Publications by authors named "Agnès Veyradier"

117 Publications

[Acquired hemophilia A: clinical and biological characteristics and therapeutic management of a series of eight patients hospitalized in Lariboisière and Saint-Louis hospitals].

Ann Biol Clin (Paris) 2021 Feb;79(1):75-82

Service d'hématologie biologique, CRMR des MAT-laboratoire ADAMTS13, CRMR de la Maladie de Willebrand, DMU BioGEM, Hôpital Lariboisière, AP-HP Nord, Université de Paris, Paris, France, EA-3518 Recherche clinique en hématologie, immunologie et transplantation, Groupe MicroAngiopathies Thrombotiques, VWF et ADAMTS13, Institut de recherche Saint-Louis, Université de Paris, Paris, France.

Acquired hemophilia A is a rare autoimmune disease, linked to the appearance of autoantibodies directed against circulating factor VIII, and characterized by a major hemorrhagic syndrome. Acquired hemophilia A is a life-threatening diagnostic and therapeutic medical emergency. We describe here the cohort of patients with acquired hemophilia A treated between 2015 and 2020 at Lariboisière and Saint-Louis University Hospitals (Paris, France). We remind you here of the measures to be taken without delay in the face of any clinical and/or biological suspicion. Management is based on three main areas published in multicentre cohort studies, essentially observational: symptomatic treatment to control the hemorrhagic syndrome, immunosuppressive treatment to eradicate autoantibodies and manage their possible complications, and etiological treatment of the underlying pathology for secondary forms.
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http://dx.doi.org/10.1684/abc.2021.1625DOI Listing
February 2021

Thrombotic Thrombocytopenic Purpura: When Basic Science Meets Clinical Research.

Hamostaseologie 2021 Feb 19. Epub 2021 Feb 19.

Centre de Référence des MicroAngiopathies Thrombotiques, Paris, France.

The therapeutic landscape of thrombotic thrombocytopenic purpura (TTP) is rapidly changing with the recent availability of new targeted therapies. This progressive shift from empiricism to pathophysiology-based treatments reflects an intensive interaction between the continuous findings in the field of basic science and an efficient collaborative clinical research and represents a convincing example of the strength of translational medicine. Despite the rarity of TTP, national and international efforts could circumvent this limitation and shed light on the epidemiology, clinical presentation, prognosis, and long-term outcome of this disease. Importantly, they also provided high-quality results and practice changing studies for the benefit of patients. We report here the most recent therapeutic findings that allowed progressively improving the prognostic of TTP, both at the acute phase and through long-term outcome.
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http://dx.doi.org/10.1055/a-1332-3066DOI Listing
February 2021

Identification of a novel genetic locus associated with immune mediated thrombotic thrombocytopenic purpura.

Haematologica 2021 Feb 18. Epub 2021 Feb 18.

Haemostasis Research Unit, UCL (London, UK); National Institute for Health Research Cardiometabolic Programme, UCLH/UCL Cardiovascular BRC (London, UK).

Not available.
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http://dx.doi.org/10.3324/haematol.2020.274639DOI Listing
February 2021

N-glycan mediated shielding of ADAMTS13 prevents binding of pathogenic autoantibodies in immune-mediated TTP.

Blood 2021 Feb 5. Epub 2021 Feb 5.

Sanquin Research Amsterdam UMC Landsteiner Laboratory, Amsterdam, Netherlands.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is an autoimmune disorder caused by the development of autoantibodies targeting different domains of ADAMTS13. Profiling studies have shown that residues R568, F592, R660, Y661 and Y665 within exosite-3 of the spacer domain provide an immunodominant region of ADAMTS13 for pathogenic autoantibodies that develop in patients with iTTP. Modification of these 5 core residues with the goal of reducing auto-antibody binding revealed a significant trade-off between autoantibody resistance and proteolytic activity. Here, we employed structural bioinformatics to identify a larger epitope landscape on the ADAMTS13 spacer domain. Models of spacer-antibody complexes predicted that residues R568, L591, F592, K608, M609, R636, L637, R639, R660, Y661, Y665 and L668 contribute to an expanded epitope within the spacer domain. Based on bioinformatics-guided predictions we designed a panel of N-glycan insertions in this expanded epitope to reduce the binding of spacer domain autoantibodies. One N-glycan variant (NGLY3-ADAMTS13, containing a K608N substitution) showed strongly reduced reactivity with TTP patient sera (28%) as compared to WT-ADAMTS13 (100%). Insertion of an N-glycan at amino acid position 608 did not interfere with processing of VWF positioning the resulting NGLY3-ADAMTS13 variant as a potential novel therapeutic option for treatment of iTTP.
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http://dx.doi.org/10.1182/blood.2020007972DOI Listing
February 2021

ADAMTS13 and von Willebrand factor assessment in steady state and acute vaso-occlusive crisis of sickle cell disease.

Res Pract Thromb Haemost 2021 Jan 18;5(1):197-203. Epub 2020 Dec 18.

Service d'Hématologie Biologique Hôpital Lariboisière AP-HP.Nord Université de Paris Paris France.

Background: Sickle cell disease (SCD) is characterized by vaso-occlusive crisis (VOC), acute chest syndrome (ACS) and multiorgan failure (MOF) complicated by thrombosis. Von Willebrand factor (VWF) is a strong marker of SCD-related endothelial injury.

Objectives: To decipher the role of VWF and its specific-cleaving metalloprotease, ADAMTS13, in the vaso-occlusive and thrombotic process of SCD.

Patients/methods: We investigated the VWF antigen (Ag), ADAMTS13 activity, ADAMTS13 Ag and ADAMTS13 IgGs in a cohort of 65 patients with SCD prospectively enrolled in a 20-month period from three centers. Patients were divided into two groups: an asymptomatic group (n = 30) with treated or untreated SCD at steady state, and a VOC/ACS group (n = 35) with SCD with VOC/ACS requiring either medical management or intensive care management for MOF.

Results And Conclusions: VWF:Ag levels were increased (median, 167 IU/dL; interquartile range [IQR], 124 - 279), especially in patients with VOC SCD (227 IU/dL; IQR, 134-305;  = .04), and positively correlated with inflammatory markers ( < .02). Median ADAMTS13 activity was normal (70 IU/dL; IQR, 60-80), but 7 patients exhibited a partial deficiency between 25 and 45 IU/dL. ADAMTS13 activity/VWF:Ag ratio, however, did not change during VOC. Median ADAMTS13:Ag was slightly decreased (611 ng/mL; IQR, 504-703) with no significant difference between groups. Surprisingly, ADAMTS13 IgGs were detected in 33 (51%) of our patients. We conclude that, in SCD, VWF:Ag and nonrelevant ADAMTS13 IgGs may reflect the severity of the inflammatory vasculopathy enhancing vaso-occlusive and thrombotic complications.
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http://dx.doi.org/10.1002/rth2.12460DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845082PMC
January 2021

Diagnosis and follow-up of thrombotic thrombocytopenic purpura with an automated chemiluminescent ADAMTS13 activity immunoassay.

Res Pract Thromb Haemost 2021 Jan 15;5(1):81-93. Epub 2020 Dec 15.

Service d'hématologie Biologique Hôpital Lariboisière, AP-HP.Nord and EA3518 Institut de Recherche Saint-Louis Université de Paris Paris France.

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 ( = .83,  < .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.
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http://dx.doi.org/10.1002/rth2.12461DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7845081PMC
January 2021

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

Blood 2021 04;137(14):1855-1861

Department of Haematology, University College London Hospital (UCLH), London, United Kingdom.

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 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 on the platelet count of caplacizumab, a novel anti-von Willebrand factor (VWF) nanobody. 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, by 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 that of anti-VWF therapy. Retrospective validation of the revised definitions is described, although they have yet 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 to highlight their clinical relevance.
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http://dx.doi.org/10.1182/blood.2020009150DOI Listing
April 2021

TTP in the setting of pregnancy: The story still has to be written.

J Thromb Haemost 2020 10;18(10):2775-2777

French Reference Center for Thrombotic Microangiopathies (CNR-MAT), Paris, France.

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http://dx.doi.org/10.1111/jth.15030DOI Listing
October 2020

Should all patients with immune-mediated thrombotic thrombocytopenic purpura receive caplacizumab?

J Thromb Haemost 2021 01 17;19(1):58-67. Epub 2020 Dec 17.

Centre National de Référence des MicroAngiopathies Thrombotiques, Paris, France.

Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is a rare, life-threatening disease that causes systemic platelet-rich microthrombi with multiorgan damage. The historical treatment is based on therapeutic plasma exchange (TPE) and immunosuppression. Despite survival rates exceeding 85%, unfavorable outcomes including refractoriness, death, and exacerbations of the disease during treatment still calls for a better management strategy. Caplacizumab (Cablivi) appeared recently as a new treatment in iTTP. By inhibiting binding of von Willebrand factor to platelets, caplacizumab prevents platelets aggregation and the formation of microthrombi. Two pivotal randomized controlled trials have provided positive results where the use of caplacizumab is associated with faster platelet count recovery and less unfavorable outcomes. The other strength of this agent is an impressive alleviation in the burden of care, consisting in less TPE sessions and lower volumes of plasma to achieve remission, as well as substantial shortening in the length of hospitalization. However, since the recent approval of caplacizumab for the treatment of iTTP on the basis of these studies, debates remain regarding its systematic use in this indication. Should all patients be benefited from caplacizumab? Should we reserve caplacizumab only to the more severe patients? Should caplacizumab be initiated frontline or as a salvage therapy? If applicable, how should we select patients for caplacizumab? Last, is caplacizumab treatment cost-effective? This review aims at addressing these specific questions at a time when iTTP is entering the area of targeted therapies.
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http://dx.doi.org/10.1111/jth.15194DOI Listing
January 2021

Refractory Auto-Immune Thrombotic Thrombocytopenic Pupura Successfully Treated With Caplacizumab.

Front Med (Lausanne) 2020 22;7:549931. Epub 2020 Oct 22.

Service de Néphrologie-Dialyse-Transplantation, Centre Hospitalier Universitaire Angers, Angers, France.

Thrombotic thrombocytopenic purpura (TTP) is a rare thrombotic microangiopathy characterized by mechanical hemolytic anemia, profound thrombocytopenia, and neurological manifestations. Acquired auto-immune TTP, the most prevalent cause of TTP, is induced by the presence of inhibitory anti-ADAMTS13 auto-antibodies. Modern treatment of acquired TTP relies on plasma exchange, rituximab, and steroids. Caplacizumab (Cablivi®), a humanized single-variable domain immunoglobulin that targets the A1 domain of the ultra-large von Willebrand factor, inhibits the interaction between ultra-large vWFand platelets. In two clinical trials, caplacizumab, in addition to conventional treatment, shortened the delay to platelet count normalization in comparison to conventional treatment plus placebo, without increasing significantly hemorrhagic complications. Moreover, caplacizumab was associated with reduced occurrence of a secondary endpoint associating death, TTP recurrence, and major thromboembolic events. Here, we report the off-label use of caplacizumab in a 68-year-old patient with confirmed acquired TTP, severe thrombocytopenia, and generalized tonic-clonic seizures requiring mechanical ventilation and admission in the intensive care unit. Conventional treatment was rapidly started. Despite the intensification of plasma exchange treatment with twice-daily sessions, steroid continuation, and a second rituximab infusion on day 6, thrombotic microangiopathy worsened with thrombocytopenia at 21 g/L on day 8 from admission. We also considered using caplacizumab, which we could obtain and start on day 12 from admission, as it was available under a temporary authorization use in France. As soon as 12 h after caplacizumab initiation, we observed a significant increase of platelet count and improvement of other hemolytic parameters. We observed resolution of encephalopathy and complete recovery of motor paralysis, allowing us to stop mechanical ventilation on day 14. Caplacizumab was maintained for 128 days until day 139 from initial admission. The patient is going well 10 months after initial admission, without any neurological sequelae, and TTP did not relapse. To the best of our knowledge, this is the first reported use of caplacizumab in such a condition. This case report suggests that caplacizumab use may help to reduce the rate of refractory TTP episodes.
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http://dx.doi.org/10.3389/fmed.2020.549931DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649819PMC
October 2020

Immunogenic hotspots in the spacer domain of ADAMTS13 in immune-mediated thrombotic thrombocytopenic purpura.

J Thromb Haemost 2021 02 31;19(2):478-488. Epub 2020 Dec 31.

Laboratory for Thrombosis Research, IRF Life Sciences, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium.

Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is caused by anti-ADAMTS13 autoantibodies inducing a severe deficiency of ADAMTS13. Epitope mapping studies on samples obtained during acute iTTP episodes have shown that the iTTP immune response is polyclonal, with almost all patients having autoantibodies targeting the spacer domain of ADAMTS13.

Objectives: To identify the immunogenic hotspots in the spacer domain of ADAMTS13.

Patients/methods: A library of 11 full-length ADAMTS13 spacer hybrids was created in which amino acid regions of the spacer domain of ADAMTS13 were exchanged by the corresponding region of the spacer domain of ADAMTS1. Next, the full-length ADAMTS13 spacer hybrids were used in enzyme-linked immunosorbent assay to epitope map anti-spacer autoantibodies in 138 samples from acute and remission iTTP patients.

Results: Sixteen different anti-spacer autoantibody profiles were identified with a similar distribution in acute and remission patients. There was no association between the anti-spacer autoantibody profiles and disease severity. Almost all iTTP samples contained anti-spacer autoantibodies against the following three regions: amino acid residues 588-592, 602-610, and 657-666 (hybrids E, G, and M). Between 31% and 57% of the samples had anti-spacer autoantibodies against amino acid regions 572-579, 629-638, 667-676 (hybrids C, J, and N). In contrast, none of the samples had anti-spacer autoantibodies against amino acid regions 556-563, 564-571, 649-656, and 677-685 (hybrids A, B, L, and O).

Conclusion: We identified three hotspot regions (amino acid regions 588-592, 602-610, and 657-666) in the spacer domain of ADAMTS13 that are targeted by anti-spacer autoantibodies found in a large cohort of iTTP patients.
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http://dx.doi.org/10.1111/jth.15170DOI Listing
February 2021

A regimen with caplacizumab, immunosuppression, and plasma exchange prevents unfavorable outcomes in immune-mediated TTP.

Blood 2021 Feb;137(6):733-742

Centre de Référence des Microangiopathies Thrombotiques, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France.

The anti-von Willebrand factor nanobody caplacizumab was licensed for adults with immune-mediated thrombotic thrombocytopenic purpura (iTTP) based on prospective controlled trials. However, few data are available on postmarketing surveillance. We treated 90 iTTP patients with a compassionate frontline triplet regimen associating therapeutic plasma exchange (TPE), immunosuppression with corticosteroids and rituximab, and caplacizumab. Outcomes were compared with 180 historical patients treated with the standard frontline treatment (TPE and corticosteroids, with rituximab as salvage therapy). The primary outcome was a composite of refractoriness and death within 30 days since diagnosis. Key secondary outcomes were exacerbations, time to platelet count recovery, the number of TPE, and the volume of plasma required to achieve durable remission. The percentage of patients in the triplet regimen with the composite primary outcome was 2.2% vs 12.2% in historical patients (P = .01). One elderly patient in the triplet regimen died of pulmonary embolism. Patients from this cohort experienced less exacerbations (3.4% vs 44%, P < .01); they recovered durable platelet count 1.8 times faster than historical patients (95% confidence interval, 1.41-2.36; P < .01), with fewer TPE sessions and lower plasma volumes (P < .01 both). The number of days in hospital was 41% lower in the triplet regimen than in the historical cohort (13 vs 22 days; P < .01). Caplacizumab-related adverse events occurred in 46 patients (51%), including 13 major or clinically relevant nonmajor hemorrhagic events. Associating caplacizumab to TPE and immunosuppression, by addressing the 3 processes of iTTP pathophysiology, prevents unfavorable outcomes and alleviates the burden of care.
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http://dx.doi.org/10.1182/blood.2020008021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7986049PMC
February 2021

Modifying ADAMTS13 to modulate binding of pathogenic autoantibodies of patients with acquired thrombotic thrombocytopenic purpura.

Haematologica 2020 11 1;105(11):2619-2630. Epub 2020 Nov 1.

Department of Molecular and Cellular Hemostasis, Sanquin-Academic Medical Center, The Netherlands.

Antibodies that develop in patients with immune thrombotic thrombocytopenic purpura (iTTP) commonly target the spacer epitope R568/F592/R660/Y661/Y665 (RFRYY). In this study we present a detailed contribution of each residue in this epitope for autoantibody binding. Different panels of mutations were introduced here to create a large collection of full-length ADAMTS13 variants comprising conservative (Y←→F), semi-conservative (Y/F→L), non-conservative (Y/F→N) or alanine (Y/F/R→A) substitutions. Previously reported Gain-of-Function (GoF, KYKFF) and truncated 'MDTCS' variants were also included. Sera of 18 patients were screened against all variants. Conservative mutations of the aromatic residues did not reduce the binding of autoantibodies. Moderate resistance was achieved by replacing R568 and R660 by lysines or alanines. Semi-conservative mutations of aromatic residues show a moderate effectiveness in autoantibody resistance. Non-conservative asparagine or alanine mutations of aromatic residues are the most effective. In the mixtures of autoantibodies from the majority (89%) of patients screened, autoantibodies targeting the spacer RFRYY epitope have preponderance compared to other epitopes. Reductions in ADAMTS13 proteolytic activity were observed for all full-length mutant variants, in varying degrees. The greatest activity reductions were observed in the most autoantibody-resistant variants (15-35% residual activity in FRETS-VWF73). Among these, a triple-alanine mutant RARAA showed activity in a VWF multimer assay. This study shows that non-conservative and alanine modifications of residues within the exosite-3 spacer RFRYY epitope in full-length ADAMTS13 resist the binding of autoantibodies from iTTP patients, while retaining residual proteolytic activity. Our study provides a framework for the design of autoantibody-resistant ADAMTS13 variants for further therapeutic development.
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http://dx.doi.org/10.3324/haematol.2019.226068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604655PMC
November 2020

A new drug for an old concept: aptamer to von Willebrand factor for prevention of arterial and microvascular thrombosis.

Authors:
Agnès Veyradier

Haematologica 2020 11 1;105(11):2512-2515. Epub 2020 Nov 1.

Hematology department, French National Reference Centre for Thrombotic Microangiopathies and von Willebrand disease, Hospital Lariboisière, AP-HP.Nord; EA3518 Saint-Louis Research Institute, Paris University, Paris, France.

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http://dx.doi.org/10.3324/haematol.2020.261081DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7604565PMC
November 2020

Understanding the Health Literacy in Patients With Thrombotic Thrombocytopenic Purpura.

Hemasphere 2020 Aug 11;4(4):e462. Epub 2020 Aug 11.

Centre de Référence des Microangiopathies Thrombotiques, AP-HP.6, Paris, France.

Following an acute thrombotic thrombocytopenic purpura (TTP) episode, patients are at risk for relapse, and a careful long-term follow-up is needed. Adherence to the follow-up by patients implies a good understanding of the disease. However, TTP literacy in patients is currently unknown. To explore the TTP literacy in patients and identify factors associated with poor disease understanding, a questionnaire was developed focusing on patient's characteristics, knowledge about TTP and patients' actions in an emergency. The questionnaire was presented to 120 TTP patients in remission from the French National Registry for Thrombotic Microangiopathies. TTP literacy was low in 24%, intermediate in 43% and high in 33% of the patients. Low TTP literacy was associated with older age and low education level. Among the knowledge gaps identified, few patients knew that plasma exchange in acute phase is mandatory and has to be done daily (39%), 47% of participants did not consider themselves at risk for relapse, and 30% of women did not know that pregnancy exposes them to a greater risk of relapse. Importantly, few patients responded about life-saving actions in an emergency. Hence, the design of educational material should pay special attention to the age and education level of the target population focusing on the events leading to TTP, the importance of the emergency treatment, controllable predisposing factors for TTP development and patient attitude in an emergency.
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http://dx.doi.org/10.1097/HS9.0000000000000462DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430230PMC
August 2020

Management of thrombotic microangiopathy in pregnancy and postpartum: report from an international working group.

Blood 2020 11;136(19):2103-2117

Maternité Port-Royal, Hôpital Cochin, Université de Paris/AP-HP, Fighting Prematurity University Hospital Federation (FHU PREMA), INSERM UMR 1139, Paris, France.

Pregnancy and postpartum are high-risk periods for different forms of thrombotic microangiopathy (TMA). However, the management of pregnancy-associated TMA remains ill defined. This report, by an international multidisciplinary working group of obstetricians, nephrologists, hematologists, intensivists, neonatologists, and complement biologists, summarizes the current knowledge of these potentially severe disorders and proposes a practical clinical approach to diagnose and manage an episode of pregnancy-associated TMA. This approach takes into account the timing of TMA in pregnancy or postpartum, coexisting symptoms, first-line laboratory workup, and probability-based assessment of possible causes of pregnancy-associated TMA. Its aims are: to rule thrombotic thrombocytopenic purpura (TTP) in or out, with urgency, using ADAMTS13 activity testing; to consider alternative disorders with features of TMA (preeclampsia/eclampsia; hemolysis elevated liver enzymes low platelets syndrome; antiphospholipid syndrome); or, ultimately, to diagnose complement-mediated atypical hemolytic uremic syndrome (aHUS; a diagnosis of exclusion). Although they are rare, diagnosing TTP and aHUS associated with pregnancy, and postpartum, is paramount as both require urgent specific treatment.
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http://dx.doi.org/10.1182/blood.2020005221DOI Listing
November 2020

Insights into ADAMTS13 structure: impact on thrombotic thrombocytopenic purpura diagnosis and management.

Curr Opin Hematol 2020 09;27(5):320-326

Laboratory for Thrombosis Research, IRF Life Sciences, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium.

Purpose Of Review: Fundamental knowledge on the role of a disintegrin and metalloprotease with thrombospondin type one repeats, member 13 (ADAMTS13) has been crucial to better understand the pathophysiology of the rare and life-threatening disease thrombotic thrombocytopenic purpura (TTP).

Recent Findings: ADAMTS13 works through a molecular zipper mechanism to proteolyze its substrate von Willebrand factor (VWF). Recent insights into the structure and function of ADAMTS13 led to the identification of an allosteric activation mechanism. Therefore, ADAMTS13 is roughly folded in two in which the N-terminal spacer (S) domain and C-terminal T7-CUB2 domains interact to adopt a closed conformation. Upon substrate binding, ADAMTS13 adopts an open conformation in which the S-T7-CUB2 interaction is abrogated to further position VWF towards the catalytic cleft, inducing activation of the latent metalloprotease domain and resulting in cleavage of VWF. Unravelling the structure function relationship of ADAMTS13 helped identifying open ADAMTS13 as a novel and unique biomarker for immune-mediated TTP (iTTP). This novel biomarker has potential in the diagnosis, treatment and follow-up of iTTP.

Summary: In this review, the most recent findings on the structure and working mechanism of ADAMTS13 are addressed. In addition, how those findings led to the identification of a novel biomarker, and how this novel biomarker could have an impact on the diagnosis, management and follow-up of iTTP patients are discussed.
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http://dx.doi.org/10.1097/MOH.0000000000000602DOI Listing
September 2020

Understanding pathophysiology of hemostasis disorders in critically ill patients with COVID-19.

Intensive Care Med 2020 Aug 15;46(8):1603-1606. Epub 2020 May 15.

EA-3518, Clinical Research in Hematology, Immunology and Transplantation, Institut de Recherche Saint-Louis, Hôpital Saint Louis, Université de Paris, Paris, France.

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http://dx.doi.org/10.1007/s00134-020-06088-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7225398PMC
August 2020

Open ADAMTS13, induced by antibodies, is a biomarker for subclinical immune-mediated thrombotic thrombocytopenic purpura.

Blood 2020 07;136(3):353-361

Laboratory for Thrombosis Research, IRF Life Sciences, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium.

Recently, we showed that ADAMTS13 circulates in an open conformation during the acute phase of immune-mediated thrombotic thrombocytopenic purpura (iTTP). Although the cause of this conformational change remains elusive, ADAMTS13 is primarily closed in iTTP patients in remission with ADAMTS13 activity >50% and undetectable anti-ADAMTS13 autoantibodies, as well as after rituximab treatment, suggesting a role for anti-ADAMTS13 autoantibodies. Therefore, immunoglobulin G from 18 acute iTTP patients was purified and added to closed ADAMTS13 in healthy donor plasma. This resulted in open ADAMTS13 in 14 of 18 (78%) samples, proving that anti-ADAMTS13 autoantibodies can induce an open ADAMTS13 conformation. To further elucidate the conformation of ADAMTS13 in iTTP patients, we studied a novel iTTP patient cohort (n = 197) that also included plasma samples from iTTP patients in remission in whom ADAMTS13 activity was <50%. The open ADAMTS13 conformation was found during acute iTTP, as well as in patients in remission with ADAMTS13 activity <50% and in half of the patients with ADAMTS13 activity >50%, although free anti-ADAMTS13 autoantibodies were not always detected. Thus, open ADAMTS13 is a hallmark of acute iTTP, as well as a novel biomarker that can be used to detect subclinical iTTP in patients in remission. Finally, a long-term follow-up study in 1 iTTP patient showed that the open conformation precedes a substantial drop in ADAMTS13 activity. In conclusion, we have shown that anti-ADAMTS13 autoantibodies from iTTP patients induce an open ADAMTS13 conformation. Most importantly, an open ADAMTS13 conformation is a biomarker for subclinical iTTP and could become an important tool in TTP management.
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http://dx.doi.org/10.1182/blood.2019004221DOI Listing
July 2020

Anti-ADAMTS13 autoantibodies in immune-mediated thrombotic thrombocytopenic purpura do not hamper ELISA-based quantification of ADAMTS13 antigen.

J Thromb Haemost 2020 04 27;18(4):985-990. Epub 2020 Feb 27.

Laboratory for Thrombosis Research, IRF Life Sciences, KU Leuven Campus Kulak Kortrijk, Kortrijk, Belgium.

Background: The biological diagnosis of immune-mediated thrombotic thrombocytopenic purpura (iTTP) is based on determination of ADAMTS13 activity (<10%) and anti-ADAMTS13 autoantibodies. ADAMTS13 antigen levels are not routinely measured in iTTP patients, but studies have shown that antigen levels are a valuable prognostic factor.

Objectives: To (a) report the validation of our in-house developed ADAMTS13 antigen enzyme-linked immunosorbent assay (ELISA) and determine ADAMTS13 antigen in a large cohort of healthy donor and iTTP patient plasma samples; and (b) to investigate whether ADAMTS13 antigen determination is not disturbed by the presence of anti-ADAMTS13 autoantibodies.

Methods: Our in-house ADAMTS13 antigen ELISA was validated in terms of sensitivity, repeatability, and reproducibility. ADAMTS13 antigen levels were determined in plasma samples from 423 healthy donors and 112 acute iTTP patients. Purified IgGs from iTTP patients were added to normal human plasma to determine whether anti-ADAMTS13 autoantibodies hampered ADAMTS13 antigen determination.

Results: Our in-house ADAMTS13 antigen ELISA has a detection limit of 3% and low intra-assay (coefficient of variation, %CV < 10%) and inter-assay (%CV < 18%) variability. ADAMTS13 antigen levels were significantly reduced (P < .0001) in acute iTTP patients (15 ± 18%) compared to healthy donors (101 ± 18%). The anti-ADAMTS13 autoantibodies in plasma of iTTP patients did not impede ADAMTS13 antigen determinations using our in-house ELISA.

Conclusions: Our in-house ADAMT13 antigen ELISA is a powerful tool to correctly determine ADAMTS13 antigen levels in iTTP patients, which supports routine ADAMTS13 antigen measurements in these patients to have better insight into disease prognosis.
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http://dx.doi.org/10.1111/jth.14747DOI Listing
April 2020

Correction to: Expert statement on the ICU management of patients with thrombotic thrombocytopenic purpura.

Intensive Care Med 2020 Mar;46(3):570-571

Division of Pulmonary and Critical Care, Penn State University College of Medicine, Hershey, PA, USA.

The original version of this article unfortunately contained a mistake. The penultimate row of Table 4 shows INR > 1.5 which is incorrect. The correct figure is INR < 1.5. The authors apologize for the mistake. The correct table is given below.
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http://dx.doi.org/10.1007/s00134-019-05904-7DOI Listing
March 2020

Amotosalen-inactivated fresh frozen plasma is comparable to solvent-detergent inactivated plasma to treat thrombotic thrombocytopenic purpura.

Transfus Apher Sci 2019 Dec 5;58(6):102665. Epub 2019 Nov 5.

Reference Center for Thrombotic Microangiopathies, Assistance Publique des Hôpitaux de Paris, Paris, France; Service d'Hématologie, Hôpital Saint-Antoine, Assistance Publique des Hôpitaux de Paris, Paris, France; Sorbonne Universités, Paris, France. Electronic address:

Background: Therapeutic Plasma Exchange (TPE) is the primary therapy of immune-mediated Thrombotic Thrombocytopenic Purpura (iTTP). Efficacy and safety data for TPE of iTTP have been assessed with Quarantine and Solvent-Detergent inactivated (SD) plasma. Here, amotosalen-UVA pathogen inactivated (AI) plasma, also in routine use, was evaluated in iTTP.

Methods: We conducted a retrospective review of iTTP cases prospectively reported to the French national registry (2010-2013). Cases reviewed underwent TPE with ≥70% of either AI or SD plasma. The primary endpoint was time to platelet count recovery; secondary endpoints were related to follow-up (sustained remission, relapses, flare-ups and refractoriness).

Results: 30 Test patients were identified in the AI group which could be timely matched to 40 Control patients in the SD group. The groups were fairly comparable for clinical presentation. Major findings were: (i) iTTP patients were exposed to lower plasma volumes in the AI group than in the SD group; (ii) Recovery rates were comparable between the groups. Median time to platelet count recovery (>150 × 10/L) trended to be shorter in the AI group though non significantly. Tolerance of AI vs SD plasma was of comparable frequency and severity in either group.

Conclusion: TPE with Amotosalen-inactivated plasma demonstrated therapeutic efficacy and tolerability for iTTP patients. In view of the retrospective design, confirmation of these results is required in larger prospective studies.
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http://dx.doi.org/10.1016/j.transci.2019.10.007DOI Listing
December 2019

Expert statement on the ICU management of patients with thrombotic thrombocytopenic purpura.

Intensive Care Med 2019 11 7;45(11):1518-1539. Epub 2019 Oct 7.

Division of Pulmonary and Critical Care, Penn State University College of Medicine, Hershey, PA, USA.

Thrombotic thrombocytopenic purpura (TTP) is fatal in 90% of patients if left untreated and must be diagnosed early to optimize patient outcomes. However, the very low incidence of TTP is an obstacle to the development of evidence-based clinical practice recommendations, and the very wide variability in survival rates across centers may be partly ascribable to differences in management strategies due to insufficient guidance. We therefore developed an expert statement to provide trustworthy guidance about the management of critically ill patients with TTP. As strong evidence was difficult to find in the literature, consensus building among experts could not be reported for most of the items. This expert statement is timely given the recent advances in the treatment of TTP, such as the use of rituximab and of the recently licensed drug caplacizumab, whose benefits will be maximized if the other components of the management strategy follow a standardized pattern. Finally, unanswered questions are identified as topics of future research on TTP.
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http://dx.doi.org/10.1007/s00134-019-05736-5DOI Listing
November 2019

Updated overview on von Willebrand disease: focus on the interest of genotyping.

Expert Rev Hematol 2019 12 6;12(12):1023-1036. Epub 2019 Oct 6.

Service d'Hématologie biologique Hôpital Lariboisière and EA-3518 Institut de Recherche Saint Louis, Assistance Publique-Hôpitaux de Paris, Université Paris Diderot, Paris, France.

: Von Willebrand disease (VWD) is the most common inherited bleeding disorder, characterized by a quantitative or qualitative defect of von Willebrand factor (VWF), a multimeric glycoprotein crucial for primary hemostasis and coagulation. VWD pathophysiology is heterogeneous as it includes several types and subtypes which therapeutic management is different. The mainstays of VWD treatment are desmopressin and replacement therapy based on both plasma-derived concentrates and a recently developed recombinant VWF. VWD definitive diagnosis is achieved by a battery of phenotypic biologic assays and genotyping is currently performed mostly for research.: This narrative review will firstly present a general overview on VWD epidemiology, pathophysiology, classification, clinics, phenotypic biologic diagnosis, and treatment. Secondly, a focus on VWD genotyping will be presented with specific emphasis on the evolution of its technical aspects, its applications for research dedicated to a better understanding of VWD pathophysiology and epidemiology and its interest in both a faster diagnosis and an optimal treatment of VWD.: Based on analysis of the literature, it can be concluded that the fast evolution of genetic techniques together with the development of innovating treatments may significantly change diagnostic flow charts for VWD and their use for specific and personalized treatment.
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http://dx.doi.org/10.1080/17474086.2019.1670638DOI Listing
December 2019

Immune thrombotic thrombocytopenic purpura in older patients: prognosis and long-term survival.

Blood 2019 12;134(24):2209-2217

Service d'Hématologie, AP-HP.6, Paris, France; and.

Older age is associated with increased mortality in immune thrombotic thrombocytopenic purpura (iTTP). Yet, data are scarce regarding iTTP occurring among older patients. To assess clinical features and long-term impact of iTTP on mortality in older patients (>60 years old), characteristics and prognoses of adult iTTP patients enrolled in the French Reference Center for Thrombotic Microangiopathies registry between 2000 and 2016 were described according to age (<60 years old or ≥60 years old). Long-term mortality of iTTP older survivors was compared with that of non-iTTP geriatric subjects. Comparing, respectively, older iTTP patients (N = 71) with younger patients (N = 340), time from hospital admission to diagnosis was longer (P < .0001); at diagnosis, delirium (P = .034), behavior impairment (P = .045), renal involvement (P < .0001), and elevated troponin level (P = .025) were more important whereas cytopenias were less profound (platelet count, 22 × 103/mm3 [9-57] vs 13 × 103/mm3 [9-21], respectively [P = .002]; hemoglobin level, 9 g/dL [8-11] vs 8 g/dL [7-10], respectively [P = .0007]). Short- and mid-term mortalities were higher (P < .0001) and increased for every 10 years of age range. Age ≥60 years, cardiac involvement, increased plasma creatinine level, and total plasma exchange volume were independently associated with 1-month mortality. Compared with a non-iTTP geriatric population, older survivors showed an increased long-term mortality (hazard ratio = 3.44; P < .001). In conclusion, older iTTP patients have atypical neurological presentation delaying the diagnosis. Age negatively impacts short-term but also long-term mortality.
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http://dx.doi.org/10.1182/blood.2019000748DOI Listing
December 2019