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Antithrombin and Heparin Cofactor II: Structure and Functions

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Recent Advances in Thrombosis and Hemostasis 2008

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Abstract

Antithrombin (AT) and heparin cofactor II (HOI) are plasma serpins that function as principal regulators of blood coagulation. These serpins inhibit their target proteinases by forming an inactive enzyme-inhibitor complex through an interaction between their reactive center and the active site of the proteinase. Among the coagulation proteinases, AT mainly inhibits factor Xa and thrombin, and HCII exclusively inhibits thrombin. However, both AT and HCII by themselves are poor inhibitors of coagulation proteinases as these reactions proceed at a slow rate and are time-dependent. These serpins also require glycosaminoglycans for their physiological functions. By binding to glycosaminoglycans, a conformational change occurs in the reactive center loop (RCL), which activates these serpins to become a more efficient inhibitor of coagulation proteinases. The physiological cofactor for AT is heparan sulfate proteoglycans on endothelial cells, and that for HCII is dermatan sulfate proteoglycans on vascular smooth muscle cells. The physiological importance of AT as an anticoagulant in the circulation is well supported by a number of thrombotic disorders in patients with AT deficiency. However, the physiological function of HCII as an anticoagulant is unclear, as HCII deficiency is not a significant risk factor for venous or arterial thrombosis. Recent crystallographic analyses of monomeric native AT variant, AT-thrombin, or factor Xa-pentasaccharide complexes, as well as HCII-thrombin complex, have revealed more detailed mechanisms of proteinase inhibition by these serpins and mechanisms of glycosaminoglycan-dependent enhancement of the reaction rates, together with some revisions of our previous knowledge.

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Authors and Affiliations

  1. Graduate School of Life Science, University of Hyogo, 3-2-1 Kouto, Kamigori-cho, Ako-gun, Hyogo, 678-1297, Japan

    Takehiko Koide

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  1. Takehiko Koide
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Editors and Affiliations

  1. Department of Pathology, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Kenzo Tanaka M.D., Ph.D. (Professor Emeritus) (Professor Emeritus)

  2. Department of Biochemistry, University of Washington, J317 Health Science Center, Box 357350, Seattle, WA, 98195, USA

    Earl W. Davie Ph.D. (Professor) (Professor)

  3. School of Medicine, Internal Medicine, Keio University, 35 Shinanomachi, Shinjuku-ku, Tokyo, 160-8582, Japan

    Yasuo Ikeda M.D., Ph.D. (Professor) (Professor)

  4. Department of Biology, Kyushu University, 6-10-1 Hakozaki, Higashi-ku, Fukuoka, 812-8581, Japan

    Sadaaki Iwanaga Ph.D. (Professor Emeritus) (Professor Emeritus)

  5. Department of Medicine, Nagoya University, 26 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan

    Hidehiko Saito M.D., Ph.D. (Professor Emeritus) (Professor Emeritus)

  6. Pathophysiological and Experimental Division, Department of Pathology, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582, Japan

    Katsuo Sueishi M.D., Ph.D. (Professor) (Professor)

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Koide, T. (2008). Antithrombin and Heparin Cofactor II: Structure and Functions. In: Tanaka, K., Davie, E.W., Ikeda, Y., Iwanaga, S., Saito, H., Sueishi, K. (eds) Recent Advances in Thrombosis and Hemostasis 2008. Springer, Tokyo. https://doi.org/10.1007/978-4-431-78847-8_10

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  • DOI: https://doi.org/10.1007/978-4-431-78847-8_10

  • Publisher Name: Springer, Tokyo

  • Print ISBN: 978-4-431-78846-1

  • Online ISBN: 978-4-431-78847-8

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