International Working Group Publishes Revised Definitions for Remission, Relapse in Immune TTP

The International Working Group (IWG) for thrombotic thrombocytopenic purpura (TTP) has published revised definitions for response, exacerbation, remission, and relapse of immune-mediated TTP (iTTP) in a recent issue of Blood. The new definitions incorporate ADAMTS13 activity and the effects of anti-von Willebrand factor (anti-VWF) therapy on platelet counts in the management of iTTP, which represent an improvement over previous guidelines regarding the assessment of remission and relapse.

According to the lead author of the IWG consensus report Adam Cuker, MD, of the University of Pennsylvania, the revised definitions offer important enhancements to prior definitions, including the clinical outcome criteria in iTTP which were first published in 2003. When the 2003 criteria were proposed, initial treatment for iTTP included therapeutic plasma exchange (TPE) and corticosteroids. Treatment with rituximab had just been reported and the association of ADAMTS13 deficiency with TTP was only recently described in the literature.

In the nearly two decades since, the measurement of ADAMTS13 activity has become easier to measure and more widely adopted in clinical practice to aid diagnosis and predict risk for disease recurrence and treatment response. The anti-VWF nanobody caplacizumab was recently approved for the initial management of iTTP, in addition to TPE and other anti-VWF agents.

Due to these advances in iTTP knowledge and treatment, the new IWG definitions mark a dramatic shift in developing outcome definitions that measure disease activity and predict remission and relapse. The revised definitions were based on a literature review by the IWG committee and a consensus of the authors.

“The new definitions acknowledge that the anti-VWF agent caplacizumab is a temporizing therapy and that a normal platelet count while the patient is receiving caplacizumab does not imply that the patient’s TTP is in remission,” Dr. Cuker told ASH Clinical News. Rather, the temporizing effects of the therapy can be used to “buy time” to allow for immunosuppressive therapy, such as rituximab, to lessen the production of anti-ADAMTS13 autoantibodies and support ADAMTS13 recovery.

Given that patients with iTTP who experience an initial clinical response to TPE may also have a clinical exacerbation because of persistent severe ADAMTS13 deficiency shortly after discontinuing TPE, the IWG committee proposed definitions to distinguish clinical remission from ADAMTS13 remission. “The new definitions also distinguish clinical remission and clinical relapse, defined primarily by the platelet count, from ADAMTS13 remission and ADAMTS13 relapse, defined by ADAMTS13 activity,” said Dr. Cuker, “thereby acknowledging that the two don’t always go together.”

Clinical remission is now defined as a sustained clinical response with either no TPE or no anti-VWF agent for ≥30 days or achievement of partial or complete ADAMTS13 remission, whichever occurs first. Partial ADAMTS13 remission is defined as ADAMTS13 activity of at least 20% but less than the lower limit of normal, while complete ADAMTS13 remission is defined as ADAMTS13 activity at the lower level of normal or higher.

“For example, a patient may have a clinical remission without an ADAMTS13 remission or an ADAMTS13 relapse without a clinical relapse,” added Dr. Cuker. “Such patients are at increased risk of clinical relapse unless they are given treatment to bring up their ADAMTS13 activity level, such as to induce an ADAMTS13 remission.”

Definitions were also made to separate clinical relapse from ADAMTS13 relapse. Clinical relapse was defined as a decrease in platelet count to <150×109/L with or without clinical evidence of new ischemic organ injury, while an ADAMTS13 relapse was defined as a decrease in ADAMTS13 activity to <20% following a complete or partial ADAMTS13 remission. Also, according to the guideline authors, recurrent iTTP episodes that occur within 30 days after caplacizumab cessation and before clinical remission should be reclassified as clinical exacerbations.

In terms of the proposed criteria’s limitations, Dr. Cuker noted that these revised definitions require validation in prospective studies.

Study authors report no relevant conflicts of interest.


Cuker A, Cataland SR, Coppo P, et al. Redefining outcomes in immune TTP: An international working group consensus report. Blood. 2021 February 2. [Epub ahead of print]