TY  - JOUR
A1  - Navarro, Stefano
A1  - Stegner, David
A1  - Nieswandt, Bernhard
A1  - Heemskerk, Johan W. M.
A1  - Kuijpers, Marijke J. E.
T1  - Temporal roles of platelet and coagulation pathways in collagen- and tissue factor-induced thrombus formation
JF  - International Journal of Molecular Sciences
N2  - In hemostasis and thrombosis, the complex process of thrombus formation involves different molecular pathways of platelet and coagulation activation. These pathways are considered as operating together at the same time, but this has not been investigated. The objective of our study was to elucidate the time-dependency of key pathways of thrombus and clot formation, initiated by collagen and tissue factor surfaces, where coagulation is triggered via the extrinsic route. Therefore, we adapted a microfluidics whole-blood assay with the Maastricht flow chamber to acutely block molecular pathways by pharmacological intervention at desired time points. Application of the technique revealed crucial roles of glycoprotein VI (GPVI)-induced platelet signaling via Syk kinase as well as factor VIIa-induced thrombin generation, which were confined to the first minutes of thrombus buildup. A novel anti-GPVI Fab EMF-1 was used for this purpose. In addition, platelet activation with the protease-activating receptors 1/4 (PAR1/4) and integrin αIIbβ3 appeared to be prolongedly active and extended to later stages of thrombus and clot formation. This work thereby revealed a more persistent contribution of thrombin receptor-induced platelet activation than of collagen receptor-induced platelet activation to the thrombotic process.
KW  - coagulation
KW  - fibrin
KW  - glycoprotein VI
KW  - platelet receptors
KW  - spatiotemporal thrombus
KW  - thrombin
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284219
SN  - 1422-0067
VL  - 23
IS  - 1
ER  - 
TY  - JOUR
A1  - Vogelsang, Anna
A1  - Eichler, Susann
A1  - Huntemann, Niklas
A1  - Masanneck, Lars
A1  - Böhnlein, Hannes
A1  - Schüngel, Lisa
A1  - Willison, Alice
A1  - Loser, Karin
A1  - Nieswandt, Bernhard
A1  - Kehrel, Beate E.
A1  - Zarbock, Alexander
A1  - Göbel, Kerstin
A1  - Meuth, Sven G.
T1  - Platelet inhibition by low-dose acetylsalicylic acid reduces neuroinflammation in an animal model of multiple sclerosis
JF  - International Journal of Molecular Sciences
N2  - Aside from the established immune-mediated etiology of multiple sclerosis (MS), compelling evidence implicates platelets as important players in disease pathogenesis. Specifically, numerous studies have highlighted that activated platelets promote the central nervous system (CNS)-directed adaptive immune response early in the disease course. Platelets, therefore, present a novel opportunity for modulating the neuroinflammatory process that characterizes MS. We hypothesized that the well-known antiplatelet agent acetylsalicylic acid (ASA) could inhibit neuroinflammation by affecting platelets if applied at low-dose and investigated its effect during experimental autoimmune encephalomyelitis (EAE) as a model to study MS. We found that oral administration of low-dose ASA alleviates symptoms of EAE accompanied by reduced inflammatory infiltrates and less extensive demyelination. Remarkably, the percentage of CNS-infiltrated CD4\(^+\) T cells, the major drivers of neuroinflammation, was decreased to 40.98 ± 3.28% in ASA-treated mice compared to 56.11 ± 1.46% in control animals at the disease maximum as revealed by flow cytometry. More interestingly, plasma levels of thromboxane A\(_2\) were decreased, while concentrations of platelet factor 4 and glycoprotein VI were not affected by low-dose ASA treatment. Overall, we demonstrate that low-dose ASA could ameliorate the platelet-dependent neuroinflammatory response in vivo, thus indicating a potential treatment approach for MS.
KW  - acetylsalicylic acid
KW  - experimental autoimmune encephalomyelitis
KW  - platelets
KW  - multiple sclerosis
KW  - thromboxane
KW  - glycoprotein VI
KW  - platelet factor 4
Y1  - 2021
U6  - http://nbn-resolving.de/urn/resolver.pl?urn:nbn:de:bvb:20-opus-284535
SN  - 1422-0067
VL  - 22
IS  - 18
ER  -