Download PDF
Thromb Haemost 1989; 61(03): 357-362
DOI: 10.1055/s-0038-1646595
Original Article
Schattauer GmbH Stuttgart

Biological Activrty and Safety of the Subcutaneous Administration of High Doses of Low Molecular Weight Heparin for 8 Days in Human Volunteers

J Harenberg
1   The Department of Medicine, Klinikum Mannheim, University of Heidelberg, Mannheim, FRG
,
Ch Giese
1   The Department of Medicine, Klinikum Mannheim, University of Heidelberg, Mannheim, FRG
,
C E Dempfle
1   The Department of Medicine, Klinikum Mannheim, University of Heidelberg, Mannheim, FRG
,
G Stehle
1   The Department of Medicine, Klinikum Mannheim, University of Heidelberg, Mannheim, FRG
,
D L Heene
1   The Department of Medicine, Klinikum Mannheim, University of Heidelberg, Mannheim, FRG
› Author Affiliations
Further Information

Publication History

Received 11 November 1988

Accepted after revision 18 January 1989

Publication Date:
24 July 2018 (online)

Also available at
  PDF Download  Permissions and Reprints

Summary

This study reports on the biological activity and safety of high dose low molecular weight (LMW) heparin therapy administered by two subcutaneous (s.C.) injections daily for 8 days in healthy human volunteers. Group 1 received 2 × 30 aPTT units LMW heparin/kg bodyweight, and group 2 received 2 × 50 aPTT units/kg per day.

In group 1, activated partial thromboplastin time (aPTT) and thrombin clotting time (TCT) were uniformly prolonged by 3-5 sec 4 hrs after s.c. administration of heparin. Heptest coagulation time values were prolonged consistently as well by 57 sec on day 1 to 68 sec on day 8. Factor Xa inhibition measured by the S 2222 chromogenic substrate method continuously increased from 0.16 units/ml on day 1 to 0.28 units/ml on day 8.

In group 2 prolongation of a aPTT and TCT values increased from 6 sec on day 1 to 15 sec on day 8 and of Heptest time from 70 sec on day 1 to 110 sec on day 8. S 2222 method showed factor Xa inhibitory activity which increased from 0.5 units/ml on day 1 to 0.75 units/ml on day 8. The clinical tolerance of the treatment was good. No changes in clinical chemistry parameters were detected, except for a reversible increase of serum transaminases.

The coagulation studies demonstrate accumulation of LMW heparin when high doses are given twice daily. The half life of LMW heparin of factor Xa inhibition increases with increasing doses.

Heptest coagulation values were prolonged to 4-6 times the normal values during administration of heparin. S 2222 chromogenic substrate values were in the same range as upon application of high doses of unfractionated heparin. aPTT and thrombin clotting time values ranged from 1.2 to 1.5 times the starting values.

Keywords

Heparin - Low molecular weight heparin - Factor Xa - Anticoagulation
 

  • References

  • 1 Barrowcliffe TW, Johnson EA, Eggleton CA, Thomas DP. Anticoagulant activities of lung and mucous heparins. Thromb Res 1977; 12: 27-36
    PubMedGoogle Scholar
  • 2 Bratt G, Törnebohm E, Lockner D, Bergström K. A human pharmacological study comparing conventional heparin and a low molecular weight heparin fragment. Thromb Haemostas 1985; 53: 208-211
    PubMedGoogle Scholar
  • 3 Harenberg J, Gnasso A, De Vries JX, Zimmermann R, Augustin J. Anticoagulant and lipolytic effects of a low molecular weight heparin fraction. Thromb Res 1985; 39: 683-692
    CrossrefPubMedGoogle Scholar
  • 4 Bratt G, Törnebohm E, Widlund L, Lockner D. Low molecular weight heparin (Kabi 2165, Fragmin): Pharmacokinetics after intravenous and subcutaneous administration in human volunteers. Thromb Res 1986; 42: 613-620
    CrossrefPubMedGoogle Scholar
  • 5 Harenberg J, Würzner B, Zimmermann R, Schettler G. Bioavailability and antagonization of the low molecular weight heparin CY 216 in man. Thromb Res 1986; 44: 549-554
    CrossrefPubMedGoogle Scholar
  • 6 Kakkar VV, Djazaeri B, Fok J, Fletcher M, Scully MF, Westwick J. Low-molecular-weight heparin and prevention of postoperative deep vein thrombosis. Br Med J 1982; 284: 375-379
    CrossrefPubMedGoogle Scholar
  • 7 Kakkar VV, Murray WJ G. Efficacy and safety of low-molecular weight heparin (CY 216) in preventing postoperative venous thromboembolism: a co-operative study. Br J Surg 1985; 72: 786-791
    CrossrefPubMedGoogle Scholar
  • 8 Bergqvist D, Burmark US, Frisell J, Hallböck T, Lindblad B, Risberg B, Tömgren S, Wallin G. Low molecular weight heparin once daily compared with conventional low-dose heparin twice daily. A prospective double-blind multicentre trial on prevention of postoperative thrombosis. Br J Surg 1986; 73: 204-208
    CrossrefPubMedGoogle Scholar
  • 9 Sasahara AA, Koppenhagen K, Häring R, Welzel D, Wolf H. Low molecular weight heparin plus dihydroergotamine for prophylaxis of postoperative deep vein thrombosis. Br J Surg 1986; 73: 697-700
    CrossrefPubMedGoogle Scholar
  • 10 Koller M, Schoch U, Buchmann P, Largiader F, von Felten A, Frick PG. Low molecular weight heparin (Kabi 2165) as thromboprophylaxis in elective visceral surgery. Thromb Haemostas 1986; 56: 243-246
    PubMedGoogle Scholar
  • 11 Turpie AG G, Hirsh J, Jay RM, Andrew M, Hull RD, Levine MN, Carter CJ, Powers PJ, Magnani HN, Gent M. Double-blind randomised trial of Org 10172 low-molecular weight heparinoid in prevention of deep-vein thrombosis in thrombotic stroke. Lancet 1987; 1: 523-526
    PubMedGoogle Scholar
  • 12 Caen JP. A randomized double-blind study between a low molecular weight heparin Kabi 2165 and standard heparin in the prevention of deep vein thrombosis in general surgery. Thromb Haemostas 1988; 59: 216-220
    PubMedGoogle Scholar
  • 13 Bratt G, Törnebohm E, Cranqvist S, Åberg W, Lockner D. A comparison between low molecular weight heparin (Kabi 2165) and standard heparin in the intravenous treatment of deep venous thrombosis. Thromb Haemostas 1985; 54: 813-817
    PubMedGoogle Scholar
  • 14 Janvier G, Winnock S, Dugrais G, Vallet A, Dardel E, Serisé JM, Calen S, Vergnes C, Toulemonde F. Treatment of deep venous thrombosis with a very low molecular weight heparin fragment (CY 222). Haemostasis 1987; 7: 49-58
    PubMedGoogle Scholar
  • 15 Holm HA, Abildgaard U. Heparin treatment of deep venous thrombosis: correlation between clinical effects and heparin assays. In: Heparin – New Biochemical and Medical Aspects. Walter de Gruyter & Co.; Berlin, New York: 1982. pp 289-300
    Google Scholar
  • 16 Villain P, Bouvier JL, Le Corff G, Elias A, Juhan-Vague I, Serradimigni A. Do aPTT and anti IIa activity permit the prediction of the efficiency of heparin therapy in patients with proximal deep vein thrombosis. Thromb Haemostas 1987; 58: 376 (Abstr 1372)
    PubMedGoogle Scholar
  • 17 Hirsh J, Barrowcliffe TW. Standardization and clinical use of LMW heparin. Thromb Haemostas 1988; 59: 333
    PubMedGoogle Scholar
  • 18 Harenberg J, Giese Ch, Knödler A, Zimmermann R. Comparative study on a new one-stage clotting assay for heparin and its low molecular weight derivatives. Haemostasis 1989; 19: 13-20
    PubMedGoogle Scholar
  • 19 Harenberg J. Modified anti-factor Xa chromogenic substrate assay for heparin and low molecular weight heparins. Ärztl Lab 1987; 33: 39-41
    PubMedGoogle Scholar
  • 20 Thomas DP, Barrowcliffe TW, Merton RE, Stocks J, Dawes J, Pepper DS. In vivo release of anti-Xa clotting activity by a heparin analogue. Thromb Res 1980; 17: 831-840
    CrossrefPubMedGoogle Scholar
  • 21 Hoylaerts M, Holmer E, de Mol M, Collen D. Covalent complexes between low molecular weight heparin fragments and antithrombin III-Inhibition kinetics and turnover parameters. Thromb Haemostas 1983; 49: 109-115
    PubMedGoogle Scholar
  • 22 Bounameaux H, Marbet GA, Lämmle B, Eichlisberger R, Duckert F. Monitoring of heparin treatment. Comparison of thrombin time, activated partial thromboplastin time, and plasma heparin concentration, and analysis of the behavior of antithrombin III. Am Soc Clin Pathol 1980; 74: 68-73
    PubMedGoogle Scholar
  • 23 Suchnian AL, Griner PF. Diagnostic uses of the activated partial thromboplastin time and prothrombin time. Ann Intern Med 1986; 104: 810-816
    CrossrefPubMedGoogle Scholar
  • 24 Fey MF, Lang M, Furlan M, Beck EA. Monitoring of heparin therapy with the activated partial thromboplastin time and chromogenic substrate assays. Thromb Haemostas 1987; 58: 853-855
    PubMedGoogle Scholar
  • 25 Dukes GE, Sanders SW, Russo J, Swenson E, Bumakis TG, Saffle JR, Warden GD. Transaminase elevations in patients receiving bovine or porcine heparin. Ann Intern Med 1984; 100: 646-650
    CrossrefPubMedGoogle Scholar
  • 26 Minar E, Ehringer H, Hirschl M, Ingerle H, Konecny U, Marosi L, Endler T, Gabl F, Deutsch E. Transaminasenanstieg: eine weitgehend unbekannte Nebenwirkung der Heparintherapie. Dtsch Med Wschr 1980; 105: 1713-1717
    Article in Thieme ConnectPubMedGoogle Scholar
  • 27 Bertoli D, Borelli G. Toxic and mutagenic effects of a low molecular weight heparin in rats. Drug Res 1986; 36: 1256-1260
    PubMedGoogle Scholar
  • 28 Marciniak E, Gockerman JP. Heparin-induced decrease in circulating antithrombin III. Lancet 1977; 1: 581-584
    PubMedGoogle Scholar
  • 29 Haas S, Stemberger A, Fritsche HM, Welzel D, Wolf H, Lechner F, BlËmel G. Prophylaxis of deep vein thrombosis in high risk patients undergoing total hip replacement with low molecular weight heparin plus dihydroergotamine. Drug Res 1987; 37: 839-843
    PubMedGoogle Scholar
  • 30 Harenberg J, Kallenbach B, Martin U, Zimmermann R. Randomized double blind study of normal and a low molecular weight heparin in general medical patients. Thromb Haemostas 1987; 58: 381 (Abstr 1392)
    PubMedGoogle Scholar
  • 31 Olsson P, Lagergren H, Ek S. The elimination from plasma of intravenous heparin. Acta Med Scand 1963; 173: 619-630
    PubMedGoogle Scholar