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Thromb Haemost 1999; 82(04): 1302-1306
DOI: 10.1055/s-0037-1614380
Review Article
Schattauer GmbH

Pretreatment with Soluble Thrombomodulin Prevents Intrasinusoidal Coagulation and Liver Dysfunction following Extensive Hepatectomy in Cirrhotic Rats

Toshimi Kaido
1   From the Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Kyoto,
,
Akira Yoshikawa
1   From the Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Kyoto,
,
Shin-ichi Seto
1   From the Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Kyoto,
,
Shoji Yamaoka
1   From the Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Kyoto,
,
Hiroaki Furuyama
1   From the Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Kyoto,
,
Shigeki Arii
1   From the Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Kyoto,
,
Yasuo Takahashi
2   Fuji Central Research Laboratory, Mochida Pharmaceutical Co., Ltd., Shizuoka, Japan
,
Masayuki Imamura
1   From the Department of Surgery and Surgical Basic Science, Graduate School of Medicine, Kyoto University, Kyoto,
› Author Affiliations
Further Information

Publication History

Received 31 December 1998

Accepted after revision 25 May 1999

Publication Date:
08 December 2017 (online)

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Summary

The major cause of posthepatectomy liver dysfunction is supposed to be microcirculatory disturbance caused by imbalance of intrasinusoidal coagulation equilibrium. Thrombomodulin (TM) is a potent anticoagulant expressed on the endothelial cell surface that regulates the coagulation system by binding thrombin and accelerating the thrombin-catalyzed activation of protein C. Therefore, we examined the effect of soluble TM purified from human urine (UTM) on intrasinusoidal coagulation in cirrhotic rats. Dimethylnitrosamine-induced cirrhotic rats underwent 70% hepatectomy and received endotoxin 48 h after. UTM or vehicle alone was intravenously administered to each rat 30 min before endotoxin injection. UTM treatment attenuated the increases in cytosolic enzymes and serum hyaluronic acid level. The UTM supply improved the survival rate of the rats at 12 h after endotoxin challenge. Histologically, intrasinusoidal fibrin depositions and massive hepatocellular necrosis observed in control rats were scarcely found in UTM-treated rats. Immunohistochemical examination revealed that marked TM stains in sinusoidal endothelial cells were well preserved in UTM-treated rats. In conclusion, UTM administration prevented intrasinusoidal fibrin depositions and attenuated posthepatectomy liver dysfunction in cirrhotic rats.

 

  • References

  • 1 Mochida S, Ohno A, Arai M, Fujiwara K. Role of adhesion between activated macrophages and endothelial cells in the development of two types of massive hepatic necrosis in rats. J Gastroenterol Hepatol 1995; 10: S38-S42.
    CrossrefPubMedSearch in Google Scholar
  • 2 Mochida S, Ogata I, Hirata K, Ohta Y, Yamada S, Fujiwara K. Provocation of massive hepatic necrosis by endotoxin after partial hepatectomy in rats. Gastroenterology 1990; 99: 771-7.
    CrossrefPubMedSearch in Google Scholar
  • 3 Nemerson Y. Tissue factor and hemostasis. Blood 1988; 71: 1-8.
    PubMedSearch in Google Scholar
  • 4 Ishii H, Horie S, Kizaki K, Kazama M. Retinoic acid counteracts both the downregulation of thrombomodulin and the induction of tissue factor in cultured human endothelial cells exposed to tumor necrosis factor. Blood 1992; 80: 2556-62.
    PubMedSearch in Google Scholar
  • 5 Maruyama I. Thrombomodulin, an endothelial anticoagulant: Its structure, function and expression. Jpn Circ J 1992; 56: 187-91.
    CrossrefPubMedSearch in Google Scholar
  • 6 Maruyama I, Bell CE, Majerus PW. Thrombomodulin is found on endothelium of arteries, veins, capillaries and lymphatics and on syncytiotrophoblast of human placenta. J Cell Biol 1985; 101: 363-71.
    CrossrefPubMedSearch in Google Scholar
  • 7 Esmon NL, Owen WG, Esmon CT. Isolation of a membrane-bound cofactor for thrombin-catalyzed activation of protein C. J Biol Chem 1982; 257: 859-64.
    PubMedSearch in Google Scholar
  • 8 Esmon CT. The roles of protein C and thrombomodulin in the regulation of blood coagulation. J Biol Chem 1989; 264: 4743-6.
    PubMedSearch in Google Scholar
  • 9 Kuratsune H, Koda T, Kurahori T. The relationship between endotoxin and the phagocytic activity of the reticuloendothelial system. Hepatogastroenterology 1983; 30: 79-82.
    PubMedSearch in Google Scholar
  • 10 Capron-Laudereau M, Gugenheim J, Gigou M, Crougneau S, Houssin D, Bismuth H. Decreased reticuloendothelial phagocytic capacity in cirrhotic and portacaval shunt rats. Eur Surg Res 1987; 19: 388-94.
    CrossrefPubMedSearch in Google Scholar
  • 11 Arai M, Mochida S, Ohno A, Ogata I, Obama H, Maruyama I, Fujiwara K. Blood coagulation equilibrium in rat liver microcirculation as evaluated by endothelial cell thrombomodulin and macrophage tissue factor. Thromb Res 1995; 80: 113-23.
    CrossrefPubMedSearch in Google Scholar
  • 12 Takahashi Y, Hasaka Y, Niina H, Nagasawa K, Naotsuka M, Sakai K, Uemura A. Soluble thrombomodulin purified from human urine exhibits a potent anticoagulant effect in vitro and in vivo. Thromb Haemost 1995; 73: 805-11.
    Thieme ConnectPubMedSearch in Google Scholar
  • 13 Jenkins SA, Grandison A, Baxter JN, Day DW, Taylor I, Shields R. A dimethylnitrosamine-induced model of cirrhosis and portal hypertension in the rat. J Hepatol 1985; 1: 489-99.
    CrossrefPubMedSearch in Google Scholar
  • 14 Jezequel AM, Mancini R, Rinaldesi ML, Macarri G, Venturini C, Orlandi F. A morphological study of the early stages of hepatic fibrosis induced by low doses of dimethylnitrosamine in the rat. J Hepatol 1987; 5: 174-81.
    CrossrefPubMedSearch in Google Scholar
  • 15 Higgins GM, Anderson RM. Experimental pathology of liver: Restoration of liver of the white rat following partial surgical removal. Arch Pathol 1931; 12: 186-202.
    PubMedSearch in Google Scholar
  • 16 Uchiba M, Okajima K, Murakami K, Johno M, Okabe H, Takatsuki K. Effect of human urinary thrombomodulin on endotoxin-induced intravascular coagulation and pulmonary vascular injury in rats. Am J Hematol 1997; 54: 118-23.
    CrossrefPubMedSearch in Google Scholar
  • 17 Takahashi Y, Hosaka Y, Imada K, Adachi T, Niina H, Watanabe M, Mochizuki H. Human urinary soluble thrombomodulin (MR-33) improves disseminated intravascular coagulation without affecting bleeding time in rats: comparison with low molecular weight heparin. Thromb Haemost 1997; 77: 789-95.
    Thieme ConnectPubMedSearch in Google Scholar
  • 18 Yamaguchi Y, Hisama N, Okajima K, Uchiba M, Murakami K, Takahashi Y, Yamada S, Mori K, Ogawa M. Pretreatment with activated protein C or active human urinary thrombomodulin attenuates the production of cytokine-induced neutrophil chemoattractant following ischemia/reperfusion in rat liver. Hepatology 1997; 25: 1136-40.
    CrossrefPubMedSearch in Google Scholar
  • 19 Rubin RN, Colman RW. Disseminated intravascular coagulation. Drugs 1992; 44: 963-71.
    CrossrefPubMedSearch in Google Scholar
  • 20 Tsuji H. Antithrombin III. Jpn J Clin Hematol 1990; 31: 750-5.
    PubMedSearch in Google Scholar
  • 21 Cines DB, Kaywin P, Bina M, Tomaski A, Schreiber AD. Heparin-associated thrombocytopenia. N Engl J Med 1980; 303: 788-95.
    CrossrefPubMedSearch in Google Scholar
  • 22 Cairo MS, Allen J, Higgins C, Baehner RL, Boxer LA. Synergistic effect of heparin and chemotactic factor on polymorphonuclear leukocyte aggregation and degranulation. Am J Pathol 1983; 113: 67-74.
    PubMedSearch in Google Scholar
  • 23 Nawa K, Itani T, Ono M, Sakano K, Marumoto Y, Iwamoto M. The glycosaminoglycan of recombinant human soluble thrombomodulin affects antithrombotic activity in a rat model of tissue factor-induced disseminated intravascular coagulation. Thromb Haemost 1992; 67: 366-70.
    Thieme ConnectPubMedSearch in Google Scholar
  • 24 Mohri M, Oka M, Aoki Y, Gonda Y, Hirata S, Gomi K, Kiyota T, Sugihara T, Yamamoto S, Ishida T, Maruyama I. Intravenous extended infusion of recombinant human soluble thrombomodulin prevented tissue factor-induced disseminated intravascular coagulation in rats. Am J Hematol 1994; 45: 298-303.
    CrossrefPubMedSearch in Google Scholar
  • 25 Taylor Jr FB, Chang A, Esmon CT, D’Angelo A, Vigano-D’Angelo S, Blick KE. Protein C prevents the coagulopathic and lethal effects of Escherichia coli infusion in the baboon. J Clin Invest 1987; 79: 918-25.
    CrossrefPubMedSearch in Google Scholar
  • 26 Grey ST, Tsuchida A, Hau H, Orthner CL, Salem HH, Hancock WW. Selective inhibitory effects of the anticoagulant activated protein C on the responses of human mononuclear phagocytes to LPS, IFN-gamma, or phorbol ester. J Immunol 1994; 153: 3664-72.
    PubMedSearch in Google Scholar
  • 27 Snow TR, Deal MT, Dickey DT, Esmon CT. Protein C activation following coronary artery occlusion in the in situ porcine heart. Circulation 1991; 84: 293-9.
    CrossrefPubMedSearch in Google Scholar
  • 28 Liver Cancer Study Group of Japan. Primary liver cancer in Japan. Clinicopathologic features and results of surgical treatment. Ann Surg 1990; 211: 277-87.
    PubMedSearch in Google Scholar