Platelet lamellipodium formation is not required for thrombus formation and stability

Schurr, Y. et al. (2019) Platelet lamellipodium formation is not required for thrombus formation and stability. Blood, 134(25), pp. 2318-2329. (doi: 10.1182/blood.2019002105) (PMID:31697813)

Abstract

During platelet spreading, the actin cytoskeleton undergoes rapid rearrangement, forming filopodia and lamellipodia. Controversial data have been published on the role of lamellipodia in thrombus formation and stability. The Wiskott-Aldrich syndrome protein-family verprolin-homologous protein (WAVE)-regulatory complex, which has been shown in other cells to drive lamellipodium formation by enhancing actin nucleation via the actin-related protein 2/3 (Arp2/3) complex, is activated by Ras-related C3 botulinum toxin substrate 1 (Rac1) interaction with the WAVE complex subunit cytoplasmic fragile X mental retardation 1–interacting protein 1 (Cyfip1). We analyzed Cyfip1flox/floxPf4-Cre mice to investigate the role of Cyfip1 in platelet function. These mice displayed normal platelet counts and a slight reduction in platelet volume. Activation of mutant platelets was only moderately reduced to all tested agonists as measured by αIIbβ3 integrin activation and P-selectin surface exposure. However, lamellipodium formation of mutant platelets was completely abolished on different matrices. Nevertheless, Cyfip1-deficient platelets formed stable thrombi on collagen fibers ex vivo and in 2 models of occlusive arterial thrombosis in vivo. Similarly, the hemostatic function and maintenance of vascular integrity during inflammation of the skin and lung were unaltered in the mutant mice. Investigation of platelet morphology in an induced thrombus under flow revealed that platelets rather form filopodia in the thrombus shell, and are flattened with filopodium-like structures when in direct contact to collagen fibers at the bottom of the thrombus. We provide for the first time direct evidence that platelet lamellipodium formation is not required for stable thrombus formation, and that morphological changes of platelets differ between a static spreading assay and thrombus formation under flow.

• Item Type: Articles
• Additional Information: This work was supported by an Emmy Noether grant (BE5084/3-1 [M.B.]) and TR240 grant with project number 374031971 (A06 [M.B.], and A07 [B.N. and M.S.]) of the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation), and by Cancer Research UK core grant numbers A17196 and A15673 [L.M.].
• Keywords: Immunology, cell biology, biochemistry, hematology.
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Bryson, Miss Sheila and Machesky, Professor Laura
• Authors: Schurr, Y., Sperr, A., Volz, J., Beck, S., Reil, L., Kusch, C., Eiring, P., Bryson, S., Sauer, M., Nieswandt, B., Machesky, L., and Bender, M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Blood
• Publisher: American Society of Hematology
• ISSN: 0006-4971
• ISSN (Online): 1528-0020
• Copyright Holders: Copyright © 2019 by The American Society of Hematology
• First Published: First published in Blood 134(25):2318-2329
• Publisher Policy: Reproduced in accordance with the publisher copyright policy