Download PDF
Thromb Haemost 1998; 80(02): 338-341
DOI: 10.1055/s-0037-1615198
Rapid Communication
Schattauer GmbH

Prevention and Therapy of Experimental Venous Thrombosis in Rabbits by Desmin 370

Mario Colucci
1   From the Department of Biomedical Sciences and Human Oncology, Section of General Pathology, University of Bari, and Alfa Wassermann, Bologna, Italy
,
Maria Rosaria Rossiello
1   From the Department of Biomedical Sciences and Human Oncology, Section of General Pathology, University of Bari, and Alfa Wassermann, Bologna, Italy
,
Miriam Barbanti
1   From the Department of Biomedical Sciences and Human Oncology, Section of General Pathology, University of Bari, and Alfa Wassermann, Bologna, Italy
,
Fiorella Calanni
1   From the Department of Biomedical Sciences and Human Oncology, Section of General Pathology, University of Bari, and Alfa Wassermann, Bologna, Italy
,
Nicola Semeraro
1   From the Department of Biomedical Sciences and Human Oncology, Section of General Pathology, University of Bari, and Alfa Wassermann, Bologna, Italy
› Author Affiliations
Further Information

Publication History

Received 27 January 1998

Accepted after revision 17 April 1998

Publication Date:
08 December 2017 (online)

Also available at
    Permissions and Reprints

Summary

Desmin 370 (D370), a low molecular weight dermatan sulfate, has been shown to reduce the size of preformed thrombi in rats, via a mechanism largely independent of its anticoagulant activity. In the present study we investigated the therapeutic efficacy of D370 in rabbits with experimental jugular vein thrombosis. Experiments performed to evaluate the antithrombotic dosages in rabbits indicated that D370 prevented the formation of venous thrombi (Wessler model) in a dose-dependent manner with complete inhibition at 20 mg/kg. When injected to rabbits bearing a 30 min aged thrombus, D370 caused a time- and dose-dependent reduction in thrombus weight. Thrombi harvested 2 h after injection of 50 mg/kg of D370 were 71% smaller than thrombi from saline-treated rabbits and 50% smaller than pretreatment thrombi, suggesting a double effect of the drug: inhibition of thrombus accretion and reduction of the existing thrombus. Interestingly, pretreatment with the fibrinolytic inhibitor EACA (1 g/kg), significantly attenuated the therapeutic efficacy of D370, suggesting a possible involvement of the fibrinolytic system. Heparin (50 and 200 U/kg) was less active as therapeutic agent, the maximal decrease in thrombus weight, as compared to untreated rabbits, amounting to 38%. Heparin, moreover, caused a more pronounced prolongation of APTT than comparable antithrombotic dosages of D370. Our present data extend previous results on the therapeutic efficacy of D370 and underscore its potential as an alternative antithrombotic drug.

 

  • References

  • 1 Tollefsen DM, Pestka CA, Monafo WJ. Activation of heparin cofactor II by dermatan sulfate. J Biol Chem 1983; 258: 6713-6.
    PubMedSearch in Google Scholar
  • 2 Ofosu FA, Modi GJ, Smith LM, Cerksus AL, Hirsh J, Buchanan MR. Heparan sulfate and dermatan sulfate inhibit the generation of thrombin activity in plasma by complementary pathways. Blood 1984; 54: 742-9.
    PubMedSearch in Google Scholar
  • 3 Fernandez F, Van Ryn J, Ofosu FA, Hirsh J, Buchanan MR. The haemorrhagic and antithrombotic effects of dermatan sulphate. Br J Haematol 1986; 64: 309-17.
    CrossrefPubMedSearch in Google Scholar
  • 4 Merton RE, Thomas DP. Experimental studies of the relative efficacy of dermatan sulphate and heparin as antithrombotic agents. Thromb Haemost 1987; 58: 839-42.
    Thieme ConnectPubMedSearch in Google Scholar
  • 5 Van Ryn-Mc Kenna J, Ofosu FA, Gray E, Hirsh J, Buchanan MR. The effects of dermatan sulfates and heparin on inhibition of thrombus growth in vivo. Ann NY Acad Sci USA 1989; 556: 304-12.
    CrossrefPubMedSearch in Google Scholar
  • 6 Mascellani G, Bianchini P. European patent 1990, No. 0221977; USA patent 1990, No. 4973580.
    PubMed
  • 7 Dol F, Petitou M, Lormeau J, Choay J, Caranobe C, Sié P, Saivin S, Houin G, Boneu B. Pharmacologic properties of a low molecular weight dermatan sulphate: Comparison with unfractionated dermatan sulphate. J Lab Clin Med 1989; 115: 43-51.
    PubMedSearch in Google Scholar
  • 8 Dettori AG, Milani MR, Manotti C, Zamboni V, Palazzini E, Barbanti M. Pharmacology of Desmin (low molecular weight dermatan sulphate) in healthy volunteers following intravenous bolus administration of different dosages (200, 400, 800 mg). Thromb Res 1995; 79: 249-60.
    CrossrefPubMedSearch in Google Scholar
  • 9 Barbanti M, Calanni F, Milani MR, Marchi E, Semeraro N, Colucci M. Therapeutic effect of a low molecular weight dermatan sulphate (Desmin 370) in rat venous thrombosis. Evidence for an anticoagulant-independent mechanism. Thromb Haemost 1993; 69: 147-51.
    Thieme ConnectPubMedSearch in Google Scholar
  • 10 Barbanti M, Calanni F, Marchi E, Semeraro N, Colucci M. Desmin 370, a low molecular weight dermatan sulfate, reduces the weight of preformed thrombi in rats made afibrinogenemic by ancrod. Thromb Haemost 1995; 73: 287-90.
    Thieme ConnectPubMedSearch in Google Scholar
  • 11 Colucci M, Sardella L, Barbanti M, Calanni F, Semeraro N. Thrombolysis enhancing activity of a low molecular weight dermatan sulfate (Desmin 370) in experimental pulmonary embolism in rats. Thromb Res 1997; 87: 441-6.
    CrossrefPubMedSearch in Google Scholar
  • 12 Wessler S. Thrombosis in the presence of vascular stasis. Am J Med; 1962; 33: 648-66.
    CrossrefPubMedSearch in Google Scholar
  • 13 Collen D, Stassen JM, Verstraete M. Thrombolysis with human extrinsic (tissue type) plasminogen activator in rabbits with experimental jugular vein thrombosis. J Clin Invest 1983; 71: 368-76.
    CrossrefPubMedSearch in Google Scholar
  • 14 Astrup T, Mullertz S. Fibrin plate method for estimating fibrinolytic activity. Arch Biochem Biophys 1952; 40: 346-51.
    CrossrefPubMedSearch in Google Scholar
  • 15 Haverkate F, Brakman P. Fibrin plate assay. In: Progress in Chemical fibrinolysis and thrombolysis, vol 1. Davidson JF, Samama MM, Desnoyers PC. eds. New York: Raven Press; 1975: 151-9.
    Search in Google Scholar
  • 16 Colucci M, Altomare DF, Chetta G, Triggiani R, Cavallo LG, Semeraro N. Impaired fibrinolysis in obstructive jaundice. Evidence from clinical and experimental studies. Thromb Haemost 1988; 60: 25-9.
    Thieme ConnectPubMedSearch in Google Scholar
  • 17 Agnelli G, Pascucci C, Cosmi B, Nenci GG. The comparative effects of recombinant hirudin (CGP 39393) and standard heparin on thrombus growth in rabbits. Thromb Haemost 1990; 63: 204-7.
    Thieme ConnectPubMedSearch in Google Scholar
  • 18 Weitz JI, Hudoba M, Massel D, Maraganore J, Hirsh J. Clot-bound thrombin is protected from inhibition by heparin-antithrombin III but is susceptible to inactivation by antithrombin III-independent inhibitors. J Clin Invest 1990; 86: 385-91.
    CrossrefPubMedSearch in Google Scholar
  • 19 Brieger D, Dawes J. Low molecular weight heparin is responsible for the anti-Xa activity of Desmin 370. Thromb Haemost 1996; 75: 286-91.
    Thieme ConnectPubMedSearch in Google Scholar
  • 20 Haremberg J, Jeschek M, Acker M, Malsch R, Huhle J, Heene DL. Effects of low-molecular-weight dermatan sulfate on coagulation, fibrinolysis and tissue factor pathway inhibitor in healthy volunteers. Blood Coagulat Fibrinol 1996; 7: 49-56.
    PubMedSearch in Google Scholar
  • 21 Legnani C, Palareti G, Biagi R, Ludovoci S, Maggiore L, Milani M, Coccheri S. Acute and chronic effects of a new low molecular weight dermatan sulphate (Desmin 370) on blood coagulation and fibrinolysis in healthy subjects. Eur J Pharmacol 1994; 47: 247-52.
    PubMedSearch in Google Scholar
  • 22 Carrie D, Caranobe C, Gabaig AM, Larroche M, Boneu B. Effects of heparin, dermatan sulfate and their association on the inhibition of venous thrombosis growth in the rabbit. Thromb Haemost 1992; 68: 637-41.
    Thieme ConnectPubMedSearch in Google Scholar