Publications by authors named "Mieke Karel"

4 Publications

  • Page 1 of 1

The multifaceted contribution of platelets in the emergence and aftermath of acute cardiovascular events.

Atherosclerosis 2021 02 16;319:132-141. Epub 2021 Jan 16.

Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands. Electronic address:

Atherosclerosis is an underlying cause of a broad array of cardiovascular diseases characterized by plaques, arterial wall thickening initiated by hyperlipidemia, pro-inflammatory signals, endothelial dysfunction and the influx of inflammatory cells. By still incompletely characterized mechanisms, these plaques can destabilize or erode, leading to thrombosis and blood vessel occlusion and becomes clinically manifest as angina pectoris, myocardial infarction (MI) or stroke. Among the several blood cell types that are involved in the development of atherosclerosis, the role of platelets during the thrombotic occlusion of ruptured or eroded plaques is well established and clinically exploited as evident by the extensive use of platelet inhibitors. However, there is increasing evidence that platelets are also involved in the earlier stages of atheroma development by exhibiting pro-inflammatory activities. The scope of this review is to describe the role of platelets in the initiation and propagation stages of atherosclerosis and beyond; in atherothrombotic complications.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.12.017DOI Listing
February 2021

Complementary roles of platelet αβ integrin, phosphatidylserine exposure and cytoskeletal rearrangement in the release of extracellular vesicles.

Atherosclerosis 2020 10 1;310:17-25. Epub 2020 Aug 1.

Department of Biochemistry, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, Maastricht, the Netherlands. Electronic address:

Background And Aims: Platelets can release extracellular vesicles (EVs) upon stimulation with various agonists. Interestingly, platelets from patients with Glanzmann thrombasthenia have reduced EV release. These platelets lack functional αβ integrins, indicating that αβ integrin is critical in vesicle release. Integrin activation is central in platelet function and is associated with e.g. adhesion, aggregation and cytoskeletal rearrangement. However, while platelet activation pathways are widely known, the mechanisms underlying EV release remain uncharacterized. We investigated the role of integrin αβ, phosphatidyl serine (PS) exposure, cytoskeletal rearrangement and their associated signalling pathways in EV release.

Methods: EVs were isolated from activated platelets. Platelet activation status was measured by multicolour flow cytometry. A panel of pharmacologic inhibitors was used to interfere in specific signalling pathways. EV release was quantified enzymatically based on membrane PS content and nanoparticle tracking analysis. In addition, real-time visualization of EV shedding with confocal microscopy and EVs with Cryo-TEM imaging was performed.

Results: Platelet activation with convulxin resulted in higher EV release than with activation by thrombin. Kinetic measurements indicated that EV release followed the pattern of αβ integrin activation and subsequent closure paralleled by PS exposure. Prevention of αβ activation with the inhibitor tirofiban dramatically suppressed EV release. Similar results were obtained using αβ-deficient platelets from patients with Glanzmann thrombasthenia. Inhibition of actin cytoskeleton rearrangement decreased EV release, whereas inhibition of individual signalling targets upstream of cytoskeletal rearrangement showed no such effects.

Conclusion: Platelet EV release requires three main events: integrin activation and closure, PS exposure, and cytoskeletal rearrangement.
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http://dx.doi.org/10.1016/j.atherosclerosis.2020.07.015DOI Listing
October 2020

SLC44A2 deficient mice have a reduced response in stenosis but not in hypercoagulability driven venous thrombosis.

J Thromb Haemost 2020 07 15;18(7):1714-1727. Epub 2020 May 15.

Aix-Marseille Univ, INSERM, INRA, C2VN, Marseille, France.

Background: Genome wide association studies (GWAS) identified SLC44A2 as a novel susceptibility gene for venous thrombosis (VT) and previous work established that SLC44A2 contributed to clot formation upon vascular injury.

Objective: To further investigate the role of SLC44A2 in VT by utilizing SLC44A2 deficient mice (Slc44a2 ) in two representative disease models.

Methods: Mice were included in a hypercoagulability model driven by siRNA-mediated hepatic gene silencing of anticoagulants Serpinc1 (antithrombin) and Proc (protein C) and a flow restriction (stenosis) model induced by partial ligation of the inferior vena cava.

Results: In the hypercoagulability model, no effect in onset was observed in Slc44a2 animals; however, a drop in plasma fibrinogen and von Willebrand factor coinciding with an increase in blood neutrophils was recorded. In the neutrophil dependent stenosis model after 48 hours, Slc44a2 mice had significantly smaller thrombi both in length and weight with less platelet accumulation as a percentage of the total thrombus area. During the initiation of thrombosis at 6 hours post-stenosis, Slc44a2 mice also had smaller thrombi both in length and weight, with circulating platelets remaining elevated in Slc44a2 animals. Platelet activation and aggregation under both static- and venous and arterial shear conditions were normal for blood from Slc44a2 mice.

Conclusions: These studies corroborate the original GWAS findings and establish a contributing role for SLC44A2 during the initiation of VT, with indications that this may be related to platelet-neutrophil interaction. The precise mechanism however remains elusive and warrants further investigation.
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http://dx.doi.org/10.1111/jth.14835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7383581PMC
July 2020

Thrombo-Inflammation in Cardiovascular Disease: An Expert Consensus Document from the Third Maastricht Consensus Conference on Thrombosis.

Thromb Haemost 2020 Apr 14;120(4):538-564. Epub 2020 Apr 14.

Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, University of Bern, Bern, Switzerland; Center for Thrombosis and Hemostasis, University Medical Center of the Johannes Gutenberg University, Mainz, Germany; Haemostasis Research Unit, University College London, London, United Kingdom.

Thrombo-inflammation describes the complex interplay between blood coagulation and inflammation that plays a critical role in cardiovascular diseases. The third Maastricht Consensus Conference on Thrombosis assembled basic, translational, and clinical scientists to discuss the origin and potential consequences of thrombo-inflammation in the etiology, diagnostics, and management of patients with cardiovascular disease, including myocardial infarction, stroke, and peripheral artery disease. This article presents a state-of-the-art reflection of expert opinions and consensus recommendations regarding the following topics: (1) challenges of the endothelial cell barrier; (2) circulating cells and thrombo-inflammation, focused on platelets, neutrophils, and neutrophil extracellular traps; (3) procoagulant mechanisms; (4) arterial vascular changes in atherogenesis; attenuating atherosclerosis and ischemia/reperfusion injury; (5) management of patients with arterial vascular disease; and (6) pathogenesis of venous thrombosis and late consequences of venous thromboembolism.
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http://dx.doi.org/10.1055/s-0040-1708035DOI Listing
April 2020
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