Ticlopidine- and clopidogrel-associated thrombotic thrombocytopenic purpura (TTP): review of clinical, laboratory, epidemiological, and pharmacovigilance findings (1989-2008).
Thrombotic thrombocytopenic purpura (TTP) is a fulminant disease characterized by platelet aggregates, thrombocytopenia, renal insufficiency, neurologic changes, and mechanical injury to erythrocytes. Most idiopathic cases of TTP are characterized by a deficiency of ADAMTS13 (a disintegrin and metalloprotease, with thrombospondin-1-like domains) metalloprotease activity. Ironically, use of anti-platelet agents, the thienopyridine derivates clopidogrel and ticlopidine, is associated with drug induced TTP. Data were abstracted from a systematic review of English-language literature for thienopyridine-associated TTP identified in MEDLINE, EMBASE, the public website of the Food and Drug Administration, and abstracts from national scientific conferences from 1991 to April 2008. Ticlopidine and clopidogrel are the two most common drugs associated with TTP in FDA safety databases. Epidemiological studies identify recent initiation of anti-platelet agents as the most common risk factor associated with risks of developing TTP. Laboratory studies indicate that most cases of thienopyridine-associated TTP involve an antibody to ADAMTS13 metalloprotease, present with severe thrombocytopenia, and respond to therapeutic plasma exchange (TPE); a minority of thienopyridine-associated TTP presents with severe renal insufficiency, involves direct endothelial cell damage, and is less responsive to TPE. The evaluation of this potentially fatal drug toxicity can serve as a template for future efforts to comprehensively characterize other severe adverse drug reactions.
Zakarija
Anaadriana
A
Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Kwaan
Hau C
HC
Moake
Joel L
JL
Bandarenko
Nicholas
N
Pandey
Dilip K
DK
McKoy
June M
JM
Yarnold
Paul R
PR
Raisch
Dennis W
DW
Winters
Jeffrey L
JL
Raife
Thomas J
TJ
Cursio
John F
JF
Luu
Thanh Ha
TH
Richey
Elizabeth A
EA
Fisher
Matthew J
MJ
Ortel
Thomas L
TL
Tallman
Martin S
MS
Zheng
X Long
XL
Matsumoto
Masanori
M
Fujimura
Yoshihiro
Y
Bennett
Charles L
CL
D051722:ADAM Proteins / Q000276:immunology; D000071120:ADAMTS13 Protein; D016907:Adverse Drug Reaction Reporting Systems; D000818:Animals; D001323:Autoantibodies / Q000097:blood; D000077144:Clopidogrel; D016021:Epidemiologic Studies; D006801:Humans; D010951:Plasma Exchange; D010975:Platelet Aggregation Inhibitors / Q000009:adverse effects*; D011697:Purpura, Thrombotic Thrombocytopenic / Q000139:chemically induced* / Q000453:epidemiology / Q000276:immunology / Q000628:therapy; D051437:Renal Insufficiency / Q000139:chemically induced; D012307:Risk Factors; D013988:Ticlopidine / Q000009:adverse effects* / Q000031:analogs & derivatives*; D016896:Treatment Outcome
D001323:Autoantibodies; D010975:Platelet Aggregation Inhibitors; D000077144:Clopidogrel; D051722:ADAM Proteins; D000071120:ADAMTS13 Protein; C099604:ADAMTS13 protein, human; D013988:Ticlopidine