ISTH guidelines for the diagnosis of thrombotic thrombocytopenic purpura

Abstract

Background: Despite an increase in our understandings of pathogenesis of thrombotic thrombocytopenic purpura (TTP), the approaches for initial diagnosis and management of TTP vary significantly.

Objective: The evidence-based guidelines of the International Society on Thrombosis and Haemostasis (ISTH) are intended to support patients, clinicians, and other health care professionals in their decisions about the initial diagnosis and management of acute TTP.

Methods: In June 2018, ISTH formed a multidisciplinary panel that included hematologists, an intensive care physician, nephrologist, clinical pathologist, biostatistician, and patient representatives, as well as a methodology team from McMaster University. The panel composition was designed to minimize the potential conflicts of interests. The panel used the Grading of Recommendations Assessment, Development, and Evaluation approach and the Population, Intervention, Comparison, Outcome framework to develop and grade their recommendations. Public comments were sought and incorporated in the final document.

Results: The panel agreed on three recommendations covering the initial diagnosis with emphasis on the importance of ADAMTS13 testing (eg, activity, anti-ADAMTS13 IgG or inhibitor) and assessment of the pretest probability of TTP by clinical assessment and/or the risk assessment models like the PLASMIC or French score. The panel noted how availability and turnaround time of ADAMTS13 test results might affect early diagnosis and management, in particular the use of caplacizumab.

Conclusions: There is a lack of high-quality evidence to support strong recommendations for the initial diagnosis and management of a suspected TTP. The panel emphasized the importance of obtaining ADAMTS13 testing in a proper clinical context. Future research should focus on how to monitor and act on ADAMTS13 levels during remission.

Keywords: ADAMTS13; TTP; diagnosis; guidelines; thrombosis.

FIGURE 1

A suggested diagnostic and early management strategy for patients with HIGH (≥90%) pretest probability of TTP. Pretest probability of TTP should be determined based on clinical parameters (eg, PLASMIC score or French score). If the pretest probability of TTP is high, start TPE and corticosteroids, and collect plasma samples for ADAMTS13 testing (eg, ADAMTS13 activity and inhibitors, anti-ADAMTS13 IgG) before therapy. Consider caplacizumab if ADAMTS13 test results are expected within 72 hours; if ADAMTS13 test results are not available, do not start caplacizumab; if ADAMTS13 <10 IU/dL (or 10% of normal), continue caplacizumab and rituximab. If ADAMTS13 is ≥20 IU/dL (or 20% of normal), consider stop caplacizumab and seek other diagnoses. However, if ADAMTS13 activity is in borderline (10–20 IU/dL or 10%−20% of normal), clinical judgment is required for continuing therapies or seeking other alternative diagnoses (All are conditional recommendations in the setting of low certainty of evidence). Here “treatment” includes caplacizumab and other therapies (eg, TPE and steroids)

FIGURE 2

A suggested diagnostic and management strategy for patients with LOW or INTERMEDIATE pretest probability of TTP. Pretest probability of TTP should be determined based on clinical presentation and laboratory results. If probability of TTP is low or intermediate, still consider TPE and corticosteroids, but withhold caplacizumab until plasma ADAMTS13 test results are available. If ADAMTS13 test is not available, no caplacizumab should be started; if ADAMTS13 activity is <10 IU/dL (or 10% of normal), consider adding caplacizumab and rituximab; if ADAMTS13 activity is ≥20 IU/dL (or 20% of normal), no caplacizumab should be used and other diagnoses should be actively sought; if ADAMTS13 activity falls borderline between 10 and 20 IU/dL (or 10%–20% of normal), consider other diagnoses. Further treatments in these patients should be based on physician’s own clinical judgment (Note: All are conditional recommendations in the setting of low certainty of evidence)