Acquired Idiopathic ADAMTS13 Activity Deficient Thrombotic Thrombocytopenic Purpura in a Population from Japan

Masanori Matsumoto,Zaina Qureshi,Ayami Isonishi,Yoko Yoshida,Charles L Bennett,Hideo Yagi,Yuji Hori,Masaki Hayakawa,Yoshihiro Fujimura,Pieter H Reitsma

doi:10.1371/journal.pone.0033029

Abstract

Thrombotic thrombocytopenic purpura (TTP) is a type of thrombotic microangiopathy (TMA). Studies report that the majority of TTP patients present with a deficiency of ADAMTS13 activity. In a database of TMA patients in Japan identified between 1998 and 2008, 186 patients with first onset of acquired idiopathic (ai) ADAMTS13-deficient TTP (ADAMTS13 activity <5%) were diagnosed. The median age of onset of TTP in this group of patients was 54 years, 54.8% were female, 75.8% had renal involvement, 79.0% had neurologic symptoms, and 97.8% had detectable inhibitors to ADAMTS13 activity. Younger patients were less likely to present with renal or neurologic dysfunction (p<0.01), while older patients were more likely to die during the TTP hospitalization (p<0.05). Findings from this cohort in Japan differ from those reported previously from the United States, Europe, and Korea with respect to age at onset (two decades younger in the other cohort) and gender composition (60% to 100% female in the other cohort). We conclude that in one of the largest cohorts of ai-TTP with severe deficiency of ADAMTS13 activity reported to date, demographic characteristics differ in Japanese patients relative to those reported from a large Caucasian registry from Western societies. Additional studies exploring these findings are needed.

Highlights

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disorder and originally defined by classic ‘‘pentad’’; thrombocytopenia, microangiopthic hemolytic anemia (MAHA), renal impairment, neurological symptoms, and fever [1]
We found four ai-TTP patients without ADAMTS13 inhibitor (,0.5 Bethesda unit (BU)/ml), whose ADAMTS13:AC, was normalized after remission
We evaluated 186 patients with initial onset of severely deficient ADAMTS13:AC levels TTP in Japan, representing the largest cohort of ai-TTP patients with ADAMTS13:AC deficiency reported from Japan

Summary

Introduction

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disorder and originally defined by classic ‘‘pentad’’; thrombocytopenia, microangiopthic hemolytic anemia (MAHA), renal impairment, neurological symptoms, and fever [1]. In 1998, two studies identified deficiency of plasma ADAMTS13 (a disintegrin-like and metalloprotease with thrombospndin type 1 motifs 13) activity (ADAMTS13:AC) among persons with TTP [2,3]. VWF is synthesized in vascular endothelial cells and megakaryocytes. Vascular endothelial cell-derived VWF is released into the plasma as unusually large VWF multimers (ULVWFMs). UL-VWFMs are degraded into smaller size VWF multimers by ADAMTS13. Severe deficiency of ADAMTS13:AC, either congenital or acquired, results in accumulation of ULVWFMs and formation of platelet thrombi in the microvasculatures. In congenital TTP (Upshaw-Schulman syndrome), ADAMTS13 deficiency is caused by mutations in the ADAMTS13 gene [4]. Acquired TTP is frequently caused by inhibitory autoantibodies against ADAMTS13 [2,3]

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Conclusion