Epithelial (E)-Cadherin is a Novel Mediator of Platelet Aggregation and Clot Stability

Vanessa M. Scanlon; Alexandra M. Teixeira; Tarun Tyagi; Siying Zou; Ping-Xia Zhang; Carmen Jane Booth; M. Anna Kowalska; Jialing Bao; John Hwa; Vincent Hayes; Michael S. Marks; Mortimer Poncz; Diane S. Krause

doi:10.1055/s-0039-1679908

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2019; 119(05): 744-757
DOI: 10.1055/s-0039-1679908

Cellular Haemostasis and Platelets

Georg Thieme Verlag KG Stuttgart · New York

Epithelial (E)-Cadherin is a Novel Mediator of Platelet Aggregation and Clot Stability

Vanessa M. Scanlon^*

¹Department of Laboratory Medicine, Yale University, New Haven, Connecticut, United States

²The Yale Stem Cell Center, Yale University, New Haven, Connecticut, United States

,

Alexandra M. Teixeira^*

³Department of Pathology, Yale University, New Haven, Connecticut, United States

,

Tarun Tyagi

⁴Department of Internal Medicine, Yale University, New Haven, Connecticut, United States

,

Siying Zou

⁵Department of Cell Biology, Yale University, New Haven, Connecticut, United States

,

Ping-Xia Zhang

¹Department of Laboratory Medicine, Yale University, New Haven, Connecticut, United States

²The Yale Stem Cell Center, Yale University, New Haven, Connecticut, United States

,

Carmen Jane Booth

⁶Department of Comparative Medicine, Yale University, New Haven, Connecticut, United States

,

M. Anna Kowalska

⁷Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

⁸Institute of Medical Biology, Polish Academy of Sciences, Philadelphia, Pennsylvania, United States

,

Jialing Bao

⁹Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

¹⁰Department of Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

¹¹University of Pennsylvania, Philadelphia, Pennsylvania, United States

,

John Hwa

⁴Department of Internal Medicine, Yale University, New Haven, Connecticut, United States

,

Vincent Hayes

¹²Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

,

Michael S. Marks

⁹Department of Pathology, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

¹⁰Department of Laboratory Medicine, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

¹¹University of Pennsylvania, Philadelphia, Pennsylvania, United States

,

Mortimer Poncz

¹¹University of Pennsylvania, Philadelphia, Pennsylvania, United States

¹²Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States

,

Diane S. Krause

¹Department of Laboratory Medicine, Yale University, New Haven, Connecticut, United States

²The Yale Stem Cell Center, Yale University, New Haven, Connecticut, United States

³Department of Pathology, Yale University, New Haven, Connecticut, United States

⁵Department of Cell Biology, Yale University, New Haven, Connecticut, United States

› Author Affiliations

Abstract

Cadherins play a major role in mediating cell–cell adhesion, which shares many parallels with platelet–platelet interactions during aggregate formation and clot stabilization. Platelets express epithelial (E)-cadherin, but its contribution to platelet function and/or platelet production is currently unknown. To assess the role of E-cadherin in platelet production and function in vitro and in vivo, we utilized a megakaryocyte-specific E-cadherin knockout mouse model. Loss of E-cadherin in megakaryocytes does not affect megakaryocyte maturation, platelet number or size. However, platelet dysfunction in the absence of E-cadherin is revealed when conditional knockout mice are challenged with acute antibody-mediated platelet depletion. Unlike wild-type mice that recover fully, knockout mice die within 72 hours post-antibody administration, likely from haemorrhage. Furthermore, conditional knockout mice have prolonged tail bleeding times, unstable clot formation, reduced clot retraction and reduced fibrin deposition in in vivo injury models. Murine platelet aggregation in vitro in response to thrombin and thrombin receptor activating peptide is compromised in E-cadherin null platelets, while aggregation in response to adenosine diphosphate (ADP) is not significantly different. Consistent with this, in vitro aggregation of primary human platelets in response to thrombin is decreased by an inhibitory E-cadherin antibody. Integrin activation and granule secretion in response to ADP and thrombin are not affected in E-cadherin null platelets, but Akt and glycogen synthase kinase 3β (GSK3β) activation are attenuated, suggesting a that E-cadherin contributes to aggregation, clot stabilization and retraction that is mediated by phosphoinositide 3-kinase/Akt/GSK3β signalling. In summary, E-cadherin plays a salient role in platelet aggregation and clot stability.

Keywords

cadherins - clot stability - haemostasis - platelet aggregation

Full Text

References

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