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Article ; Online: At the MERcy of platelet primers.

Cosemans, J M E M

Journal of thrombosis and haemostasis : JTH

2018 Volume 16, Issue 2, Page(s) 349–351

MeSH term(s)	Adenine/analogs & derivatives ; Blood Platelets ; Humans ; Piperazines ; Platelet Activation ; Thrombosis ; c-Mer Tyrosine Kinase
Chemical Substances	Piperazines ; UNC2025 ; MERTK protein, human (EC 2.7.10.1) ; c-Mer Tyrosine Kinase (EC 2.7.10.1) ; Adenine (JAC85A2161)
Language	English
Publishing date	2018-01-12
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2112661-6
ISSN	1538-7836 ; 1538-7933
ISSN (online)	1538-7836
ISSN	1538-7933
DOI	10.1111/jth.13915
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Article ; Online: Fundamental considerations for designing endothelialized in vitro models of thrombosis.

Lemmens, Titus P / Bröker, Vanessa / Rijpkema, Minke / Hughes, Christopher C W / Schurgers, Leon J / Cosemans, Judith M E M

Thrombosis research

2024 Volume 236, Page(s) 179–190

Abstract: Endothelialized in vitro models for cardiovascular disease have contributed greatly to our current understanding of the complex molecular mechanisms underlying thrombosis. To further elucidate these mechanisms, it is important to consider which ... ...

Abstract	Endothelialized in vitro models for cardiovascular disease have contributed greatly to our current understanding of the complex molecular mechanisms underlying thrombosis. To further elucidate these mechanisms, it is important to consider which fundamental aspects to incorporate into an in vitro model. In this review, we will focus on the design of in vitro endothelialized models of thrombosis. Expanding our understanding of the relation and interplay between the different pathways involved will rely in part on complex models that incorporate endothelial cells, blood, the extracellular matrix, and flow. Importantly, the use of tissue-specific endothelial cells will help in understanding the heterogeneity in thrombotic responses between different vascular beds. The dynamic and complex responses of endothelial cells to different shear rates underlines the importance of incorporating appropriate shear in in vitro models. Alterations in vascular extracellular matrix composition, availability of bioactive molecules, and gradients in concentration and composition of these molecules can all regulate the function of both endothelial cells and perivascular cells. Factors modulating these elements in in vitro models should therefore be considered carefully depending on the research question at hand. As the complexity of in vitro models increases, so can the variability. A bottom-up approach to designing such models will remain an important tool for researchers studying thrombosis. As new techniques are continuously being developed and new pathways are brought to light, research question-dependent considerations will have to be made regarding what aspects of thrombosis to include in in vitro models.
MeSH term(s)	Humans ; Endothelial Cells/metabolism ; Endothelium, Vascular ; Thrombosis/metabolism
Language	English
Publishing date	2024-03-05
Publishing country	United States
Document type	Journal Article ; Review
ZDB-ID	121852-9
ISSN	1879-2472 ; 0049-3848
ISSN (online)	1879-2472
ISSN	0049-3848
DOI	10.1016/j.thromres.2024.03.004
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Article ; Online: Characterization of cerebral small vessel disease by neutrophil and platelet activation markers using artificial intelligence.

Karel, M F A / Roosen, M G C H / Tullemans, B M E / Zhang, C Eleana / Staals, J / Cosemans, J M E M / Koenen, R R

Journal of neuroimmunology

2022 Volume 367, Page(s) 577863

Abstract: Cerebral small vessel disease (cSVD) accounts for 25% of ischemic strokes and is a major cause of cognitive decline. Inflammatory processes, involving immune cells and platelets might drive development and progression of cSVD. The aim of the study was to ...

Abstract	Cerebral small vessel disease (cSVD) accounts for 25% of ischemic strokes and is a major cause of cognitive decline. Inflammatory processes, involving immune cells and platelets might drive development and progression of cSVD. The aim of the study was to identify potential novel biomarkers for cSVD, gaining new insights into its pathophysiology. We measured inflammation and platelet and neutrophil activation markers in patients with cSVD and age-matched controls. It was hypothesized that cSVD is accompanied by altered levels of these markers. The levels of interleukin 1β, CX
MeSH term(s)	Artificial Intelligence ; Biomarkers ; Cerebral Small Vessel Diseases/complications ; Cerebral Small Vessel Diseases/diagnostic imaging ; DNA ; Humans ; Inflammation/complications ; Neutrophils ; Peroxidase ; Platelet Activation
Chemical Substances	Biomarkers ; DNA (9007-49-2) ; Peroxidase (EC 1.11.1.7)
Language	English
Publishing date	2022-04-09
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	8335-5
ISSN	1872-8421 ; 0165-5728
ISSN (online)	1872-8421
ISSN	0165-5728
DOI	10.1016/j.jneuroim.2022.577863
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Article ; Online: Corrigendum to "The effect of Bruton's tyrosine kinase inhibitor ibrutinib on atherothrombus formation under stenotic flow conditions" [Thromb. Res. 212 (2022) 72-80].

Karel, M F A / Tullemans, B M E / D'Italia, G / Lemmens, T P / Claushuis, T A M / Kuijpers, M J E / Cosemans, J M E M

Thrombosis research

2022 Volume 213, Page(s) 113

Language	English
Publishing date	2022-03-22
Publishing country	United States
Document type	Published Erratum
ZDB-ID	121852-9
ISSN	1879-2472 ; 0049-3848
ISSN (online)	1879-2472
ISSN	0049-3848
DOI	10.1016/j.thromres.2022.03.012
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Article ; Online: The effect of Bruton's tyrosine kinase inhibitor ibrutinib on atherothrombus formation under stenotic flow conditions.

Karel, M F A / Tullemans, B M E / D'Italia, G / Lemmens, T P / Claushuis, T A M / Kuijpers, M J E / Cosemans, J M E M

Thrombosis research

2022 Volume 212, Page(s) 72–80

Abstract: Background: Bruton's kinase (Btk) is critical for collagen-triggered platelet signal transduction. The Btk inhibitor ibrutinib has been shown to selectively block platelet adhesion to atherosclerotic plaque material under laminar arterial flow. However, ...

Abstract	Background: Bruton's kinase (Btk) is critical for collagen-triggered platelet signal transduction. The Btk inhibitor ibrutinib has been shown to selectively block platelet adhesion to atherosclerotic plaque material under laminar arterial flow. However, this has not been studied under a shear gradient, which is characteristic for atherothrombosis. Objective: To determine the effect of ibrutinib treatment on in vitro thrombus formation on collagen and atherosclerotic plaque material in the absence or presence of a shear gradient. Methods: Blood was obtained from patients with chronic lymphocytic leukemia, mantle-cell lymphoma and Waldenström macroglobulinemia with and without ibrutinib treatment and perfused through a microfluidic channel with(out) 60% stenosis over Horm type I collagen or human atherosclerotic plaque homogenate. Results: At a constant shear rate of 1500 s Conclusion: Treatment of patients with haematological disorders with the Btk inhibitor ibrutinib reduces in vitro platelet deposition, thrombus size and contraction on human atherosclerotic plaque around a stenosis when compared to patients not receiving ibrutinib.
MeSH term(s)	Adenine/analogs & derivatives ; Adenine/pharmacology ; Adult ; Constriction, Pathologic ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell/drug therapy ; Piperidines/pharmacology ; Piperidines/therapeutic use ; Protein Kinase Inhibitors/pharmacology ; Protein Kinase Inhibitors/therapeutic use
Chemical Substances	Piperidines ; Protein Kinase Inhibitors ; ibrutinib (1X70OSD4VX) ; Adenine (JAC85A2161)
Language	English
Publishing date	2022-02-26
Publishing country	United States
Document type	Journal Article
ZDB-ID	121852-9
ISSN	1879-2472 ; 0049-3848
ISSN (online)	1879-2472
ISSN	0049-3848
DOI	10.1016/j.thromres.2022.02.020
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Article ; Online: Antagonistic Roles of Human Platelet Integrin αIIbβ3 and Chemokines in Regulating Neutrophil Activation and Fate on Arterial Thrombi Under Flow.

Schönichen, Claudia / Montague, Samantha J / Brouns, Sanne L N / Burston, James J / Cosemans, Judith M E M / Jurk, Kerstin / Kehrel, Beate E / Koenen, Rory R / Ní Áinle, Fionnuala / O'Donnell, Valerie B / Soehnlein, Oliver / Watson, Steve P / Kuijpers, Marijke J E / Heemskerk, Johan W M / Nagy, Magdolna

Arteriosclerosis, thrombosis, and vascular biology

2023 Volume 43, Issue 9, Page(s) 1700–1712

Abstract: Background: Platelets and neutrophils are the first blood cells accumulating at sites of arterial thrombus formation, and both cell types contribute to the pathology of thrombotic events. We aimed to identify key interaction mechanisms between these ... ...

Abstract	Background: Platelets and neutrophils are the first blood cells accumulating at sites of arterial thrombus formation, and both cell types contribute to the pathology of thrombotic events. We aimed to identify key interaction mechanisms between these cells using microfluidic approaches. Methods: Whole-blood perfusion was performed over a collagen surface at arterial shear rate. Platelet and leukocyte (in majority neutrophil) activation were microscopically visualized using fluorescent markers. The contributions of platelet-adhesive receptors (integrin, P-selectin, CD40L) and chemokines were studied by using inhibitors or antibodies and using blood from patients with GT (Glanzmann thrombasthenia) lacking platelet-expressed αIIbβ3. Results: We observed (1) an unknown role of activated platelet integrin αIIbß3 preventing leukocyte adhesion, which was overcome by short-term flow disturbance provoking massive adhesion; (2) that platelet-expressed CD40L controls the crawling pattern and thrombus fidelity of the cells on a thrombus; (3) that continued secretion of platelet substances promotes activation of identified neutrophils, as assessed by (fMLP [ Conclusions: Together, these findings reveal a multifaceted regulation of adhesion and activation of neutrophils by platelets in a thrombus, with a balanced role of several platelet-adhesive receptors and a promoting role of platelet-released substances. This multivalent nature of neutrophil-thrombus interactions offers novel prospects for pharmacological intervention.
MeSH term(s)	Blood Platelets/immunology ; Blood Platelets/metabolism ; Platelet Glycoprotein GPIIb-IIIa Complex/metabolism ; Chemokines/metabolism ; Thrombosis/immunology ; Neutrophil Activation ; CD40 Ligand ; Neutrophils/immunology ; Neutrophils/metabolism ; Cell Adhesion ; Humans ; Arteries
Chemical Substances	Platelet Glycoprotein GPIIb-IIIa Complex ; Chemokines ; CD40 Ligand (147205-72-9)
Language	English
Publishing date	2023-07-06
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.122.318767
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Article: Characterization of Atherosclerotic Plaque Coating for Thrombosis Microfluidics Assays.

Karel, M F A / Lemmens, T P / Tullemans, B M E / Wielders, S J H / Gubbins, E / van Beurden, D / van Rijt, S / Cosemans, J M E M

Cellular and molecular bioengineering

2021 Volume 15, Issue 1, Page(s) 55–65

Abstract: Introduction: Studying arterial thrombus formation by : Methods: A homogenate of human atherosclerotic plaques was coated on glass coverslips by conventional manual droplet coating or by spin coating. Prior to coating, a subset of coverslips was ... ...

Abstract	Introduction: Studying arterial thrombus formation by Methods: A homogenate of human atherosclerotic plaques was coated on glass coverslips by conventional manual droplet coating or by spin coating. Prior to coating, a subset of coverslips was plasma treated. Water contact angle measurements were performed as an indicator for the hydrophilicity of the coverslips. Homogeneity of plaque coatings was determined using profilometric analysis and scanning electron microscopy. Thrombogenicity of the plaque material was assessed in real time by microscopic imaging while perfusing whole blood at a shear rate of 1500 s Results: Plasma treatment of glass coverslips, prior to spin coating with plaque material, increased the hydrophilicity of the coverslip compared to no plasma treatment. The most homogeneous plaque coating and highest platelet adhesion was obtained upon plasma treatment followed by spin coating of the plaque material. Manual plaque coating on non-plasma treated coverslips yielded lowest coating homogeneity and platelet adhesion and activation. Conclusion: Spin coating of atherosclerotic plaque material on plasma treated coverslips leads to a more homogenous coating and improved platelet adhesion to the plaque when compared to conventional droplet coating on non-plasma treated coverslips. These properties are beneficial in ensuring the quality and reproducibility of flow experiments. Supplementary information: The online version contains supplementary material available at 10.1007/s12195-021-00713-9.
Language	English
Publishing date	2021-10-27
Publishing country	United States
Document type	Journal Article
ZDB-ID	2416037-4
ISSN	1865-5033 ; 1865-5025
ISSN (online)	1865-5033
ISSN	1865-5025
DOI	10.1007/s12195-021-00713-9
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Article ; Online: Inhibition of Phosphodiesterase 3A by Cilostazol Dampens Proinflammatory Platelet Functions.

Coenen, Daniëlle M / Heinzmann, Alexandra C A / Oggero, Silvia / Albers, Hugo J / Nagy, Magdolna / Hagué, Perrine / Kuijpers, Marijke J E / Vanderwinden, Jean-Marie / van der Meer, Andries D / Perretti, Mauro / Koenen, Rory R / Cosemans, Judith M E M

Cells

2021 Volume 10, Issue 8

Abstract: Objective: platelets possess not only haemostatic but also inflammatory properties, which combined are thought to play a detrimental role in thromboinflammatory diseases such as acute coronary syndromes and stroke. Phosphodiesterase (PDE) 3 and -5 ... ...

Abstract	Objective: platelets possess not only haemostatic but also inflammatory properties, which combined are thought to play a detrimental role in thromboinflammatory diseases such as acute coronary syndromes and stroke. Phosphodiesterase (PDE) 3 and -5 inhibitors have demonstrated efficacy in secondary prevention of arterial thrombosis, partially mediated by their antiplatelet action. Yet it is unclear whether such inhibitors also affect platelets' inflammatory functions. Here, we aimed to examine the effect of the PDE3A inhibitor cilostazol and the PDE5 inhibitor tadalafil on platelet function in various aspects of thromboinflammation. Approach and results: cilostazol, but not tadalafil, delayed ex vivo platelet-dependent fibrin formation under whole blood flow over type I collagen at 1000 s Conclusions: this study demonstrated yet unrecognised roles for platelet PDE3A and platelet PDE5 in platelet procoagulant and proinflammatory responses.
MeSH term(s)	Animals ; Anti-Inflammatory Agents/pharmacology ; Blood Coagulation/drug effects ; Blood Platelets/drug effects ; Blood Platelets/enzymology ; Blood Platelets/immunology ; Cells, Cultured ; Chemokines/metabolism ; Cilostazol/pharmacology ; Cyclic Nucleotide Phosphodiesterases, Type 3/genetics ; Cyclic Nucleotide Phosphodiesterases, Type 3/metabolism ; Fibrin/metabolism ; Fibrinolytic Agents/pharmacology ; Humans ; Inflammation Mediators/metabolism ; Mice, Inbred C57BL ; Mice, Knockout ; Phosphodiesterase 3 Inhibitors/pharmacology ; Phosphodiesterase 5 Inhibitors/pharmacology ; Platelet Activation/drug effects ; Platelet Adhesiveness/drug effects ; Signal Transduction ; Tadalafil/pharmacology ; Mice
Chemical Substances	Anti-Inflammatory Agents ; Chemokines ; Fibrinolytic Agents ; Inflammation Mediators ; Phosphodiesterase 3 Inhibitors ; Phosphodiesterase 5 Inhibitors ; Tadalafil (742SXX0ICT) ; Fibrin (9001-31-4) ; Cyclic Nucleotide Phosphodiesterases, Type 3 (EC 3.1.4.17) ; PDE3A protein, human (EC 3.1.4.17) ; Pde3a protein, mouse (EC 3.1.4.17) ; Cilostazol (N7Z035406B)
Language	English
Publishing date	2021-08-05
Publishing country	Switzerland
Document type	Comparative Study ; Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10081998
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Article ; Online: Finding the "switch" in platelet activation: prediction of key mediators involved in reversal of platelet activation using a novel network biology approach.

Lemmens, T P / Coenen, D M / Swieringa, F / Niessen, I C L / Coort, S L M / Koenen, R R / Kutmon, M / Cosemans, J M E M

Journal of proteomics

2022 Volume 261, Page(s) 104577

Abstract: The cAMP-protein kinase A (PKA) pathway in platelets is important for both platelet activation and inactivation. We hypothesize that proteins/processes downstream of the cAMP-PKA pathway that are regulated after platelet activation ánd subsequent ... ...

Abstract	The cAMP-protein kinase A (PKA) pathway in platelets is important for both platelet activation and inactivation. We hypothesize that proteins/processes downstream of the cAMP-PKA pathway that are regulated after platelet activation ánd subsequent inactivation can serve as a "switch" in platelet activation and inhibition. We used a STRING-based protein-protein interaction network from proteins of interest distilled from publicly available quantitative platelet proteome datasets. The protein network was integrated with biological pathway information by functional enrichment analysis, phosphorylation by PKA, and drug-target information. Functional enrichment analysis revealed biological processes related to vesicle secretion and cytoskeletal reorganization to be overrepresented among these 30 proteins coinciding with topological clusters in the network. Our method identified proteins/processes with functions related to vesicle transport, cyclin-dependent protein kinases, tight junctions, and small GTPases as potential switches in platelet activation and inhibition. Next to established enzymes in cAMP-PKA signaling, such as PDE3A, proteins with an unknown/less well-known role in platelet biology, such as Stonin-2 and ABLIM-3, emerged from our analysis as interesting candidates for reversal of platelet activation. Our method can be used to repurpose existing datasets and provide a coherent overview of mechanisms involved to predict novel connections, by visually integrating multiple datasets. SIGNIFICANCE: This article presents a novel approach of visually incorporating multiple existing tools and proteomics datasets and in doing so provides novel insight into the complex molecular mechanisms involved in platelet activation. Using our approach, we also highlight several interesting candidates for future research into pathologies with high platelet reactivity.
MeSH term(s)	Blood Platelets/metabolism ; Cyclic AMP/metabolism ; Phosphorylation ; Platelet Activation/physiology ; Proteomics
Chemical Substances	Cyclic AMP (E0399OZS9N)
Language	English
Publishing date	2022-03-26
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2400835-7
ISSN	1876-7737 ; 1874-3919
ISSN (online)	1876-7737
ISSN	1874-3919
DOI	10.1016/j.jprot.2022.104577
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Article ; Online: Vascular protective effect of aspirin and rivaroxaban upon endothelial denudation of the mouse carotid artery.

Mastenbroek, T G / Karel, M F A / Nagy, M / Chayoua, W / Korsten, E I J / Coenen, D M / Debets, J / Konings, J / Brouns, A E / Leenders, P J A / van Essen, H / van Oerle, R / Heitmeier, S / Spronk, H M / Kuijpers, M J E / Cosemans, J M E M

Scientific reports

2020 Volume 10, Issue 1, Page(s) 19360

Abstract: While in recent trials the dual pathway inhibition with aspirin plus rivaroxaban has shown to be efficacious in patients with atherosclerotic cardiovascular disease, little is known about the effects of this combination treatment on thrombus formation ... ...

Abstract	While in recent trials the dual pathway inhibition with aspirin plus rivaroxaban has shown to be efficacious in patients with atherosclerotic cardiovascular disease, little is known about the effects of this combination treatment on thrombus formation and vascular remodelling upon vascular damage. The aim of this study was to examine the effects of aspirin and/or rivaroxaban on injury-induced murine arterial thrombus formation in vivo and in vitro, vessel-wall remodelling, and platelet-leukocyte aggregates. Temporary ligation of the carotid artery of C57BL/6 mice, fed a western type diet, led to endothelial denudation and sub-occlusive thrombus formation. At the site of ligation, the vessel wall stiffened and the intima-media thickened. Aspirin treatment antagonized vascular stiffening and rivaroxaban treatment led to a positive trend towards reduced stiffening. Local intima-media thickening was antagonized by both aspirin or rivaroxaban treatment. Platelet-leukocyte aggregates and the number of platelets per leukocyte were reduced in aspirin and/or rivaroxaban treatment groups. Furthermore, rivaroxaban restricted thrombus growth and height in vitro. In sum, this study shows vascular protective effects of aspirin and rivaroxaban, upon vascular injury of the mouse artery.
MeSH term(s)	Animals ; Arteries/drug effects ; Aspirin/pharmacology ; Blood Platelets/metabolism ; Carotid Arteries/drug effects ; Carotid Arteries/surgery ; Carotid Artery Diseases/drug therapy ; Carotid Intima-Media Thickness ; Factor Xa Inhibitors/pharmacology ; Leukocytes/metabolism ; Male ; Mice ; Mice, Inbred C57BL ; Microscopy, Electron, Scanning ; Platelet Aggregation Inhibitors/therapeutic use ; Rivaroxaban/pharmacology ; Thrombosis/drug therapy ; Thrombosis/metabolism ; Thrombosis/physiopathology
Chemical Substances	Factor Xa Inhibitors ; Platelet Aggregation Inhibitors ; Rivaroxaban (9NDF7JZ4M3) ; Aspirin (R16CO5Y76E)
Language	English
Publishing date	2020-11-09
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2615211-3
ISSN	2045-2322 ; 2045-2322
ISSN (online)	2045-2322
ISSN	2045-2322
DOI	10.1038/s41598-020-76377-8
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