Article
Hematology
Natalie J. J. Jooss, Yvonne M. C. Henskens, Steve P. P. Watson, Richard W. W. Farndale, Meinrad P. P. Gawaz, Martine Jandrot-Perrus, Natalie S. S. Poulter, Johan W. M. Heemskerk
Summary: In this study, four inhibitors of platelet-collagen interactions were compared for their antithrombotic potential. The results showed that Revacept and 9O12-Fab had strong inhibitory effects on highly GPVI-activating surfaces, while 9O12-Fab had varying inhibitory effects on all surfaces. The effects of GPVI-directed interventions were surpassed by Syk inhibition, and 6F1 mAb had the strongest intervention effect on collagen substrates compared to Revacept and 9O12-Fab. These findings reveal the unique pharmacological profiles of these drugs and provide insights into additive antithrombotic mechanisms.
THROMBOSIS AND HAEMOSTASIS
(2023)
Review
Cell Biology
Angelika Mojzisch, Maria A. Brehm
Summary: Von Willebrand factor (VWF) is synthesized exclusively in endothelial cells and megakaryocytes, and plays multiple roles in cellular processes such as angiogenesis, leukocyte adhesion, and tumor cell metastasis. Its dysregulation can lead to various pathophysiological consequences.
Article
Biochemistry & Molecular Biology
Dan Shu, Ying Zhu, Meng Lu, Ao-Di He, Jiang-Bin Chen, Ding-Song Ye, Yue Liu, Xiang-Bin Zeng, Rong Ma, Zhang-Yin Ming
Summary: Sanguinarine demonstrates antiplatelet activity by inhibiting thrombus formation and platelet activation through multiple molecular mechanisms. This indicates its potential clinical value in treating cardiovascular diseases involving excessive platelet activation.
Article
Biochemistry & Molecular Biology
Isabella Provenzale, Ilaria De Simone, Jonathan M. Gibbins, Johan W. M. Heemskerk, Paola E. J. van der Meijden, Chris I. Jones
Summary: This study investigated the roles of different extracellular matrix proteoglycans in platelet responses and thrombus formation. It was found that one proteoglycan (perlecan) enhanced platelet activation and promoted thrombus formation, but also reduced platelet adhesion under flow. This suggests that proteoglycans play an important role in platelet activation and thrombus formation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Cardiac & Cardiovascular Systems
Monica Bray, Melda A. Guzel, Fong Lam, Andrew Yee, Miguel A. Cruz, Rolando E. Rumbaut
Summary: COVID-19 is associated with changes in the activity and quality of VWF, but these changes are not specific to COVID-19. Similar changes in VWF activity and quality are observed in hospitalized patients with or without COVID-19. Further research is needed to understand the mechanisms responsible for qualitative changes in VWF in COVID-19 and other critical illnesses.
JOURNAL OF THROMBOSIS AND THROMBOLYSIS
(2022)
Article
Hematology
Hiroaki Yaoi, Yasuaki Shida, Takehisa Kitazawa, Midori Shima, Keiji Nogami
Summary: Patients with Type 2N von Willebrand disease showed defective thrombus formation correlated with bleeding phenotype, which was improved by Emicizumab, enhancing thrombin generation and fibrin formation. The interactions between FVIII and VWF play an important role in platelet-fibrin interactions during thrombus formation and may be targeted as an alternative therapy for these patients.
THROMBOSIS RESEARCH
(2021)
Review
Biochemistry & Molecular Biology
Jinmi Zou, Frauke Swieringa, Bas de Laat, Philip G. de Groot, Mark Roest, Johan W. M. Heemskerk
Summary: This paper reviews the functional reversibility of integrin alpha IIb beta 3 activation and transient aggregation and discusses the signaling pathways involved. The study finds that ADP P2Y(1) and P2Y(12) receptor signaling via phosphoinositide 3-kinases and Akt are the principal pathways linked to reversible integrin activation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Hematology
Harrison E. R. O'Brien, X. Frank Zhang, Maximo Sanz-Hernandez, Alain Chion, Susan Shapiro, Golzar Mobayen, Yan Xu, Alfonso De Simone, Michael A. Laffan, Thomas A. J. McKinnon
Summary: The presence of free thiols in Von Willebrand factor (VWF) affects its interaction with collagen and platelet capture under high shear stress, demonstrating a previously unrecognized role of free thiols in VWF function. Experimental and simulations results show that free thiols increase the flexibility of VWF molecules and alter the binding to collagen, providing new insights into the impact of free thiols on VWF function.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2021)
Article
Biochemistry & Molecular Biology
Johana Hrdinova, Delia I. Fernandez, Bogac Ercig, Bibian M. E. Tullemans, Dennis P. L. Suylen, Stijn M. Agten, Kerstin Jurk, Tilman M. Hackeng, Karen Vanhoorelbeke, Jan Voorberg, Chris P. M. Reutelingsperger, Kanin Wichapong, Johan W. M. Heemskerk, Gerry A. F. Nicolaes
Summary: This study designed and synthesized stable cyclic peptides to interfere with the interaction between VWF A1 domain and GPIb alpha. The selected peptides showed low binding free energy and retained their interference in the binding of VWF to GPIb-V-IX, as confirmed by flow cytometry. These peptides phenotypically mimicked the changes seen with the anti-VWF A1 domain antibody CLB-RAg35, although they were less potent. The improved peptide opt-mono-ORbIT demonstrated increased inhibitory activity under flow.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Hematology
Catarina Monteiro, Ana Goncalves, Monica Pereira, Catarina Lau, Sara Morais, Rosario Santos
Summary: Platelet-type von Willebrand disease (PT-VWD) is a rare autosomal dominant bleeding disorder characterized by increased platelet aggregation and enhanced affinity of GPIba to VWF. A novel heterozygous variant of GP1BA, likely causing the PT-VWD phenotype, was identified in the patient through genetic sequencing.
BRITISH JOURNAL OF HAEMATOLOGY
(2023)
Review
Pharmacology & Pharmacy
Oliver Borst, Meinrad Gawaz
Summary: Subendothelial collagen exposed to platelets after rupture of atherosclerotic plaques is the main trigger of platelet activation and acute arterial thrombotic occlusion. Developing antiplatelet strategies that selectively inhibit atherothrombosis without interfering with bleeding control is an unmet clinical need. Platelet glycoprotein VI (GPVI) plays a crucial role in collagen-induced platelet activation and aggregation, making it a potential target for novel therapeutic strategies in thrombotic and inflammatory diseases.
PHARMACOLOGY & THERAPEUTICS
(2021)
Article
Hematology
Hiroaki Yaoi, Yasuaki Shida, Kenichi Ogiwara, Keiji Nogami
Summary: The effects of high levels of rVWF and peg-EHL-rFVIII on thrombus formation were comparable to conventional therapeutic products in a patient's whole blood with VWD under high shear flow.
THROMBOSIS JOURNAL
(2023)
Article
Biology
Klaus Bonazza, Roxana E. Iacob, Nathan E. Hudson, Jing Li, Chafen Lu, John R. Engen, Timothy A. Springer
Summary: This study investigates the regulatory role of N-linker and C-linker in the binding of A1 to GPIb alpha. The results show that the N-linker decreases the affinity of A1 for GPIb alpha, with a stronger contribution from its O-glycan moiety. Additionally, the N-linker regulates the hydrogen deuterium exchange, thermal stability, and urea-induced unfolding of A1. In contrast, the C-linker has no significant effect on the affinity of A1 for GPIb alpha.
Article
Hematology
Paola Colpani, Luciano Baronciani, Francesca Stufano, Giovanna Cozzi, Marco Boscarino, Maria Teresa Pagliari, Eugenia Biguzzi, Flora Peyvandi
Summary: This study evaluated four different assays to diagnose and detect various von Willebrand disease (VWD) variants. The VWF:GPIbM-automated assay was the most effective in diagnosing type 2B, while the VWF:RCo assays were the most effective in detecting type 2M and 2M/2A variants. The VWF:GPIbM ELISA overestimated the activity of type 2B patients lacking high-molecular-weight multimers (HMWM). Using a VWF activity/VWF:antigen ratio cut-off of 0.70 reduced the number of misdiagnosed patients by half.
RESEARCH AND PRACTICE IN THROMBOSIS AND HAEMOSTASIS
(2023)
Article
Hematology
Hiroaki Yaoi, Yasuaki Shida, Takehisa Kitazawa, Midori Shima, Keiji Nogami
Summary: Emicizumab was found to enhance thrombus formation in type 2A VWD, although less potent than the presence of VWF. FVIII seemed to contribute more to thrombus height rather than surface coverage. The effect of emicizumab on thrombus formation appeared to be more rapid than that of FVIII, while FVIII showed more impact on thrombus formation at the late phase.
Article
Biochemistry & Molecular Biology
Johana Hrdinova, Delia I. Fernandez, Bogac Ercig, Bibian M. E. Tullemans, Dennis P. L. Suylen, Stijn M. Agten, Kerstin Jurk, Tilman M. Hackeng, Karen Vanhoorelbeke, Jan Voorberg, Chris P. M. Reutelingsperger, Kanin Wichapong, Johan W. M. Heemskerk, Gerry A. F. Nicolaes
Summary: This study designed and synthesized stable cyclic peptides to interfere with the interaction between VWF A1 domain and GPIb alpha. The selected peptides showed low binding free energy and retained their interference in the binding of VWF to GPIb-V-IX, as confirmed by flow cytometry. These peptides phenotypically mimicked the changes seen with the anti-VWF A1 domain antibody CLB-RAg35, although they were less potent. The improved peptide opt-mono-ORbIT demonstrated increased inhibitory activity under flow.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Hematology
Alicia Veninga, Constance C. F. M. J. Baaten, Ilaria De Simone, Bibian M. E. Tullemans, Marijke J. E. Kuijpers, Johan W. M. Heemskerk, Paola E. J. van der Meijden
Summary: Platelets from healthy donors exhibit heterogeneity in response to agonists, with activation thresholds controlled by various bioactive molecules. Elevated levels of priming substances like adenosine and succinate have been associated with hypercoagulability in patients with ischaemic heart disease. An improved flow cytometry methodology was employed to analyze platelet populations following activation and priming, revealing distinct responses based on the type of agonist used. The study identified five platelet populations post-activation, each with different characteristics depending on the agonist utilized, highlighting the complex and dynamic nature of platelet activation.
THROMBOSIS AND HAEMOSTASIS
(2022)
Article
Multidisciplinary Sciences
Athanasios Blanas, Haiko Karsjens, Aafke de Ligt, Elisabeth J. M. Huijbers, Karlijn van Loon, Stepan S. Denisov, Canan Durukan, Diederik J. M. Engbersen, Jan Groen, Sven Hennig, Tilman M. Hackeng, Judy R. van Beijnum, Arjan W. Griffioen
Summary: The conjugation of a target protein to a chimeric designer peptide (CDP) can enhance the immune response against the receptor-binding domain (RBD) of the SARS-CoV-2 spike glycoprotein. In mouse and hamster studies, the CDP-RBD vaccine induced potent immune responses and cross-reactive antibody reactions against the Delta and Omicron variants. This study demonstrates that the iBoost conjugate vaccine technology can quantitatively and qualitatively enhance anti-viral immunity.
Review
Biochemistry & Molecular Biology
Jinmi Zou, Frauke Swieringa, Bas de Laat, Philip G. de Groot, Mark Roest, Johan W. M. Heemskerk
Summary: This paper reviews the functional reversibility of integrin alpha IIb beta 3 activation and transient aggregation and discusses the signaling pathways involved. The study finds that ADP P2Y(1) and P2Y(12) receptor signaling via phosphoinositide 3-kinases and Akt are the principal pathways linked to reversible integrin activation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Biochemistry & Molecular Biology
Ilaria De Simone, Constance C. F. M. J. Baaten, Martine Jandrot-Perrus, Jonathan M. Gibbins, Hugo ten Cate, Johan W. M. Heemskerk, Chris Jones, Paola E. J. van der Meijden
Summary: Platelet and coagulation activation are reciprocal processes, and factors other than thrombin or fibrin can induce platelet activation via GPVI and PAR receptors.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2022)
Article
Hematology
Danique L. van den Kerkhof, Magdolna Nagy, Kanin Wichapong, Sanne L. N. Brouns, Dennis P. L. Suylen, Tilman M. Hackeng, I. Dijkgraaf
Summary: The study aimed to unravel the importance of the homoarginine residue in eptifibatide in platelet activation and aggregation. The results showed that eptifibatide inhibited collagen-and ADP-induced platelet aggregation, while substitution of the homoarginine residue resulted in loss of inhibitory activity.
THROMBOSIS RESEARCH
(2022)
Article
Cardiac & Cardiovascular Systems
Tom W. van de Berg, Mark M. G. Mulder, Teba Alnima, Magdolna Nagy, Rene van Oerle, Erik A. M. Beckers, Tilman M. Hackeng, Anne-Marije Hulshof, Jan-Willem E. M. Sels, Yvonne M. C. Henskens, Iwan C. C. van der Horst, Hugo ten Cate, Henri M. H. Spronk, Bas C. T. van Bussel
Summary: The use of prophylactic heparins in the management of COVID-19 associated coagulopathy (CAC) in intensive care patients is still uncertain. This study measured thrombin generation (TG) in ICU patients receiving thromboprophylaxis with low molecular weight heparin (LMWH) or unfractionated heparin (UFH), and analyzed the correlation between TG parameters, patient characteristics, and clinical parameters. The results suggest that direct thrombin inhibitors may be a more effective alternative to LMWH in anticoagulation therapy for COVID-19.
FRONTIERS IN CARDIOVASCULAR MEDICINE
(2022)
Article
Medicine, Research & Experimental
Robert Dzhanaev, Christian Hasberg, Andrea Gorgels, Carlo Schmitz, Camilla Franziska Winkler, Hanna Malyaran, Steffen Graeber, Anouk Gentier, Armand Jaminon, Stijn Agten, Tilman Hackeng, Asim Cengiz Akbulut, Leon Schurgers, Felix Manuel Mottaghy, Claudia Goettsch, Willi Jahnen-Dechent
Summary: This study developed a novel highly sensitive fluorescent probe based on fetuin-A for imaging microcalcifications. The probe showed non-toxicity and the ability to detect microcalcifications beyond the detection limit of conventional staining techniques. This fetuin-A-based probe has the potential for clinical applications.
Article
Engineering, Biomedical
Tianyu Yao, Honglin Chen, Rong Wang, Rebeca Rivero, Fengyu Wang, Lilian Kessels, Stijn M. Agten, Tilman M. Hackeng, Tim G. A. M. Wolfs, Daidi Fan, Matthew B. Baker, Lorenzo Moroni
Summary: This study focuses on the functionalization of scaffolds using a polymer mixing approach to immobilize VEGF-mimetic peptides. The functionalized scaffolds were validated and tested, showing potential for promoting angiogenesis and vascular tissue regeneration.
BIOACTIVE MATERIALS
(2023)
Article
Cell Biology
Katariina Maaninka, Maarit Neuvonen, Erja Kerkela, Kati Hyvarinen, Mari Palviainen, Masood Kamali-Moghaddam, Antonio Federico, Dario Greco, Saara Laitinen, Katariina Oorni, Pia R. M. Siljander
Summary: Platelet extracellular vesicles (PEVs) generated upon platelet activation, particularly in the presence of oxLDL, contribute to the pathogenesis of atherosclerosis by promoting inflammation and macrophage dysfunction. The combination of thrombin, collagen, and oxLDL induces the formation of PEVs that contain inflammatory proteins and alter macrophage gene expression. Scavenger receptor CD36 plays a significant role in oxLDL-induced PEV formation, while HDL has a slight suppressive effect. Pathways related to cell cycle, gene expression regulation, and immune system signaling are affected in macrophages treated with oxLDL-induced PEVs.
EUROPEAN JOURNAL OF CELL BIOLOGY
(2023)
Article
Hematology
Tom W. Van de Berg, Erik A. M. Beckers, Floor C. J. I. Heubel-Moenen, Yvonne M. C. Henskens, M. Christella L. G. D. Thomassen, Tilman M. Hackeng
Summary: This study aims to optimize thrombin generation assays (TGAs) for better measurement of low factor VIII (FVIII) levels in severe hemophilia A (HA) patients. The use of low concentrations of tissue factor (TF) and FXIa appears to increase the sensitivity of TG to detect changes in low FVIII ranges.
THROMBOSIS AND HAEMOSTASIS
(2023)
Review
Nutrition & Dietetics
Lu Dai, Denise Mafra, Paul G. Shiels, Tilman M. Hackeng, Peter Stenvinkel, Leon J. Schurgers
Summary: Vitamin K and vitamin K-dependent proteins are associated with age-related diseases. The direct impact of vitamin K on cellular senescence is yet to be proven, but its status reflects the complex interactions between dietary intake, gut microbiome activity, and health. It is proposed to emphasize food quality and explore healthy eating patterns containing vitamin K rather than focusing on a single nutrient for dietary recommendations.
Article
Biochemistry & Molecular Biology
Isabella Provenzale, Ilaria De Simone, Jonathan M. Gibbins, Johan W. M. Heemskerk, Paola E. J. van der Meijden, Chris I. Jones
Summary: This study investigated the roles of different extracellular matrix proteoglycans in platelet responses and thrombus formation. It was found that one proteoglycan (perlecan) enhanced platelet activation and promoted thrombus formation, but also reduced platelet adhesion under flow. This suggests that proteoglycans play an important role in platelet activation and thrombus formation.
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
(2023)
Article
Chemistry, Medicinal
Jinwei Chai, Jiena Wu, Jinqiao Li, Hang Liao, Wancheng Lu, Ruiyin Guo, Zuoyan Shao, Mohamed Amine Jmel, Larissa Almeida Martins, Tilman Hackeng, Hans Ippel, Ingrid Dijkgraaf, Michail Kotsyfakis, Xueqing Xu
Summary: A novel Ranacyclin peptide called Ranacin was identified from the skin of Pelophylax nigromaculatus frog. Ranacin effectively inhibited trypsin and exhibited anticoagulant and antioxidant activities in vitro. Treatment with Ranacin significantly alleviated the severity of pancreatitis in L-Arg-induced AP mice. Structure-activity studies suggested that sequences outside the trypsin inhibitory loop (TIL) of Ranacin may play an important role in its efficacy.
JOURNAL OF MEDICINAL CHEMISTRY
(2023)
Article
Hematology
M. Christella L. G. D. Thomassen, Bryan R. C. Bouwens, Kanin Wichapong, Dennis P. Suylen, Freek G. Bouwman, Tilman M. Hackeng, Rory R. Koenen
Summary: This study found that PAD4 inactivates TFPI by citrullination of its arginines, and this process is time- and concentration-dependent. Furthermore, inducers of PAD4 blocked the citrullination of TFPI. This process may play a crucial role in the increased thrombosis risk associated with inflammation.
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
(2023)