Thromb Haemost 1997; 77(06): 1148-1153
DOI: 10.1055/s-0038-1656128
Coagulation
Schattauer GmbH Stuttgart

The Anticoagulant and Hemorrhagic Effects of DHG, a New Depolymerized Holothurian Glycosaminoglycan, on Experimental Hemodialysis in Dogs

Kazuhisa G Minamiguchi
The Taiho Pharmaceutical Co., Ltd., Tokushima, Japan
,
Keiko T Kitazato
The Taiho Pharmaceutical Co., Ltd., Tokushima, Japan
,
Eiji Sasaki
The Taiho Pharmaceutical Co., Ltd., Tokushima, Japan
,
Hideki Nagase
The Taiho Pharmaceutical Co., Ltd., Tokushima, Japan
,
Kenji Kitazato
The Taiho Pharmaceutical Co., Ltd., Tokushima, Japan
› Author Affiliations
Further Information

Publication History

Received 10 December 1996

Accepted after revision 12 February 1997

Publication Date:
12 July 2018 (online)

Summary

We studied the use of depolymerized holothurian glycosaminoglycan (DHG) as an anticoagulant in experimental beagle-dog hemodialysis using a hollow-fiber dialyzer compared to that using unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), and nafamostat mesilate (FUT). Effectiveness was based on 5 h hemodialysis and no marked clot deposition in the extracorporeal circuit. At effective doses, UFH and LMWH significantly prolonged template bleeding time, in sharp contrast to FUT and DHG, which scarcely prolonged bleeding time during hemodialysis. DHG prolonged activated partial thromboplastin time (APTT) about 6 times that of normal plasma and prolonged thrombin clotting time (TCT) markedly; FUT showed marked APTT prolongation but hardly prolonged TCT in the hemodialysis circuit at the effective dose. The anticoagulant profile of DHG thus differs completely from that of FUT. These results suggest that DHG may be useful as anticoagulant for hemodialysis with low hemorrhagic risk.

 
  • References

  • 1 Swartz RD. Hemorrhage during high-risk hemodialysis using controlled heparinization. Nephron 1981; 28: 65-69
  • 2 Agresti J, Conroy JD, Olshan A, Conroy F, Schwarta A, Brodsky I, Krevolin L, Chinitz J. Heparin-free hemodialysis with cuprophan hollow fiber dialyzer by a frequent-saline-flush, high-blood-flow technique. Am Soc Artif Intern Organs 1985; 31: 590-594
  • 3 Bergrem H, Leivestad T. Dialysis death and increased free fatty acids. Lancet 1978; 02: 1160
  • 4 Ljungberg B, Blombäck M, Johnsson H, Lins LE. A single dose of a low-molecular-weight heparin fragment for anticoagulation during hemodialysis. Clin Nephrol 1987; 27: 31-35
  • 5 Maurin N, Kierdorf H. A low-molecular-weight heparin in hemodialysis. Klin Wochenschr 1988; 66: 246-249
  • 6 Ireland H, Lane DA, Flynn A, Pegrum AC, Curits JR. Low-molecular-weight heparin in hemodialysis for chronic renal failure: Dose finding study of CY222. Thromb Haemost 1988; 59: 240-247
  • 7 Kinugasa E, Kojima H, Tamura K, Takahashi J, Morikawa K, Sekiguchi T, Nakayama F, Takahashi K, Akizawa T, Sato M, Kitaoka T, Ideura T, Koshikawa S, Fujii S. Utility of FUT-175, an enzyme inhibitor, in hemodialysis - Its anticoagulative and anti-complement actions. J Jpn Soc Dial Ther 1982; 15: 546
  • 8 Morikawa K, Tamura K, Kojima H, Takahashi J, Kinugasa E, Sekiguchi T, Nakayama F, Takahashi K, Akizawa T, Sato M, Kitaoka T, Ideura T, Koshikawa A, Fujii S. Application of FUT-175, a protease inhibitor, as an anticoagulant to hemodialysis. Jpn J Artif Organs 1983; 12: 75-78
  • 9 Akizawa T, Sato M, Kitaoka T, Koshikawa S, Asano Y, Hirasawa Y, Iida N, Mimura N, Nakamura K, Kazama M, Ota K. The usefulness of the multienzyme inhibitor nafamostat mesilate in high-bleeding-risk hemodialysis. Proc Eur Dial Transplant Assoc 1985; 22: 334-338
  • 10 Akizawa T, Koshikawa S, Ota K, Kazama M, Mimura N, Hirasawa Y. Nafamostatmesilate: a regional anticoagulant for hemodialysis in patients at high risk for bleeding. Nephron 1993; 64: 376-381
  • 11 Hory B. Hemodialysis with low-molecular-weight heparin in high- risk hemorrhagic patients with acute renal failure. Am J Med 1988; 84: 566
  • 12 Suzuki N, Kitazato K, Takamatsu J, Saito H. Antithrombotic and anticoagulant activity of depolymerized fragment of glycosaminoglycan extracted from Stichopus japonicus Selenka. Thromb Haemost 1991; 65: 369-373
  • 13 Yoshida K, Minami Y, Nemoto H, Numata K, Yamanaka E. Structure of DHG, a depolymerized glycosaminoglycan from sea cucumber, Stichopus japonicus. Tetrahedron Lett 1992; 33: 4959-4962
  • 14 Nagase H, Enjoji K, Minamiguchi K, Kitazato KT, Kitazato K, Saito H, Kato H. Depolymerized holothurian glycosaminoglycan with novel anticoagulant actions: Antithrombin III- and heparin cofactor II-independent inhibition of factor X activation by factor IXa-factor Villa complex and heparin cofactor II-dependent inhibition of thrombin. Blood 1995; 85: 1527-1534
  • 15 Nagase H, Enjoji K, Shima M, Kitazato K, Yoshioka A, Saito H, Kato H. Effect of depolymerized holothurian glycosaminoglycan (DHG) on the activation of factor VIII and factor V by thrombin. J Biochem 1996; 119: 63-69
  • 16 Minamiguchi K, Nagase H, Kitazato KT, Kitazato K. Interaction of a new depolymerized holothurian glycosaminoglycan with proteins in human plasma. Thromb Res 1996; 83: 253-264
  • 17 Kitazato K, Kitazato KT, Nagase H, Minamiguchi K. DHG, a new depolymerized holothurian glycosaminoglycan, exerts an antithrombotic effect with less bleeding than unfractionated or low-molecular-weight heparin, in rats. Thromb Res 1996; 84: 111-120
  • 18 Nagase H, Kitazato KT, Sasaki E, Hattori M, Kitazato K, Saito H. Antithrombin III-independent effect of a new depolymerized holothurian glycosaminoglycan (DHG) on acute thromboembolism in mice. Thromb Haemost 1997; 77: 399-402
  • 19 Hashimoto N, Morita T, Iwanaga S. A method for systematic purification from bovine plasma of six vitamin-K-dependent coagulation factors: Prothrombin, factor X, factor IX, protein S, protein C, and protein Z. J Biochem 1985; 97: 1347-1355
  • 20 Owen WG, Esmon CT, Jackson CM. The conversion of prothrombin to thrombin. J Biol Chem 1974; 249: 594-605
  • 21 Craddock PR, Fehr J, Dalmasso AP, Brigham KL, Jacob HS. Hemodialysis leukopenia. Pulmonary vascular leukostasis resulting from complement activation by dialyzer cellophane membranes. J Clin Invest 1977; 59: 879-888
  • 22 Tamura Y, Hirado M, Okamura K, Minato Y, Fujii S. Synthetic inhibitors of trypsin, plasmin, kallikrein, thrombin, Clr, and Cl esterase. Biochim Biophys Acta 1977; 484: 417-422
  • 23 Sundarm S, Gikakis N, Hack CE, Niewiarowski S, Edmunds Jr LH, Rao AK, Sun L, Cooper SL, Colman RW. Nafamostat mesilate, a broad-spectrum protease inhibitor, modulates platelet, neutrophil and contact activation in simulated extracorporeal circulation. Thromb Haemost 1996; 75 (01) 76-82
  • 24 Rosenberg RD, Damus PS. The purification and mechanism of action of human antithrombin-heparin cofactor. J Biol Chem 1973; 248: 6490-6497
  • 25 Rosenberg RD, Rosenberg JS. Natural anticoagulant mechanism. J Clin Invest 1984; 74: 01-06
  • 26 Béguin S, Lindhout T, Hemker HC. The mode of action of heparin in plasma. Thromb Haemost 1988; 60: 457-462
  • 27 Ofosu FA, Sié P, Modi GJ, Fernandes F, Buchanan MR, Blajchman MA, Boneu B, Hirsh J. The inhibition of thrombin-dependent positive feedback reaction is critical to the expression of the anticoagulant effect of heparin. Biochem J 1987; 243: 579-588
  • 28 Tollefsen DM, Petska CA, Monafo WJ. Activation of heparin cofactor II by dermatan sulfate. J Biol Chem 1983; 258: 6713-6716
  • 29 Lane DA, Ryan K, Ireland H, Curtis JR, Nurmohamed MT, Krediet RT, Roggekamp MC, Stevens P, ten CateJW. Dermatan sulphate in haemo-dialysis. Lancet 1992; 339: 334-335