Danielson, Constance

Abstract Background : Many idiopathic thrombotic thrombocytopenia purpura (TTP) patients have severe deficiency of ADAMTS13, an enzyme that cleaves ultralarge von Willebrand multimers. We recently reported that thienopyridine-associated TTP is characterized by an immunologic pathway with severe ADAMTS13 deficiency and a non-immunologic pathway with higher ADAMTS13 activity levels. We now compare findings for idiopathic and thienopyridine-associated TTP patients. Methods : Clinical findings and laboratory findings were evaluated for 51 idiopathic and 39 thienopyridine-associated TTP. Results: Clinical findings were similar between idiopathic and thienopyridine-associated TTP for both severe ADAMTS13 deficient and non-deficient patients. Differences were noted in gender and age, relapse rates, and survival. Conclusion : Among TTP patients with ADAMTS13 deficiency, relapses are frequent in idiopathic TTP patients and Rituximab may be useful, while for thienopyridine-associated TTP patients spontaneous relapse are rare as long as no re-exposure occurs. Among ADAMTS13 non-deficient patients, survival is high following therapeutic plasma exchange (TPE) for idiopathic patients but not for thienopyridine-associated TTP patients. Despite similarities, idiopathic and thienopyridine associated TTP probably have different initiating factors. ADAMTS13 activity and clinical characteristics in idiopathic and thienopyridine-associated TTP Idiopathic severe ADAMTS13 deficiency (n=29) †Thienopyridine severe ADAMTS13 deficiency (n=26) Idiopathic non-severe ADAMTS13 deficiency (n=22) †Thienopyridine non-severe ADAMTS13 deficiency (n=13) *p<0.05 for comparison of severe ADAMTS13 deficiency versus non-severe ADAMTS13 deficiency. †Thienopyridine-associated TTP clinical and presenting neutralizing autoantibody data was summarized from the Journal of the American College of Cardiology publication by Bennett et al. in 2007. ‡Thienopyridine-associated TTP remission autoantibody data was summarized Tsai et al, 2002, Bennett et al, 2000, and Orimo et al, 2002, and included 3 patients. §Data from average of ADAMTS13 deficient and non-deficient cohorts. Mean Age 41 67 47 60 Sex (% female) 79% 54% 86% 39% Platelet count/mm3 (mean)* 18,978 9,269 51,409 35,000 Platelet count <20,000/mm3* 69% 96% 23% 38% Hemoglobin (mg/dl; mean) 8.5 8.3 9.0 8.4 Creatinine (mg/dl; mean)* 1.5 2.2 3.2 3.0 Creatinine >2.5 mg/dl* 11% 27% 48% 46% 30-day survival 96% 85% 90% 62% Long-term relapse* 42% 8% 0% 0% Neutralizing autoantibodies to ADAMTS13 (prior to TPE) § 79% 100% 27% 0% Neutralizing autoantibodies to ADAMTS 13 (measured at remission) § 55% 33%‡ 33% 0%

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 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.