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International audience; Background: Thrombotic thrombocytopenic purpura (TTP) is a life‐threatening thrombotic microangiopathy (TMA) caused by a severe functional deficiency in ADAMTS13 (a disintegrin and metalloprotease with thrombospondin type I repeats‐13), the specific von Willebrand factor (VWF) cleaving protease. ADAMTS13 activity is essential to diagnose TTP but remains challenging to assess, as reference ADAMTS13 activity assays are manual and time consuming. Current techniques also lack robustness in low detectable ADAMTS13 activity range, which could prove problematic for therapy‐driven monitoring.Objectives: The HemosIL AcuStar ADAMTS13 activity assay is a fast, automated chemiluminescent assay, the performance of which remains to be evaluated prospectively on very large cohorts of patients with TMA and in real‐life conditions.Patients and Methods: Our study was conducted over two successive sequences: a retrospective evaluation followed by a “real‐life” prospective evaluation. Overall, we evaluated the HemosIL AcuStar ADAMTS13 activity assay on 539 citrated plasma samples. We extensively studied linearity, limit of detection, contamination, intra‐assay and interassay precisions with a specific focus on levels < 25 IU/dL. Diagnostic performances for the detection of < 10 IU/dL ADAMTS13 activity and overall method comparison were conducted with the fluorescence resonance energy transfer (FRETS)‐VWF73 assay as the reference method.Results: Technical performance proved excellent. Robustness in low detectable ADAMTS13 activity range was good, potentially qualifying this assay for therapy‐driven monitoring. Comparison with the FRETS‐VWF73 assay was satisfactory (r2 = .83, P < .0001) as were the diagnostic performances for acute‐phase TTP (specificity, 99.7%; positive predictive value, 99.2%).Conclusion: The HemosIL AcuStar ADAMTS13 activity assay is a fast, reliable, automated technique well adapted as a first‐line ADAMTS13 activity assay for TTP diagnosis and follow‐up.

Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy (TMA) that requires prompt plasma exchange. Clinical prediction tools may facilitate decision-making in institutions with delayed turnaround time or limited access to ADAMTS13 assays. The PLASMIC score and Bentley score have been shown to predict severe ADAMTS13 deficiency with excellent sensitivity and specificity.To validate the PLASMIC score using a population of suspected TTP, and evaluate its discriminatory power in predicting severe ADAMTS13 deficiency in comparison with Bentley score and clinical gestalt.Adults presenting with suspected TTP in Alberta, Canada between 2008 and 2018 with available ADAMTS13 results were included. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for PLASMIC score, Bentley score and clinical gestalt. Receiver operator characteristics analysis assessed the performance of the scoring systems.Among 163 individuals with suspected TTP, ADAMTS13 activity was available in 117 (72%). Severe ADAMTS13 deficiency10% was present in 62 (53%). High-risk PLASMIC score (≥6) predicted severe ADAMTS13 deficiency with a sensitivity of 81.7%, specificity 71.4%, PPV 75.4% and NPV 78.4% (c-statistic 0.80). Intermediate-high risk Bentley score (≥20) had a lower sensitivity (59.5%) and higher specificity (93.9%) with similar c-statistic (0.77). Clinical gestalt had similar sensitivity as PLASMIC score but very low specificity (16.1%).Both PLASMIC and Bentley scores had good discriminatory power in identifying severe ADAMTS13 deficiency in a Canadian TMA population compared to clinical gestalt. Integration into institutional clinical pathways may help supplement clinical judgment and reduce costs.

Background Despite advances in treatment options for thrombotic thrombocytopenic purpura (TTP), there are still limited high quality data to inform clinicians regarding its appropriate treatment. Methods In June 2018, the ISTH formed a multidisciplinary guideline panel to issue recommendations about treatment of TTP. The panel discussed 12 treatment questions related to immune-mediated TTP (iTTP) and hereditary or congenital TTP (cTTP). The panel used the Grading of Recommendations Assessment, Development, and Evaluation approach, including evidence-to-decision frameworks, to appraise evidence and formulate recommendations. Results The panel agreed on 11 recommendations based on evidence ranging from very low to moderate certainty. For first acute episode and relapses of iTTP, the panel made a strong recommendation for adding corticosteroids to therapeutic plasma exchange (TPE) and a conditional recommendation for adding rituximab and caplacizumab. For asymptomatic iTTP with low plasma ADAMTS13 activity, the panel made a conditional recommendation for the use of rituximab outside of pregnancy, but prophylactic TPE during pregnancy. For asymptomatic cTTP, the panel made a strong recommendation for prophylactic plasma infusion during pregnancy, and a conditional recommendation for plasma infusion or a wait and watch approach outside of pregnancy. Conclusions The panel's recommendations are based on all the available evidence for the effects of an individual component of various treatment approaches, including suppressing inflammation, blocking platelet clumping, replacing the missing and/or inhibited ADAMTS13, and suppressing the formation of ADAMTS13 autoantibody. There was insufficient evidence for further comparing different treatment approaches (eg, TPE, corticosteroids, rituximab, and caplacizumab, etc.), for which high quality studies are needed.

Background: Thrombotic thrombocytopenic purpura (TTP) is a potentially fatal disease that requires early diagnosis and treatment that can be made possible by applying the PLASMIC score. This study aims to evaluate this score applicability for patients with suspected TTP in a developing country. Methods: This was a retrospective study performed at a tertiary hospital in the northeastern region of Brazil. Patients were analyzed in two groups: ADAMTS13 activity 10%. Patients were stratified according to the PLASMIC score, and the level of agreement between the PLASMIC score and the ADAMTS13 activity was evaluated. Results: Eight patients with thrombotic microangiopathy were included. Four patients had ADAMTS13 activity 10%, all with a score

ADAMTS13 (A Disintegrin and Metalloprotease with ThromboSpondin type 1 motifs) activity is a key tool in differential diagnosis of thrombotic microangiopathies (TMAs). Due to the lack of availability of ADAMTS13 testing, PLASMIC/PLASIC scores have been suggested to predict ADAMTS13 deficiency. The importance of differentiating TTP from other complement-mediated TMAs is highlighted by the need to urgently start plasma exchange and utility of treatments such as caplacizumab or eculuzimab. Therefore, we aimed to evaluate ADAMTS13 activity, PLASMIC/PLASIC scores, and complement testing in guiding management of a real-world TMA cohort. We enrolled consecutive TMA patients with samples referred to our Center (01/2018–2020). If ADAMTS13 ​> ​10%, soluble C5b-9 was measured. Among 80 TMA patients, ADAMTS13 activity was ≤10% in 50 patients, while 28 had a relapsing disease. PLASMIC/PLASIC were excellent predictors of ADAMTS13 deficiency, especially in patients without secondary causes. Soluble C5b-9 levels were elevated (median 525 ​ng/ml, range 313–913 ​ng/ml) in 7 patients without secondary causes and ADAMTS13 ​> ​10% (hemolytic uremic syndrome/HUS). Two were shiga-toxin associated; while 5 atypical HUS. Only 1/5 patients received eculizumab and achieved TMA resolution implemented by guidance based on soluble C5b-9 levels. In transplant-associated TMA, 8/16 patients not responding to first-line treatment received eculizumab due to elevated C5b-9 levels (median 353 ​ng/ml, range 281–1252 ​ng/ml) and achieved TMA resolution. In conclusion, our real-world data confirm that ADAMTS13, complement testing, and PLASMIC/PLASIC are valuable tools in diagnosis and management of TMAs, but also highlight the unmet need of using available markers and treatments in clinical practice.

The standard dose of rituximab used in B-cell hematological malignancies, 375 mg/m2 weekly, may be excessive for autoimmune conditions. Successful use of a low, fixed dose of 100-200 mg of rituximab, weekly for 4 weeks, has been reported in the literature in the treatment of autoimmune thrombotic thrombocytopenic purpura (aTTP). We retrospectively analyzed our rituximab data in aTTP over a 13-year-period for 39 patients, with the aim of comparing response and outcomes with a standard lymphoma-dose course versus a low fixed 100 mg-dose course. Compared to the standard dose (17 patients, 17 courses of 4 infusions), our patients who received a low dose (8 patients, 9 courses of 4 infusions) had a possibly lower baseline risk but did achieve a similar time to remission and number of plasma exchange procedures to remission. Preemptive low-dose courses for ADAMTS13 activity

ADAMTS13 is a metalloproteinase that cleaves von Willebrand factor (VWF) into smaller multimers in vivo. This cleavage creates both the typical multimeric size distribution and the characteristic triplet band distribution of VWF. Here we analysed ADAMTS13 content, VWF multimeric size distribution and VWF triplet structure in five commercial VWF/factor VIII (FVIII) concentrates. The relative distribution of ADAMTS13 activity values corresponded well to the ADAMTS13 antigen values for all examined concentrates except Haemate HS®, which had markedly higher ADAMTS13 antigen/activity ratio, with Fanhdi® and Haemate HS® displaying the most intense ADAMTS13 signal. Interestingly, ADAMTS13 levels did not correlate with the high molecular weight multimer content of the concentrates, but did correlate with VWF triplet distribution. Densitometric quantification showed that Wilate®, Immunate® and Willfact® displayed human plasma-like VWF triplet distribution, whereas Fanhdi® and Haemate HS® showed enhanced content of the faster migrating triplet band, which corresponded well to their higher ADAMTS13 content. In summary, Immunate®, Willfact® and Wilate® had lower levels of ADAMTS13 antigen and activity and exhibited a plasma-like VWF triplet structure. Fanhdi® and Haemate HS® had higher ADAMTS13 content and an altered triplet structure. The possible impact of these observations on function and clinical efficacy of VWF/FVIII concentrates is discussed.

Thrombotic thrombocytopenic purpura (TTP) is a rare but potentially fatal condition. In women with a previous history of TTP there is increased risk of recurrence during pregnancy and the puerperium. There is some evidence that the risk of relapse during pregnancy is increased if the interval between the event and conception is short. We present a case in which pregnancy was achieved a few days after full recovery from an acute episode of severe acquired TTP (ADAMTS13 activity

The increased understanding of the pathophysiology of both atypical hemolytic uremic syndrome (aHUS) and thrombotic thrombocytopenic purpura (TTP) in recent years has led to significant therapeutic advances for both conditions. These advances have placed an increased emphasis on a more rapid differentiation of both disorders which remain clinical diagnoses. In particular, recent data demonstrating the effectiveness of complement inhibition in patients with aHUS have increased the need for a more rapid and accurate differentiation of aHUS and TTP. Previously utilized criteria have used the presence or absence of neurologic or renal injury and the pretreatment ADAMTS13 activity to differentiate aHUS from TTP. The use of presenting clinical symptoms and findings alone to differentiate these conditions is problematic given their overlapping clinical presentations. Similarly, the use of the pretreatment ADAMTS13 activity alone to differentiate aHUS from TTP is also problematic, and could lead to the inappropriate witholding of plasma exchange (PEX) therapy. However, when used collectively, the pretreatment clinical findings (symptoms and laboratory data) and ADAMTS13 activity in the context of the patient's response to PEX therapy can allow for a more effective differentiation of these two disorders in a timely fashion that will allow for the prompt initiation of the most appropriate therapy.