Paradigm shift of childhood thrombotic thrombocytopenic purpura with severe ADAMTS13 deficiency

Abstract

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening generalized disease with pathological conditions termed thrombotic microangiopathy (TMA). TTP is thought to predominantly affect adults and to rarely occur in children. Currently, TTP is defined by a severe deficiency in the activity of ADAMTS13, a metalloprotease that specifically cleaves unusually large von Willebrand factor multimers under high shear stress. Genetic mutations in and acquired autoantibodies to ADAMTS13 cause congenital TTP (termed Upshaw-Schulman syndrome [USS]) and acquired TTP, respectively. Because of very few overt clinical signs for TTP, USS is often misdiagnosed as chronic idiopathic thrombocytopenic purpura or overlooked during childhood. However, in women with USS, pregnancy can induce thrombocytopenia followed by the development of TTP. Furthermore, early childhood cases of acquired idiopathic TTP have not been characterized. From 1998 to 2008, our institution at Nara Medical University functioned as a TMA referral center in Japan and collected a large dataset on 919 TMA patients (Intern Med 2010;49:7-15). This registry contains 324 patients with a severe deficiency in ADAMTS13 activity, including 41 patients with USS and 283 patients with acquired TTP. Of note, the latter population contains 17 patients who were enrolled as children (≤ 15years old), including 14 children with idiopathic TTP and three with connective tissue disease-associated TTP. Of the 14 patients with idiopathic TTP, five were very young children (under 2 years old). This study focused on these 58 patients (41 USS and 17 acquired TTP) who were diagnosed with a severe deficiency in ADAMTS13 activity during childhood, causing a paradigm shift in our concept of TTP.