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  1. Article ; Online: Hemophilia A treatment innovation: factor VIII mimetic bispecific antibodies-generational enhancement.

    Lillicrap, David / Lenting, Peter

    Journal of thrombosis and haemostasis : JTH

    2023  Volume 22, Issue 2, Page(s) 352–355

    MeSH term(s) Humans ; Factor VIII/therapeutic use ; Hemophilia A/drug therapy ; Antibodies, Bispecific/pharmacology ; Antibodies, Bispecific/therapeutic use ; Hemostatics ; Factor X
    Chemical Substances Factor VIII (9001-27-8) ; Antibodies, Bispecific ; Hemostatics ; Factor X (9001-29-0)
    Language English
    Publishing date 2023-09-20
    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.2023.10.026
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  2. Article ; Online: Laboratory monitoring of hemophilia A treatments: new challenges.

    Lenting, Peter J

    Blood advances

    2020  Volume 4, Issue 9, Page(s) 2111–2118

    Abstract: Monitoring factor VIII (FVIII) activity has traditionally been complicated by discrepancies between assays for the various sorts of FVIII molecules. The advent of novel nonfactor therapies (emicizumab, fitusiran, and anti-tissue factor pathway inhibitor ... ...

    Abstract Monitoring factor VIII (FVIII) activity has traditionally been complicated by discrepancies between assays for the various sorts of FVIII molecules. The advent of novel nonfactor therapies (emicizumab, fitusiran, and anti-tissue factor pathway inhibitor antibodies) in hemophilia A poses a new level of difficulty on the laboratory monitoring of these patients. To use the correct assays and for a proper interpretation of their results, it is pertinent to understand the mode of action of these nonfactor agents. Furthermore, the biochemical consequences for the different types of activity assays (whether it be specific FVIII activity assays or global coagulation assays) should be taken into account as well. In this review, these aspects will be discussed. In addition, the use of various animal models to estimate FVIII-equivalence of the nonfactor therapies will be presented.
    MeSH term(s) Animals ; Blood Coagulation ; Blood Coagulation Tests ; Hemophilia A/diagnosis ; Hemophilia A/drug therapy ; Hemostatics ; Humans ; Laboratories
    Chemical Substances Hemostatics
    Language English
    Publishing date 2020-05-11
    Publishing country United States
    Document type Journal Article ; Review
    ZDB-ID 2915908-8
    ISSN 2473-9537 ; 2473-9529
    ISSN (online) 2473-9537
    ISSN 2473-9529
    DOI 10.1182/bloodadvances.2019000849
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  3. Article ; Online: How to keep the factor VIII/von Willebrand factor complex in the circulation.

    Denis, Cécile V / Lenting, Peter J

    Haematologica

    2022  Volume 107, Issue 9, Page(s) 2011–2013

    MeSH term(s) Factor VIII/metabolism ; Humans ; Protein Binding ; von Willebrand Diseases ; von Willebrand Factor/metabolism
    Chemical Substances von Willebrand Factor ; Factor VIII (9001-27-8)
    Language English
    Publishing date 2022-09-01
    Publishing country Italy
    Document type Journal Article
    ZDB-ID 2333-4
    ISSN 1592-8721 ; 0017-6567 ; 0390-6078
    ISSN (online) 1592-8721
    ISSN 0017-6567 ; 0390-6078
    DOI 10.3324/haematol.2021.280222
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  4. Article ; Online: von Willebrand factor: from figurant to main character in the scene of inflammation.

    Lenting, Peter J / Texier, Alexis / Casari, Caterina

    Journal of thrombosis and haemostasis : JTH

    2023  Volume 21, Issue 4, Page(s) 710–713

    MeSH term(s) Humans ; von Willebrand Factor ; Inflammation ; von Willebrand Diseases ; Factor VIII
    Chemical Substances von Willebrand Factor ; Factor VIII (9001-27-8)
    Language English
    Publishing date 2023-01-21
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2112661-6
    ISSN 1538-7836 ; 1538-7933
    ISSN (online) 1538-7836
    ISSN 1538-7933
    DOI 10.1016/j.jtha.2023.01.014
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  5. Article ; Online: Antibodies in the Treatment of Haemophilia A-A Biochemical Perspective.

    Ferrière, Stephen / Lenting, Peter J

    Hamostaseologie

    2019  Volume 39, Issue 1, Page(s) 36–41

    Abstract: Replacement therapy has been proven effective in the management of bleedings in haemophilia A. Nevertheless, this approach comes with several shortcomings, like the need for frequent intravenous infusions and the development of neutralizing antibodies in ...

    Abstract Replacement therapy has been proven effective in the management of bleedings in haemophilia A. Nevertheless, this approach comes with several shortcomings, like the need for frequent intravenous infusions and the development of neutralizing antibodies in 20 to 30% of the patients with severe haemophilia A replacement. This has led to the development of novel strategies to expand the spectrum of treatment options, some of which are based on antibody technology. These include a bispecific antibody that bridges enzyme factor IXa and substrate factor X, monoclonal antibodies that block the function of tissue factor pathway inhibitor, and a factor VIII-nanobody fusion protein with strongly enhanced von Willebrand factor binding. In this review, functional and mechanistic considerations on the use of these antibody variants will be discussed.
    MeSH term(s) Animals ; Antibodies, Bispecific/therapeutic use ; Antibodies, Monoclonal, Humanized/therapeutic use ; Coagulants/therapeutic use ; Factor VIII/antagonists & inhibitors ; Hemophilia A/blood ; Hemophilia A/therapy ; Humans ; Lipoproteins/antagonists & inhibitors ; Recombinant Fusion Proteins/therapeutic use ; Single-Domain Antibodies/therapeutic use
    Chemical Substances Antibodies, Bispecific ; Antibodies, Monoclonal, Humanized ; Coagulants ; Lipoproteins ; Recombinant Fusion Proteins ; Single-Domain Antibodies ; lipoprotein-associated coagulation inhibitor ; emicizumab (7NL2E3F6K3) ; Factor VIII (9001-27-8)
    Language English
    Publishing date 2019-01-29
    Publishing country Germany
    Document type Journal Article ; Review
    ZDB-ID 801512-0
    ISSN 2567-5761 ; 0720-9355
    ISSN (online) 2567-5761
    ISSN 0720-9355
    DOI 10.1055/s-0038-1677521
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  6. Article ; Online: TaSER: Combining forces to stop the clot.

    Denis, Cécile V / Lenting, Peter J / Wahl, Denis

    Journal of thrombosis and haemostasis : JTH

    2021  Volume 20, Issue 2, Page(s) 293–295

    MeSH term(s) Humans ; Thrombosis ; Weapons
    Language English
    Publishing date 2021-12-21
    Publishing country England
    Document type Journal Article
    ZDB-ID 2112661-6
    ISSN 1538-7836 ; 1538-7933
    ISSN (online) 1538-7836
    ISSN 1538-7933
    DOI 10.1111/jth.15597
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  7. Article ; Online: von Willebrand disease: what does the future hold?

    Denis, Cécile V / Susen, Sophie / Lenting, Peter J

    Blood

    2021  Volume 137, Issue 17, Page(s) 2299–2306

    Abstract: von Willebrand disease (VWD) is characterized by its heterogeneous clinical manifestation, which complicates its diagnosis and management. The clinical management of VWD has remained essentially unchanged over the last 30 years or so, using von ... ...

    Abstract von Willebrand disease (VWD) is characterized by its heterogeneous clinical manifestation, which complicates its diagnosis and management. The clinical management of VWD has remained essentially unchanged over the last 30 years or so, using von Willebrand factor (VWF) concentrates, desmopressin, and anti-fibrinolytic agents as main tools to control bleeding. This is in contrast to hemophilia A, for which a continuous innovative path has led to novel treatment modalities. Despite current VWD management being considered effective, quality-of-life studies consistently reveal a higher than anticipated burden of VWD on patients, which is particularly true for women. Apparently, despite our perceived notion of current therapeutic efficiency, there is space for innovation with the goal of reaching superior efficacy. Developing innovative treatments for VWD is complex, especially given the heterogeneity of the disease and the multifunctional nature of VWF. In this perspective article, we describe several potential strategies that could provide the basis for future VWD treatments. These include genetic approaches, such as gene therapy using dual-vector adenoassociated virus and transcriptional silencing of mutant alleles. Furthermore, protein-based approaches to increase factor FVIII levels in VWD-type 3 or 2N patients are discussed. Finally, antibody-based options to interfere with VWF degradation (for congenital VWD-type 2A or acquired von Willebrand syndrome-type 2A) or increase endogenous VWF levels (for VWD-type 1) are presented. By highlighting these potential strategies, we hope to initiate an innovative path, which ultimately would allow us to better serve VWD patients and their specific needs.
    MeSH term(s) Factor VIII/administration & dosage ; Factor VIII/genetics ; Genetic Therapy ; Humans ; Mutation ; von Willebrand Diseases/pathology ; von Willebrand Diseases/therapy ; von Willebrand Factor/genetics
    Chemical Substances von Willebrand Factor ; Factor VIII (9001-27-8)
    Language English
    Publishing date 2021-03-04
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 80069-7
    ISSN 1528-0020 ; 0006-4971
    ISSN (online) 1528-0020
    ISSN 0006-4971
    DOI 10.1182/blood.2020008501
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  8. Article ; Online: Towards novel treatment options in von Willebrand disease.

    Lenting, Peter J / Kizlik-Manson, Claire / Casari, Caterina

    Haemophilia : the official journal of the World Federation of Hemophilia

    2021  Volume 28 Suppl 4, Page(s) 5–10

    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 ... ...

    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.
    MeSH term(s) Antifibrinolytic Agents/therapeutic use ; Deamino Arginine Vasopressin/therapeutic use ; Factor VIII/therapeutic use ; Female ; Hemorrhage/drug therapy ; Hemostatics/therapeutic use ; Humans ; von Willebrand Diseases/drug therapy ; von Willebrand Factor/therapeutic use
    Chemical Substances Antifibrinolytic Agents ; Hemostatics ; von Willebrand Factor ; Factor VIII (9001-27-8) ; Deamino Arginine Vasopressin (ENR1LLB0FP)
    Language English
    Publishing date 2021-02-09
    Publishing country England
    Document type Journal Article
    ZDB-ID 1229713-6
    ISSN 1365-2516 ; 1351-8216 ; 1355-0691
    ISSN (online) 1365-2516
    ISSN 1351-8216 ; 1355-0691
    DOI 10.1111/hae.14518
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  9. Article ; Online: Plasmin-cleaved Von Willebrand Factor as a biomarker for microvascular thrombosis.

    El Otmani, Hinde / Frunt, Rowan / Smits, Simone / Barendrecht, Arjan D / de Maat, Steven / Fijnheer, Rob / Lenting, Peter J / Tersteeg, Claudia

    Blood

    2024  

    Abstract: Von Willebrand factor (VWF) is an essential contributor to microvascular thrombosis. Physiological cleavage by ADAMTS13 limits its prothrombotic properties, explaining why ADAMTS13 deficiency leads to attacks of microthrombosis in patients with ... ...

    Abstract Von Willebrand factor (VWF) is an essential contributor to microvascular thrombosis. Physiological cleavage by ADAMTS13 limits its prothrombotic properties, explaining why ADAMTS13 deficiency leads to attacks of microthrombosis in patients with thrombotic thrombocytopenic purpura (TTP). We previously reported that plasminogen activation takes place during TTP attacks in these patients. Furthermore, stimulation of plasminogen activation attenuates pathogenesis in preclinical TTP models in vivo. This suggests that plasmin is an endogenous regulator of VWF thrombogenicity, in particular when ADAMTS13 falls short to prevent microvascular occlusions. VWF cleavage by plasmin is biochemically distinct from cleavage by ADAMTS13. We hypothesized that plasmin-cleaved VWF (cVWF) holds value as a biomarker of microvascular thrombosis. We here describe the development of a VHH-based bioassay that can distinguish cVWF from intact and ADAMTS13-cleaved VWF in plasma. We validate this assay by tracking cVWF release during degradation of microthombi in vitro. We demonstrate that endogenous cVWF formation takes place in TTP patients during acute attacks of thrombotic microangiopathy, but not in remission. Finally, we show that therapeutic plasminogen activation in a mouse model for TTP amplifies cVWF formation, which is accompanied by VWF clearance. Our combined findings indicate that cVWF is released from microthrombi in the context of microvascular occlusion.
    Language English
    Publishing date 2024-01-25
    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.2023021265
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  10. Article ; Online: Angiopoietin-2 binds to multiple interactive sites within von Willebrand factor.

    Texier, Alexis / Lenting, Peter J / Denis, Cécile V / Roullet, Stéphanie / Christophe, Olivier D

    Research and practice in thrombosis and haemostasis

    2023  Volume 7, Issue 7, Page(s) 102204

    Abstract: Background: Biosynthesis of von Willebrand factor (VWF) in endothelial cells drives the formation of storage-organelles known as Weibel-Palade bodies (WPBs). WPBs also contain several other proteins, including angiopoietin-2 (Ang-2).: Objectives: At ... ...

    Abstract Background: Biosynthesis of von Willebrand factor (VWF) in endothelial cells drives the formation of storage-organelles known as Weibel-Palade bodies (WPBs). WPBs also contain several other proteins, including angiopoietin-2 (Ang-2).
    Objectives: At present, the molecular basis of the VWF-Ang-2 interaction is poorly understood. Here, we used immunosorbent-binding assays and specific recombinant VWF fragments to analyze VWF-Ang-2 interactions.
    Results: We found that VWF bound to immobilized Ang-2 most efficiently (half-maximal binding at 0.5 ± 0.1 μg/mL) under conditions of high CaCl
    Conclusion: Our data show that both Ang-1 and Ang-2 bind to VWF, seemingly using different interactive sites. Ang-2 modulates the binding of VWF to Ang-1, the (patho)-physiological consequences of which remain to be investigated.
    Language English
    Publishing date 2023-09-19
    Publishing country United States
    Document type Journal Article
    ISSN 2475-0379
    ISSN (online) 2475-0379
    DOI 10.1016/j.rpth.2023.102204
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