Abstract

Abstract 2203

Background:

Thrombotic thrombocytopenic purpura (TTP) is frequently characterized by severe ADAMTS13 deficiency, the cause of which is unknown. An important exception is ticlopidine-associated TTP (tc-TTP), the most common drug-induced TTP syndrome. In 1998, a possible association of TTP with ticlopidine was reported. In 1999, two additional series reported this association. In 2000, a fourth study reported severe A DAMTS13 deficiency among six of seven tc-TTP persons- suggesting a causal pathway. All of these reports were from the United States. Recently, we reported characteristics of 186 acquired idiopathic (ai)- TTP patients in Japan with severe ADAMTS13 deficiency, noting that clinical and laboratory findings for ai-TTP patients in Japan differed from those for cohorts of ai-TTP patients in Europe and North America- raising concern that TTP findings vary by region of the world. (PLOS One 2011) We now on report clinical and laboratory characteristics of a cohort of TTP patients from Japan with tc-TTP, and compare these findings to three cohorts of tc-TTP in the United States and one cohort of ai-TTP patients from Japan.

Methods:

We queried a database of thrombotic microangiopathy patients identified from a national TTP referral laboratory in Japan of cases identified between 1998 and 2008.

Severe ADAMTS13 deficiency was characterized by activity levels < 5%. All tc-TTP patients and 186 of 911 ai-TTP patients in the database had severe ADAMTS13 deficiency and first onset of TTP. Comparisons were made to tc-TTP patients reported previously from the United States.

Results:

Characteristics of ai- TTP with severe ADAMTS13 deficiency in Japan and tc-TTP in Japan and US

Matsumoto (n= 186)Bennett (n=22)Bennett (n= 98)Tsai (n=7)Steinhubl (n=19)
Source PLOS One 2011 This paper Arch Int Med 1999 Ann Int Med 2000 JAMA 1999 
Country Japan Japan US US US 
Etiology Idiopathic Ticlopidine Ticlopidine Ticlopidine Ticlopidine 
% female 55.1% 45.5% 46.6% 70.0% 30.0% 
Median Age (yrs) 54 (8 mos-87) 69 (41-89) 64.2 (11.1= SD) 57 (42-89) 62 (38-75) 
Plt < 20k/mm3 100.0% 96.0% 71.9% 100.0% 89.4% 
Hgb < 9 g/dl NA 72.7% 26,9% 42.3% 66.7% 
Cr > 2.0 mg/dl 75.8% 31.2% 30.1% NA 47.0% 
Neuro abn 79.0% 63.6% 73.1% 70.0% 73.7% 
Median days ticlopidine (range) NA 27.5 (14-36) 21 (7-112) 21 (14-56) 21 (14-28) 
% w/ coronary stent Not applicable 13.6% 42.3% 57.1% 100.0% 
% w/ other CAD indication NA 31.2% 0.0% 14.3% 0.0% 
% CVA prevention Not applicable 55.8% 57.7% 14.3% 0.0% 
Survival 84.3% 91.0% 84.9% 100.0% 78.9% 
% TPE NA 63.6% 74.2% 100.0% 68.4% 
Survival w/o TPE Not available 75.0% 42.1% NA 33.3% 
Survival w/ TPE 83.9% 100.0% 81.7% 100.0% 100.0% 
% w/ ADAMTS13:AC deficiency (<5%) 100.0% 100.0% 100.0% 83.3% NA 
% with ADAMTS13 inhibitors 97.8% 100.0% 100.0% 100.0% NA 
Matsumoto (n= 186)Bennett (n=22)Bennett (n= 98)Tsai (n=7)Steinhubl (n=19)
Source PLOS One 2011 This paper Arch Int Med 1999 Ann Int Med 2000 JAMA 1999 
Country Japan Japan US US US 
Etiology Idiopathic Ticlopidine Ticlopidine Ticlopidine Ticlopidine 
% female 55.1% 45.5% 46.6% 70.0% 30.0% 
Median Age (yrs) 54 (8 mos-87) 69 (41-89) 64.2 (11.1= SD) 57 (42-89) 62 (38-75) 
Plt < 20k/mm3 100.0% 96.0% 71.9% 100.0% 89.4% 
Hgb < 9 g/dl NA 72.7% 26,9% 42.3% 66.7% 
Cr > 2.0 mg/dl 75.8% 31.2% 30.1% NA 47.0% 
Neuro abn 79.0% 63.6% 73.1% 70.0% 73.7% 
Median days ticlopidine (range) NA 27.5 (14-36) 21 (7-112) 21 (14-56) 21 (14-28) 
% w/ coronary stent Not applicable 13.6% 42.3% 57.1% 100.0% 
% w/ other CAD indication NA 31.2% 0.0% 14.3% 0.0% 
% CVA prevention Not applicable 55.8% 57.7% 14.3% 0.0% 
Survival 84.3% 91.0% 84.9% 100.0% 78.9% 
% TPE NA 63.6% 74.2% 100.0% 68.4% 
Survival w/o TPE Not available 75.0% 42.1% NA 33.3% 
Survival w/ TPE 83.9% 100.0% 81.7% 100.0% 100.0% 
% w/ ADAMTS13:AC deficiency (<5%) 100.0% 100.0% 100.0% 83.3% NA 
% with ADAMTS13 inhibitors 97.8% 100.0% 100.0% 100.0% NA 
Conclusions:

These data from Japan validate insights about tc-TTP initially proposed in 1998, 1999, and 2000 in the United States. Ticlopidine is a likely cause of TTP, the mechanism is via a cross-reactive antibody to ADAMTS13:AC resulting in formation of an ADAMTS13:INH, and therapeutic plasma exchange is necessary for treatment.

Disclosures:

Ortel:Eisai: Research Funding; Glaxo SmithKline: Research Funding; Pfizer: Research Funding; Instrumentation Laboratory, Inc: Consultancy, Research Funding; Boehringer Ingelheim: Consultancy. Fujimura:Baxter BioScience: Membership on an entity's Board of Directors or advisory committees; Alexion Pharma: Membership on an entity's Board of Directors or advisory committees.

Author notes

*

Asterisk with author names denotes non-ASH members.