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

Journal of Veterinary Internal Medicine

J.W. Norris¹  M. Pombo³  E. Shirley⁴  G. Blevins² 

[1] 5A60 Johns Hopkins Asthma and Allergy Center, Johns Hopkins Medical Institute – Sidney Kimmel Comprehensive Cancer Center, Baltimore, MD;19463 James Monroe HWY, Leesburg, VA;Department of Anatomy, Physiology and Cell Biology, School of Veterinary Medicine, University of California, Davis, CA;Hunters Glen Veterinary Hospital, Inc., Veterinary Acupuncture Services of Tulsa LLC, Tulsa, OK

关键词: Factor V;    AKT;    Bleeding Diathesis;    Horse;   

DOI  :  10.1111/jvim.13595

来源: Wiley

【 摘 要 】

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.

【 授权许可】

CC BY-NC   
Copyright © The Authors. Journal of Veterinary Internal Medicine published by Wiley Periodicals, Inc. on behalf of American College of Veterinary Internal Medicine.

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