Two mechanistic pathways for thienopyridine-associated thrombotic thrombocytopenic purpura: a report from the SERF-TTP Research Group and the RADAR Project.
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.
Bennett
Charles L
CL
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
Kim
Benjamin
B
Zakarija
Anaadriana
A
Bandarenko
Nicholas
N
Pandey
Dilip K
DK
Buffie
Charlie G
CG
McKoy
June M
JM
Tevar
Amul D
AD
Cursio
John F
JF
Yarnold
Paul R
PR
Kwaan
Hau C
HC
De Masi
Davide
D
Sarode
Ravindra
R
Raife
Thomas J
TJ
Kiss
Joseph E
JE
Raisch
Dennis W
DW
Davidson
Charles
C
Sadler
J Evan
JE
Ortel
Thomas L
TL
Zheng
X Long
XL
Kato
Seiji
S
Matsumoto
Masanori
M
Uemura
Masahito
M
Fujimura
Yoshihiro
Y
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
D010975:Platelet Aggregation Inhibitors; D011725:Pyridines; C446540:thienopyridine; D000077144:Clopidogrel; D013988:Ticlopidine