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Thrombomodulin: An Anticoagulant Cell Surface Proteoglycan With Physiologically Relevant Glycosaminoglycan Moiety

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Heparin and Related Polysaccharides

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 313))

Abstract

The vessel wall forms the barrier between the circulating blood and the underlying tissues and it provides a continuous luminal endothelial cell layer which is actively and dynamically involved in the balance of the haemostatic system. Different coagulation and fibrinolytic components are synthesized, secreted or bound by the vascular endothelium, but the intact vessel wall prevents the activation of the haemostatic system by provision of its thrombo-resistant surface. At least two major anticoagulant mechanisms contribute to this control and regulation of blood coagulation, once it is initiated by injury of the vessel wall: (a) Endothelial cell surface-expressed thrombin receptors, in particular thrombomodulin (TM) (Esmon and Owen, 1981; Owen and Esmon, 1981), and (b) endothelial cell surface-associated reactions involving serine protease inhibitors such as antithrombin III (AT III), heparin cofactor II (HC II), or protease nexin I and their possible interaction with heparan sulfate proteoglycans (Preissner, 1990). When bound to intact TM, thrombin effectively invokes the onset of the protein C pathway, involving activation of the circulating pro-enzyme protein C, subsequent complex formation of activated protein C with cofactor protein S, and the ultimate proteolytic degradation of coagulation cofactors Va and VIIIa (Esmon, 1987). Thus, the central role of TM as anticoagulant cofactor thereby converts thrombin from a pro- into an anticoagulant enzyme that initiates a negative feedback loop which leads to inhibition of thrombin formation by eliminating the critical cofactors. The central physiological function of the protein C pathway has been demonstrated by a strong correlation between the occurence of recurrent thromboembolic complications and congenital deficiencies of protein C or protein S (Bertina, 1988). In the following, structure/function relationships of TM will be summarized indicating that a major O-linked glycan moiety of the thrombin receptor acts as main modulator of receptor function.

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Authors and Affiliations

  1. Lilly Research Laboratories, Indianapolis, Indiana, USA

    John F. Parkinson & Nils U. Bang

  2. Tokyo Medical and Dental University, Tokyo, Japan

    Takatoshi Koyama

  3. Haemostasis Research Unit, Kerckhoff-Klinik, Max-Planck-Gesellschaft, Bad Nauheim, Germany

    Klaus T. Preissner

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  1. John F. Parkinson
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  2. Takatoshi Koyama
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  3. Nils U. Bang
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  4. Klaus T. Preissner
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Editors and Affiliations

  1. Charing Cross and Westminster Medical School, London, UK

    David A. Lane

  2. The Swedish University of Agricultural Sciences, Uppsala, Sweden

    Ingemar Björk

  3. Uppsala University, Uppsala, Sweden

    Ulf Lindahl

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Parkinson, J.F., Koyama, T., Bang, N.U., Preissner, K.T. (1992). Thrombomodulin: An Anticoagulant Cell Surface Proteoglycan With Physiologically Relevant Glycosaminoglycan Moiety. In: Lane, D.A., Björk, I., Lindahl, U. (eds) Heparin and Related Polysaccharides. Advances in Experimental Medicine and Biology, vol 313. Springer, Boston, MA. https://doi.org/10.1007/978-1-4899-2444-5_18

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  • DOI: https://doi.org/10.1007/978-1-4899-2444-5_18

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