RSS-Feed abonnieren
DOI: 10.1055/s-0038-1649598
Evidence that the Protein C Activation Pathway Amplifies the lnhibition of Thrombin Generation by Recombinant Human Thrombomodulin in Plasma
Publikationsverlauf
Received 16. Juli 1992
Accepted after revision 12. März 1993
Publikationsdatum:
05. Juli 2018 (online)
![](https://www.thieme-connect.de/media/10.1055-s-00035024/199303/lookinside/thumbnails/10-1055-s-0038-1649598-1.jpg)
Summary
Thrombomodulin (TM) is a cofactor for the thrombin-catalyzed activation of anticoagulant protein C. However, we have no evidence that thrombomodulin actually activates protein C during blood coagulation processing, nor do we know whether this activated protein C acts as an anticoagulant. We studied the inhibitory action of recombinant human soluble TM (rhs-TM) on thrombin generation in whole plasma. Human plasma was activated with small amounts of tissue factor using phospholipid vesicles in place of activated platelets. Thrombin generation was observed. The addition of only 2 nM of rhs-TM prevented rapid generation of thrombin and reduced the total amount of thrombin generated. In order to study the influence of the protein C activation pathway on this inhibitory action of rhs-TM, protein C-depleted plasma was used. rhs-TM had little inhibitory effect on protein C-depleted plasma. However, the addition of protein C caused a delay in thrombin generation and a reduction of the maximum thrombin concentration. We concluded that the anticoagulant activity of rhs-TM was amplified by the protein C activation pathway.
-
References
- 1 Esmon NL, Owen WG, Esmon CT. Isolation of a membrane-bound cofactor for thrombin-catalyzed activation of protein C. J Biol Chem 1982; 257: 859-864
- 2 Esmon CT, Esmon NL, Harris KW. Complex formation between thrombin and thrombomodulin inhibits both thrombin-catalyzed fibrin formation and factor V activation. J Biol Chem 1982; 257: 7944-7947
- 3 Esmon NL, Carroll RC, Esmon CT. Thrombomodulin blocks the ability of thrombin to activate platelets. J Biol Chem 1983; 258: 12238-12242
- 4 Vehar GA, Davie EW. Preparation and properties of bovine factor-VIII (antihemophilic factor). Biochemistry 1980; 19: 401-410
- 5 Suzuki K, Stenflo J, Dahlbäck B, Teodorsson B. Inactivation of human coagulation factor V by activated protein C. J Biol Chem 1983; 258: 1914-1920
- 6 Suzuki K, Kusumoto H, Deyashiki Y, Nishioka J, Maruyama I, Zushi M, Kawahara S, Honda G, Yamamoto S, Horiguchi S. Structure and expression of human thrombomodulin, a thrombin receptor on endothelium acting as a cofactor for protein C activation. EMBO J 1987; 6: 1891-1897
- 7 Zushi M, Gomi K, Yamamoto S, Maruyama I, Hayashi T, Suzuki K. The last three consecutive epidermal growth factor-like structures of human thrombomodulin comprise the minimum functional domain for protein C-activating cofactor activity and anticoagulant activity. J Biol Chem 1989; 264: 10351-10353
- 8 Gomi K, Zushi M, Honda G, Kawahara S, Matsuzaki O, Kanabayashi T, Yamamoto S, Maruyama I, Suzuki K. Antithrombotic effect of recombinant human thrombomodulin on thrombin-induced thromboembolism in mice. Blood 1990; 75: 1396-1399
- 9 Zushi M, Gomi K, Honda G, Kondo S, Yamamoto S, Hayashi T, Suzuki K. Aspartic acid 349 in fourth epidermal growth factor-like structure of human thrombomodulin plays a role in its Ca2+-mediated binding to protein C. J Biol Chem 1991; 266: 19886-19889
- 10 Beguin S, Lindhout T, Hemker HC. The effect of trace amounts of tissue factor on thrombin generation in platelet rieh plasma, its inhibition by heparin. Thromb Haemostas 1989; 61: 25-29
- 11 Takano S, Kimura S, Ohdama S, Aoki N. Plasma thrombomodulin in health and diseases. Blood 1990; 76: 2024-2029
- 12 Ishi H, Majerus PW. Thrombomodulin is present in human plasma and urine. J Clin Invest 1985; 76: 2178-2181