Immune-Mediated Thrombotic Thrombocytopenic Purpura: A Narrative Review of Diagnosis and Treatment in Adults

Abstract

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare and potentially lethal disease characterized by fragmentary hemolysis, moderate-to-severe thrombocytopenia, end-organ dysfunction, and severely reduced ADAMTS13 levels (< 10%). Survival in iTTP has improved significantly since the introduction of plasma exchange as standard therapy combined with immune suppression to address the underlying pathophysiology. A host of challenges remain including prompt recognition of the disease, treatment of the end-organ effects of the disease, improving the early mortality rate, significantly reducing the relapse rate as well as addressing refractory disease. Discussed in this narrative review of iTTP are the recent measures aimed at addressing these issues, including improvements in clinical prediction models, postremission maintenance approaches with early retreatment as well as the development of novel therapies.

A multicenter laboratory assessment of a new automated chemiluminescent assay for ADAMTS13 activity

“…Thrombotic thrombocytopenic purpura (TTP) is a rare but potentially fatal disorder, first characterized by Karl Singer and colleagues in 1947, 1 following pathological findings of thrombotic microangiopathy (TMA) by Eli Moschcowitz in 1924 2 . The pathogenesis of TTP is now understood to be caused by deficiency of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), 3 due to pioneering work of Moake et al in 1982, 4 and Furlan et al and Tsai et al in 1996 5,6 . ADAMTS13 deficiency results in accumulation of prothrombotic ultra‐large von Willebrand factor (VWF) multimers, and occurs either congenitally (ie, Upshaw Schulman Syndrome), or (more commonly) as an acquired event, typically due to ADAMTS13 antibodies (“inhibitors”) 3,7‐9 .…”

“…The pathogenesis of TTP is now understood to be caused by deficiency of ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), 3 due to pioneering work of Moake et al in 1982, 4 and Furlan et al and Tsai et al in 1996 5,6 . ADAMTS13 deficiency results in accumulation of prothrombotic ultra‐large von Willebrand factor (VWF) multimers, and occurs either congenitally (ie, Upshaw Schulman Syndrome), or (more commonly) as an acquired event, typically due to ADAMTS13 antibodies (“inhibitors”) 3,7‐9 . The annual incidence of acquired ADAMTS13 deficiency was reported as 2.1 per million population in Germany, as compared with 1.5 to 6.0 per million in France, the United States, and the UK 10 .…”

“…Given serious clinical sequelae associated with TTP, and difficulty in distinguishing TTP from other TMAs, laboratory testing for ADAMTS13 is undertaken. In practice, ADAMTS13 levels ≤ 10% (“severe deficiency”) are considered “diagnostic” for TTP 3 . Nevertheless, the 10% cut‐off is relatively arbitrary, and International Society on Thrombosis and Haemostasis (ISTH) guidance identifies results of 10% to 20% as potentially “equivocal.” 11 …”

“…Additional therapies may include immunosuppression and other agents (ie, steroids ± rituximab/caplacizumab) 3 . ADAMTS13 is also called VWF cleaving protease, as the main function of ADAMTS13 is to cleave VWF into smaller multimers, and thus moderate VWF activity 3 . Thus, deficiency of ADAMTS13 causes accumulation of large or ultra‐large VWF multimers, thereby increasing thrombosis risk and arising pathological sequalae.…”

“…Original assays utilized plasma‐derived VWF multimers as substrate and required time‐consuming steps of conformational unfolding 8,14 . Currently, most commonly utilized assays for measuring ADAMTS13 activity are based on enzyme‐linked immunosorbent assay (ELISA) or fluorescence resonance energy transfer (FRET)‐based technologies utilizing recombinant VWF substrates 3 . Although some institutions utilize in‐house assays, one commercial ELISA assay (Technozym ® ADAMTS‐13 Activity, Technoclone) is widely used.…”