title: Two mechanistic pathways for thienopyridine-associated thrombotic thrombocytopenic purpura: a report from the SERF-TTP Research Group and the RADAR Project.
abstract: OBJECTIVE
  We sought to describe clinical and laboratory findings for a large cohort of patients with thienopyridine-associated thrombotic thrombocytopenic purpura (TTP).
  
  
  BACKGROUND
  The thienopyridine derivatives, ticlopidine and clopidogrel, are the 2 most common drugs associated with TTP in databases maintained by the U.S. Food and Drug Administration (FDA).
  
  
  METHODS
  Clinical reports of TTP associated with clopidogrel and ticlopidine were identified from medical records, published case reports, and FDA case reports (n = 128). Duration of thienopyridine exposure, clinical and laboratory findings, and survival were recorded. ADAMTS13 activity (n = 39) and inhibitor (n = 30) were measured for a subset of individuals.
  
  
  RESULTS
  Compared with clopidogrel-associated TTP cases (n = 35), ticlopidine-associated TTP cases (n = 93) were more likely to have received more than 2 weeks of drug (90% vs. 26%), to be severely thrombocytopenic (84% vs. 60%), and to have normal renal function (72% vs. 45%) (p < 0.01 for each). Compared with TTP patients with ADAMTS13 activity >15% (n = 13), TTP patients with severely deficient ADAMTS13 activity (n = 26) were more likely to have received ticlopidine (92.3% vs. 46.2%, p < 0.003). Among patients who developed TTP >2 weeks after thienopyridine, therapeutic plasma exchange (TPE) increased likelihood of survival (84% vs. 38%, p < 0.05). Among patients who developed TTP within 2 weeks of starting thienopyridines, survival was 77% with TPE and 78% without.
  
  
  CONCLUSIONS
  Thrombotic thrombocytopenic purpura is a rare complication of thienopyridine treatment. This drug toxicity appears to occur by 2 different mechanistic pathways, characterized primarily by time of onset before versus after 2 weeks of thienopyridine administration. If TTP occurs after 2 weeks of ticlopidine or clopidogrel therapy, therapeutic plasma exchange must be promptly instituted to enhance likelihood of survival.
authors.affiliation: VA Center for Management of Complex Chronic Care at Jesse Brown VA Medical Center, Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. cbenne@northwestern.edu
authors.forename: Charles L
authors.initials: CL
authors.lastname: Bennett
authors.forename: Benjamin
authors.initials: B
authors.lastname: Kim
authors.forename: Anaadriana
authors.initials: A
authors.lastname: Zakarija
authors.forename: Nicholas
authors.initials: N
authors.lastname: Bandarenko
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Pandey
authors.forename: Charlie G
authors.initials: CG
authors.lastname: Buffie
authors.forename: June M
authors.initials: JM
authors.lastname: McKoy
authors.forename: Amul D
authors.initials: AD
authors.lastname: Tevar
authors.forename: John F
authors.initials: JF
authors.lastname: Cursio
authors.forename: Paul R
authors.initials: PR
authors.lastname: Yarnold
authors.forename: Hau C
authors.initials: HC
authors.lastname: Kwaan
authors.forename: Davide
authors.initials: D
authors.lastname: De Masi
authors.forename: Ravindra
authors.initials: R
authors.lastname: Sarode
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Raife
authors.forename: Joseph E
authors.initials: JE
authors.lastname: Kiss
authors.forename: Dennis W
authors.initials: DW
authors.lastname: Raisch
authors.forename: Charles
authors.initials: C
authors.lastname: Davidson
authors.forename: J Evan
authors.initials: JE
authors.lastname: Sadler
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Ortel
authors.forename: X Long
authors.initials: XL
authors.lastname: Zheng
authors.forename: Seiji
authors.initials: S
authors.lastname: Kato
authors.forename: Masanori
authors.initials: M
authors.lastname: Matsumoto
authors.forename: Masahito
authors.initials: M
authors.lastname: Uemura
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Fujimura
mesh_terms: D016907:Adverse Drug Reaction Reporting Systems / Q000706:statistics & numerical data*; D017677:Age Distribution; D000368:Aged; D000704:Analysis of Variance; D000077144:Clopidogrel; D015331:Cohort Studies; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D015994:Incidence; D008297:Male; D008875:Middle Aged; D010951:Plasma Exchange; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects* / Q000627:therapeutic use; D011336:Probability; D011697:Purpura, Thrombotic Thrombocytopenic / Q000139:chemically induced* / Q000401:mortality* / Q000628:therapy; D011725:Pyridines / Q000009:adverse effects* / Q000627:therapeutic use; D018570:Risk Assessment; D012720:Severity of Illness Index; D017678:Sex Distribution; D016019:Survival Analysis; D013988:Ticlopidine / Q000009:adverse effects / Q000031:analogs & derivatives / Q000627:therapeutic use
chemical_list: D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; C446540:thienopyridine; D000077144:Clopidogrel; D013988:Ticlopidine