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Gray platelet syndrome and defective thrombo-inflammation in Nbeal2-deficient mice
Open accessAbstract
Platelets are anuclear organelle-rich cell fragments derived from bone marrow megakaryocytes (MKs) that safeguard vascular integrity. The major platelet organelles, α-granules, release proteins that participate in thrombus formation and hemostasis. Proteins stored in α-granules are also thought to play a role in inflammation and wound healing, but their functional significance in vivo is unknown. Mutations in NBEAL2 have been linked to gray platelet syndrome (GPS), a rare bleeding disorder characterized by macrothrombocytopenia, with platelets lacking α-granules. Here we show that Nbeal2-knockout mice display the characteristics of human GPS, with defective α-granule biogenesis in MKs and their absence from platelets. Nbeal2 deficiency did not affect MK differentiation and proplatelet formation in vitro or platelet life span in vivo. Nbeal2-deficient platelets displayed impaired adhesion, aggregation, and coagulant activity ex vivo that translated into defective arterial thrombus formation and protection from thrombo-inflammatory brain infarction following focal cerebral ischemia. In a model of excisional skin wound repair, Nbeal2-deficient mice exhibited impaired development of functional granulation tissue due to severely reduced differentiation of myofibroblasts in the absence of α-granule secretion. This study demonstrates that platelet α-granule constituents are critically required not only for hemostasis but also thrombosis, acute thrombo-inflammatory disease states, and tissue reconstitution after injury.
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“The relevance of platelets and their products for successful tissue reconstitution is reflected in the clinical use of platelet-rich plasma to promote healing (22) and impaired healing in preclinical models recapitulating platelet disorders (23).”
From Wound repair and regeneration: Mechanisms, signaling, and translation (2014) · cites this paper as [23]
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“Inflammatory cell recruitment and activation are a consequence of many signals that occur at the wound site. Some of the earliest signals include factors released by degranulating platelets (23) and by damage- and pathogen-associated molecular patterns (DAMPs and PAMPs, respectively) where cells are damaged and microbes gain access (107).”
From Wound repair and regeneration: Mechanisms, signaling, and translation (2014) · cites this paper as [23]
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Self-citation
Metadata
- Authors
- Deppermann, C., Cherpokova, D., Nurden, P., Schulz, J.-N., Thielmann, I., Kraft, P., Vögtle, T., Kleinschnitz, C., Dütting, S., Krohne, G., Eming, S. A., Nurden, A. T., Eckes, B., Stoll, G., Stegner, D., & Nieswandt, B.
- Affiliations
- University of Würzburg (DE)
- University of Cologne (DE)
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2013-07-01
- Volume
- 123
- Issue
- 8
- Pages
- 3331-3342
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC4011026
- OpenAlex
- W1982213737
- Cited by
- 200
- References
- 66
- Citations by year
- 2026: 9 · 2025: 12 · 2024: 13 · 2023: 9 · 2022: 6 · 2021: 16 · 2020: 15 · 2019: 18 · 2018: 18 · 2017: 16 · 2016: 22 · 2015: 19 · 2014: 22 · 2013: 5
- FWCI
- 16.24
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (SFB829, SFB 688)
- Julius-Maximilians-Universität Würzburg
- Graduate School of Life Sciences, Julius-Maximilians-Universität Würzburg
- Topics
- Health Sciences › Medicine › Hematology › Platelet Disorders and Treatments
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Life Sciences › Immunology and Microbiology › Immunology › Complement system in diseases
- Keywords
- gray platelet syndrome, NBEAL2, alpha-granules, megakaryocytes, thromboinflammation, arterial thrombus formation, focal cerebral ischemia, cerebral infarction, platelet adhesion and aggregation, coagulant activity, hemostasis, wound healing, myofibroblast differentiation, granulation tissue, bleeding disorders
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