137 results on '"De Meyer SF"'
Search Results
2. EP45* Beyond proximal large vessel occlusions: outcome of mechanical thrombectomy in distal vessel occlusions in the EXCELLENT registry – Interim analysis
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Zaidat, OO, primary, Nogueira, RG, additional, Siddiqui, AH, additional, Yoo, AJ, additional, Hanel, RA, additional, Hacke, W, additional, Jovin, T, additional, Fiehler, J, additional, De Meyer, SF, additional, Liebeskind, DS, additional, Haussen, D, additional, Inoa, V, additional, Humphries, W, additional, Woodward, KB, additional, Jabbour, PM, additional, Francois, O, additional, Levy, EI, additional, Bozorgchami, H, additional, Cohen, J, additional, Boor, S, additional, Dashti, SR, additional, Taqi, MA, additional, Budzik, RF, additional, Schirmer, CM, additional, Hussain, MS, additional, Estrade, L, additional, De Leacy, RA, additional, Puri, AS, additional, Chitale, R, additional, Brekenfeld, C, additional, and Andersson, T, additional
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- 2021
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3. Histological stroke clot analysis after thrombectomy: Technical aspects and recommendations
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Staessens, S, primary, Fitzgerald, S, additional, Andersson, T, additional, Clarençon, F, additional, Denorme, F, additional, Gounis, MJ, additional, Hacke, W, additional, Liebeskind, DS, additional, Szikora, I, additional, van Es, ACGM, additional, Brinjikji, W, additional, Doyle, KM, additional, and De Meyer, SF, additional
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- 2019
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4. Illustrated State-of-the-Art Capsules of the ISTH 2019 Congress in Melbourne, Australia
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Ward, CM, Andrews, RK, Wolberg, A, Lip, GYH, Eikelboom, J, De Meyer, SF, Mast, A, Flick, M, Urano, T, Ny, T, Cutler, D, Ju, LA, Zhu, C, Randi, AM, O'Donnell, JS, O'Brien, SH, Fijnvandraat, K, Shima, M, Nathwani, A, Luyendyk, J, Vanhoorelbeke, K, Barco, S, Chuansumrit, A, Stanworth, SJ, Curry, N, Del Rio, JM, Battinelli, EM, Bos, MHA, Reinhardt, C, Peter, K, Gomez, K, Danese, E, Rak, J, Flaumenhaft, R, Di Paola, J, Nilsson, S, Severin, S, Eto, K, Hitchcock, IS, Ni, H, Despotovic, J, Boilard, E, Rondina, M, Mangin, P, Hamilton, JR, Suzuki-Inoue, K, Tsukiji, N, Conway, EM, Maas, C, Emsley, J, Jenne, CN, Fuchs, TA, Weitz, J, Johnsen, JM, Rauova, L, Spyropoulos, A, Goto, S, Verhamme, P, Miranda, S, Rodger, M, Ni Ainle, F, Schreiber, K, Thomas, M, Le Gal, G, Zentner, D, McLintock, C, Magnusson, M, Ward, CM, Andrews, RK, Wolberg, A, Lip, GYH, Eikelboom, J, De Meyer, SF, Mast, A, Flick, M, Urano, T, Ny, T, Cutler, D, Ju, LA, Zhu, C, Randi, AM, O'Donnell, JS, O'Brien, SH, Fijnvandraat, K, Shima, M, Nathwani, A, Luyendyk, J, Vanhoorelbeke, K, Barco, S, Chuansumrit, A, Stanworth, SJ, Curry, N, Del Rio, JM, Battinelli, EM, Bos, MHA, Reinhardt, C, Peter, K, Gomez, K, Danese, E, Rak, J, Flaumenhaft, R, Di Paola, J, Nilsson, S, Severin, S, Eto, K, Hitchcock, IS, Ni, H, Despotovic, J, Boilard, E, Rondina, M, Mangin, P, Hamilton, JR, Suzuki-Inoue, K, Tsukiji, N, Conway, EM, Maas, C, Emsley, J, Jenne, CN, Fuchs, TA, Weitz, J, Johnsen, JM, Rauova, L, Spyropoulos, A, Goto, S, Verhamme, P, Miranda, S, Rodger, M, Ni Ainle, F, Schreiber, K, Thomas, M, Le Gal, G, Zentner, D, McLintock, C, and Magnusson, M
- Abstract
The 27th Congress of the International Society of Thrombosis and Haemostasis (ISTH) is an international conference held July 6-10, 2019, in Melbourne, the capital of the state of Victoria, Australia. The ISTH congress has previously been held every other year, with the Scientific and Standardization Committee (SSC) meeting held annually, until 2019 when it became one combined annual meeting of the ISTH and SSC. The conference covers clinical and basic aspects of hemostasis and thrombosis, and this year includes 5 Plenary lectures and >50 State of Art (SOA) lectures, presented by internationally recognized speakers, as well as numerous oral session and poster presentations selected from submitted abstracts, including many early career and reach the world support recipients. This SOA review article in RPTH contains concise Illustrated Review Articles or 'Capsules' consisting of short text, three references and a figure, with topics including stroke, cancer-associated thrombosis, hemophilia, coagulation, the interface between infection and inflammation, and in the experimental and discovery areas, megakaryocyte biology and platelet production, structure-function of key receptors and coagulation factors, and emerging new roles for thrombotic/hemostatic factors. Together, these articles highlight novel findings which will advance knowledge and with the potential to change clinical practice and improve outcomes. It is hoped that conference attendees and followers will enjoy utilizing the images for ongoing education and during the conference for live tweeting during sessions, to assist in the broadcasting and promotion of the science to those unable to attend, or who have chosen to attend a concurrent session. Use #IllustratedReview and #ISTH2019 on social media.
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- 2019
5. Analyses of thrombi in acute ischemic stroke: A consensus statement on current knowledge and future directions
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De Meyer, SF, Andersson, T, Baxter, B, Bendszus, M, Brouwer, P, Brinjikji, W, Campbell, BCV, Costalat, V, Davalos, A, Demchuk, A, Dippel, D, Fiehler, J, Fischer, U, Gilvarry, M, Gounis, MJ, Gralla, J, Jansen, O, Jovin, T, Kallmes, D, Khatri, P, Lees, KR, Lopez-Cancio, E, Majoie, C, Marquering, H, Narata, AP, Nogueira, R, Ringleb, P, Siddiqui, A, Szikora, I, Vale, D, von Kummer, R, Yoo, AJ, Hacke, W, and Liebeskind, DS
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Stroke ,immunohistochemistry ,interventional neuroradiology ,imaging ,thrombosis - Abstract
Limited data exist on clot composition and detailed characteristics of arterial thrombi associated with large vessel occlusion in acute ischemic stroke. Advances in endovascular thrombectomy and related imaging modalities have created a unique opportunity to analyze thrombi removed from cerebral arteries. Insights into thrombus composition, etiology, physical properties and neurovascular interactions may lead to future advancements in acute ischemic stroke treatment and improved clinical outcomes. Advances in imaging techniques may enhance clot characterization and inform therapeutic decision-making prior to treatment and reveal stroke etiology to guide secondary prevention. Current imaging techniques can provide some information about thrombi, but there remains much to evaluate about relationships that may exist among thrombus composition, occlusion characteristics and treatment outcomes. Improved pathophysiological characterization of clot types, their properties and how these properties change over time, together with clinical correlates from ongoing studies, may facilitate revascularization with thrombolysis and thrombectomy. Interdisciplinary approaches covering clinical, engineering and scientific aspects of thrombus research will be key to advancing the understanding of thrombi and improving acute ischemic stroke therapy. This consensus statement integrates recent research on clots and thrombi retrieved from cerebral arteries and provides a rationale for further analyses, including current opportunities and limitations.
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- 2017
6. Histological stroke clot analysis after thrombectomy: Technical aspects and recommendations.
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Staessens, S, Fitzgerald, S, Andersson, T, Clarençon, F, Denorme, F, Gounis, MJ, Hacke, W, Liebeskind, DS, Szikora, I, van Es, ACGM, Brinjikji, W, Doyle, KM, and De Meyer, SF
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ENDOVASCULAR surgery ,STROKE ,CEREBRAL arteries - Abstract
The recent advent of endovascular procedures has created the unique opportunity to collect and analyze thrombi removed from cerebral arteries, instigating a novel subfield in stroke research. Insights into thrombus characteristics and composition could play an important role in ongoing efforts to improve acute ischemic stroke therapy. An increasing number of centers are collecting stroke thrombi. This paper aims at providing guiding information on thrombus handling, procedures, and analysis in order to facilitate and standardize this emerging research field. [ABSTRACT FROM AUTHOR]
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- 2020
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7. von Willebrand factor: an emerging target in stroke therapy.
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De Meyer SF, Stoll G, Wagner DD, Kleinschnitz C, De Meyer, Simon F, Stoll, Guido, Wagner, Denisa D, and Kleinschnitz, Christoph
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- 2012
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8. Letter by De Meyer et al regarding article "High von Willebrand factor levels increase the risk of stroke: the Rotterdam study".
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De Meyer SF, Stoll G, Kleinschnitzj C, De Meyer, Simon F, Stoll, Guido, and Kleinschnitz, Christoph
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- 2011
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9. Emerging Adjuvant Thrombolytic Therapies for Acute Ischemic Stroke Reperfusion.
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Yogendrakumar V, Vandelanotte S, Mistry EA, Hill MD, Coutts SB, Nogueira RG, Nguyen TN, Medcalf RL, Broderick JP, De Meyer SF, and Campbell BCV
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- Humans, Fibrinolytic Agents therapeutic use, Reperfusion methods, Thrombectomy methods, Brain Ischemia drug therapy, Brain Ischemia therapy, Animals, Stroke drug therapy, Stroke therapy, Ischemic Stroke drug therapy, Ischemic Stroke therapy, Thrombolytic Therapy methods
- Abstract
Thrombolytic therapies for acute ischemic stroke are widely available but only result in recanalization early enough, to be therapeutically useful, in 10% to 30% of cases. This large gap in treatment effectiveness could be filled by novel therapies that can increase the effectiveness of thrombus clearance without significantly increasing the risk of harm. This focused update will describe the current state of emerging adjuvant treatments for acute ischemic stroke reperfusion. We focus on new treatments that are designed to (1) target different components that make up a stroke thrombus, (2) enhance endogenous fibrinolytic systems, (3) reduce stagnant blood flow, and (4) improve recanalization of distal thrombi and postendovascular thrombectomy., Competing Interests: Dr Mistry reports compensation from American Heart Association, AbbVie, RAPID AI, and American Heart Association for consultant services; compensation from Silver Creek Pharmaceuticals Inc and Translational Sciences for other services; employment by University of Cincinnati; and grants from National Institutes of Health, Society of Vascular and Interventional Neurology, National Institute of Neurological Disorders and Stroke, Patient-Centered Outcomes Research Institute, and National Institutes of Health. Dr Hill reports grants from Boehringer Ingelheim, Canadian Institutes of Health Research, Medtronic, and NoNO Inc; employment by University of Calgary; stock options in Basking Bioscience LLC; and compensation from Brainsgate Ltd for consultant services. Dr Coutts reports employment by Hotchkiss Brain Institute, University of Calgary. Dr Nogueira reports compensation from Anaconda Biomed, Medtronic USA Inc, Cerenovus, Genentech, Viz-AI, Prolong Pharmaceuticals, Perfuze, Biogen Inc, Shanghai Wallaby, Brainomix, Hybernia, RapidPulse, Imperative Care, Corindus Inc, NeuroVasc Technologies Inc, Corindus Vascular Robotics, Vesalio, Cerebrotech, Astrocyte, Ceretrieve, Phenox Inc, Philips, Anaconda, and Stryker Corporation for consultant services; compensation from Synchron for data and safety monitoring services; stock options in Ceretrieve, Brainomix, Corindus Inc, Perfuze, Truvic, Viz-AI, Reist/Q?Apel Medical, Vesalio, Cerebrotech, and Viseon Inc; stock holdings in Piraeus Medical, Brain4Care, and Quantanosis AI; and grants from Stryker and Cerenovus. Dr Nguyen reports compensation from Brainomix and Aruna for consultant services; and compensation from American Stroke Association for other services. Dr Medcalf reports grants from National Health and Medical Research Council. Dr Broderick reports grants from Genentech to other; compensation from Brainsgate, F. Hoffmann-La Roche, Basking Bioscience, and Kroger Prescription Plans Inc for consultant services; and grants from Novo Nordisk to other. Dr De Meyer reports grants from KU Leuven and Research Foundation Flanders. The other authors report no conflicts.
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- 2024
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10. Association between thrombus composition and first-pass recanalization after thrombectomy in acute ischemic stroke.
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Vandelanotte S, Staessens S, François O, De Wilde M, Desender L, De Sloovere AS, Dewaele T, Tersteeg C, Vanhoorelbeke K, Vanacker P, Andersson T, and De Meyer SF
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- Humans, Male, Aged, Female, Middle Aged, Treatment Outcome, Aged, 80 and over, Fibrin metabolism, Fibrin analysis, Extracellular Traps metabolism, Histones blood, Thrombosis blood, Thrombosis etiology, Blood Platelets metabolism, von Willebrand Factor metabolism, von Willebrand Factor analysis, DNA blood, Leukocytes, Belgium, Thrombectomy, Ischemic Stroke blood, Ischemic Stroke surgery, Ischemic Stroke therapy, Erythrocytes
- Abstract
Background: Achieving first-pass recanalization (FPR) has become the primary procedural objective during thrombectomy in acute ischemic stroke patients as it correlates with the best clinical outcome. Understanding factors contributing to FPR failures is essential to enhance FPR success rates. As the central target of thrombectomy, the thrombus itself may be a significant factor influencing FPR., Objectives: This study aimed to investigate the association between thrombus composition and FPR success rates., Methods: In total, thrombi from 267 ischemic stroke patients were collected in the AZ Groeninge Hospital (Kortrijk, Belgium). Thrombus composition was determined via detailed histologic analysis of red blood cells (RBCs), fibrin, von Willebrand factor, platelets, leukocytes, citrullinated histone 3 (marker for neutrophil extracellular traps), and intracellular and extracellular DNA. FPR was defined as obtaining a modified thrombolysis in cerebral infarction (mTICI) score of 2c/3 after the first pass., Results: An mTICI score of 2c/3 was obtained in 180 patients, which was achieved via a successful FPR procedure in 126 cases or after multiple passes in 54 cases. Interestingly, thrombi from FPR cases had a different composition from thrombi that needed multiple passes to obtain an mTICI score of 2c/3. FPR thrombi contained significantly more RBCs (P = .0264), less fibrin (P = .0196), and less extracellular DNA (P = .0457)., Conclusion: Our results indicate that thrombi characterized by lower RBC content, higher fibrin levels, and increased extracellular DNA are less likely to result in an FPR. These results are important to guide future research aiming at improving procedures or technologies to obtain FPR rates in RBC-poor thrombi., Competing Interests: Declaration of competing interests P.V. received speaker fees from Boehringer-Ingelheim, BMS, Pfizer, Daiichi-Sankyo, and Medtronic. T.A. holds equity for Cereflo Ltd and is a consultant for Anaconda, Cerenovus/Neuravi, Optimize Neurovascular, and Rapid Medical. O.F. is a consultant for iVascular. All other authors have no conflicting interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)
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- 2024
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11. Acute Ischemic Stroke Thrombus Composition.
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Vandelanotte S and De Meyer SF
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- Humans, Animals, Thrombolytic Therapy methods, Fibrinolytic Agents therapeutic use, Tissue Plasminogen Activator therapeutic use, Thrombosis, Brain Ischemia drug therapy, Ischemic Stroke drug therapy
- Abstract
Ischemic stroke is caused by a thrombus blocking one or multiple arteries in the brain, resulting in irreversible damage in the associated brain tissue. The aim of therapy is to restore the blood flow as fast as possible. Two recanalization strategies are currently available: pharmacological thrombolysis using recombinant tissue plasminogen activator (rt-PA) and mechanical removal of the thrombus. Despite recent advancements, achieving efficient recanalization remains a challenge. The precise causes of therapy failure are not fully understood but thrombus composition is likely a key factor in successful recanalization. This review explores acute ischemic stroke thrombus composition, its recently identified components, and how it affects stroke treatment. It also discusses how new insights could enhance current recanalization strategies for ischemic stroke patients., (Copyright © 2024 IBRO. Published by Elsevier Inc. All rights reserved.)
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- 2024
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12. Diagnosis of thrombotic thrombocytopenic purpura: easy-to-use fiber optic surface plasmon resonance immunoassays for automated ADAMTS-13 antigen and conformation evaluation.
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Bonnez Q, Dekimpe C, Bekaert T, Tellier E, Kaplanski G, Joly BS, Veyradier A, Coppo P, Lammertyn J, Tersteeg C, De Meyer SF, and Vanhoorelbeke K
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- Humans, Case-Control Studies, Biomarkers blood, Reproducibility of Results, Protein Conformation, Predictive Value of Tests, Immunoassay methods, Automation, Laboratory, Female, Male, ADAMTS13 Protein blood, ADAMTS13 Protein immunology, Purpura, Thrombotic Thrombocytopenic diagnosis, Purpura, Thrombotic Thrombocytopenic blood, Purpura, Thrombotic Thrombocytopenic immunology, Surface Plasmon Resonance, Enzyme-Linked Immunosorbent Assay methods
- Abstract
Background: Laboratory diagnosis of immune-mediated thrombotic thrombocytopenic purpura (iTTP) remains challenging when ADAMTS-13 activity ranges between 10% and 20%. To prevent misdiagnosis, open ADAMTS-13 conformation gained clinical attention as a novel biomarker, especially to diagnose acute iTTP in patients with diagnostic undecisive ADAMTS-13 activity. Plasma ADAMTS-13 conformation analysis corrects for ADAMTS-13 antigen, with both parameters being characterized in enzyme-linked immunosorbent assay (ELISA)-based reference assays requiring expert technicians., Objectives: To design ADAMTS-13 antigen and conformation assays on automated, easy-to-use fiber optic surface plasmon resonance (FO-SPR) technology to promote assay accessibility and diagnose challenging iTTP patients., Methods: ADAMTS-13 antigen and conformation assays were designed on FO-SPR technology. Plasma of 20 healthy donors and 20 acute iTTP patients were quantified, and data from FO-SPR and ELISA reference assays were compared., Results: Following assay design, both antigen and conformation FO-SPR assays were optimized and characterized, presenting strong analytical sensitivity (detection limit of 0.001 μg/mL) and repeatability (interassay variation of 14.4%). Comparative analysis suggested positive correlation (Spearman r of 0.92) and good agreement between FO-SPR and ELISA assays. As expected, FO-SPR assays showed a closed or open ADAMTS-13 conformation in healthy donors and acute iTTP patients, respectively., Conclusion: Both ADAMTS-13 antigen and conformation assays were transferred onto automated, easy-to-use FO-SPR technology, displaying potent analytical sensitivity and reproducibility. ADAMTS-13 antigen and conformation were determined for healthy donors and acute iTTP patients showing strong correlation with ELISA reference. Introducing FO-SPR technology in clinical context could support routine diagnosis of acute iTTP patients, notably when ADAMTS-13 activity fluctuates between 10% and 20%., Competing Interests: Declaration of competing interests J.L. is a member of the Board of Directors of FOx Biosystems. Q.B., C.D., T.B., E.T., G.K., B.S.J., A.V., P.C., C.T., S.F.D.M., and K.V. have no conflicts of interest to disclose., (Copyright © 2024 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
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- 2024
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13. R-tPA Resistance Is Specific for Platelet-Rich Stroke Thrombi and Can Be Overcome by Targeting Nonfibrin Components.
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Vandelanotte S, François O, Desender L, Staessens S, Vanhoorne A, Van Gool F, Tersteeg C, Vanhoorelbeke K, Vanacker P, Andersson T, and De Meyer SF
- Abstract
Background: Resistance to r-tPA (recombinant tissue-type plasminogen activator) is a well-known but poorly understood phenomenon that hampers successful recanalization in patients with acute ischemic stroke. Using clinically relevant thrombi from patients with acute ischemic stroke, we investigated if and how thrombus composition impacts r-tPA-mediated lysis. In addition, we explored strategies to overcome r-tPA resistance., Methods: Thrombi were split into 2 parts, 1 of which was used for thrombolysis and the other for detailed histological analysis. Thrombolysis was performed in normal human plasma using r-tPA alone, using r-tPA in combination with DNase-1 or using r-tPA in combination with N,N'-diacetyl-l-cystine. Thrombus lysis was calculated as the percentage of residual thrombus weight compared with its initial weight and the degree of lysis was linked to thrombus composition determined via histology., Results: Interestingly, we found that the efficacy of r-tPA-mediated thrombolysis was strongly correlated with the composition of the thrombi. Thrombi containing high amounts of red blood cells and low amounts of DNA and von Willebrand Factor were efficiently degraded by r-tPA, whereas thrombi containing low amounts of red blood cells and higher amounts of DNA and von Willebrand Factor were resistant to r-tPA. Importantly, combination of r-tPA with DNase-1 or N,N'-diacetyl-l-cystine significantly and specifically improved the lysis of these r-tPA-resistant thrombi., Conclusions: Using patient thrombus material, our results for the first time show that the composition of stroke thrombi largely determines their susceptibility to r-tPA-mediated thrombolysis. Red blood cell-poor thrombi have a specific resistance to r-tPA, which can be overcome by targeting nonfibrin components using DNase-1 or N,N'-diacetyl-l-cystine., Competing Interests: Disclosures Dr François is a consultant for iVascular. Dr Vanacker received speaker fees from Boehringer-Ingelheim, BMS, Pfizer, Daiichi-Sankyo, and Medtronic. Dr Andersson holds equity for Cereflo Ltd and is a consultant for Anaconda, Cerenovus/Neuravi, Optimize Neurovascular and Rapid medical. The other authors report no conflicts.
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- 2024
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14. Pretreatment with a dual antiplatelet and anticoagulant (APAC) reduces ischemia-reperfusion injury in a mouse model of temporary middle cerebral artery occlusion-implications for neurovascular procedures.
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Denorme F, Frösen J, Jouppila A, Lindgren A, Resendiz-Nieves JC, Manninen H, De Meyer SF, and Lassila R
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- Mice, Animals, Anticoagulants pharmacology, Anticoagulants therapeutic use, Infarction, Middle Cerebral Artery drug therapy, Brain metabolism, Heparin pharmacology, Heparin therapeutic use, Brain Ischemia drug therapy, Brain Ischemia metabolism, Reperfusion Injury drug therapy, Brain Injuries
- Abstract
Background: Several neurovascular procedures require temporary occlusion of cerebral arteries, leading to ischemia of unpredictable length, occasionally causing brain infarction. Experimental models of cerebral ischemia-reperfusion injury have established that platelet adhesion and coagulation play detrimental roles in reperfusion injury following transient cerebral ischemia. Therefore, in a model of cerebral ischemia-reperfusion injury (IRI), we investigated the therapeutic potential of a dual antiplatelet and anticoagulant (APAC) heparin proteoglycan mimetic which is able to bind to vascular injury sites., Methods: Brain ischemia was induced in mice by transient occlusion of the right middle cerebral artery for 60 min. APAC, unfractionated heparin (UFH) (both at heparin equivalent doses of 0.5 mg/kg), or vehicle was intravenously administered 10 min before or 60 min after the start of ischemia. At 24 h later, mice were scored for their neurological and motor behavior, and brain damage was quantified., Results: Both APAC and UFH administered before the onset of ischemia reduced brain injury. APAC and UFH pretreated mice had better neurological and motor functions (p < 0.05 and p < 0.01, respectively) and had significantly reduced cerebral infarct sizes (p < 0.01 and p < 0.001, respectively) at 24 h after transient occlusion compared with vehicle-treated mice. Importantly, no macroscopic bleeding complications were observed in either APAC- or UFH-treated animals. However, when APAC or UFH was administered 60 min after the start of ischemia, the therapeutic effect was lost, but without hemorrhaging either., Conclusions: Pretreatment with APAC or UFH was safe and effective in reducing brain injury in a model of cerebral ischemia induced by transient middle cerebral artery occlusion. Further studies on the use of APAC to limit ischemic injury during temporary occlusion in neurovascular procedures are indicated., (© 2024. The Author(s).)
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- 2024
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15. White blood cell subtypes and neutrophil extracellular traps content as biomarkers for stroke etiology in acute ischemic stroke clots retrieved by mechanical thrombectomy.
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Jabrah D, Rossi R, Molina S, Douglas A, Pandit A, McCarthy R, Gilvarry M, Ceder E, Fitzgerald S, Dunker D, Nordanstig A, Redfors P, Tatlisumak T, O'Hare A, Power S, Brennan P, Owens P, Nagy A, Vadász Á, De Meyer SF, Tsivgoulis G, Psychogios K, Szikora I, Jood K, Rentzos A, Thornton J, and Doyle K
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- Humans, Biomarkers metabolism, Leukocytes pathology, Thrombectomy methods, Ischemic Stroke, Brain Ischemia, Extracellular Traps metabolism, Stroke complications
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Background: Lymphocytes, macrophages, neutrophils, and neutrophil extracellular traps (NETs) associate with stroke risk factors and form a thrombus through different mechanisms. We investigated the total WBCs, WBC subtypes and NETs composition in acute ischemic stroke (AIS) clots to identify possible etiological differences that could help us further understand the process of thrombosis that leads to AIS., Methods: AIS clots from 100 cases each of atherothrombotic (AT), cardioembolic (CE) and cryptogenic stroke etiology were collected per-pass as part of the CÚRAM RESTORE registry of AIS clots. Martius Scarlet Blue stain was used to identify the main histological components of the clots. Immunohistochemical staining was used to identify neutrophils, lymphocytes, macrophages, and NETs patterns. The cellular and histological components were quantified using Orbit Image Analysis software., Results: AT clots were larger, with more red blood cells and fewer WBCs than CE clots. AT clots had more lymphocytes and cryptogenic clots had fewer macrophages than other etiologies. Most significantly, CE clots showed higher expression of neutrophils and extracellular web-like NETs compared to AT and cryptogenic clots. There was also a significantly higher distribution of web-like NETs around the periphery of the CE clots while a mixed distribution was observed in AT clots., Conclusion: The difference in neutrophil and NETs expression in clots from different etiologies may provide insight into the mechanism of clot formation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)
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- 2024
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16. Open ADAMTS-13 conformation index predicts earlier relapse in immune-mediated thrombotic thrombocytopenic purpura.
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De Waele L, Sakai K, Mancini I, Sinkovits G, Falter T, Inoue T, Agosti P, Rossmann H, Von Auer C, Tersteeg C, De Meyer SF, Joly BS, Veyradier A, Coppo P, Fijnheer R, Peyvandi F, Prohászka Z, Lämmle B, and Vanhoorelbeke K
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- Humans, Autoantibodies, Proportional Hazards Models, Recurrence, Risk Factors, ADAMTS13 Protein, Purpura, Thrombotic Thrombocytopenic diagnosis, Purpura, Thrombotic Thrombocytopenic therapy
- Abstract
Background: ADAMTS-13 adopts an open conformation in patients with immune-mediated thrombotic thrombocytopenic purpura (iTTP) in acute phase while being closed in healthy donors. We reported that a substantial number of patients with iTTP in remission with restored ADAMTS-13 activity (>50%) still had an open ADAMTS-13 conformation, although a closed conformation is expected given the extent of remission., Objectives: To investigate whether open ADAMTS-13, represented by a conformation index >0.5, is associated with a risk of earlier ADAMTS-13 and/or clinical relapse., Methods: We collected follow-up data (ADAMTS-13 parameters, ADAMTS-13 and clinical relapse, and treatment) from 81 patients with iTTP in remission with ADAMTS-13 activity >50%., Results: During follow-up, 19 ADAMTS-13 and 10 clinical relapses were reported (median follow-up period, 20 months). First, open or closed ADAMTS-13 conformation was dichotomized based on the 0.5 conformation index cutoff. Open ADAMTS-13 (conformation index, >0.5) was not identified as a risk factor for ADAMTS-13 and clinical relapse (log-rank test and Cox regression model). In contrast, by identifying the optimal conformation index cutoff for relapse prediction, using classification and regression tree analysis, a conformation index >0.645 and >0.835 was shown to be a risk factor for ADAMTS-13 relapse (hazard ratio, 3.3; 95% CI, 1.3-8.3; P = .01) and clinical relapse (hazard ratio, 4.4; 95% CI, 1.3-15.3; P = .02), respectively., Conclusion: Patients with open ADAMTS-13 with a conformation index >0.645 and >0.835 have a >3- and >4-fold higher risk of earlier ADAMTS-13 and clinical relapse, respectively. Hence, ADAMTS-13 conformation index could be used to complement ADAMTS-13 activity monitoring to timely notice ADAMTS-13 relapse and prevent clinical relapse., Competing Interests: Declaration of competing interests K.V. is a member of the advisory board of Takeda. I.M. received honoraria for participating as a speaker at educational meetings organized by Instrumentation Laboratory and Sanofi. F.P. has received honoraria for participating as a speaker in education meetings organized by Grifols and Roche, and she is a member of the scientific advisory boards of BioMarin, Roche, Sanofi, Sobi, and Takeda. B.L. is chairman of the Data Monitoring Committees of studies of recombinant ADAMTS-13 in patients with congenital thrombotic thrombocytopenic purpura (TTP) and immune-mediated TTP by Takeda (Takeda 2811 02, TAK-755-3002, Takeda SHP 605-201). He is chairman of the Data Monitoring Committees of a study investigating therapy of immune-mediated TTP with caplacizumab and immunosuppression without plasma exchange by Sanofi. He received lecture fees and/or congress travel support from Ablynx, Alexion, Siemens, Bayer, Roche, Sanofi, and Takeda. P.C. is a member of the Clinical Advisory Board of and received speaker fees from Alexion, Sanofi, and Takeda. A.V. is a member of the Advisory board for caplacizumab Sanofi and rhADAMTS-13 Takeda. Other coauthors do not have any conflicts of interest to disclose., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
- Published
- 2024
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17. Endotheliitis and cytokine storm as a mechanism of clot formation in COVID-19 ischemic stroke patients: A histopathologic study of retrieved clots.
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Brinjikji W, Kallmes DF, Virmani R, de Meyer SF, Yoo AJ, Humphries W, Zaidat OO, Teleb MS, Jones JG, Siddiqui AH, Andersson T, Nogueira RG, Gil SM, Douglas A, Rossi R, Rentzos A, Ceder E, Carlqvist J, Dunker D, Jood K, Tatlisumak T, and Doyle KM
- Abstract
Background: Studies during the COVID-19 pandemic have demonstrated an association between COVID-19 virus infection and the development of acute ischemic stroke, particularly large vessel occlusion (LVO). Studying the characteristics and immunohistochemistry of retrieved stroke emboli during mechanical thrombectomy for LVO may offer insights into the pathogenesis of LVO in COVID-19 patients. We examined retrieved COVID-19 emboli from the STRIP, EXCELLENT, and RESTORE registries and compared their characteristics to a control group., Methods: We identified COVID-positive LVO patients from the STRIP, RESTORE, and EXCELLENT studies who underwent mechanical thrombectomy. These patients were matched to a control group controlling for stroke etiology based on Trial of Org 10172 in Acute Stroke Treatment criteria. All clots were stained with Martius Scarlet Blue (MSB) along with immunohistochemistry for interleukin-6 (IL-6), C-reactive protein (CRP), von Willebrand factor (vWF), CD66b, fibrinogen, and citrullinated Histone H3. Clot composition was compared between groups., Results: Nineteen COVID-19-positive patients and 38 controls were included. COVID-19-positive patients had a significantly higher percentage of CRP and vWF. There was no difference in IL-6, fibrin, CD66b, or citrullinated Histone H3 between groups. Based on MSB staining, there was no statistically significant difference regarding the percentage of red blood cells, white blood cells, fibrin, and platelets., Conclusions: Our study found higher concentrations of CRP and vWF in retrieved clots of COVID-19-positive stroke patients compared to COVID-19-negative controls. These findings support the potential role of systemic inflammation as indicated by elevated CRP and endothelial injury as indicated by elevated vWF as precipitating factors in thrombus development in these patients.
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- 2023
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18. Measuring ADAMTS-13 activity to diagnose thrombotic thrombocytopenic purpura: a novel, fast fiber-optic surface plasmon resonance immunoassay.
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Bonnez Q, Dekimpe C, Tellier E, Kaplanski G, Verhamme P, Tersteeg C, De Meyer SF, Lammertyn J, Joly B, Coppo P, Veyradier A, and Vanhoorelbeke K
- Abstract
Background: Thrombotic thrombocytopenic purpura (TTP) is characterized by severe ADAMTS-13 activity deficiency (<10%). Diagnostic testing is challenging because of unavailability, high cost, and expert technician requirement of ADAMTS-13 enzyme assays. Cost-effective, automated fiber-optic surface plasmon resonance (FO-SPR) platforms show potential for developing diagnostic tests. Yet, FO-SPR has never been explored to measure enzymatic activities., Objectives: To develop an easy-to-use ADAMTS-13 activity assay utilizing optical fibers to rapidly diagnose TTP., Methods: The ADAMTS-13 activity assay was designed and optimized using FO-SPR technology based on a previously described enzyme-linked immunosorbent assay setup. A calibration curve was generated to quantify ADAMTS-13 activity in plasma of healthy donors and patients with acute immune-mediated TTP (iTTP), hemolytic uremic syndrome, or sepsis. ADAMTS-13 activity data from FO-SPR and fluorescence resonance energy transfer-based strategies (FRETS)-VWF73 reference assays were compared., Results: After initial assay development, optimization improved read-out magnitude and signal-to-noise ratio and reduced variation. Further characterization demonstrated a detection limit (6.8%) and inter-assay variation (Coefficient of variation, 7.2%) that showed good analytical sensitivity and repeatability. From diverse plasma samples, only plasma from patients with acute iTTP showed ADAMTS-13 activities below 10%. Strong Pearson correlation ( r = 0.854) between FO-SPR and reference FRETS-VWF73 assays were observed for all measured samples., Conclusions: A fast ADAMTS-13 activity assay was designed onto automated FO-SPR technology. Optimization resulted in sensitive ADAMTS-13 activity measurements with a detection limit enabling clinical diagnosis of TTP within 3 hours. The FO-SPR assay proved strong correlation with the reference FRETS-VWF73 assay. For the first time, this assay demonstrated the capacity of FO-SPR technology to measure enzymatic activity in pre-clinical context., (© 2023 The Author(s).)
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- 2023
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19. Mechanical thrombectomy for acute ischemic stroke revealing a cardiac myxoma: histological and immunohistochemical study to determine myxomatous emboli.
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Vantyghem S, Staessens S, Francois O, De Meyer SF, and Vanacker P
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- Humans, Thrombectomy, Tissue Plasminogen Activator, Treatment Outcome, Ischemic Stroke complications, Ischemic Stroke diagnostic imaging, Stroke complications, Stroke diagnostic imaging, Brain Ischemia complications, Brain Ischemia diagnostic imaging, Myxoma complications, Myxoma diagnostic imaging, Myxoma pathology
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- 2023
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20. Identifying ex vivo acute ischemic stroke thrombus composition using electrochemical impedance spectroscopy.
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Darcourt J, Brinjikji W, François O, Giraud A, Johnson CR, Patil S, Staessens S, Kadirvel R, Mohammaden MH, Pisani L, Rodrigues GM, Cancelliere NM, Pereira VM, Bozsak F, Doyle K, De Meyer SF, Messina P, Kallmes D, Cognard C, and Nogueira RG
- Abstract
Background: Intra-procedural characterization of stroke thromboemboli might guide mechanical thrombectomy (MT) device choice to improve recanalization rates. Electrochemical impedance spectroscopy (EIS) has been used to characterize various biological tissues in real time but has not been used in thrombus., Objective: To perform a feasibility study of EIS analysis of thrombi retrieved by MT to evaluate: (1) the ability of EIS and machine learning to predict red blood cell (RBC) percentage content of thrombi and (2) to classify the thrombi as "RBC-rich" or "RBC-poor" based on a range of cutoff values of RBC., Methods: ClotbasePilot was a multicentric, international, prospective feasibility study. Retrieved thrombi underwent histological analysis to identify proportions of RBC and other components. EIS results were analyzed with machine learning. Linear regression was used to evaluate the correlation between the histology and EIS. Sensitivity and specificity of the model to classify the thrombus as RBC-rich or RBC-poor were also evaluated., Results: Among 514 MT,179 thrombi were included for EIS and histological analysis. The mean composition in RBC of the thrombi was 36% ± 24. Good correlation between the impedance-based prediction and histology was achieved (slope of 0.9, R
2 = 0.53, Pearson coefficient = 0.72). Depending on the chosen cutoff, ranging from 20 to 60% of RBC, the calculated sensitivity for classification of thrombi ranged from 77 to 85% and the specificity from 72 to 88%., Conclusion: Combination of EIS and machine learning can reliably predict the RBC composition of retrieved ex vivo AIS thrombi and then classify them into groups according to their RBC composition with good sensitivity and specificity.- Published
- 2023
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21. Toward gene therapy for congenital thrombotic thrombocytopenic purpura.
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Dekimpe C, Roose E, Sakai K, Tersteeg C, De Meyer SF, and Vanhoorelbeke K
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- Humans, ADAMTS13 Protein, Plasma, Blood Transfusion, Genetic Therapy adverse effects, Purpura, Thrombotic Thrombocytopenic genetics, Purpura, Thrombotic Thrombocytopenic therapy
- Abstract
Congenital thrombotic thrombocytopenic purpura (cTTP) is caused by a severe deficiency in the plasma metalloprotease ADAMTS-13. The current management of cTTP is dependent on the prophylactic administration of ADAMTS-13 via plasma infusion. This is a demanding therapy for patients because transfusions are lifelong and time-consuming and allergic reactions frequently occur. Although current management of cTTP controls acute episodes, it does not provide a long-lasting cure for this disease. The endogenous expression of ADAMTS-13 after gene transfer would provide a curative therapy and ongoing research explores various preclinical gene therapeutic approaches for cTTP. This review focuses on the current state of the literature regarding preclinical gene therapy studies for cTTP and on the challenges of developing a gene therapy medicinal product for cTTP., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)
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- 2023
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22. Small-Molecule Cyclophilin Inhibitors Potently Reduce Platelet Procoagulant Activity.
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Van Bael J, Vandenbulcke A, Ahmed-Belkacem A, Guichou JF, Pawlotsky JM, Samyn J, Barendrecht AD, Maas C, De Meyer SF, Vanhoorelbeke K, and Tersteeg C
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- Mice, Animals, Humans, Mice, Knockout, Blood Platelets metabolism, Platelet Activation, Platelet Glycoprotein GPIIb-IIIa Complex metabolism, Cyclophilins metabolism, Thrombosis metabolism
- Abstract
Procoagulant platelets are associated with an increased risk for thrombosis. Procoagulant platelet formation is mediated via Cyclophilin D (CypD) mediated opening of the mitochondrial permeability transition pore. Inhibiting CypD activity could therefore be an interesting approach to limiting thrombosis. In this study, we investigated the potential of two novel, non-immunosuppressive, non-peptidic small-molecule cyclophilin inhibitors (SMCypIs) to limit thrombosis in vitro, in comparison with the cyclophilin inhibitor and immunosuppressant Cyclosporin A (CsA). Both cyclophilin inhibitors significantly decreased procoagulant platelet formation upon dual-agonist stimulation, shown by a decreased phosphatidylserine (PS) exposure, as well as a reduction in the loss of mitochondrial membrane potential. Furthermore, the SMCypIs potently reduced procoagulant platelet-dependent clotting time, as well as fibrin formation under flow, comparable to CsA. No effect was observed on agonist-induced platelet activation measured by P-selectin expression, as well as CypA-mediated integrin α
IIb β3 activation. Importantly, whereas CsA increased Adenosine 5'-diphosphate (ADP)-induced platelet aggregation, this was unaffected in the presence of the SMCypIs. We here demonstrate specific cyclophilin inhibition does not affect normal platelet function, while a clear reduction in procoagulant platelets is observed. Reducing platelet procoagulant activity by inhibiting cyclophilins with SMCypIs forms a promising strategy to limit thrombosis.- Published
- 2023
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23. In vitro characterization of a novel Arg102 mutation in the ADAMTS13 metalloprotease domain.
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De Waele L, Vermeersch L, Nguyen TT, Tersteeg C, De Meyer SF, Voet A, Pavenski K, and Vanhoorelbeke K
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- Humans, ADAM Proteins chemistry, HEK293 Cells, Mutation, Epitopes, ADAMTS13 Protein genetics, Purpura, Thrombotic Thrombocytopenic genetics
- Abstract
Background: Congenital thrombotic thrombocytopenic purpura is caused by defects in the ADAMTS13 gene. ADAMTS13 is normally preactivated by conformational changes of the Metalloprotease (M) domain. Studying a novel congenital thrombotic thrombocytopenic purpura p.R102S mutation in the M domain, which results in undetectable ADAMTS13 activity in the patient, could help to explain the patients' phenotype and to elucidate the currently unclear mechanism of allosteric preactivation., Objectives: To investigate the in vitro effect of p.R102S mutation on ADAMTS13 secretion, activity, and allosteric preactivation., Methods: Molecular modeling was used to study the effect of the mutation on the stability of ADAMTS13. Recombinant mutant ADAMTS13 was generated by transient and stable transfection of, respectively, CHO K1 and HEK293-T cells. ADAMTS13 antigen was measured in enzyme-linked immunosorbent assay. ADAMTS13 activity was measured in a FRETS-VWF73 assay. Allosteric preactivation was assessed in FRETS-VWF73 assay, using monoclonal antibody (mAb) 17G2 that normally induces a ∼2-fold increase in activity, and in enzyme-linked immunosorbent assay using mAb 6A6 recognizing a cryptic epitope in the M domain that becomes exposed after binding of 17G2., Results: p.R102S mutation destabilizes the interactions between the M and Disintegrin-like (D) domain. p.R102S mutant secretion was impaired (35% of wild type) and activity was severely reduced (12% of wild type). p.R102S mutant could still be activated and the cryptic epitope of 6A6 was still fully exposed by 17G2 addition., Conclusion: p.R102S mutation destabilizes the M-D domain interactions, causing impaired ADAMTS13 secretion and activity, which explains the patients' phenotype. Allosteric preactivation of ADAMTS13 remains conserved in the presence of the p.R102S mutation., (Copyright © 2022 International Society on Thrombosis and Haemostasis. All rights reserved.)
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- 2023
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24. ADAMTS13 conformation and immunoprofiles in Japanese patients with immune-mediated thrombotic thrombocytopenic purpura.
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Sakai K, Matsumoto M, De Waele L, Dekimpe C, Hamada E, Kubo M, Tersteeg C, De Meyer SF, and Vanhoorelbeke K
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- Humans, East Asian People, Autoantibodies, Biomarkers, Molecular Conformation, ADAMTS13 Protein metabolism, Purpura, Thrombotic Thrombocytopenic diagnosis, Purpura, Thrombotic Thrombocytopenic therapy
- Abstract
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is an ultrarare thrombotic disease caused by autoantibody-induced ADAMTS13 deficiency. Open ADAMST13 conformation, induced by autoantibodies, was identified as a novel biomarker for iTTP. Determining immunoprofiles in patients with iTTP has been shown to guide the development of novel targeted therapies. However, these studies were done in mainly Caucasian iTTP cohorts. To validate those findings across other ethnic cohorts, we investigated 195 acute TTP plasma samples from the Japanese iTTP registry. Seventy-six of the 195 samples had detectable ADAMTS13 antigen levels, of which 94.7% were shown to have an open ADAMTS13 conformation. A positive correlation was observed between ADAMTS13 inhibitor titers (a diagnostic parameter in Japan) and anti-ADAMTS13 immunoglobulin G autoantibody titers. Studying anti-M, anti-DT, anti-CS, anti-T2-T5, anti-T6-T8, anti-CUB1-2 autoantibodies and the corresponding immunoprofile showed that 73% of the patients had anti-CS autoantibodies and 25.8% had anti-M autoantibodies, with the latter being higher than in Caucasians. Stratifying patients according to their immunoprofiles revealed that the profile with only anti-CS autoantibodies was the most common immunoprofile similar to that in Caucasians (28.9%). Although this profile did not affect the 1-year TTP-related mortality rate, patients with autoantibodies against all 6 ADAMTS13 fragments had a higher risk for TTP-related death than other patients (P = .02). We here validated open ADAMTS13 as a novel biomarker for acute iTTP and determined the dominant immunoprofiling in the Japanese cohort, contributing to setting up the diagnosis and managing guidelines across different ethnic cohorts and developing ADAMTS13 variants that do not bind to the anti-CS autoantibodies., (© 2023 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2023
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25. Spatiotemporal profile of neutrophil extracellular trap formation in a mouse model of ischemic stroke.
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De Wilde M, Desender L, Tersteeg C, Vanhoorelbeke K, and De Meyer SF
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Background: Thromboinflammatory processes modulate the complex pathophysiology of cerebral ischemia-reperfusion (I/R) injury in ischemic stroke, but the exact underlying mechanisms remain poorly understood. Emerging evidence indicates that neutrophil extracellular traps (NETs) might play an important role in the thromboinflammatory cascade. In addition, the link between von Willebrand factor (VWF) and neutrophil recruitment in the ischemic brain might promote thromboinflammation, possibly by the formation of NETs., Objectives: To study NET formation in a murine model of cerebral I/R injury in ischemic stroke., Methods: The filament-induced transient middle cerebral artery occlusion model was used to induce 60 minutes of focal cerebral ischemia after which reperfusion was allowed. At different time points postischemia, NETs were identified in the ischemic mouse brain using quantitative immunofluorescence microscopy., Results: NETs could be identified in the ipsilateral brain hemisphere. Interestingly, NETs could already be detected at 6 hours poststroke. Their presence increased at 12 hours, was highest at 24 hours, and decreased again 48 hours postischemia. Remarkably, NETs were predominantly localized within the brain vasculature postischemia, suggesting that NETs play a role in secondary microthrombosis. Strikingly, NET formation was significantly decreased in VWF-deficient mice compared to littermate wild-type mice 24 hours postischemia, indicating a possible role for VWF in promoting NETosis in the ischemic brain., Conclusion: This study identified the spatiotemporal profile of NET formation in a mouse model of cerebral I/R injury in ischemic stroke. NETs, potentially in combination with VWF, might be attractive targets for the development of novel therapeutic strategies in ischemic stroke treatment., (© 2022 The Authors.)
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- 2022
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26. ADAMTS13 inhibition to treat acquired von Willebrand syndrome during mechanical circulatory support device implantation.
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Deconinck SJ, Nix C, Barth S, Bennek-Schöpping E, Rauch A, Schelpe AS, Roose E, Feys HB, Pareyn I, Vandenbulcke A, Muia J, Vandenbriele C, Susen S, Meyns B, Tersteeg C, Jacobs S, De Meyer SF, and Vanhoorelbeke K
- Subjects
- Animals, Cattle, Humans, von Willebrand Factor metabolism, ADAMTS13 Protein, Hemostasis, Collagen, von Willebrand Diseases, Heart-Assist Devices adverse effects
- Abstract
Background: Acquired von Willebrand syndrome (aVWS) is common in patients with mechanical circulatory support (MCS) devices. In these patients, the high shear stress in the device leads to increased shear-induced proteolysis of von Willebrand factor (VWF) by A Disintegrin And Metalloprotease with Thrombospondin type 1 repeats, number 13 (ADAMTS13). As a result, the high molecular weight (HMW) VWF multimers are lost, leading to a decreased VWF function and impaired hemostasis that could explain the bleeding complications that are frequently observed in these patients. To counteract this abnormal VWF degradation by ADAMTS13, we developed a novel targeted therapy, using an anti-ADAMTS13 monoclonal antibody (mAb) that inhibits the shear-induced proteolysis of VWF by ADAMTS13., Methods: Human or bovine blood was circulated through in vitro MCS device systems with either inhibitory anti-ADAMTS13 mAb 3H9 or 17C7 (20 μg/ml) or control anti-ADAMTS13 mAb 5C11 or phosphate buffered saline (PBS). VWF multimers and function (collagen binding activity) were determined at different time points. Next, Impella pumps were implanted in calves and the calves were injected with PBS and subsequently treated with mAb 17C7. VWF, ADAMTS13, and blood parameters were determined., Results: We demonstrated that blocking ADAMTS13 could prevent the loss of HMW VWF multimers in in vitro MCS device systems. Importantly, our antibody could reverse aVWS in a preclinical Impella-induced aVWS calf model., Conclusion: Hence, inhibition of ADAMTS13 could become a novel therapeutic strategy to manage aVWS in MCS device patients., (© 2022 International Society on Thrombosis and Haemostasis.)
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- 2022
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27. Thrombus formation during ECMO: Insights from a detailed histological analysis of thrombus composition.
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Staessens S, Moussa MD, Pierache A, Rauch A, Rousse N, Boulleaux E, Ung A, Desender L, Pradines B, Vincentelli A, Mercier O, Labreuche J, Duhamel A, Van Belle E, Vincent F, Dupont A, Vanhoorelbeke K, Corseaux D, De Meyer SF, and Susen S
- Subjects
- Anticoagulants, Fibrin analysis, Humans, von Willebrand Factor, Extracorporeal Membrane Oxygenation adverse effects, Thrombosis
- Abstract
Objectives: Intra-device thrombosis remains one of the most common complications during extracorporeal membrane oxygenation (ECMO). Despite anticoagulation, approximately 35% of patients develop thrombi in the membrane oxygenator, pump heads, or tubing. The aim of this study was to describe the molecular and cellular features of ECMO thrombi and to study the main drivers of thrombus formation at different sites in the ECMO circuits., Approach and Results: Thrombi (n = 85) were collected immediately after veno-arterial-(VA)-ECMO circuit removal from 25 patients: 23 thrombi from the pump, 25 from the oxygenator, and 37 from the tubing. Quantitative histological analysis was performed for the amount of red blood cells (RBCs), platelets, fibrin, von Willebrand factor (VWF), leukocytes, and citrullinated histone H3 (H3Cit). ECMO thrombi consist of a heterogenous composition with fibrin and VWF being the major thrombus components. A clustering analysis of the four major histological parameters identified two typical thrombus types: RBC-rich and RBC-poor/fibrin-rich thrombi with no significant differences in VWF and platelet content. Thrombus composition was not associated with the thrombus location, except for higher amounts of H3Cit that were found in pump and oxygenator thrombi compared to tubing samples. We observed higher blood leukocyte count and lactate dehydrogenase levels in patients with fibrin-rich thrombi., Conclusion: We found that thrombus composition is heterogenous, independent of their location, consisting of two types: RBC-rich and a fibrin-rich types. We also found that NETs play a minor role. These findings are important to improve current anticoagulation strategies in ECMO., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)
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- 2022
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28. Embotrap Extraction & Clot Evaluation & Lesion Evaluation for NeuroThrombectomy (EXCELLENT) Registry design and methods.
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Siddiqui AH, Waqas M, Brinjikji W, De Meyer SF, Doyle K, Fiehler J, Hacke W, Hanel RA, Jovin TG, Liebeskind DS, Yoo AJ, Zaidat OO, Andersson T, and Nogueira RG
- Subjects
- Adult, Humans, Prospective Studies, Registries, Stents, Thrombectomy methods, Treatment Outcome, Brain Ischemia therapy, Stroke diagnostic imaging, Stroke surgery, Thrombosis
- Abstract
Background: Relationships between occlusive clot histopathology, baseline characteristics, imaging findings, revascularization rates, and clinical outcomes of stroke patients with large vessel occlusion (LVO) are not well understood. This study will assess the real-world experience on the efficacy and safety of using the EmboTrap device as the first approach in LVO patients and explore the associations between clot histological characteristics, imaging and clinical findings, revascularization rates, and clinical outcomes., Methods: Prospective, global, multicenter, single-arm, imaging core laboratory, and clot analysis central laboratory observational registry. Adult patients (>18 years) with LVO, treated with EmboTrap as the first attempted device, will be eligible for study participation., Results: Up to 1000 subjects at 50 international sites may be enrolled. Occlusive clots will be collected from at least 500 subjects. Independent central and imaging core laboratories will perform clot analysis and image adjudication. Statistical analysis will assess the association between imaging and clinical findings, clot characteristics, subject comorbidities, revascularization, and clinical outcomes. Study endpoints are functional independence (modified Rankin Scale score ≤2 at 90 days), expanded Thrombolysis In Cerebral Infarction (eTICI) score ≥2b50 rate, first-pass effect, number of passes, embolization into new territory, symptomatic intracranial hemorrhage, and 90-day mortality., Conclusions: The EXCELLENT registry will provide reproducible effectiveness and safety data of EmboTrap for its use for mechanical thrombectomy. Additionally, the study will characterize the blood clots retrieved during mechanical thrombectomy with respect to their composition and histopathological analysis and potential correlations with clinical and imaging findings., Trial Registration Number: NCT03685578., Competing Interests: Competing interests: AHS: Co-investigator NIH/NINDS 1R01NS091075; Amnis Therapeutics, Boston Scientific, Canon Medical Systems USA Inc, Cerebrotech Medical Systems, Cerenovus, Corindus Inc, Endostream Medical Ltd, Guidepoint Global Consulting, Imperative Care, Integra LifeSciences Corp, Medtronic, MicroVention, Q’Apel Medical Inc, Rapid Medical, Rebound Therapeutics Corp, Serenity Medical Inc, Silk Road Medical, StimMed, Stryker, Three Rivers Medical, VasSol, W.L. Gore & Associates; Amnis Therapeutics, Apama Medical, Blink TBI Inc, Buffalo Technology Partners Inc, Cardinal Consultants, Cerebrotech Medical Systems, Cognition Medical, Endostream Medical Ltd, Imperative Care, International Medical Distribution Partners, Neurovascular Diagnostics Inc, Q’Apel Medical Inc, Rebound Therapeutics Corp, Rist Neurovascular Inc, Serenity Medical, Silk Road Medical, StimMed, Synchron, Three Rivers Medical Inc, Viseon Spine. TA: Neuravi, Ablynx, Amnis Therapeutics, Medtronic, Rapid Medical, Stryker. RGN: Neuravi, Medtronic, Penumbra, Stryker., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)
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- 2022
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29. High Incidence of SARS-CoV-2 Variant of Concern Breakthrough Infections Despite Residual Humoral and Cellular Immunity Induced by BNT162b2 Vaccination in Healthcare Workers: A Long-Term Follow-Up Study in Belgium.
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Calcoen B, Callewaert N, Vandenbulcke A, Kerstens W, Imbrechts M, Vercruysse T, Dallmeier K, Van Weyenbergh J, Maes P, Bossuyt X, Zapf D, Dieckmann K, Callebaut K, Thibaut HJ, Vanhoorelbeke K, De Meyer SF, Maes W, and Geukens N
- Subjects
- Antibodies, Neutralizing, Antibodies, Viral, BNT162 Vaccine, Belgium, CD8-Positive T-Lymphocytes, Disease Progression, Follow-Up Studies, Health Personnel, Humans, Immunity, Cellular, Immunity, Humoral, Incidence, Vaccination, COVID-19 epidemiology, COVID-19 prevention & control, SARS-CoV-2 genetics
- Abstract
To mitigate the massive COVID-19 burden caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), several vaccination campaigns were initiated. We performed a single-center observational trial to monitor the mid- (3 months) and long-term (10 months) adaptive immune response and to document breakthrough infections (BTI) in healthcare workers ( n = 84) upon BNT162b2 vaccination in a real-world setting. Firstly, serology was determined through immunoassays. Secondly, antibody functionality was analyzed via in vitro binding inhibition and pseudovirus neutralization and circulating receptor-binding domain (RBD)-specific B cells were assessed. Moreover, the induction of SARS-CoV-2-specific T cells was investigated by an interferon-γ release assay combined with flowcytometric profiling of activated CD4
+ and CD8+ T cells. Within individuals that did not experience BTI ( n = 62), vaccine-induced humoral and cellular immune responses were not correlated. Interestingly, waning over time was more pronounced within humoral compared to cellular immunity. In particular, 45 of these 62 subjects no longer displayed functional neutralization against the delta variant of concern (VoC) at long-term follow-up. Noteworthily, we reported a high incidence of symptomatic BTI cases (17.11%) caused by alpha and delta VoCs, although vaccine-induced immunity was only slightly reduced compared to subjects without BTI at mid-term follow-up.- Published
- 2022
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30. Basic science research opportunities in thrombosis and hemostasis: Communication from the SSC of the ISTH.
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Mutch NJ, Walters S, Gardiner EE, McCarty OJT, De Meyer SF, Schroeder V, and Meijers JCM
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- Communication, Hemorrhage, Hemostasis, Humans, Hemostatics, Thrombosis diagnosis, Thrombosis therapy
- Abstract
Bleeding and thrombosis are major clinical problems with high morbidity and mortality. Treatment modalities for these diseases have improved in recent years, but there are many clinical questions remaining and a need to advance diagnosis, management, and therapeutic options. Basic research plays a fundamental role in understanding normal and disease processes, yet this sector has observed a steady decline in funding prospects thereby hindering support for studies of mechanisms of disease and therapeutic development opportunities. With the financial constraints faced by basic scientists, the ISTH organized a basic science task force (BSTF), comprising Scientific and Standardization Committee subcommittee chairs and co-chairs, to identify research opportunities for basic science in hemostasis and thrombosis. The goal of the BSTF was to develop a set of recommended priorities to build support in the thrombosis and hemostasis community and to inform ISTH basic science programs and policy making. The BSTF identified three principal opportunity areas that were of significant overarching relevance: mechanisms causing bleeding, innate immunity and thrombosis, and venous thrombosis. Within these, five fundamental research areas were highlighted: blood rheology, platelet biogenesis, cellular contributions to thrombosis and hemostasis, structure-function protein analyses, and visualization of hemostasis. This position paper discusses the importance and relevance of these opportunities and research areas, and the rationale for their inclusion. These findings have implications for the future of fundamental research in thrombosis and hemostasis to make transformative scientific discoveries and tackle key clinical questions. This will permit better understanding, prevention, diagnosis, and treatment of hemostatic and thrombotic conditions., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)
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- 2022
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31. Unusual Histopathological Findings in Mechanically Removed Stroke Thrombi - A Multicenter Experience.
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Aspegren O, Staessens S, Vandelanotte S, Desender L, Cordonnier C, Puy L, Bricout N, De Meyer SF, Andersson T, and Arnberg F
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Background: Several studies have investigated the histopathology of mechanically retrieved thrombi from stroke patients. Thrombi with unusual components constitute about 1-2% of all stroke thrombi in clinical practice. Knowledge about these rare components is limited., Objectives: To characterize the histopathology of unusual stroke thrombi from a real-world setting with relation to clinical presentation, patient characteristics and procedural aspects of mechanical thrombectomy., Methods: One-thousand and eight thrombi retrieved from stroke patients with mechanical thrombectomy at three different hospitals were retrospectively reviewed for unusual histological components. Fifteen thrombi were included in the study for further histopathological analysis. Clinical data and data on procedural aspects were collected., Results: We identified six cases with large amounts of extracellular DNA, of which three were calcified. All six cases except one received anticoagulant therapy. We describe two types of calcifications that differ with respect to general calcification morphology, von Kossa staining pattern, macrophage immunophenotype and presence of multinucleated giant cells. Cholesterol-rich ( n = 3), adipocyte-like pattern-rich ( n = 2), collagen-rich ( n = 2) and myxomatous ( n = 1) thrombi were also identified and are discussed with regard to pathogenesis and clinical and intervention characteristics. Finally, a thrombus with parts of a vascular wall is described. Suggestions for future studies are made and clinical and technical aspects of the management for these rare but important patients are discussed., Conclusion: In our retrospective multicenter study, we characterized stroke thrombi histopathologically and found subgroups of thrombi defined by presence of rarely seen components. These defined subgroups showed relation to underlying cardiovascular disease, patient characteristics, and mechanical thrombectomy technique. Knowledge about these components may increase our understanding of stroke pathophysiology and influence interventional procedures., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Aspegren, Staessens, Vandelanotte, Desender, Cordonnier, Puy, Bricout, De Meyer, Andersson and Arnberg.)
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- 2022
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32. Thromboinflammation in Brain Ischemia: Recent Updates and Future Perspectives.
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De Meyer SF, Langhauser F, Haupeltshofer S, Kleinschnitz C, and Casas AI
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- Humans, Inflammation, Thromboinflammation, Brain Ischemia drug therapy, Stroke drug therapy, Thrombosis
- Abstract
Despite decades of promising preclinical validation and clinical translation, ischemic stroke still remains as one of the leading causes of death and disability worldwide. Within its complex pathophysiological signatures, thrombosis and inflammation, that is, thromboinflammation, are highly interconnected processes leading to cerebral vessel occlusion, inflammatory responses, and severe neuronal damage following the ischemic event. Hence, we here review the most recent updates on thromboinflammatory-dependent mediators relevant after stroke focusing on recent discoveries on platelet modulation, a potential regulation of the innate and adaptive immune system in thromboinflammation, utterly providing a thorough up-to-date overview of all therapeutic approaches currently undergoing clinical trial.
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- 2022
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33. Anti-cysteine/spacer antibodies that open ADAMTS13 are a common feature in iTTP.
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De Waele L, Curie A, Kangro K, Tellier E, Kaplanski G, Männik A, Tersteeg C, Joly BS, Coppo P, Veyradier A, De Meyer SF, Roose E, and Vanhoorelbeke K
- Subjects
- ADAMTS13 Protein, Autoantibodies, Cysteine, Humans, Immunoglobulin G, Purpura, Thrombocytopenic, Idiopathic, Purpura, Thrombotic Thrombocytopenic
- Abstract
Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is caused by an autoantibody-mediated deficiency in ADAMTS13. In healthy individuals, ADAMTS13 has a folded conformation in which the central spacer (S) domain interacts with the C-terminal CUB domains. We recently showed that ADAMTS13 adopts an open conformation in iTTP and that patient immunoglobulin G antibodies (IgGs) can open ADAMTS13. Anti-ADAMTS13 autoantibodies in patients with iTTP are directed against the different ADAMTS13 domains, but almost all patients have autoantibodies binding to the cysteine/spacer (CS) domains. In this study, we investigated whether the autoantibodies against the CS and CUB domains can disrupt the S-CUB interaction of folded ADAMTS13, thereby opening ADAMTS13. To this end, we purified anti-CS and anti-CUB autoantibodies from 13 patients with acute iTTP by affinity chromatography. The successfully purified anti-CS (10/13 patients) and anti-CUB (4/13 patients) autoantibody fractions were tested further in our ADAMTS13 conformation enzyme-linked immunosorbent assay to study whether they could open ADAMTS13. Interestingly, all purified anti-CS fractions (10/10 patients) were able to open ADAMTS13. On the other hand, only half of the purified anti-CUB fractions (2/4 patients) opened ADAMTS13. Our finding highlights that anti-CS autoantibodies that open ADAMTS13 are a common feature of the autoimmune response in iTTP., (© 2021 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)
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- 2021
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34. Studying Stroke Thrombus Composition After Thrombectomy: What Can We Learn?
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Staessens S, François O, Brinjikji W, Doyle KM, Vanacker P, Andersson T, and De Meyer SF
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- Humans, Thrombectomy, Ischemic Stroke, Thrombosis
- Abstract
The composition of ischemic stroke thrombi has gained an increasing amount of interest in recent years. The implementation of endovascular procedures in standard stroke care has granted researchers the unique opportunity to examine patient thrombus material. Increasing evidence indicates that stroke thrombi are complex and heterogenous, consisting of various biochemical (eg, fibrin, von Willebrand Factor, and neutrophil extracellular traps) and cellular (eg, red blood cells, platelets, leukocytes, and bacteria) components. This complex composition may explain therapeutic limitations and also offer novel insights in several aspects of stroke management. Better understanding of thrombus characteristics could, therefore, potentially lead to improvements in the management of patients with stroke. In this review, we provide a comprehensive overview of the lessons learned by examining stroke thrombus composition after endovascular thrombectomy and its potential relevance for thrombectomy success rates, thrombolysis, clinical outcomes, stroke etiology, and radiological imaging.
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- 2021
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35. Anti-ADAMTS13 autoantibody profiling in patients with immune-mediated thrombotic thrombocytopenic purpura.
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Kangro K, Roose E, Joly BS, Sinkovits G, Falter T, von Auer C, Rossmann H, Reti M, Voorberg J, Prohászka Z, Lämmle B, Coppo P, Veyradier A, De Meyer SF, Männik A, and Vanhoorelbeke K
- Subjects
- Aged, Autoantibodies, Cohort Studies, Humans, Thrombospondin 1, Purpura, Thrombocytopenic, Idiopathic, Purpura, Thrombotic Thrombocytopenic
- Abstract
Anti-A Disintegrin and Metalloproteinase with a ThromboSpondin type 1 motif, member 13 (ADAMTS13) autoantibodies cause a severe ADAMTS13 deficiency in immune-mediated thrombotic thrombocytopenic purpura (iTTP). ADAMTS13 consists of a metalloprotease (M), a disintegrin-like (D) domain, 8 thrombospondin type 1 repeats (T1-T8), a cysteine-rich (C), a spacer (S), and 2 CUB domains (CUB1-2). We recently developed a high-throughput epitope mapping assay based on small, nonoverlapping ADAMTS13 fragments (M, DT, CS, T2-T5, T6-T8, CUB1-2). With this assay, we performed a comprehensive epitope mapping using 131 acute-phase samples and for the first time a large group of remission samples (n = 50). Next, samples were stratified according to their immunoprofiles, a field that is largely unexplored in iTTP. Three dominant immunoprofiles were found in acute-phase samples: profile 1: only anti-CS autoantibodies (26.7%); profile 2: both anti-CS and anti-CUB1-2 autoantibodies (12.2%); and profile 3: anti-DT, anti-CS, anti-T2-T5, anti-T6-T8, and anti-CUB1-2 autoantibodies (8.4%). Interestingly, profile 1 was the only dominant immunoprofile in remission samples (52.0%). Clinical data were available for a relatively small number of patients with acute iTTP (>68), and no correlation was found between immunoprofiles and disease severity. Nevertheless, profile 1 was linked with younger and anti-T2-T5 autoantibodies with older age and the absence of anti-CUB1-2 autoantibodies with cerebral involvement. In conclusion, identifying acute phase and remission immunoprofiles in iTTP revealed that anti-CS autoantibodies seem to persist or reappear during remission providing further support for the clinical development of a targeted anti-CS autoantibody therapy. A large cohort study with acute iTTP samples will validate possible links between immunoprofiles or anti-domain autoantibodies and clinical data., (© 2021 by The American Society of Hematology.)
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- 2021
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36. Determination of anti-ADAMTS-13 autoantibody titers in ELISA: Influence of ADAMTS-13 presentation and autoantibody detection.
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Dekimpe C, Roose E, Kangro K, Bonnez Q, Vandenbulcke A, Tellier E, Kaplanski G, Feys HB, Tersteeg C, Männik A, De Meyer SF, and Vanhoorelbeke K
- Subjects
- ADAMTS13 Protein, Autoantibodies, Enzyme-Linked Immunosorbent Assay, Humans, Purpura, Thrombotic Thrombocytopenic diagnosis, Thrombospondin 1
- Abstract
Background: Immune-mediated thrombotic thrombocytopenic purpura (iTTP) is caused by inhibitory and/or clearing anti-ADAMTS-13 (A Disintegrin and Metalloprotease with ThromboSpondin type 1 repeats, member 13) autoantibodies. To determine the presence and total level of anti-ADAMTS-13 autoantibodies, commercial and in-house developed ELISAs are performed. However, different ELISA methods vary in relation to the presentation of recombinant (r)ADAMTS-13 and the detection method of the anti-ADAMTS-13 autoantibodies. Currently, the influence of those different approaches on anti-ADAMTS-13 autoantibody titers is not known., Objectives: To assess the influence of different ADAMTS-13 presentation- and autoantibody detection methods on anti-ADAMTS-13 autoantibody titers in ELISA., Materials/methods: Anti-ADAMTS-13 autoantibody titers from 18 iTTP patients were determined using four different set-ups of anti-ADAMTS-13 autoantibody ELISAs. The ELISAs varied in the used presentation of rADAMTS-13 (directly coated full-length rADAMTS-13, directly coated rMDTCS and rT2C2, or antibody-captured full-length rADAMTS-13) and the detection antibodies (polyclonal anti-human IgG or monoclonal anti-human IgG
1-4 antibodies)., Results: Strong correlations between the different anti-ADAMTS-13 autoantibody ELISA approaches were observed, when using polyclonal anti-human IgG detection antibodies recognizing all IgG subclasses similarly, independent of the method of rADAMTS-13 presentation. Anti-ADAMTS-13 autoantibody titers correlated less when using a mixture of monoclonal anti-human IgG1-4 , because not all IgG subclasses were recognized with similar affinities., Conclusion: Anti-ADAMTS-13 autoantibody levels using different methods of rADAMTS-13 presentation strongly correlate. However, the levels of anti-ADAMTS-13 autoantibodies are highly dependent on the detection antibody used, which should detect all IgG subclasses (IgG1-4 ) equally well., (© 2021 International Society on Thrombosis and Haemostasis.)- Published
- 2021
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37. Mechanical Characterization of Thrombi Retrieved With Endovascular Thrombectomy in Patients With Acute Ischemic Stroke.
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Boodt N, Snouckaert van Schauburg PRW, Hund HM, Fereidoonnezhad B, McGarry JP, Akyildiz AC, van Es ACGM, De Meyer SF, Dippel DWJ, Lingsma HF, van Beusekom HMM, van der Lugt A, and Gijsen FJH
- Subjects
- Aged, Aged, 80 and over, Brain Ischemia pathology, Brain Ischemia physiopathology, Endovascular Procedures instrumentation, Female, Humans, Ischemic Stroke pathology, Ischemic Stroke physiopathology, Male, Middle Aged, Thrombectomy instrumentation, Thrombosis pathology, Thrombosis physiopathology, Biomechanical Phenomena physiology, Brain Ischemia surgery, Endovascular Procedures methods, Ischemic Stroke surgery, Thrombectomy methods, Thrombosis surgery
- Abstract
Background and Purpose: Mechanical properties of thromboemboli play an important role in the efficacy of endovascular thrombectomy (EVT) for acute ischemic stroke. However, very limited data on mechanical properties of human stroke thrombi are available. We aimed to mechanically characterize thrombi retrieved with EVT, and to assess the relationship between thrombus composition and thrombus stiffness., Methods: Forty-one thrombi from 19 patients with acute stroke who underwent EVT between July and October 2019 were mechanically analyzed, directly after EVT. We performed unconfined compression experiments and determined tangent modulus at 75% strain (Et75) as a measure for thrombus stiffness. Thrombi were histologically analyzed for fibrin/platelets, erythrocytes, leukocytes, and platelets, and we assessed the relationship between histological components and Et75 with univariable and multivariable linear mixed regression., Results: Median Et75 was 560 (interquartile range, 393–1161) kPa. In the multivariable analysis, fibrin/platelets were associated with increased Et75 (aβ, 9 [95% CI, 5 to 13]) kPa, erythrocytes were associated with decreased Et75% (aβ, −9 [95% CI, −5 to −13]) kPa. We found no association between leukocytes and Et75. High platelet values were strongly associated with increased Et75 (aβ, 56 [95% CI, 38–73])., Conclusions: Fibrin/platelet content of thrombi retrieved with EVT for acute ischemic stroke is strongly associated with increased thrombus stiffness. For thrombi with high platelet values, there was a very strong relationship with thrombus stiffness. Our data provide a basis for future research on the development of next-generation EVT devices tailored to thrombus composition.
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- 2021
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38. Vascular Endothelial Damage in the Pathogenesis of Organ Injury in Severe COVID-19.
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Dupont A, Rauch A, Staessens S, Moussa M, Rosa M, Corseaux D, Jeanpierre E, Goutay J, Caplan M, Varlet P, Lefevre G, Lassalle F, Bauters A, Faure K, Lambert M, Duhamel A, Labreuche J, Garrigue D, De Meyer SF, Staels B, Vincent F, Rousse N, Kipnis E, Lenting P, Poissy J, and Susen S
- Subjects
- Biomarkers blood, COVID-19 immunology, Complement Activation, Critical Care, Cytokines blood, Female, Humans, Liver Failure, Acute virology, Male, Microcirculation, Middle Aged, Nucleosomes metabolism, Respiratory Insufficiency virology, SARS-CoV-2, COVID-19 complications, COVID-19 pathology, Endothelium, Vascular pathology, Multiple Organ Failure virology, Thrombosis virology
- Abstract
[Figure: see text].
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- 2021
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39. Thrombus heterogeneity in ischemic stroke.
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Staessens S and De Meyer SF
- Subjects
- Female, Genetic Heterogeneity, Humans, Ischemic Stroke pathology, Male, Ischemic Stroke complications, Ischemic Stroke genetics, Thrombectomy methods, Thrombosis genetics
- Abstract
The structure of stroke thrombi has gained an increasing amount of interest in recent years. The advent of endovascular thrombectomy has offered the unique opportunity to provide and analyze thrombi removed from ischemic stroke patients. It has become clear that the composition of ischemic stroke thrombi is relatively heterogenous and various molecular and cellular patterns become apparent. Good understanding of the histopathologic characteristics of thrombi is important to lead future advancements in acute ischemic stroke treatment. In this review, we give a brief overview of the main stroke thrombus components that have been recently characterized in this rapidly evolving field. We also summarize how thrombus heterogeneity can affect stroke treatment.
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- 2021
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40. The von Willebrand Factor A1 domain mediates thromboinflammation, aggravating ischemic stroke outcome in mice.
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Denorme F, Martinod K, Vandenbulcke A, Denis CV, Lenting PJ, Deckmyn H, Vanhoorelbeke K, and De Meyer SF
- Subjects
- Animals, Inflammation, Mice, Mice, Inbred C57BL, von Willebrand Factor genetics, Brain Ischemia, Ischemic Stroke, Stroke, Thrombosis
- Abstract
von Willebrand factor (VWF) plays an important role in ischemic stroke. However, the exact mechanism by which VWF mediates progression of ischemic stroke brain damage is not completely understood. Using flow cytometric analysis of single cell suspensions prepared from brain tissue and immunohistochemistry, we investigated the potential inflammatory mechanisms by which VWF contributes to ischemic stroke brain damage in a mouse model of cerebral ischemia/reperfusion injury. Twenty-four hours after stroke, flow cytometric analysis of brain tissue revealed that overall white blood cell recruitment in the ipsilesional brain hemisphere of VWF KO mice was 2 times lower than WT mice. More detailed analysis showed a specific reduction of proinflammatory monocytes, neutrophils and T-cells in the ischemic brain of VWF KO mice compared to WT mice. Interestingly, histological analysis revealed a substantial number of neutrophils and T-cells still within the microcirculation of the stroke brain, potentially contributing to the no-reflow phenomenon. Specific therapeutic targeting of the VWF A1 domain in WT mice resulted in reduced immune cell numbers in the affected brain and protected mice from ischemic stroke brain damage. More specifically, recruitment of proinflammatory monocytes was reduced two-fold, neutrophil recruitment was reduced five-fold and T-cell recruitment was reduced two-fold in mice treated with a VWF A1-targeting nanobody compared to mice receiving a control nanobody. In conclusion, our data identify a potential role for VWF in the recruitment of proinflammatory monocytes, neutrophils and T-cells to the ischemic brain via a mechanism that is mediated by its A1 domain.
- Published
- 2021
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41. Detailed histological analysis of a thrombectomy-resistant ischemic stroke thrombus: a case report.
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Staessens S, François O, Desender L, Vanacker P, Dewaele T, Sciot R, Vanhoorelbeke K, Andersson T, and De Meyer SF
- Abstract
Background: Mechanical removal of a thrombus by thrombectomy can be quite challenging. For reasons that are not fully understood, some thrombi require multiple passes to achieve successful recanalization, whereas other thrombi are efficiently removed in a single pass. Since first pass success is associated with better clinical outcome, it is important to better understand the nature of thrombectomy resistant thrombi. The aim of this study was therefore to characterize the cellular and molecular composition of a thrombus that was very hard to retrieve via mechanical thrombectomy., Case Presentation: In a patient that was admitted with a right middle cerebral artery M1-occlusion, 11 attempts using various thrombectomy devices and techniques were required for removal of the thrombus. This peculiar case provided a rare opportunity to perform an in-depth histopathological study of a difficult to retrieve thrombus. Thrombus material was histologically analyzed using hematoxylin and eosin, Martius Scarlet Blue stain (red blood cells and fibrin), Feulgen stain (DNA), von Kossa stain (calcifications) and immunohistochemical analysis of von Willebrand factor, platelets, leukocytes and neutrophil extracellular traps. Histological analysis revealed abnormally high amounts of extracellular DNA, leukocytes, von Willebrand factor and calcifications. Extracellular DNA stained positive for markers of leukocytes and NETs, suggesting that a significant portion of DNA is derived from neutrophil extracellular traps., Conclusion: In this unique case of a nearly thrombectomy-resistant stroke thrombus, our study showed an atypical composition compared to the common structural features found in ischemic stroke thrombi. The core of the retrieved thrombus consisted of extracellular DNA that colocalized with von Willebrand factor and microcalcifications. These results support the hypothesis that von Willebrand factor, neutrophil extracellular traps and microcalcifications contribute to mechanical thrombectomy resistance. Such information is important to identify novel targets in order to optimize technical treatment protocols and techniques to increase first pass success rates.
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- 2021
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42. Immunogenic hotspots in the spacer domain of ADAMTS13 in immune-mediated thrombotic thrombocytopenic purpura.
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Velásquez Pereira LC, Roose E, Graça NAG, Sinkovits G, Kangro K, Joly BS, Tellier E, Kaplanski G, Falter T, Von Auer C, Rossmann H, Feys HB, Reti M, Prohászka Z, Lämmle B, Voorberg J, Coppo P, Veyradier A, De Meyer SF, Männik A, and Vanhoorelbeke K
- Subjects
- DNA, Intergenic, Epitopes, Humans, Immunoglobulin G, ADAMTS13 Protein immunology, Autoantibodies immunology, Purpura, Thrombotic Thrombocytopenic diagnosis
- Abstract
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., (© 2020 International Society on Thrombosis and Haemostasis.)
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- 2021
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43. Endotheliopathy Is Induced by Plasma From Critically Ill Patients and Associated With Organ Failure in Severe COVID-19.
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Rauch A, Dupont A, Goutay J, Caplan M, Staessens S, Moussa M, Jeanpierre E, Corseaux D, Lefevre G, Lassalle F, Faure K, Lambert M, Duhamel A, Labreuche J, Garrigue D, De Meyer SF, Staels B, Van Belle E, Vincent F, Kipnis E, Lenting PJ, Poissy J, and Susen S
- Subjects
- Betacoronavirus isolation & purification, COVID-19, Cell Survival, Cell-Free Nucleic Acids metabolism, Cells, Cultured, Coronavirus Infections complications, Coronavirus Infections virology, Critical Illness, Endothelial Cells cytology, Endothelial Cells metabolism, Humans, Interleukin-6 metabolism, Microvessels cytology, Multiple Organ Failure etiology, Pandemics, Plasma metabolism, Pneumonia, Viral complications, Pneumonia, Viral virology, SARS-CoV-2, Severity of Illness Index, Syndecan-1 metabolism, Coronavirus Infections pathology, Plasma chemistry, Pneumonia, Viral pathology
- Published
- 2020
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44. von Willebrand factor increases in experimental cerebral malaria but is not essential for late-stage pathogenesis in mice.
- Author
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Kraisin S, Martinod K, Desender L, Pareyn I, Verhenne S, Deckmyn H, Vanhoorelbeke K, Van den Steen PE, and De Meyer SF
- Subjects
- ADAMTS13 Protein genetics, Animals, Blood Platelets, Mice, Plasmodium berghei, von Willebrand Factor, Malaria, Cerebral, Thrombocytopenia
- Abstract
Background: Cerebral malaria (CM) is the most severe complication of malaria. Endothelial activation, cytokine release, and vascular obstruction are essential hallmarks of CM. Clinical studies have suggested a link between von Willebrand factor (VWF) and malaria pathology., Objectives: To investigate the contribution of VWF in the pathogenesis of experimental cerebral malaria (ECM)., Methods: Both Vwf
+/+ and Vwf-/- mice were infected with Plasmodium berghei ANKA (PbANKA) to induce ECM. Alterations of plasma VWF and ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13), platelet count, neurological features, and accumulation of platelets and leukocytes in the brain were examined following infection., Results: Plasma VWF levels significantly increased upon PbANKA infection in Vwf+/+ animals. While ADAMTS13 activity was not affected, high molecular weight VWF multimers disappeared at the end-stage ECM, possibly due to an ongoing hypercoagulability. Although the number of reticulocytes, a preferential target for the parasites, was increased in Vwf-/- mice compared to Vwf+/+ mice early after infection, parasitemia levels did not markedly differ between the two groups. Interestingly, Vwf-/- mice manifested overall clinical ECM features similar to those observed in Vwf+/+ animals. At day 8.5 post-infection, however, clinical ECM features in Vwf-/- mice were slightly more beneficial than in Vwf+/+ animals. Despite these minor differences, overall survival was not different between Vwf-/- and Vwf+/+ mice. Similarly, PbANKA-induced thrombocytopenia, leukocyte, and platelet accumulations in the brain were not altered by the absence of VWF., Conclusions: Our study suggests that increased VWF concentration is a hallmark of ECM. However, VWF does not have a major influence in modulating late-stage ECM pathogenesis., (© 2020 International Society on Thrombosis and Haemostasis.)- Published
- 2020
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45. Open ADAMTS13, induced by antibodies, is a biomarker for subclinical immune-mediated thrombotic thrombocytopenic purpura.
- Author
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Roose E, Schelpe AS, Tellier E, Sinkovits G, Joly BS, Dekimpe C, Kaplanski G, Le Besnerais M, Mancini I, Falter T, Von Auer C, Feys HB, Reti M, Rossmann H, Vandenbulcke A, Pareyn I, Voorberg J, Greinacher A, Benhamou Y, Deckmyn H, Fijnheer R, Prohászka Z, Peyvandi F, Lämmle B, Coppo P, De Meyer SF, Veyradier A, and Vanhoorelbeke K
- Subjects
- Biomarkers blood, Female, Follow-Up Studies, Humans, Male, Middle Aged, Protein Conformation, Purpura, Thrombocytopenic, Idiopathic drug therapy, Rituximab administration & dosage, ADAMTS13 Protein blood, Autoantibodies blood, Purpura, Thrombocytopenic, Idiopathic blood
- Abstract
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., (© 2020 by The American Society of Hematology.)
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- 2020
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46. Generation and validation of small ADAMTS13 fragments for epitope mapping of anti-ADAMTS13 autoantibodies in immune-mediated thrombotic thrombocytopenic purpura.
- Author
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Kangro K, Roose E, Schelpe AS, Tellier E, Kaplanski G, Voorberg J, De Meyer SF, Männik A, and Vanhoorelbeke K
- Abstract
Background: In immune-mediated thrombotic thrombocytopenic purpura (iTTP), patients develop an immune response against the multidomain enzyme ADAMTS13. ADAMTS13 consists of a metalloprotease (M) and disintegrin-like (D) domain, 8 thrombospondin type 1 repeats (T1-T8), a cysteine-rich (C), a spacer (S), and 2 CUB domains (CUB1-2). Previous epitope mapping studies have used relatively large overlapping ADAMTS13 fragments., Objectives: We aimed at developing small nonoverlapping ADAMTS13 fragments to fine map anti-ADAMTS13 autoantibodies in iTTP patients., Methods: A library of 16 ADAMTS13 fragments, comprising several small (M, DT, C, S, T2-T5, T6-T8, CUB1, CUB2), and some larger fragments with overlapping domains (MDT, MDTC, DTC, CS, T2-T8, CUB1-2, MDTCS, T2-C2), were generated. All fragments, and ADAMTS13, were expressed as a fusion protein with albumin domain 1, and purified. The folding of the fragments was tested using 17 anti-ADAMTS13 monoclonal antibodies with known epitopes. An epitope mapping assay using small ADAMTS13 fragments was set up, and validated by analyzing 18 iTTP patient samples., Results: Validation with the monoclonal antibodies demonstrated that single S and CUB1 were not correctly folded, and therefore CS and CUB1-2 fragments were selected instead of single C, S, CUB1, and CUB2 fragments. Epitope mapping of antibodies of patients with iTTP confirmed that 6 nonoverlapping ADAMTS13 fragments M, DT, CS, T2-T5, T6-T8, and CUB1-2 were sufficient to accurately determine the antibody-binding sites., Conclusion: We have developed a tool to profile patients with iTTP according to their anti-ADAMTS13 antibodies for a better insight in their immune response., (© 2020 Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)
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- 2020
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47. Anti-ADAMTS13 autoantibodies in immune-mediated thrombotic thrombocytopenic purpura do not hamper ELISA-based quantification of ADAMTS13 antigen.
- Author
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Dekimpe C, Roose E, Tersteeg C, Joly BS, Dewaele A, Horta S, Pareyn I, Vandenbulcke A, Deckmyn H, Feys HB, Tellier E, Kaplanski G, Scully M, Coppo P, De Meyer SF, Veyradier A, and Vanhoorelbeke K
- Subjects
- ADAMTS13 Protein, Autoantibodies, Enzyme-Linked Immunosorbent Assay, Humans, Reproducibility of Results, Purpura, Thrombocytopenic, Idiopathic, Purpura, Thrombotic Thrombocytopenic diagnosis
- Abstract
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., (© 2020 International Society on Thrombosis and Haemostasis.)
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- 2020
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48. Antibodies that conformationally activate ADAMTS13 allosterically enhance metalloprotease domain function.
- Author
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Schelpe AS, Petri A, Roose E, Pareyn I, Deckmyn H, De Meyer SF, Crawley JTB, and Vanhoorelbeke K
- Subjects
- ADAMTS13 Protein, Animals, Catalytic Domain, Mice, Protein Binding, Proteolysis, Metalloproteases, von Willebrand Factor metabolism
- Abstract
Plasma ADAMTS13 circulates in a folded conformation that is stabilized by an interaction between the central Spacer domain and the C-terminal CUB (complement components C1r and C1s, sea urchin protein Uegf, and bone morphogenetic protein-1) domains. Binding of ADAMTS13 to the VWF D4(-CK) domains or to certain activating murine monoclonal antibodies (mAbs) induces a structural change that extends ADAMTS13 into an open conformation that enhances its function. The objective was to characterize the mechanism by which conformational activation enhances ADAMTS13-mediated proteolysis of VWF. The activating effects of a novel anti-Spacer (3E4) and the anti-CUB1 (17G2) mAbs on the kinetics of proteolysis of VWF A2 domain fragments by ADAMTS13 were analyzed. mAb-induced conformational changes in ADAMTS13 were investigated by enzyme-linked immunosorbent assay. Both mAbs enhanced ADAMTS13 catalytic efficiency (kcat/Km) by ∼twofold (3E4: 2.0-fold; 17G2: 1.8-fold). Contrary to previous hypotheses, ADAMTS13 activation was not mediated through exposure of the Spacer or cysteine-rich domain exosites. Kinetic analyses revealed that mAb-induced conformational extension of ADAMTS13 enhances the proteolytic function of the metalloprotease domain (kcat), rather than augmenting substrate binding (Km). A conformational effect on the metalloprotease domain was further corroborated by the finding that incubation of ADAMTS13 with either mAb exposed a cryptic epitope in the metalloprotease domain that is normally concealed when ADAMTS13 is in a closed conformation. We show for the first time that the primary mechanism of mAb-induced conformational activation of ADAMTS13 is not a consequence of functional exosite exposure. Rather, our data are consistent with an allosteric activation mechanism on the metalloprotease domain that augments active site function., (© 2020 by The American Society of Hematology.)
- Published
- 2020
- Full Text
- View/download PDF
49. Von Willebrand factor and ADAMTS13 impact on the outcome of Staphylococcus aureus sepsis.
- Author
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Peetermans M, Meyers S, Liesenborghs L, Vanhoorelbeke K, De Meyer SF, Vandenbriele C, Lox M, Hoylaerts MF, Martinod K, Jacquemin M, Vanassche T, and Verhamme P
- Subjects
- Animals, Humans, Mice, Staphylococcus aureus, ADAMTS13 Protein genetics, Bacteremia mortality, Sepsis mortality, Staphylococcal Infections mortality, von Willebrand Factor
- Abstract
Background: Previous clinical evidence correlates levels of von Willebrand factor (VWF) and its cleaving protease ADAMTS13 with outcome in septic patients. No previous studies addressed if VWF and ADAMTS13 affected the outcome of Staphylococcus aureus sepsis., Objectives: We studied the role of VWF and ADAMTS13 in S. aureus sepsis both in patients and in mice., Methods: VWF levels and ADAMTS13 activity levels were measured in plasma samples from 89 S. aureus bacteremia patients by chemiluminescent assays and were correlated with clinical sepsis outcome parameters. In wild-type mice and mice deficient in VWF and ADAMTS13, we investigated the outcome of S. aureus sepsis and quantified bacterial clearance and organ microthrombi., Results: In patients with S. aureus bloodstream infections, high VWF levels and low ADAMTS13 activity levels correlated with disease severity and with parameters of inflammation and disseminated intravascular coagulation. In septic mice, VWF deficiency attenuated mortality, whereas ADAMTS13 deficiency increased mortality. Bacterial clearance was enhanced in VWF-deficient mice. The differences in mortality for the studied genotypes were associated with differential loads of organ microthrombi in both liver and kidneys., Conclusions: In conclusion, this study reports the consistent relation of VWF, ADAMTS13 and their ratio to disease severity in patients and mice with S. aureus sepsis. Targeting VWF multimers and/or the relative ADAMTS13 deficiency that occurs in sepsis should be explored as a potential new therapeutic target in S. aureus endovascular infections., (© 2019 International Society on Thrombosis and Haemostasis.)
- Published
- 2020
- Full Text
- View/download PDF
50. Structural analysis of ischemic stroke thrombi: histological indications for therapy resistance.
- Author
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Staessens S, Denorme F, Francois O, Desender L, Dewaele T, Vanacker P, Deckmyn H, Vanhoorelbeke K, Andersson T, and De Meyer SF
- Subjects
- Humans, Thrombectomy, Brain Ischemia therapy, Ischemic Stroke, Stroke therapy, Thrombosis etiology, Thrombosis therapy
- Abstract
Ischemic stroke is caused by a thromboembolic occlusion of cerebral arteries. Treatment is focused on fast and efficient removal of the occluding thrombus, either via intravenous thrombolysis or via endovascular thrombectomy. Recanalization, however, is not always successful and factors contributing to failure are not completely understood. Although the occluding thrombus is the primary target of acute treatment, little is known about its internal organization and composition. The aim of this study, therefore, was to better understand the internal organization of ischemic stroke thrombi on a molecular and cellular level. A total of 188 thrombi were collected from endovascularly treated ischemic stroke patients and analyzed histologically for fibrin, red blood cells (RBC), von Willebrand factor (vWF), platelets, leukocytes and DNA, using bright field and fluorescence microscopy. Our results show that stroke thrombi are composed of two main types of areas: RBC-rich areas and platelet-rich areas. RBC-rich areas have limited complexity as they consist of RBC that are entangled in a meshwork of thin fibrin. In contrast, platelet-rich areas are characterized by dense fibrin structures aligned with vWF and abundant amounts of leukocytes and DNA that accumulate around and in these platelet-rich areas. These findings are important to better understand why platelet-rich thrombi are resistant to thrombolysis and difficult to retrieve via thrombectomy, and can guide further improvements of acute ischemic stroke therapy., (Copyright© 2020 Ferrata Storti Foundation.)
- Published
- 2020
- Full Text
- View/download PDF
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