INHIBITION BY AURINTRICARBOXYLIC ACID OF VON-WILLEBRAND-FACTOR BINDING TO PLATELET GPIB, PLATELET RETENTION, AND THROMBUS FORMATION IN-VIVO

Commercial aurintricarboxylic acid (ATA) was separated into molecular-weight (MW) fractions of <210 to >25,000, using gel permeation chromatography. Fractions with MW >1,300 effectively inhibited both botrocetin-induced vWF and bovine vWF binding to fixed human platelets. These activities decreased with a MW >17,000. Platelet retention for a human in vitro was reduced by ATA at 150 mu M, as was that for rats ex vivo at 3 mg/kg. ATA prolonged tail transection bleeding time in rats but had only a weak effect on buccal mucosal bleeding time in dogs. ATA had no effect on platelet count but markedly prolonged PTT. ATA at 10 mg/kg exhibited antithrombotic activity and caused a marked improvement in patency status following successful thrombolysis by t-PA in electrically and copper coil-induced thrombosis models. These results suggest that specific inhibitors of the vWF-GPIb interaction such as ATA may prove useful as antithrombotic agents. (C) 1994 Wiley-Liss, Inc.