10 results on '"Lenting, Peter J."'
Search Results
2. Towards novel treatment options in von Willebrand disease.
- Author
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Lenting, Peter J., Kizlik‐Manson, Claire, and Casari, Caterina
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VON Willebrand disease , *VON Hippel-Lindau disease , *HEMOPHILIA , *VON Willebrand factor , *SYMPTOMS , *EMICIZUMAB - Abstract
Deficiency or dysfunction of von Willebrand factor (VWF) is associated with a bleeding disorder known as von Willebrand disease (VWD). The clinical manifestations of VWD are heterogeneous, and are in part dictated by the structural or functional defects of VWF. The tools to control bleeding in VWD are dominated by VWF concentrates, desmopressin and antifibrinolytic therapy. In view of these treatments being considered as effective, it is surprising that quality‐of‐life studies consistently demonstrate a significant mental and physical burden in VWD patients, particularly in women. Apparently, the current weaponry to support the management of VWD is insufficient to fully address the needs of the patients. It is important therefore to continue to search for innovative treatment options which could better serve the VWD patients. In this short review, two of such options are discussed in more detail: emicizumab to correct for the deficiency of factor VIII (FVIII), and the pegylated aptamer BT200 to increase endogenous levels of the VWF/FVIII complex. [ABSTRACT FROM AUTHOR]
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- 2022
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3. Von Willebrand Factor Abnormalities Studied in the Mouse Model: What We Learned about VWF Functions
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Casari, Caterina, Lenting, Peter J., Christophe, Olivier D., and Denis, Cécile V.
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biology ,business.industry ,lcsh:RC633-647.5 ,Transgene ,Hematology ,lcsh:Diseases of the blood and blood-forming organs ,Review Article ,Bioinformatics ,medicine.disease ,In vitro ,Cell biology ,Infectious Diseases ,Von Willebrand factor ,In vivo ,Hemostasis ,hemic and lymphatic diseases ,biology.protein ,Von Willebrand disease ,Medicine ,Platelet ,business ,Receptor ,circulatory and respiratory physiology - Abstract
Up until recently, von Willebrand Factor (VWF) structure-function relationships have only been studied through in vitro approaches. A powerful technique known as hydrodynamic gene transfer, which allows transient expression of a transgene by mouse hepatocytes, has led to an important shift in VWF research. Indeed this approach has now enabled us to transiently express a number of VWF mutants in VWF-deficient mice in order to test the relative importance of specific residues in different aspects of VWF biology and functions in an in vivo setting. As a result, mice reproducing various types of von Willebrand disease have been generated, models that will be useful to test new therapies. This approach also allowed a more precise identification of the importance of VWF interaction with subendothelial collagens and with platelets receptors in hemostasis and thrombosis. The recent advances gathered from these studies as well as the pros and cons of the technique will be reviewed here.
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- 2013
4. ON THE VERSATILITY OF VON WILLEBRAND FACTOR
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Rauch, Antoine, Wohner, Nikolett, Christophe, Olivier D., Denis, Cécile V., Susen, Sophie, and Lenting, Peter J.
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congenital, hereditary, and neonatal diseases and abnormalities ,Integrin ,Context (language use) ,Hemorrhage ,Review Article ,Von Willebrand factor ,hemic and lymphatic diseases ,von Willebrand Factor ,Von Willebrand disease ,medicine ,Thrombosis, ADAMTS 13 ,chemistry.chemical_classification ,biology ,business.industry ,lcsh:RC633-647.5 ,Hematology ,lcsh:Diseases of the blood and blood-forming organs ,medicine.disease ,ADAMTS13 ,Infectious Diseases ,Increased risk ,chemistry ,Plasma concentration ,Immunology ,biology.protein ,cardiovascular system ,Glycoprotein ,business ,circulatory and respiratory physiology - Abstract
Von Willebrand factor (VWF) is a large multimeric protein, the function of which has been demonstrated to be pivotal to the haemostatic system. Indeed, quantitative and/or qualitative abnormalities of VWF are associated with the bleeding disorder Von Willebrand disease (VWD). Moreover, increased plasma concentrations of VWF have been linked to an increased risk for thrombotic complications. In the previous decades, many studies have contributed to our understanding of how VWF is connected to the haemostatic system, particularly with regard to structure-function relationships. Interactive sites for important ligands of VWF (such as factor VIII, collagen, glycoprotein Iba, integrin aIIbb3 and protease ADAMTS13) have been identified, and mutagenesis studies have confirmed the physiological relevance of the interactions between VWF and these ligands. However, we have also become aware that VWF has a more versatile character than previously thought, given its potential role in various non-hemostatic processes, like intimal thickening, tumor cell apoptosis and inflammatory processes. In the presence review, a summary of our knowledge on VWF structure-function relationships is provided in the context of the "classical" haemostatic task of VWF and in perspective of pathological processes beyond haemostasis.
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- 2013
5. Transient von Willebrand factor-mediated platelet influx stimulates liver regeneration after partial hepatectomy in mice.
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Kirschbaum, Marc, Jenne, Craig N., Veldhuis, Zwanida J., Sjollema, Klaas A., Lenting, Peter J., Giepmans, Ben N. G., Porte, Robert J., Kubes, Paul, Denis, Cécile V., and Lisman, Ton
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LIVER regeneration ,LIVER diseases ,HEPATECTOMY ,LIVER surgery ,VON Willebrand disease ,GENETICS - Abstract
Background & Aims In addition to their function in thrombosis and haemostasis, platelets play an important role in the stimulation of liver regeneration. It has been suggested that platelets deliver mitogenic cargo to the regenerating liver, and accumulation of platelets in the regenerating liver has been demonstrated. We studied kinetics of platelet influx in the regenerating liver and investigated the signal that initiates platelet influx. Methods We visualized platelets in the liver remnant after partial hepatectomy in mice using intravital microscopy and assessed liver regeneration by examination of liver/body weight ratio and the number of proliferating hepatocytes examined by immunohistochemistry. Results We demonstrated rapid but transient platelet influx into the liver remnant after a partial liver resection. Liver regeneration in thrombocytopenic mice was substantially impaired as evidenced by a reduced liver-to-body weight ratio and decreased numbers of proliferating hepatocytes at day 3 compared to mice with normal platelet counts. In contrast, liver regeneration was only mildly impaired when thrombocytopaenia was induced 2 hours after partial liver resection. Platelet influx into the liver remnant was virtually absent in the presence of an antibody to von Willebrand factor ( VWF) suggesting that VWF release from liver sinusoidal endothelial cells mediates platelet influx. Additionally, liver regeneration in mice deficient in VWF was markedly impaired. Conclusions A rapid but transient VWF-dependent platelet influx into the liver remnant drives platelet-mediated liver regeneration. [ABSTRACT FROM AUTHOR]
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- 2017
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6. Apoptotic Platelet Events Are Not Observed in Severe von Willebrand Disease-Type 2B Mutation p.V1316M.
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Berrou, Eliane, Kauskot, Alexandre, Adam, Frédéric, Harel, Amélie, Legendre, Paulette, Lavenu Bombled, Cécile, Rothschild, Chantal, Prevost, Nicolas, Christophe, Olivier D., Lenting, Peter J., Denis, Cécile V., Rosa, Jean-Philippe, and Bryckaert, Marijke
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APOPTOSIS ,BLOOD platelets ,VON Willebrand disease ,GENETIC mutation ,THROMBOCYTOPENIA ,GLYCOPROTEINS - Abstract
Thrombocytopenia and increased platelet clearance observed in von Willebrand disease-type 2B (VWD-2B) may be explained by platelet apoptosis triggered by the constitutive binding of VWF to its receptor, glycoprotein Ib (GPIb). Apoptosis was assessed in platelets from two patients with a severe VWD-2B mutation VWF/p.V1316M and from mice transiently expressing VWF/p.V1316M. We now report that the VWD-2B mutation VWF/p.V1316M which binds spontaneously to its receptor GPIbα does not induce apoptosis. In 2 unrelated patients (P1 and P2) exhibiting different VWF plasma levels (70% and 36%, respectively, compared with normal pooled human plasma given as 100%), inner transmembrane depolarization of mitochondria, characteristic of apoptotic events was undetectable in platelets, whether washed or in whole blood. No or a moderate phosphatidyl serine (PS) exposure as measured by annexin-V staining was observed for P1 and P2, respectively. Expression of pro-apoptotic proteins Bak and Bax, and caspase-3 activity were similar to control platelets. In the VWD-2B mouse model expressing high levels of mVWF/p.V1316M (423%), similar to what is found in inflammatory pathologies, no significant difference was observed between mice expressing mVWF/WT and mVWF/p.V1316M. These results strongly argue against apoptosis as a mechanism for the thrombocytopenia of severe VWD-2B exhibiting the VWF/p.V1316M mutation. [ABSTRACT FROM AUTHOR]
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- 2015
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7. von Willebrand factor biosynthesis, secretion, and clearance: connecting the far ends.
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Lenting, Peter J., Christophe, Olivier D., and Denis, Cécile V.
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ANTIBIOTICS , *BIOSYNTHESIS , *VON Willebrand disease , *PROTEINS , *EXTRACELLULAR enzymes , *BLOOD coagulation , *ORGANELLES - Abstract
To understand the placement of a certain protein in a physiological system and the pathogenesis of related d isorders, it is not only of interest to determine its function but also important to describe the sequential steps in its life cycle, from synthesis to secretion and ultimately its clearance, von Willebrand factor (VWF) is a particularly intriguing case in this regard because of its important auxiliary roles (both intra- and extracellular) that implicate a wide range of other proteins: its presence is required for the formation and regulated release of endothelial storage organelles, the Weibel-Palade bodies (WPBs), whereas VWF is also a key determinant in the clearance of coagulation factor VIII. Thus, understanding the molecular and cellular basis of the VWF life cycle will help us gain insight into the pathogenesis of von Willebrand disease, design alternative treatment options to prolong the factor VIII half-life, and delineate the role of VWF and coresidents of the WPBs in the prothrombotic and proinflammatory response of endothelial cells. In this review, an update on our current knowledge on VWF biosynthesis, secretion, and clearance is provided and we will discuss how they can be affected by the presence of protein defects. [ABSTRACT FROM AUTHOR]
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- 2015
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8. VWF clearance: it's glycomplicated.
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Denis, Cécile V. and Lenting, Peter J.
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SIALIC acids , *VON Willebrand disease , *VON Willebrand factor , *MACROPHAGES , *GALACTOSE , *GENETIC code - Abstract
The article discusses loss of sialic acids turns von Willebrand factor (VWF) into a ligand for the scavenger-receptor macrophage galactose-type lectin. It mentions abnormal clearance of VWF contributes to the pathogenesis of von Willebrand disease (VWD). It discusses the need of investigation of polymorphisms in the gene encoding lectin-like receptor (MGL).
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- 2018
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9. A factor VIII-nanobody fusion protein forming an ultrastable complex with VWF: effect on clearance and antibody formation.
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Muczynski, Vincent, Casari, Caterina, Moreau, François, Aymé, Gabriel, Kawecki, Charlotte, Legendre, Paulette, Proulle, Valerie, Christophe, Olivier D., Denis, Cécile V., and Lenting, Peter J.
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BLOOD coagulation disorders , *BLOOD coagulation factors , *VON Willebrand factor , *VON Willebrand disease , *IMMUNE response - Abstract
Von Willebrand factor (VWF) modulates factor VIII (FVIII) clearance and the anti-FVIII immune response. Despite the high affinity that defines the FVIII/VWF interaction, association/dissociation kinetics dictates 2% to 5% FVIII being present as free protein. To avoid free FVIII when studying the FVIII-VWF complex in vivo, we designed a FVIII-nanobody fusion protein, with the nanobody part being directed against VWF. This fusion protein, designated FVIII-KB013bv, had a 25-fold higher affinity compared with B-domainless FVIII (BDD-FVIII) for VWF. In vitro analysis revealed full cofactor activity in 1-stage clotting and chromogenic assays (activity/antigen ratio 1.0 ± 0.3 and 1.1 ± 0.3, respectively). In vivo, FVIII-013bv displayed a twofold increased mean residence time compared with BDD-FVIII (3.0 hours vs 1.6 hours). In a tail clip-bleeding assay performed 24 hours after FVIII infusion, blood loss was significantly reduced in mice receiving FVIII-KB013bv vs BDD-FVIII (15 ± 7 μL vs 194 ± 146 μL; P = .0043). Unexpectedly, when examining anti-FVIII antibody formation in FVIII-deficient mice, the immune-response toward FVIII-KB013bv was significantly reduced compared with BDD-FVIII (1/8 vs 14/16 mice produced anti-FVIII antibodies after treatment with FVIII-KB013bv and BDD-FVIII, respectively). Our data show that a stabilized interaction between FVIII and VWF is associated with a prolonged survival of FVIII and a reduced immune response against FVIII. [ABSTRACT FROM AUTHOR]
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- 2018
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10. Accelerated uptake of VWF/platelet complexes in macrophages contributes to VWD type 2B-associated thrombocytopenia.
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Casari, Caterina, Du, Vivian, Ya-Ping Wu, Kauskot, Alexandre, De Groot, Philip G., Christophe, Olivier D., Denis, Cecile V., Laat, Bas de, and Lenting, Peter J.
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VON Willebrand disease , *BLOOD platelets , *THROMBOCYTOPENIA , *MACROPHAGES , *LABORATORY mice , *PHAGOCYTOSIS - Abstract
Von Willebrand disease (VWD) type 2B is characterized by mutations causing enhanced binding of von Willebrand factor (VWF) to platelets. Bleeding tendency is associated with heterogeneous clinical manifestations, including moderate to severe thrombocytopenia. The underlying mechanism of the thrombocytopenia has remained unclear. Here, a mouse model of VWD type 2B was used to investigate pathways contributing to thrombocytopenia. Immunohistochemical analysis of blood smears revealed that mutant VWF was exclusively detected on platelets of thrombocytopenic VWD type 2B mice, suggesting that thrombocytopenic VWD type 2B mice were elevated two- to threefold upon chemical macrophage depletion. Colocalization of platelets with CD68-positive Kupffer cells and CD168-positive marginal macrophages in liver and spleen, respectively, confirmed the involvement of macrophages in the removal of VWF/platelet complexes. Significantly more platelets were found in liver and spleen of VWD type 2B mice compared with control mice. Finally, platelet survival was significantly shorter in VWD type 2B mice compared with control mice, providing a rationale for lower platelet counts in VWD type 2B mice. In conclusion, our data indicate that VWF type 2B binds to platelets and that this is a signal for clearance by macrophages, which could contribute to the thrombocytopenia in patients with VWD type 2B. [ABSTRACT FROM AUTHOR]
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- 2013
- Full Text
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