mitomycin C (11), gemcitabine (2), gemcitabine/taxotere (1), pentostatin (1), and BCNU (1). 32 patients, including patients in all 5 drugs categories, had ADAMTS13 activity measured; all were ≥ 25%. Patients were predominantly women (81%), similar to patients with severe ADAMTS13 deficiency, and almost all white (94%), distinct from patients with severe ADAMTS13 deficiency (J Thromb Haemost2005;3:1432). The short interval between exposure to quinine, ticlopidine, and clopidogrel and the diagnosis of TTP-HUS was consistent with an acute, immune-mediated mechanism, while the long interval between chemotherapy exposure and diagnosis of TTP-HUS was consistent with a cumulative dose-dependent toxicity. Calcineurin inhibitor-induced TTP-HUS has previously been described as dose-dependent toxicity. Although PEX was requested for all patients, 5 were not treated: 3 died before PEX was begun (quinine, ticlopidine, cyclosporine); 1 responded to plasma infusion (ticlopidine); 1 refused treatment and died (mitomycin C). Response to PEX, defined as achieving a platelet count ≥150,000/mL, occurred in 96% of patients following quinine or clopidogrel compared to 42% of patients following calcineurin inhibitors or chemotherapy. Death within 30 days, attributed to TTP-HUS, occurred with all drugs except clopidogrel; death at 1 year increased only among patients treated with chemotherapy, caused by their metastatic malignancy.

Conclusions:

Quinine was the most common drug associated with TTP-HUS. Drug-associated TTP-HUS appears to have 2 distinct etiologic mechanisms: acute and potentially immune-mediated reactions (quinine, ticlopidine, clopidogrel) and cumulative, dose-dependent toxicity (calcineurin inhibitors, chemotherapy agents). Although the role of PEX in the recovery of patients with drug-associated TTP-HUS is unclear, PEX may be appropriate initial treatment since some patients appear to respond and since a drug-associated etiology cannot be certain when patients initially present.