Platelet protein disulfide isomerase is required for thrombus formation but not for hemostasis in mice

Kyungho Kim, Eunsil Hahm, Jing Li, Lisa Marie Holbrook, Parvathy Sasikumar, Ronald G. Stanley, Masuko Fukai, Jonathan M. Gibbins, Jaehyung Cho

Research output: Contribution to journalArticle

83 Scopus citations

Abstract

Protein disulfide isomerase (PDI) derived from intravascular cells is required for thrombus formation. However, it remains unclear whether platelet PDI contributes to the process. Using platelet-specific PDI–deficient mice, we demonstrate that PDI-null platelets have defects in aggregation and adenosine triphosphate secretion induced by thrombin, collagen, and adenosine diphosphate. Such defects were rescued by wild-type but not mutant PDI, indicating that the isomerase activity of platelet surface PDI is critical for the regulatory effect. PDI-deficient platelets expressed increased levels of intracellular ER protein 57 (ERp57) and ERp72. Platelet PDI regulated αIIbβ3 integrin activation but not P-selectin exposure, Ca2+ mobilization, β3–talin1 interaction, or platelet spreading on immobilized fibrinogen. Inhibition of ERp57 further diminished αIIbβ3 integrin activation and aggregation of activated PDI-deficient platelets, suggesting distinct roles of PDI and ERp57 in platelet functions. We found that platelet PDI is important for thrombus formation on collagen-coated surfaces under shear. Intravital microscopy demonstrates that platelet PDI is important for platelet accumulation but not initial adhesion and fibrin generation following laser-induced arteriolar injury. Tail bleeding time in platelet-specific PDI–deficient mice were not significantly increased. Our results provide important evidence that platelet PDI is essential for thrombus formation but not for hemostasis in mice.

Original languageEnglish (US)
Pages (from-to)1052-1061
Number of pages10
JournalBlood
Volume122
Issue number6
DOIs
StatePublished - Aug 8 2013

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Kim, K., Hahm, E., Li, J., Holbrook, L. M., Sasikumar, P., Stanley, R. G., Fukai, M., Gibbins, J. M., & Cho, J. (2013). Platelet protein disulfide isomerase is required for thrombus formation but not for hemostasis in mice. Blood, 122(6), 1052-1061. https://doi.org/10.1182/blood-2013-03-492504