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Thromb Haemost 1994; 71(05): 558-562
DOI: 10.1055/s-0038-1642482
Review Article
Schattauer GmbH Stuttgart

A Pilot Study of Subcutaneous Recombinant Hirudin (HBW 023) in the Treatment of Deep Vein Thrombosis

F Schiele
1   The Centre Hospitalier Saint Jacques, Service de Cardiologie, Besançon, France
,
A Vuillemenot
1   The Centre Hospitalier Saint Jacques, Service de Cardiologie, Besançon, France
,
Ph Kramarz
1   The Centre Hospitalier Saint Jacques, Service de Cardiologie, Besançon, France
,
Y Kieffer
2   Centre de Transfusion Sanguine, Besançon, France
,
J Soria
3   Laboratoire Sainte Marie, Hôpital de l’Hôtel Dieu, Paris, France
,
C Soria
4   lnstitut des vais seaux et du sang, Laboratoire d’Hématologie, INSERM U 150, URA 184 CNRS, Hopitai Lariboisiére, Paris, France
,
A Camez
4   lnstitut des vais seaux et du sang, Laboratoire d’Hématologie, INSERM U 150, URA 184 CNRS, Hopitai Lariboisiére, Paris, France
,
M C Mirshahi
3   Laboratoire Sainte Marie, Hôpital de l’Hôtel Dieu, Paris, France
,
J P Bassand
1   The Centre Hospitalier Saint Jacques, Service de Cardiologie, Besançon, France
› Author Affiliations
Further Information

Publication History

Received 11 October 1993

Accepted after revision 19 January 1994

Publication Date:
06 July 2018 (online)

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Summary

Background: Recombinant hirudin, a pure, specific antithrombin could be more effective than heparin in the treatment of deep vein thrombosis, but its short half-life requires constant intravenous infusion, whereas subcutaneous administration of recombinant hirudin can ensure stable and prolonged plasma levels. The aim of our study was to assess the pharmacokinetics, the results on the coagulation variables, and the safety of a recombinant hirudin (HBW 023) administered subcutaneously in patients suffering from deep vein thrombosis.

Methods: Recombinant hirudin (HBW 023) was administered subcutaneously to 10 patients with recent deep vein thrombosis, at a dose of 0.75 mg/kg of body weight twice daily for 5 days, after which standard heparin and acenocoumarol were introduced. Bilateral lower limb venography, and pulmonary angiography, and/or ventilation-perfusion lung scan were carried out on day 1 prior to recombinant hirudin injection and repeated on day 5. aPTT and recombinant hirudin plasma levels were serially assessed after the 1st and the 10th injections. Prothrombin fragments 1 + 2, thrombin-antithrombin III complexes, fibrin degradation products were collected on days 1 and 5.

Results: Clinical evolution was uneventful in all but one patient who had a probable recurrence of pulmonary embolism on day 4. No hemorrhagic complication, no untoward biological event was observed. On days 5, Mardcr score was unchanged or had decreased. Plasma levels of recombinant hirudin peaked in between 3 and 4 h following the injection. aPTT values paralleled, and were significantly correlated with plasma levels of recombinant hirudin on day 1 as well on day 5 (r = 0.903, r = 0.948 respectively). Fragment 1 + 2, and thrombin antithrombin complexes non-significantly decreased from day 1 to day 5.

Conclusions: Subcutaneous administration of recombinant hirudin ensures prolonged stable plasma levels of recombinant hirudin which results in efficient anticoagulation. A dose-ranging study conducted with subcutaneous recombinant hirudin in comparison to conventional heparin therapy may answer the question as to efficacy.

 

  • References

  • 1 Bentley PG, Kakkar VV, Scully MF. et al. An objective study of alternative methods of heparin administration. Thromb Res 1980; 18: 177-187
    CrossrefPubMedSearch in Google Scholar
  • 2 Holm HA, Finnanger B, Hartmann A. et al Heparin treatment of deep venous thrombosis in 280 patients: Symptoms related to dosage. Acta Med Scand 1984; 215: 47-53
    PubMedSearch in Google Scholar
  • 3 Hull RD, Raskob GE, Hirsh J. Continuous intravenous heparin compared with intermittent subcutaneous heparin in the treatment of proximalvein hrombosis. N Engl J Med 1986; 315: 1109-1114
    CrossrefPubMedSearch in Google Scholar
  • 4 Walker MG, Shaw JW, Thomson GJL. et al Subcutaneous calcium heparin versus intravenous sodium heparin in treatment of established acute deep vein thrombosis of the legs: A multicentre prospective randomised trial. Br Med J 1987; 294: 1189-1192
    CrossrefPubMedSearch in Google Scholar
  • 5 Doyle DJ, Turpie AGG, Hirsh J. et al. Adjusted subcutaneous heparin or continuous intravenous heparin in patients with acute deep vein thrombosis. Annals Int Med 1987; 107: 441-445
    CrossrefPubMedSearch in Google Scholar
  • 6 Hull RD, Raskob GE, Hirsh J. Heparin for 5 days as compared with 10 days in the initial treatment of proximal-vein thrombosis. N Engl J Med 1990; 322: 1260-1266
    CrossrefPubMedSearch in Google Scholar
  • 7 Hirsh J, Heparin N. Engl J Med 1991; 315: 1109-1114
    PubMedSearch in Google Scholar
  • 8 Hull RD, Raskob GE, Pineo GF. et al Subcutaneous low-molecular-weight heparin compared with continous intravenous heparin in the treatment of proximal-vein thrombosis. New Engl J Med 1992; 326: 975-982
    CrossrefPubMedSearch in Google Scholar
  • 9 Albada J, Nieuwenhuis HK, Sixma JJ. Treatment of acute venous thromboembolism with low molecular weight heparin (Fragmin). Results of a double-blind randomized study. Circulation 1989; 80: 935-940
    CrossrefPubMedSearch in Google Scholar
  • 10 Holm HA, Ly B, Handeland GF. et al Subcutaneous heparin treatment of deep vein thrombosis: a comparison of unfractionated and low molecular weight heparin. Haemostasis 1986; 16 (suppl) 30-37
    PubMedSearch in Google Scholar
  • 11 Bratt G, Aberg W, Johansson M, Tornebohm E, Grandqvist S, Lockner D. Two daily subcutaneous injections of Fragmin as compared with intravenous standard heparin in the treatment of deep venous thrombosis. Thromb Haemost 1990; 64: 506-512
    Thieme ConnectPubMedSearch in Google Scholar
  • 12 Collaborative European Multicentre Study. A randomised trial of subcutaneous low molecular weight heparin (CY 216) compared with intravenous unfractionated heparin in the treatment of deep vein thrombosis. Thromb Haemost 1991; 65: 251-256
    Thieme ConnectPubMedSearch in Google Scholar
  • 13 Prandoni P, Lensing AWA, Biiller HR. et al Comparison of subcutaneous low-molecular-weight heparin with intravenous standard heparin in proximal deep-vein thrombosis. Lancet 1992; 339: 441-445
    CrossrefPubMedSearch in Google Scholar
  • 14 Bar-Shavit R, Eldor A, Vlodavsky I. Binding of thrombin to subendothelial extracellular matrix. Protection and expression of functional properties. J Clin Invest 1989; 84: 1096-104
    CrossrefPubMedSearch in Google Scholar
  • 15 Weitz JI, Hudoba M, Masscl D, Maraganorc J, Hirsh J. Clot bound throm bin is protected from inhibition by hepaiin-antithiombiii TIT but is susceptible to inactivation by antithrombin Ill-independent inhibitors. J Clin Invest 1990; 86: 385-391
    CrossrefPubMedSearch in Google Scholar
  • 16 Mirshashi M, Soria J, Soria C. et al Evaluation of the inhibition by heparin and hirudin of coagulation activation during rtPA-induced thrombolysis. Blood 1989; 74: 1025-1030
    PubMedSearch 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 1190; 63: 204-207
    PubMedSearch in Google Scholar
  • 18 Parent F, Bridey F, Dreyfus M. et al Treatment of severe venous thromboembolism with intravenous hirudin (HBW 023): an open pilot study. Thromb Res 1992; 65 (suppl I) 118 (abstract)
    PubMedSearch in Google Scholar
  • 19 Miller GAH, Sutton GC, Kerr IH, Gibson RV, Honey M. Comparison of streptokinase and heparin in the treatment of isolated acute massive pulmonary embolism. Br Med J 1971; 681-684
    PubMedSearch in Google Scholar
  • 20 Marder VJ, Soulen RL, Atichartakarn V. et al. Quantitative venographic assessment of deep vein thrombosis in the evaluation of streptokinase and heparin therapy. J Lab Clin Med 1977; 89: 1018-1029
    PubMedSearch in Google Scholar
  • 21 Griessbach U, Stürzebecher J, Markwardt F. Assay of hirudin in plasma using a chromogenic thrombin substrate. Thromb Res 1985; 37: 347-350
    CrossrefPubMedSearch in Google Scholar
  • 22 Grötsch H, Berscheid G, Hropot M, Ben Youssef R. Interference of heparin and analogues with hirudin in the chromogenic thrombin substrate assay. Thromb Res 1991; 64: 285-290
    CrossrefPubMedSearch in Google Scholar