Binding of heparin to plasma proteins and endothelial surfaces is inhibited by covalent linkage to antithrombin

Anthony K. C. Chan; Nethnapha Paredes; Bruce Thong; Paul Chindemi; Bosco Paes; Leslie R. Berry; Paul Monagle

doi:10.1160/TH03-06-0365

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2004; 91(05): 1009-1018
DOI: 10.1160/TH03-06-0365

Endothelium and Vascular Development

Schattauer GmbH

Binding of heparin to plasma proteins and endothelial surfaces is inhibited by covalent linkage to antithrombin

Anthony K. C. Chan

¹The Henderson Research Centre, Hamilton, Ontario, Canada

²Departments of Pediatrics and Hamilton, Ontario, Canada

,

Nethnapha Paredes

¹The Henderson Research Centre, Hamilton, Ontario, Canada

²Departments of Pediatrics and Hamilton, Ontario, Canada

,

Bruce Thong

¹The Henderson Research Centre, Hamilton, Ontario, Canada

³Departments of Medicine, McMaster University, Hamilton, Ontario, Canada

,

Paul Chindemi

¹The Henderson Research Centre, Hamilton, Ontario, Canada

³Departments of Medicine, McMaster University, Hamilton, Ontario, Canada

,

Bosco Paes

²Departments of Pediatrics and Hamilton, Ontario, Canada

,

Leslie R. Berry

¹The Henderson Research Centre, Hamilton, Ontario, Canada

²Departments of Pediatrics and Hamilton, Ontario, Canada

,

Paul Monagle

⁴Royal Children’s Hospital, Melbourne, Australia

› Author Affiliations

Abstract

Summary

Unfractionated heparin (UFH) and low molecular weight heparin (LMWH) are used for prophylaxis and treatment of thrombosis. However, UFH has a short plasma half-life and variable anticoagulant response in vivo due to plasma or vessel wall protein binding and LMWH has a decreased ability to inactivate thrombin, the pivotal enzyme in the coagulation cascade. Covalent linkage of antithrombin to heparin gave a complex (ATH) with superior anticoagulant activity compared to UFH and LMWH, and longer intravenous half-life compared to UFH. We found that plasma proteins bound more to UFH than ATH, and least to LMWH. Also, UFH bound significantly more to endothelial cells than ATH, with 100% of UFH and 94% of ATH binding being on the cell surface and the remainder was endocytosed. Competition studies with UFH confirmed that ATH binding was likely through its heparin moiety. These findings suggest that differences in plasma protein and endothelial cell binding may be due to available heparin chain length. Although ATH is polydisperse, the covalently-linked antithrombin may shield a portion of the heparin chain from association with plasma or endothelial cell surface proteins. This model is consistent with ATH’s better bioavailability and more predictable dose response.

Keywords

Anticoagulant - vessel wall - protein binding - heparinoid - endocytosis

Full Text

References

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