Association of Factor V Secretion with Protein Kinase B Signaling in Platelets from Horses with Atypical Equine Thrombasthenia

J. W. Norris, M. Pombo, E. Shirley, G. Blevins, Fern Tablin

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Background: Two congenital bleeding diatheses have been identified in Thoroughbred horses: Glanzmann thrombasthenia (GT) and a second, novel diathesis associated with abnormal platelet function in response to collagen and thrombin stimulation. Hypothesis/Objectives: Platelet dysfunction in horses with this second thrombasthenia results from a secretory defect. Animals: Two affected and 6 clinically normal horses. Methods: Ex vivo study. Washed platelets were examined for (1) expression of the αIIb-β3 integrin; (2) fibrinogen binding capacity in response to ADP and thrombin; (3) secretion of dense and α-granules; (4) activation of the mammalian target of rapamycin (mTOR)-protein kinase B (AKT) signaling pathway; and (5) cellular distribution of phosphatidylinositol-4-phosphate-3-kinase, class 2B (PIK3C2B) and SH2 containing inositol-5′-phosphatase 1 (SHIP1). Results: Platelets from affected horses expressed normal amounts of αIIb-β3 integrin and bound fibrinogen normally in response to ADP, but bound 80% less fibrinogen in response to thrombin. α-granules only released 50% as much Factor V as control platelets, but dense granules released their contents normally. Protein kinase B (AKT) phosphorylation was reduced after thrombin activation, but mTOR Complex 2 (mTORC2) and phosphoinositide-dependent kinase 1 (PDK1) signaling were normal. SH2-containing inositol-5'-phosphatase 1 (SHIP1) did not localize to the cytoskeleton of affected platelets and was decreased overall consistent with reduced AKT phosphorylation. Conclusions and clinical significance: Defects in fibrinogen binding, granule secretion, and signal transduction are unique to this thrombasthenia, which we designate as atypical equine thrombasthenia.

Original languageEnglish (US)
Pages (from-to)1387-1394
Number of pages8
JournalJournal of Veterinary Internal Medicine
Volume29
Issue number5
DOIs
StatePublished - Sep 1 2015

Keywords

  • AKT
  • Bleeding Diathesis
  • Factor V
  • Horse

ASJC Scopus subject areas

  • veterinary(all)

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