CHARACTERIZATION OF A NOVEL SERIES OF APROTININ-DERIVED ANTICOAGULANTS .2. COMPARATIVE ANTITHROMBOTIC EFFECTS ON PRIMARY THROMBUS FORMATIONIN-VIVO

Upon vascular damage platelet activation and blood coagulation are ini tiated. Interference at the initial level of the activation of the coa gulation cascade can result in effective inhibition of thrombus format ion. The in vivo antithrombotic properties of a series of bovine pancr eatic trypsin inhibitor mutants (BPTI, aprotinin) 4C2, 7L22, 5L15, 5L1 5-PEG, 6L15 and 5L84, as described in the accompanying paper, with a c ombined inhibitory activity on factor Xa, factor VIIa-tissue factor co mplex, factor XIa and plasma kallikrein were compared to rTAP, r-hirud in, heparin and enoxaparin in a platelet rich thrombosis model in hams ters. Platelet dependent thrombus deposition was quantified by dedicat ed image analysis after transillumination of the femoral vein to which a standardised vascular trauma was applied. After increasing intraven ous bolus injections all tested agents, except for aprotinin, induced a dose dependent decrease of thrombus formation and a concomitant prol ongation of the aPTT. From the linear correlation between these two pa rameters it was found that 5 out of the 6 tested aprotinin analogues, rTAP and r-hirudin completely inhibited thrombus formation at a therap eutical (2- to 3-fold) aPTT prolongation while 4C2, heparin and enoxap arin only inhibited thrombus formation for 40 to 50 percent at a 2-fol d aPTT prolongation Based on the calculated IC50 values for thrombus f ormation rTAP was found to be the most active compound in this model. It is concluded that acceptable interference at the initial level of t he blood coagulation, e.g. within a therapeutical aPTT prolongation, c an significantly inhibit platelet deposition at a site of vascular inj ury.