Thromb Haemost 1986; 56(02): 225-228
DOI: 10.1055/s-0038-1661645
Original Article
Schattauer GmbH Stuttgart

Dose Response Relationships of Anticoagulant Activities After Subcutaneous Administration of Two Low Molecular Weight Heparins in Healthy Individuals

P Hellstern
The Abteilung für Klinische Haemostaseologie und Transfusionsmedizin, Universitat des Saarlandes, Homburg/Saar, FRG
,
R Kiehl
The Abteilung für Klinische Haemostaseologie und Transfusionsmedizin, Universitat des Saarlandes, Homburg/Saar, FRG
,
G von Blohn
The Abteilung für Klinische Haemostaseologie und Transfusionsmedizin, Universitat des Saarlandes, Homburg/Saar, FRG
,
M Köhler
The Abteilung für Klinische Haemostaseologie und Transfusionsmedizin, Universitat des Saarlandes, Homburg/Saar, FRG
,
U Meierhenrich
The Abteilung für Klinische Haemostaseologie und Transfusionsmedizin, Universitat des Saarlandes, Homburg/Saar, FRG
,
E Wenzel
The Abteilung für Klinische Haemostaseologie und Transfusionsmedizin, Universitat des Saarlandes, Homburg/Saar, FRG
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received 12. Mai 1986

Accepted after revision 22. Juli 1986

Publikationsdatum:
20. Juli 2018 (online)

Summary

This study was performed to estimate appropriate dosages of two low molecular weight heparins (LMWH) for clinical trials on subcutaneous perioperative thrombosis prophylaxis. Anticoagulatory activities and platelet function were investigated after single doses of two LMWH and of unfractionated sodium heparin (UFH) in 24 healthy individuals. Twelve subjects received subcutaneous injections of 1000, 1500, and 2500 i.u. (aPTT) of LMHW 1, and the other 12 received LMWH 2 at same dosages. The following parameters were determined before 30 min, 1 h, 90 min, 2 h, 3 h, 4 h, 6 h, 8 h, and 10 h after either LMWH or 5000 i.u. (aPTT) UFH: aPTT, thrombin time, anti-Xa activity (S 2222, Coatest heparin), and anti-IIa activity (Chromozym TH). Bleeding time, platelet count, and adrenalin-, collagen-, and ADP-induced platelet aggregation were assessed before and 3 h after administration.

After application of 1500 i.u. LMWH 1 and LMWH 2, the anti-Xa and anti-IIa levels were already significantly higher than after 5000 i.u. UFH. 2500 i.u. LMWH 1 and LMWH 2 evoked significantly greater prolongations of aPTT and thrombin time values than did 5000 i.u. UFH. This was not the case after 1000 and 1500 i.u. LMWH. The half-lives of anticoagulatory effects after LMWH were markedly longer than after UFH. Platelet function was not altered by any of the heparins tested. Our results indicate that LMWH cause anticoagulatory effects in vivo that cannot be predicted by in vitro studies and that the appropriate single dosages of LMWH in subcutaneous perioperative thrombosis prophylaxis have to be estimated by dosage determinations in healthy subjects.

 
  • References

  • 1 Holmer E, Kurachi K, Söderström G. The molecular-weight dependence of the rate-enhancing effect of heparin on the inhibition of thrombin, factor Xa, factor IXa, factor XIa, factor XIIa and kalli-krein by antithrombin. Biochem J 1981; 193: 395-400
  • 2 Barrowcliffe TW, Johnson EA, Eggleton CA, Kemball-Cook G, Thomas DP. Anticoagulant activities of high and low molecular weight heparin fractions. Brit J Haematol 1979; 41: 573-583
  • 3 Carter CJ, Kelton JG, Hirsh J, Cerskus A, Santos AV, Gent M. The relationship between the hemorrhagic and antithrombotic properties of low molecular weight heparin in rabbits. Blood 1982; 59: 1239-1245
  • 4 Doutremepuich C, Gestreau JL, Maury MO, Quilichini R, Boisseau MR, Toulemonde F, Vairel E. Experimental venous thrombosis in rats treated with heparin and low molecular weight heparin fraction. Haemostasis 1983; 13: 109-112
  • 5 Kakkar VV, Djazaeri B, Fok J, Fletcher M, Scully MF, Westwick J. Low-molecular-weight heparin and prevention of postoperative deep venous thrombosis. Brit Med J 1982; 284: 375-379
  • 6 Kakkar VV. Prevention of post-operative venous thromboembolism by a new low molecular weight heparin fraction. Nouv Rev Fr Hematol 1984; 26: 277-282
  • 7 Bratt G, Törnebohm E, Granqvist S, Aberg 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
  • 8 Thomas DP, Merton RE. A low molecular weight heparin compared with unfractionated heparin. Thromb Res 1982; 28: 343-350
  • 9 Aiach M, Michaud A, Balian J, Lefebre M, Woler M, Fourtillan J. A new low molecular weight heparin derivative. Thromb Res 1983; 31: 611-621
  • 10 Bara L, Billaud E, Gramond G, Kher A, Samama M. Comparative pharmacokinetics of a low molecular weight heparin (PK 10169) and unfractionated heparin after intravenous and subcutaneous administration. Thromb Res 1985; 39: 631-636
  • 11 Barrowcliffe TW, Curtis AD, Tomlinson TP, Hubbard AR, Johnson EA, Thomas DP. Standardization of low molecular weight heparins: a collaborative study. Thromb Haemostas 1985; 54: 675-679
  • 12 Schmitz-Huebner U, Bünte H, Freise G, Reers B, Rüschemeyer C, Scherer R, Schulte H, Van de Loo J. Clinical efficacy of low molecular weight heparin in postoperative thrombosis prophylaxis. Klin Wochenschr 1984; 62: 349-353
  • 13 Mielke CH, Kaneshiro MM, Maher IA, Weinere JM, Rapaport SI. The standardized normal Ivy bleeding time and its prolongation by aspirin. Blood 1969; 34: 204-215
  • 14 Teien AN, Lie M. Evaluation of an amidolytic heparin assay method: increased sensitivity by adding purified antithrombin III. Thromb Res 1977; 10: 399-410
  • 15 Van Putten J, Van de Ruit M, Beunis M, Hemker HC. Determination of low molecular weight heparin in clinical laboratory. Haemostasis 1984; 14: 205-210
  • 16 Lane DA, Mac Gregor IR, Van Ross M, Cella G, Kakkar VV. Molecular weight dependence of the anticoagulant properties of heparin: intravenous and subcutaneous administration of fractionated heparins to man. Thromb Res 1979; 16: 651-662
  • 17 Harenberg J, De Vries JX, Weber E, Zimmermann R. BeeinfluBung der Blutgerinnung durch ein niedermolekulares Heparin. Dtsch med Wschr 1984; 109: 951-954
  • 18 Bergqvist D, Hedner V, Sjörin E, Holmer E. Anticoagulant effects of two types of low molecular weight heparin administered subcutaneously. Thromb Res 1983; 32: 381-391
  • 19 Schmitz-Huebner U, Röschemeyer C, Schulte H, Van de Loo J. Infuence of low molecular weight heparin on the hemostatic system after abdominal surgery. Thromb Haemostas 1985; 53: 297-300