Redefining outcomes in immune TTP: an international working group consensus report

Abstract

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a potentially fatal thrombotic microangiopathy caused by autoantibody-mediated severe deficiency of ADAMTS13. Standardized definitions of response, exacerbation, remission and relapse were initially proposed in 2003 and modified by the International Working Group (IWG) for TTP in 2017. These definitions, which have been widely used in clinical practice and research, are based primarily on the platelet count and are benchmarked against the timing of discontinuation of therapeutic plasma exchange (TPE). They do not incorporate ADAMTS13 activity or the temporizing effects of caplacizumab, a novel anti-von Willebrand factor (VWF) nanobody, on the platelet count. In light of these limitations, the IWG aimed to develop revised consensus outcome definitions that incorporate ADAMTS13 activity and the effects of anti-VWF therapy using an estimate-talk-estimate approach. The updated definitions distinguish clinical remission and clinical relapse (defined primarily by platelet count) from ADAMTS13 remission and ADAMTS13 relapse (defined by ADAMTS13 activity). The revised definitions of exacerbation and remission are benchmarked against not only the timing of discontinuation of TPE, but also of anti-VWF therapy. Retrospective validation of the revised definitions is described, though they remain to be prospectively validated. Clinical implications of the updated outcome definitions are also discussed and an example of their application to clinical practice is provided in order to highlight their clinical relevance.

The standard of care for immune thrombotic thrombocytopenic purpura today

“…One can assume that caplacizumab may be safely stopped once clinical remission and at least partial biochemical (ADAMTS‐13) recovery are achieved. This includes normalization of platelet counts, reduction of LDH to <2 × upper limit of normal (ULN), and plasma ADAMTS‐13 activity (>20 IU/dl or >20% of normal) according to the expert concensus 81 . In almost all cases experiencing an exacerbation of iTTP prior to the use of caplacizumab in our previous cohort 61 or after stopping of caplacizumab 65,74 had plasma ADAMTS‐13 activity at the levels of <10 IU/dl (or 10% of normal) while platelet counts were in the normal range.…”

Post Approval Experience with Caplacizumab for Acquired Thrombotic Thrombocytopenic Purpura at a Single Institution

“…We used the definitions for outcomes in aTTP from the International Working Group Consensus in aTTP [ 15 ]. Response was defined as a platelet count more than 150,000/uL and LDH less than 1.5 times the upper limit of normal (ULN).…”

Unresponsive Thrombotic Thrombocytopenic Purpura (TTP): Challenges and Solutions

“…The 2021 consensus introduced several new notions. 19 First, clinical response now also requires the absence of signs of new or progressive signs of ischemic organ injury, in addition to platelet and LDH rates improvement. Second, it introduces the notion of biological recovery, based on ADAMTS13 activity normalization, underpinned by the fact that TTP patients failing to reach ADAMTS13 activity recovery at the end of treatment are at very high risk of clinical relapse.…”