Potentiation by Heparin Fragments of Thrombolysis Induced with Human Tissue-Type Plasminogen Activator or Human Single-Chain Urokinase-Type Plasminogen Activator

Summary

The effect of heparin and of two low molecular weight (low M _r) fractions of heparin on thrombolysis with recombinant human tissue-type plasminogen activator (rt-PA, Genentech Inc., So. San Francisco, CA) or human single chain urokinase-type plasminogen activator (scu-PA, Sandoz AG, Basle, Switzerland) was measured in a rabbit jugular vein thrombosis model. Four bolus injections of 200 anti-Factor Xa units/kg body weight of heparin (Liquemine, Hoffmann-La Roche, Basle, Switzerland), of 90 units/kg of CY 216 (Choay, Paris, France) or of 90 units/kg of CY 222 (Choay, Paris, France) were given intravenously, immediately after the start of the infusion of rt-PA or scu-PA and at hourly intervals during their intravenous infusion over 4 hours. The bolus injections resulted in anti-Factor Xa levels in plasma of 5.7 ± 1.2 units/ml just before the repeat bolus injections of heparin with corresponding values of 3.9 ± 0.2 units/ml for CY 216 and 1.6 ± 0.2 units/ml for CY 222.

Thrombolysis with 0.25 mg/kg rt-PA was 36 ± 1 percent (n = 9) in the absence of anticoagulant, 40 ± 1 percent (n = 7, p <0.05) in the presence of heparin, 49 ± 5 percent (n = 7, p <0.02) with CY 216 and 62 ± 5 percent (n = 7, p <0.01) with CY 222. Thrombolysis with 0.5 mg/kg scu-PA was 23 ± 1 percent (n = 4) without heparin, and increased to 24 ± 1 percent (n = 4, p >0.1) with heparin, to 32 ± 2 percent (n = 4, p <0.01) with CY 216 and to 33 ± 3 percent (n = 4, p <0.01) with CY 222.

It is concluded that, at these high doses, the two low M _r heparin fractions CY 216 and CY 222, potentiate thrombolysis by rt-PA and scu-PA in this animal model.

Keywords

Human tissue-type plasminogen activator (t-PA) - Single-chain urokinase-type plasminogen activator (scu-PA) - Heparin - Low molecular weight heparin - Thrombolysis

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