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Article ; Online: Mortality, cardiac and cerebral damages reduction by IL-1 inhibition in a murine model of TTP.

Muller, Romain / Cauchois, Raphael / Lagarde, Marie / Roffino, Sandrine / Genovesio, Cecile / Fernandez, Samantha / Hache, Guillaume / Guillet, Benjamin / Kara, Yeter / Marlinge, Marion / Lenting, Peter J / Poullin, Pascale / Dignat-George, Françoise / Tellier, Edwige / Kaplanski, Gilles

Blood

2024

Abstract: ... days and evaluated the efficacy of this treatment. Anakinra significantly reduced mortality of mice (P ...

Abstract	Thrombotic thrombocytopenic purpura (TTP), a rare but fatal disease if untreated, is due to alteration in Von Willebrand factor cleavage resulting in capillary microthrombi formation and ischemic organ damage. Interleukin-1 (IL-1), has been shown to drive sterile inflammation following ischemia and could play an essential contribution to post-ischemic organ damage in TTP. Our objectives were to evaluate IL-1 involvement during TTP and to test the efficacy of the recombinant IL-1 receptor antagonist, anakinra, in a murine TTP model. We retrospectively measured plasmatic IL-1 concentrations in TTP patients and controls. TTP patients exhibited elevated plasma IL-1α and β concentrations, which correlated with disease course and survival. In a TTP mouse model, we administered anakinra (IL-1 inhibitor) or placebo for 5 days and evaluated the efficacy of this treatment. Anakinra significantly reduced mortality of mice (P<0.001). Anakinra significantly decreased TTP-induced cardiac damages as assessed by blood troponin concentrations, evaluation of left ventricular function by echocardiography, [18F]FDG PET of myocardial glucose metabolism, and cardiac histology. Anakinra also significantly reduced brain TTP-induced damages, evaluated through blood PS100b concentrations, nuclear imaging and histology. We finally showed that IL-1α and β trigger endothelial degranulation in vitro, leading to the release of Von Willebrand factor. In conclusion, Anakinra significantly reduced TTP mortality in a pre-clinical model of the disease by inhibiting both endothelial degranulation and post-ischemic inflammation, supporting further evaluations in humans.
Language	English
Publishing date	2024-04-05
Publishing country	United States
Document type	Journal Article
ZDB-ID	80069-7
ISSN	1528-0020 ; 0006-4971
ISSN (online)	1528-0020
ISSN	0006-4971
DOI	10.1182/blood.2023021974
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Zs.MO 364: Show issues

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Article ; Online: Thrombin generation on vascular cells in the presence of factor VIII and/or emicizumab.

Atsou, Sénadé / Schellenberg, Célia / Lagrange, Jeremy / Lacolley, Patrick / Lenting, Peter J / Denis, Cécile V / Christophe, Olivier D / Regnault, Véronique

Journal of thrombosis and haemostasis : JTH

2023 Volume 22, Issue 1, Page(s) 112–125

Abstract: Background: The effect of factor VIII (FVIII) or emicizumab on thrombin generation is usually assessed in assays using synthetic phospholipids. Here, we assessed thrombin generation at the surface of human arterial cells (aortic endothelial cells [hAECs] ...

Abstract	Background: The effect of factor VIII (FVIII) or emicizumab on thrombin generation is usually assessed in assays using synthetic phospholipids. Here, we assessed thrombin generation at the surface of human arterial cells (aortic endothelial cells [hAECs] and aortic vascular smooth muscle cells [hVSMCs]). Objectives: To explore the capacity of hAECs (resting or stimulated) and hVSMCs to support thrombin generation by FVIII or emicizumab. Methods: Primary hVSMCs and hAECs were analyzed for tissue factor (TF)-activity and antigen, phosphatidylserine (PS)-exposure, tissue factor pathway inhibitor (TFPI)-content and thrombomodulin expression. Cells were incubated with FVIII-deficient plasma spiked with FVIII, emicizumab, activated prothrombin complex concentrate (APCC) or combinations thereof. Results: TF activity and PS-exposure were present on both hVSMCs and hAECs. In contrast, thrombomodulin and TFPI were expressed on hAECs, while virtually lacking on hVSMCs, confirming the procoagulant nature of hVSMCs. Tumor necrosis factor α-mediated stimulation of hAECs increased not only TF antigen, TF activity, and PS-exposure but also TFPI and thrombomodulin expression. As expected, FVIII and emicizumab promoted thrombin generation on nonstimulated hAECs and hVSMCs, with more thrombin being generated on hVSMCs. Unexpectedly, FVIII and emicizumab increased thrombin generation to a lesser extent on stimulated hAECs compared with nonstimulated hAECs. Finally, adding emicizumab to FVIII did not further increase thrombin generation, whereas the addition of emicizumab to APCC resulted in exaggerated thrombin generation. Conclusion: Tumor necrosis factor stimulation of hAECs increases both pro- and anticoagulant activity. Unexpectedly, the increased anticoagulant activity is sufficient to limit both FVIII- and emicizumab-induced thrombin generation. This protective effect disappears when emicizumab is combined with APCC.
MeSH term(s)	Humans ; Factor VIII/metabolism ; Thrombin/metabolism ; Thrombomodulin ; Endothelial Cells/metabolism ; Hemostatics ; Antibodies, Bispecific/pharmacology ; Factor VIIa ; Factor IX ; Anticoagulants ; Hemophilia A
Chemical Substances	Factor VIII (9001-27-8) ; Thrombin (EC 3.4.21.5) ; emicizumab (7NL2E3F6K3) ; Thrombomodulin ; Hemostatics ; Antibodies, Bispecific ; Factor VIIa (EC 3.4.21.21) ; Factor IX (9001-28-9) ; Anticoagulants
Language	English
Publishing date	2023-09-29
Publishing country	England
Document type	Journal Article
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1016/j.jtha.2023.09.017
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Article ; Online: Previous Exercise Levels and Outcome in Patients with New Atrial Fibrillation: 'Past Achievements Do Not Predict the Future'.

Lenting, Charlotte J / Wijtvliet, E P J Petra / Koldenhof, Tim / Bessem, Bram / Pluymaekers, Nikki A H A / Rienstra, Michiel / Folkeringa, Richard J / Bronzwaer, Patrick / Elvan, Arif / Elders, Jan / Tukkie, Raymond / Luermans, Justin G L M / Van Kuijk, Sander M J / Tijssen, Jan G P / Van Gelder, Isabelle C / Crijns, Harry J G M / Tieleman, Robert G

Medicine and science in sports and exercise

2024

Abstract: ... of activity patients (28%) (p = 0.74). During follow up 42 high lifetime hours of high dynamic activity- (35 ... with paroxysmal AF received electrical or chemical cardioversion or atrial ablation (p = 0.90).: Conclusions ...

Abstract	Introduction: Long-term endurance exercise is suspect to elevate the risk of atrial fibrillation (AF),but little is known about cardiovascular outcome and disease progression in this subgroup of AF patients. We investigated whether previous exercise level determines cardiovascular outcome. Methods: In this post hoc analysis of the RACE 4 randomized trial, we analyzed all patients with a completed questionnaire on sports participation. Three subgroups were made based on lifetime sports hours up to randomization and previous compliance to the international physical activity guidelines. High lifetime hours of high dynamic activity patients were defined as more than 150 min/week of high intense physical exercise. The primary endpoint was a composite of cardiovascular death and hospital admissions. Results: A total of 879 patients were analyzed, divided in 203 high lifetime hours of high dynamic activity -, 192 high lifetime hours of activity- and 484 low lifetime hours of activity patients. Over a mean follow up of 36 months (±14), the primary endpoint occurred in 61 out of 203 (30%) high lifetime hours of high dynamic activity -, 53 out of 192 (27%) high lifetime hours of activity- and 135 out of 484 low lifetime hours of activity patients (28%) (p = 0.74). During follow up 42 high lifetime hours of high dynamic activity- (35%), 43 high lifetime hours of activity- (32%) and 104 low lifetime hours of activity patients (34%) with paroxysmal AF received electrical or chemical cardioversion or atrial ablation (p = 0.90). Conclusions: In patients included in the RACE 4, there appears to be no relation between previous activity levels and cardiovascular outcome and the need for electrical or chemical cardioversion or atrial ablation. Cardiovascular outcome was driven by AF related arrhythmic events.
Language	English
Publishing date	2024-04-10
Publishing country	United States
Document type	Journal Article
ZDB-ID	603994-7
ISSN	1530-0315 ; 0195-9131 ; 0025-7990
ISSN (online)	1530-0315
ISSN	0195-9131 ; 0025-7990
DOI	10.1249/MSS.0000000000003424
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Zs.A 869: Show issues

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Article ; Online: von Willebrand factor and inflammation.

Kawecki, C / Lenting, P J / Denis, C V

Journal of thrombosis and haemostasis : JTH

2017 Volume 15, Issue 7, Page(s) 1285–1294

Abstract: ... inflammation players such as P-selectin. Finally, a more direct link between VWF and inflammation has become ...

Abstract	Von Willebrand factor (VWF) is a plasma glycoprotein best known for its crucial hemostatic role in serving as a molecular bridge linking platelets to subendothelial components following vascular injury. In addition, VWF functions as chaperone for coagulation factor VIII. In pathological settings, VWF is recognized as a risk factor for both arterial and venous thrombosis, as well as a molecular player that directly promotes the thrombotic process. Recent years have seen the emergence of the concept of immuno-thrombosis by which inflammatory cells participate in thrombotic processes. In return, reports about the involvement of hemostatic proteins or cells (such as platelets) in inflammatory responses have become increasingly common, emphasizing the intricate link between hemostasis and inflammation. However, evidence of a link between VWF and inflammation arose much earlier than these recent developments. At first, VWF was considered only as a marker of inflammation in various pathologies, due to its acute release by the activated endothelium. Later on, a more complex role of VWF in inflammation was uncovered, owing to its capacity to direct the biogenesis of specific endothelial organelles, the Weibel-Palade bodies that contain known inflammation players such as P-selectin. Finally, a more direct link between VWF and inflammation has become apparent with the discovery that VWF is able to recruit leukocytes, either via direct leukocyte binding or by recruiting platelets which in turn will attract leukocytes. This review will focus on these different aspects of the connection between VWF and inflammation, with particular emphasis on VWF-leukocyte interactions.
MeSH term(s)	ADAMTS13 Protein/metabolism ; Animals ; Blood Platelets/metabolism ; Endothelial Cells/metabolism ; Endothelium, Vascular/metabolism ; Glycoproteins/metabolism ; Hemostasis ; Humans ; Inflammation ; Leukocytes/cytology ; Ligands ; Mice ; Neutrophils/metabolism ; P-Selectin/metabolism ; Platelet Glycoprotein GPIb-IX Complex/metabolism ; Risk Factors ; Venous Thrombosis/metabolism ; Weibel-Palade Bodies ; von Willebrand Factor/metabolism
Chemical Substances	Glycoproteins ; Ligands ; P-Selectin ; Platelet Glycoprotein GPIb-IX Complex ; SELP protein, human ; von Willebrand Factor ; ADAMTS13 Protein (EC 3.4.24.87) ; ADAMTS13 protein, human (EC 3.4.24.87)
Language	English
Publishing date	2017-08-17
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1111/jth.13696
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Article ; Online: The role of platelets and von Willebrand factor in the procoagulant phenotype of inflammatory bowel disease.

Schellenberg, Célia / Lagrange, Jérémy / Ahmed, Muhammad Usman / Arnone, Djésia / Campoli, Philippe / Louis, Huguette / Touly, Nina / Caron, Bénédicte / Plénat, François / Perrin, Julien / Lenting, Peter J / Regnault, Véronique / Lacolley, Patrick / Denis, Cécile V / Peyrin-Biroulet, Laurent

Journal of Crohn's & colitis

2023

Abstract: Objective: Although the risk for thrombosis is well documented for inflammatory bowel disease (IBD) patients, the underlying pathological mechanism seems to be different from other thrombotic conditions. Deciphering the actors responsible for the ... ...

Abstract	Objective: Although the risk for thrombosis is well documented for inflammatory bowel disease (IBD) patients, the underlying pathological mechanism seems to be different from other thrombotic conditions. Deciphering the actors responsible for the increased risk of thrombosis in IBD would help to improve management of this frequent complication. Design: We studied the interplay between platelets, coagulation, and von Willebrand factor (VWF) in 193 IBD patients and in experimental models (acute and chronic) of colitis in wild-type and VWF-deficient mice. Results: We found a platelet-dependent increase in thrombin generation in IBD patients and in our mouse model of colitis. Agglutinated platelets were present in the blood of patients and mice. Interestingly, we observed not only a significant increase in total VWF antigen, but we were able to detect the presence of active VWF (VWF in its platelet-binding conformation; 3.2±2.7µg/ml) in the plasma of 30% of all IBD patients. In healthy controls, active VWF levels were below 0.3µg/ml. This led us to further explore experimental colitis in VWF-deficient mice and we observed that these mice were protected against the procoagulant state triggered by the colitis. Unexpectedly, these mice also manifested a significant worsening of colitis severity both in acute and chronic models. Conclusion: Platelets and VWF (including its active form) appear to be central players in the procoagulant phenotype in IBD. We observed that the role of VWF in hemostasis differs from its role in colic tissue healing, potentially opening new therapeutic avenues for a life-threatening complication in IBD patients.
Language	English
Publishing date	2023-11-27
Publishing country	England
Document type	Journal Article
ZDB-ID	2390120-2
ISSN	1876-4479 ; 1873-9946
ISSN (online)	1876-4479
ISSN	1873-9946
DOI	10.1093/ecco-jcc/jjad198
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Article: Causes of adult mortality in two populations of New Zealand sea lions (Phocarctos hookeri)

Lenting, B / Gartrell, B / Kokosinska, A / Duignan, P.J / Michael, S / Hunter, S / Roe, W.D

Veterinary and Animal Science. 2019 June, v. 7

2019

Abstract: The New Zealand sea lion is an endangered species endemic to New Zealand. While causes of death are well described for pups of this species, mortality in adults is poorly characterised. This study investigated causes of death in 136 New Zealand sea lions ...

Abstract	The New Zealand sea lion is an endangered species endemic to New Zealand. While causes of death are well described for pups of this species, mortality in adults is poorly characterised. This study investigated causes of death in 136 New Zealand sea lions in two different populations: a major breeding site on remote, uninhabited Enderby Island in the sub-Antarctic, and a slowly increasing recolonising population on the inhabited mainland. For animals with at least a partial diagnostic investigation (n = 112), the most frequently diagnosed causes of mortality were infectious disease (41/112; 37%), particularly tuberculosis due to M. pinnipedii (20/112; 18%), and conspecific trauma (27/112; 24%). Anthropogenic trauma was an important cause of death in mainland sea lions (9/33; 26%). Deliberate anthropogenic mortality has previously been identified as the greatest potential threat to population recovery for mainland sea lions, and as human and pinniped populations increase, managing interactions between these species will become increasingly important.
Keywords	Phocarctos hookeri ; adults ; breeding sites ; death ; endangered species ; humans ; mortality ; pups ; tuberculosis ; New Zealand
Language	English
Dates of publication	2019-06
Publishing place	Elsevier Ltd
Document type	Article
ISSN	2451-943X
DOI	10.1016/j.vas.2019.100057
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Article ; Online: Identification of von Willebrand factor D4 domain mutations in patients of Afro-Caribbean descent: In vitro characterization.

Dubois, Marie-Daniéla / Peyron, Ivan / Pierre-Louis, Olivier-Nicolas / Pierre-Louis, Serge / Rabout, Johalène / Boisseau, Pierre / de Jong, Annika / Susen, Sophie / Goudemand, Jenny / Neviere, Rémi / Fuseau, Pascal / Christophe, Olivier D / Lenting, Peter J / Denis, Cécile V / Casari, Caterina

Research and practice in thrombosis and haemostasis

2022 Volume 6, Issue 4, Page(s) e12737

Abstract: ... of the VWF gene (: Objectives: Our goal was to characterize how the D4 variants p.(Pro2145Thrfs*5) and p ... Homozygous expression of the p.(Cys2216Phefs*9)-rVWF mutation resulted in an almost complete intracellular ... logically capable of normal interaction with the different ligands. In contrast, the p.(Pro2145Thrfs*5)-rVWF ...

Abstract	Background: Von Willebrand disease was diagnosed in two Afro-Caribbean patients and sequencing of the VWF gene ( Objectives: Our goal was to characterize how the D4 variants p.(Pro2145Thrfs5) and p.(Cys2216Phefs9) influenced VWF biosynthesis/secretion and functions using in vitro assays. Methods: Recombinant VWF (rVWF), mutant or wild-type, was produced via transient transfection of the human embryonic kidney cell line 293T. The use of different tags for the wild-type and the mutant allele allowed us to distinguish between the two forms when measuring VWF antigen in medium and cell lysates. Binding of rVWF to its ligands, collagen, factor VIII, ADAMTS13, and platelet receptors was also investigated. Results: Homozygous expression of the p.(Cys2216Phefs9)-rVWF mutation resulted in an almost complete intracellular retention of the protein. Heterozygous expression led to secretion of almost exclusively wild-type-rVWF, logically capable of normal interaction with the different ligands. In contrast, the p.(Pro2145Thrfs5)-rVWF exhibited reduced binding to type III collagen and αIIbβ3 integrin compared to wild-type-rVWF. Conclusions: We report two mutations of the D4 domains that induced combined qualitative and quantitative defects.
Language	English
Publishing date	2022-06-15
Publishing country	United States
Document type	Journal Article
ISSN	2475-0379
ISSN (online)	2475-0379
DOI	10.1002/rth2.12737
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Article ; Online: ADAMTS-13: double trouble for von Willebrand factor.

Lenting, P J / Rastegarlari, G

Journal of thrombosis and haemostasis : JTH

2010 Volume 8, Issue 12, Page(s) 2775–2777

MeSH term(s)	ADAM Proteins/blood ; ADAMTS13 Protein ; Humans ; Substrate Specificity ; von Willebrand Factor/metabolism
Chemical Substances	von Willebrand Factor ; ADAM Proteins (EC 3.4.24.-) ; ADAMTS13 Protein (EC 3.4.24.87) ; ADAMTS13 protein, human (EC 3.4.24.87)
Language	English
Publishing date	2010-06-14
Publishing country	England
Document type	Journal Article ; Comment
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1111/j.1538-7836.2010.04124.x
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Article ; Online: von Willebrand Factor Is a Critical Mediator of Deep Vein Thrombosis in a Mouse Model of Diet-Induced Obesity.

Michels, Alison / Dwyer, Courtney N / Mewburn, Jeffrey / Nesbitt, Kate / Kawecki, Charlotte / Lenting, Peter / Swystun, Laura L / Lillicrap, David

Arteriosclerosis, thrombosis, and vascular biology

2020 Volume 40, Issue 12, Page(s) 2860–2874

Abstract: Objective: Obesity is characterized by chronic low-grade inflammation and consequentially a hypercoagulable state, associating with an increased incidence of venous thromboembolism. Increased VWF (von Willebrand factor) plasma concentration and ... ...

Abstract	Objective: Obesity is characterized by chronic low-grade inflammation and consequentially a hypercoagulable state, associating with an increased incidence of venous thromboembolism. Increased VWF (von Willebrand factor) plasma concentration and procoagulant function are independent risk factors for venous thromboembolism and are elevated in obese patients. Here, we explore the pathobiological role of VWF in obesity-associated venous thrombosis using murine models. Approach and Results: We first showed that diet-induced obese mice have increased VWF plasma levels and FVIII (factor VIII) activity compared with littermate controls. Elevated VWF levels appeared to be because of both increased synthesis and impaired clearance. Diet-induced obesity-associated venous thrombosis was assessed using the inferior vena cava-stenosis model of deep vein thrombosis. Diet-induced obese mice developed larger venous thrombi that were rich in VWF, erythrocytes, and leukocytes. Administering a polyclonal anti-VWF antibody or an anti-VWF A1 domain nanobody was protective against obesity-mediated thrombogenicity. Delayed administration (3 hours post-inferior vena cava stenosis) similarly reduced thrombus weight in diet-induced obese mice. Conclusions: This study demonstrates the critical role of VWF in the complex, thrombo-inflammatory state of obesity. It adds to the growing rationale for targeting VWF-specific interactions in thrombotic disease.
MeSH term(s)	ADAMTS13 Protein/genetics ; ADAMTS13 Protein/metabolism ; Animals ; Diet, High-Fat ; Disease Models, Animal ; Female ; Fibrinolytic Agents/pharmacology ; Male ; Mice, Inbred C57BL ; Mice, Knockout ; Obesity/complications ; Obesity/metabolism ; Signal Transduction ; Single-Domain Antibodies/pharmacology ; Vena Cava, Inferior/drug effects ; Vena Cava, Inferior/metabolism ; Vena Cava, Inferior/pathology ; Venous Thrombosis/etiology ; Venous Thrombosis/metabolism ; Venous Thrombosis/pathology ; Venous Thrombosis/prevention & control ; von Willebrand Factor/antagonists & inhibitors ; von Willebrand Factor/genetics ; von Willebrand Factor/metabolism
Chemical Substances	Fibrinolytic Agents ; Single-Domain Antibodies ; von Willebrand Factor ; ADAMTS13 protein, mouse (EC 3.4.24.-) ; ADAMTS13 Protein (EC 3.4.24.87)
Language	English
Publishing date	2020-09-24
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	1221433-4
ISSN	1524-4636 ; 1079-5642
ISSN (online)	1524-4636
ISSN	1079-5642
DOI	10.1161/ATVBAHA.120.314690
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Article ; Online: In silico gene expression analysis reveals glycolysis and acetate anaplerosis in IDH1 wild-type glioma and lactate and glutamate anaplerosis in IDH1-mutated glioma.

Khurshed, Mohammed / Molenaar, Remco J / Lenting, Krissie / Leenders, William P / van Noorden, Cornelis J F

Oncotarget

2017 Volume 8, Issue 30, Page(s) 49165–49177

Abstract: Hotspot mutations in isocitrate dehydrogenase 1 (IDH1) initiate low-grade glioma and secondary glioblastoma and induce a neomorphic activity that converts α-ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (D-2-HG). It causes metabolic ... ...

Abstract	Hotspot mutations in isocitrate dehydrogenase 1 (IDH1) initiate low-grade glioma and secondary glioblastoma and induce a neomorphic activity that converts α-ketoglutarate (α-KG) to the oncometabolite D-2-hydroxyglutarate (D-2-HG). It causes metabolic rewiring that is not fully understood. We investigated the effects of IDH1 mutations (IDH1MUT) on expression of genes that encode for metabolic enzymes by data mining The Cancer Genome Atlas. We analyzed 112 IDH1 wild-type (IDH1WT) versus 399 IDH1MUT low-grade glioma and 157 IDH1WT versus 9 IDH1MUT glioblastoma samples. In both glioma types, IDH1WT was associated with high expression levels of genes encoding enzymes that are involved in glycolysis and acetate anaplerosis, whereas IDH1MUT glioma overexpress genes encoding enzymes that are involved in the oxidative tricarboxylic acid (TCA) cycle. In vitro, we observed that IDH1MUT cancer cells have a higher basal respiration compared to IDH1WT cancer cells and inhibition of the IDH1MUT shifts the metabolism by decreasing oxygen consumption and increasing glycolysis. Our findings indicate that IDH1WT glioma have a typical Warburg phenotype whereas in IDH1MUT glioma the TCA cycle, rather than glycolytic lactate production, is the predominant metabolic pathway. Our data further suggest that the TCA in IDH1MUT glioma is driven by lactate and glutamate anaplerosis to facilitate production of α-KG, and ultimately D-2-HG. This metabolic rewiring may be a basis for novel therapies for IDH1MUT and IDH1WT glioma.
Language	English
Publishing date	2017-07-25
Publishing country	United States
Document type	Journal Article
ZDB-ID	2560162-3
ISSN	1949-2553 ; 1949-2553
ISSN (online)	1949-2553
ISSN	1949-2553
DOI	10.18632/oncotarget.17106
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