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

Kim, K., Hahm, E., Li, J., Holbrook, L.-M., Sasikumar, P., Stanley, R. G., Ushio-Fukai, M., Gibbins, J. M. ORCID: https://orcid.org/0000-0002-0372-5352 and Cho, J. (2013) Platelet protein disulfide isomerase is required for thrombus formation but not essential for hemostasis in mice. Blood, 122 (6). pp. 1052-1061. ISSN 0006-4971 doi: 10.1182/blood-2013-03-492504

Abstract/Summary

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 ATP secretion induced by thrombin, collagen, and ADP. Such defects were rescued by exogenously-added 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 ERp57 and ERp72. Platelet PDI regulated αIIbβ3 integrin activation but not P-selectin exposure, Ca2+ mobilization, β3-talin interaction, and platelet spreading on immobilized fibrinogen. Inhibition of ERp57 further diminished αIIbβ3 integrin activation, aggregation and ATP secretion 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 arteriolar 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 and blood loss 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.

Item Type	Article
URI	https://reading-clone.eprints-hosting.org/id/eprint/33131
Item Type	Article
Refereed	Yes
Divisions	Interdisciplinary centres and themes > Institute for Cardiovascular and Metabolic Research (ICMR) Life Sciences > School of Biological Sciences > Biomedical Sciences
Uncontrolled Keywords	Platelets, thrombus, thrombosis, haemostasis, protein disulfide isomerase, PDI, ERp57
Publisher	American Society of Hematology
Download/View statistics	View download statistics for this item