Low molecular weight heparins prevent thrombin-induced thromboembolism in mice despite low antithrombin activity. Evidence that the inhibition of feed-back activation of thrombin generation confers safety advantages over direct thrombin inhibition

Background and Objectives. Thrombin-induced thromboembolism in mice is a mo del in which the feed-back clotting activation produced by the injected enz yme greatly contributes to fibrin accumulation in lungs and to mortality, U sing this model we have previously shown that activated human protein C (aP C), by interrupting endogenous clotting activation at a high level (factors Va and Villa), prevents mortality inducing only a minor hemostatic impairm ent. With the same model we have now compared the antithrombotic and prohem orrhagic effects of two low molecular weight heparins (LMWHs), reviparin an d tinzaparin, which are expected to inhibit preferentially the positive fee d-back triggered by thrombin (anti Xa activity), with those of unfractionat ed heparin (UFH) and PEG-hirudin, which inhibit mainly or exclusively throm bin activity. (anti IIa activity). Design and Methods, Pulmonary thromboembolism was induced in mice by i.v. i njection of bovine thrombin (1,000U/kg). Drugs (from 0.12 to 1.2 mg/kg) wer e given as bolus injection 2 min prior to thrombin challenge and mortality was assessed within 15 min. The bleeding time was assessed by a tail tip tr ansection model. Activated partial thromboplastin time (aPTT), thrombin clo tting time (TcT), fibrinogen assay and anti Xa activity determination were performed in citrated plasma from saline- or drug-treated animals. Results. All drugs protected mice from thrombin-induced mortality in a dose -dependent way. At comparable antithrombotic dosages, the anti IIa activity generated in plasma (assessed by TcT) was highest with UFH, intermediate w ith tinzaparin and very low with reviparin. Accordingly, the fibrinogen dro p, which is caused mainly by the injected thrombin, was prevented by the he parins to an extent that was fairly well related to their anti IIa activity . aPTT and bleeding time, used as measures of hemorrhagic risk, were marked ly more prolonged by UFH than by reviparin. Tinzaparin, instead, had an int ermediate effect. Interestingly, PEG-hirudin, at equipotent antithrombotic dosages, caused a prolongation of bleeding time comparable to that observed with UFH. Interpretations and Conclusions. Our data show that, in our model, drugs ac ting at a high level of the blood clotting cascade, like LMWHs with a high anti Xa/anti IIa ratio, display a better antithrombotic/prohemorrhagic prof ile than drugs acting prevalently on thrombin. (C) 2001, Ferrata Storti Fou ndation.