Platelet-specific SLFN14 deletion causes macrothrombocytopenia and platelet dysfunction through dysregulated megakaryocyte and platelet gene expression

Rachel J. Stapley; Xenia Sawkulycz; Gabriel H.M. Da Mota Araujo; Maximilian Englert; Lourdes Garcia-Quintanilla; Sophie R.M. Smith; Amna Ahmed; Elizabeth J. Haining; Nayandeep Kaur; Andrea Bacon; Andrey V. Pisarev; Natalie S. Poulter; Dean P.J. Kavanagh; Steven G. Thomas; Samantha J. Montague; Julie Rayes; Zoltan Nagy; Neil V. Morgan

doi:10.1172/JCI189100

¹Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom

²Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

³MRC Centre for Immune Regulation, Transgenics Facility, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

⁴Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States of America

⁵Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Burmingham, United Kingdom

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¹Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom

²Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

³MRC Centre for Immune Regulation, Transgenics Facility, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

⁴Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States of America

⁵Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Burmingham, United Kingdom

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¹Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom

²Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

³MRC Centre for Immune Regulation, Transgenics Facility, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

⁴Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States of America

⁵Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Burmingham, United Kingdom

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¹Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom

²Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

³MRC Centre for Immune Regulation, Transgenics Facility, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

⁴Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States of America

⁵Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Burmingham, United Kingdom

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¹Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom

²Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

³MRC Centre for Immune Regulation, Transgenics Facility, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

⁴Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States of America

⁵Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Burmingham, United Kingdom

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¹Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom

²Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

³MRC Centre for Immune Regulation, Transgenics Facility, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

⁴Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States of America

⁵Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Burmingham, United Kingdom

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¹Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom

²Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

³MRC Centre for Immune Regulation, Transgenics Facility, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

⁴Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States of America

⁵Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Burmingham, United Kingdom

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¹Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom

²Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

³MRC Centre for Immune Regulation, Transgenics Facility, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

⁴Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States of America

⁵Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Burmingham, United Kingdom

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¹Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom

²Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

³MRC Centre for Immune Regulation, Transgenics Facility, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

⁴Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States of America

⁵Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Burmingham, United Kingdom

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¹Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom

²Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

³MRC Centre for Immune Regulation, Transgenics Facility, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

⁴Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States of America

⁵Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Burmingham, United Kingdom

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¹Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom

²Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

³MRC Centre for Immune Regulation, Transgenics Facility, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

⁴Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States of America

⁵Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Burmingham, United Kingdom

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¹Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom

²Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

³MRC Centre for Immune Regulation, Transgenics Facility, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

⁴Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States of America

⁵Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Burmingham, United Kingdom

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¹Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom

²Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

³MRC Centre for Immune Regulation, Transgenics Facility, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

⁴Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States of America

⁵Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Burmingham, United Kingdom

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¹Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom

²Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

³MRC Centre for Immune Regulation, Transgenics Facility, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

⁴Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States of America

⁵Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Burmingham, United Kingdom

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¹Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom

²Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

³MRC Centre for Immune Regulation, Transgenics Facility, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

⁴Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States of America

⁵Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Burmingham, United Kingdom

Find articles by Montague, S. in: PubMed | Google Scholar

¹Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom

²Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

³MRC Centre for Immune Regulation, Transgenics Facility, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

⁴Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States of America

⁵Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Burmingham, United Kingdom

Find articles by Rayes, J. in: PubMed | Google Scholar |

¹Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom

²Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

³MRC Centre for Immune Regulation, Transgenics Facility, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

⁴Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States of America

⁵Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Burmingham, United Kingdom

Find articles by Nagy, Z. in: PubMed | Google Scholar

¹Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Birmingham, United Kingdom

²Institute of Experimental Biomedicine, University Hospital Würzburg, Würzburg, Germany

³MRC Centre for Immune Regulation, Transgenics Facility, College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom

⁴Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, United States of America

⁵Department of Cardiovascular Sciences, School of Medical Sciences, College of Medicine and Health, University of Birmingham, Burmingham, United Kingdom

Find articles by Morgan, N. in: PubMed | Google Scholar |

J Clin Invest. https://doi.org/10.1172/JCI189100.
Copyright © 2025, Stapley et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

Published August 12, 2025 - Version history

SLFN14-related thrombocytopenia is a rare bleeding disorder caused by SLFN14 mutations altering hemostasis in patients with platelet dysfunction. Schlafen (SLFN) proteins are highly conserved in mammals where SLFN14 is specifically expressed in megakaryocyte (MK) and erythroblast lineages. The role of SLFN14 in megakaryopoiesis and platelet function has not been elucidated. We generated a new murine model with a platelet- and MK-specific SLFN14 deletion using platelet factor-4 (PF4) cre-mediated deletion of exons 2 and 3 in Slfn14 (Slfn14;PF4-Cre) to decipher the molecular mechanisms driving the bleeding phenotype. SLFN14;PF4-Cre⁺ platelets displayed reduced platelet signaling to thrombin, reduced thrombin formation, increased bleeding tendency, and delayed thrombus formation as assessed by intravital imaging. Moreover, fewer in situ bone marrow MKs compared to controls. RNA sequencing and gene ontology analysis of MKs and platelets from Slfn14;PF4-Cre homozygous mice revealed altered pathways of ubiquitination, ATP activity, cytoskeleton and molecular function. In summary, we investigated how SLFN14 deletion in MKs and platelets leads to platelet dysfunction and alters their transcriptome, explaining the platelet dysfunction and bleeding in humans and mice with SLFN14 mutations.

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Platelet-specific SLFN14 deletion causes macrothrombocytopenia and platelet dysfunction through dysregulated megakaryocyte and platelet gene expression

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Platelet-specific SLFN14 deletion causes macrothrombocytopenia and platelet dysfunction through dysregulated megakaryocyte and platelet gene expression

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