@article{NavarroStegnerNieswandtetal.2021,
  author    = {Navarro, Stefano and Stegner, David and Nieswandt, Bernhard and Heemskerk, Johan W. M. and Kuijpers, Marijke J. E.},
  title     = {Temporal roles of platelet and coagulation pathways in collagen- and tissue factor-induced thrombus formation},
  series = {International Journal of Molecular Sciences},
  volume    = {23},
  journal   = {International Journal of Molecular Sciences},
  number    = {1},
  issn      = {1422-0067},
  doi       = {10.3390/ijms23010358},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-284219},
  year      = {2021},
  abstract  = {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.},
  language  = {en}
}
@article{PoppThielmanNieswandtetal.2015,
  author    = {Popp, Michael and Thielman, Ina and Nieswandt, Bernhard and Stegner, David},
  title     = {Normal Platelet Integrin Function in Mice Lacking Hydrogen Peroxide-Induced Clone-5 (Hic-5)},
  series = {PLoS One},
  volume    = {10},
  journal   = {PLoS One},
  number    = {7},
  doi       = {10.1371/journal.pone.0133429},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-125724},
  pages     = {e0133429},
  year      = {2015},
  abstract  = {Integrin αIIbβ3 plays a central role in the adhesion and aggregation of platelets and thus is essential for hemostasis and thrombosis. Integrin activation requires the transmission of a signal from the small cytoplasmic tails of the α or β subunit to the large extracellular domains resulting in conformational changes of the extracellular domains to enable ligand binding. Hydrogen peroxide-inducible clone-5 (Hic-5), a member of the paxillin family, serves as a focal adhesion adaptor protein associated with αIIbβ3 at its cytoplasmic tails. Previous studies suggested Hic-5 as a novel regulator of integrin αIIbβ3 activation and platelet aggregation in mice. To assess this in more detail, we generated Hic-5-null mice and analyzed activation and aggregation of their platelets in vitro and in vivo. Surprisingly, lack of Hic-5 had no detectable effect on platelet integrin activation and function in vitro and in vivo under all tested conditions. These results indicate that Hic-5 is dispensable for integrin αIIbβ3 activation and consequently for arterial thrombosis and hemostasis in mice.},
  language  = {en}
}
@article{NieswandtMorowskiBrachsetal.2014,
  author    = {Nieswandt, Bernhard and Morowski, Martina and Brachs, Sebastian and Mielenz, Dirk and D{\"u}tting, Sebastian},
  title     = {The Adaptor Protein Swiprosin-1/EFhd2 Is Dispensable for Platelet Function in Mice},
  doi       = {10.1371/journal.pone.0107139},
  url       = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-113316},
  year      = {2014},
  abstract  = {Background Platelets are anuclear cell fragments derived from bone marrow megakaryocytes that safeguard vascular integrity, but may also cause pathological vessel occlusion. Reorganizations of the platelet cytoskeleton and agonist-induced intracellular Ca2+-mobilization are crucial for platelet hemostatic function. EF-hand domain containing 2 (EFhd2, Swiprosin-1) is a Ca2+-binding cytoskeletal adaptor protein involved in actin remodeling in different cell types, but its function in platelets is unknown. Objective Based on the described functions of EFhd2 in immune cells, we tested the hypothesis that EFhd2 is a crucial adaptor protein for platelet function acting as a regulator of Ca2+-mobilization and cytoskeletal rearrangements. Methods and Results We generated EFhd2-deficient mice and analyzed their platelets in vitro and in vivo. Efhd2-/- mice displayed normal platelet count and size, exhibited an unaltered in vivo life span and showed normal Ca2+-mobilization and activation/aggregation responses to classic agonists. Interestingly, upon stimulation of the immunoreceptor tyrosine-based activation motif-coupled receptor glycoprotein (GP) VI, Efhd2-/- platelets showed a slightly increased coagulant activity. Furthermore, absence of EFhd2 had no significant impact on integrin-mediated clot retraction, actomyosin rearrangements and spreading of activated platelets on fibrinogen. In vivo EFhd2-deficiency resulted in unaltered hemostatic function and unaffected arterial thrombus formation. Conclusion These results show that EFhd2 is not essential for platelet function in mice indicating that other cytoskeletal adaptors may functionally compensate its loss.},
  language  = {en}
}