Ticlopidine-, Clopidogrel-, and Prasugrel-Associated Thrombotic Thrombocytopenic Purpura: A 20-Year Review from the Southern Network on Adverse Reactions (SONAR)

Abstract

Thienopyridine-derivatives (ticlopidine, clopidogrel, and prasugrel) are the primary antiplatelet agents. Thrombotic thrombocytopenic purpura (TTP) is a rare drug-associated syndrome, with the thienopyridines being the most common drugs implicated in this syndrome. We reviewed 20 years of information on clinical, epidemiologic, and laboratory findings for thienopyridine-associated TTP. Four, 11, and 11 cases of thienopyridine-associated TTP were reported in the first year of marketing of ticlopidine (1989), clopidogrel (1998), and prasugrel (2010), respectively. As of 2011, the FDA received reports of 97 ticlopidine-, 197 clopidogrel-, and 14 prasugrel-associated TTP cases. Severe deficiency of ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) was present in 80% and antibodies to 100% of these TTP patients on ticlopidine, 0% of the patients with clopidogrel-associated TTP (p < 0.05), and an unknown percentage of patients with prasugrel-associated TTP. TTP is associated with use of each of the three thienopyridines, although the mechanistic pathways may differ.

An Atypical Cause Of Atypical Hemolytic Uremic Syndrome

“…Our patient had been on Plavix for years making Plavix induced TTP/HUS unlikely in this case. 9 aHUS has been strongly associated with transplant surgeries and infections but never with Coronary Artery Bypass Grafting. TTP, on the other hand, has had a strong correlation with this procedure.…”

Drug-Induced Glomerular Disease

“…Ticlopidine, clopidogrel, and prasugrel are antiplatelet agents that target the P2Y 12 ADP receptor, and they are used to prevent and/or treat cerebrovascular accidents and coronary artery events, including stent thrombosis (55,56). Paradoxically, this class of drugs is one of the most commonly implicated in drug-induced TMA (55,56).…”

“…Paradoxically, this class of drugs is one of the most commonly implicated in drug-induced TMA (55,56).…”

Prasugrel and Acquired Thrombotic Thrombocytopenic Purpura Associated with ADAMTS13 Activity Deficiency

“…The Oklahoma TTP-HUS Registry, conducted between 1998 and 2014 and including 487 patients, only described 5% of cases of druginduced TTP [3] . A study carried out in the US between 1991 and 2011 stated that clopidogrel was most commonly associated with TTP (197 cases), followed by ticlopidine (97 cases) and prasugrel 14 cases [4] . Interestingly, TTP is mainly described as appearing early after drug initiation.…”

“…It is unusual for cases of drug-induced TTP to show a severely decreased activity of ADAMTS13 (activity <10%), yet a relatively normal or slightly decreased activity in the absence of inhibitory antibodies would help in its diagnosis. Thienopyridines are the only drugs pathophysiologically related to the presence of neutralizing antibodies against ADAMTS13 and present a good response to plasmapheresis [4] . Even though 14 cases of prasugrel-related TTP have been reported by the FDA, there has been no evidence until now of the biological significance of ADAMTS13 activity, as shown in our patient.…”