Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Physician-Scientist Development
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • In-Press Preview
    • Resource and Technical Advances
    • Clinical Research and Public Health
    • Research Letters
    • Editorials
    • Perspectives
    • Physician-Scientist Development
    • Reviews
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Resource and Technical Advances
  • Clinical Research and Public Health
  • Research Letters
  • Editorials
  • Perspectives
  • Physician-Scientist Development
  • Reviews
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Transfers
  • Advertising
  • Job board
  • Contact

Submit a comment

Rasa3 deficiency minimally affects thrombopoiesis but promotes severe thrombocytopenia due to integrin-dependent platelet clearance
Robert H. Lee, … , Anita Eckly, Wolfgang Bergmeier
Robert H. Lee, … , Anita Eckly, Wolfgang Bergmeier
Published March 15, 2022
Citation Information: JCI Insight. 2022;7(8):e155676. https://doi.org/10.1172/jci.insight.155676.
View: Text | PDF
Research Article Cell biology Hematology Article has an altmetric score of 3

Rasa3 deficiency minimally affects thrombopoiesis but promotes severe thrombocytopenia due to integrin-dependent platelet clearance

  • Text
  • PDF
Abstract

Platelet homeostasis is dependent on a tight regulation of both platelet production and clearance. The small GTPase Rap1 mediates platelet adhesion and hemostatic plug formation. However, Rap1 signaling is also critical for platelet homeostasis as both Rap1 deficiency and uninhibited Rap1 signaling lead to marked thrombocytopenia in mice. Here, we investigated the mechanism by which deficiency in Rasa3, a critical negative regulator of Rap1, causes macrothrombocytopenia in mice. Despite marked morphological and ultrastructural abnormalities, megakaryocytes in hypomorphic Rasa3hlb/hlb (R3hlb/hlb) or Rasa3–/– mice demonstrated robust proplatelet formation in vivo, suggesting that defective thrombopoiesis is not the main cause of thrombocytopenia. Rather, we observed that R3hlb/hlb platelets became trapped in the spleen marginal zone/red pulp interface, with evidence of platelet phagocytosis by macrophages. Clearance of mutant platelets was also observed in the liver, especially in splenectomized mice. Platelet count and platelet life span in Rasa3-mutant mice were restored by genetic or pharmacological approaches to inhibit the Rap1/talin1/αIIbβ3 integrin axis. A similar pattern of splenic clearance was observed in mice injected with anti-αIIbβ3 but not anti–glycoprotein Ibα platelet-depleting antibodies. In summary, we describe a potentially novel, integrin-based mechanism of platelet clearance that could be critical for our understanding of select inherited and acquired thrombocytopenias.

Authors

Robert H. Lee, Dorsaf Ghalloussi, Gabriel L. Harousseau, Joseph P. Kenny, Patrick A. Kramer, Fabienne Proamer, Bernhard Nieswandt, Matthew J. Flick, Christian Gachet, Caterina Casari, Anita Eckly, Wolfgang Bergmeier

×

Guidelines

The Editorial Board will only consider comments that are deemed relevant and of interest to readers. The Journal will not post data that have not been subjected to peer review; or a comment that is essentially a reiteration of another comment.

  • Comments appear on the Journal’s website and are linked from the original article’s web page.
  • Authors are notified by email if their comments are posted.
  • The Journal reserves the right to edit comments for length and clarity.
  • No appeals will be considered.
  • Comments are not indexed in PubMed.

Specific requirements

  • Maximum length, 400 words
  • Entered as plain text or HTML
  • Author’s name and email address, to be posted with the comment
  • Declaration of all potential conflicts of interest (even if these are not ultimately posted); see the Journal’s conflict-of-interest policy
  • Comments may not include figures
This field is required
This field is required
This field is required
This field is required
This field is required
This field is required
Rich Text Editor, eletter_body
Editor toolbarsClipboard/Undo CutKeyboard shortcut Ctrl+X CopyKeyboard shortcut Ctrl+C PasteKeyboard shortcut Ctrl+V Paste as plain textKeyboard shortcut Ctrl+Alt+Shift+V Paste from Word UndoKeyboard shortcut Ctrl+Z RedoKeyboard shortcut Ctrl+YEditing Find Replace Select All Spell Check As You TypeLinks LinkKeyboard shortcut Ctrl+K Unlink AnchorForms Form Checkbox Radio Button Text Field Textarea Selection Field Button Image Button Hidden FieldTools Maximize Show BlocksDocument Source Save New Page Preview Print TemplatesBasic Styles BoldKeyboard shortcut Ctrl+B ItalicKeyboard shortcut Ctrl+I UnderlineKeyboard shortcut Ctrl+U Strikethrough Subscript Superscript Copy FormattingKeyboard shortcut Ctrl+Shift+C Remove FormatParagraph Insert/Remove Numbered List Insert/Remove Bulleted List Decrease Indent Increase Indent Block Quote Create Div Container Align Left Center Align Right Justify Text direction from left to right Text direction from right to left Set languageStylesStylesStylesFormatFormatFontFontSizeSizeColors Text Color Background Color
Press ALT 0 for help
◢Elements path 

Copyright © 2025 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts

Posted by 5 X users
6 readers on Mendeley
See more details