The antithrombotic effect of aurin tricarboxylic acid in the guinea pig is not solely due to its interaction with the von Willebrand factor-GPIb axis.

Commercial aurin tricarboxylic acid (ATA) has been reported to interfere specifically with von Willebrand factor-glycoprotein Ib (vWF-GPIb) axis. This study was designed to explore the antithrombotic effects of ATA by examining its effects on guinea pig platelet function in vitro, in vivo and ex vivo. In vitro, addition of various concentrations of ATA to platelet-rich guinea pig plasma totally inhibited ristocetin-induced platelet aggregation, as expected. Unexpectedly, however, ATA similarly inhibited the aggregation induced by ADP, PAF, collagen, I-BOP (a thromboxane A2/prostaglandin H2 analogue) and arachidonic acid. In vivo, the antithrombotic action of ATA was assessed in a model of acute platelet-dependent guinea pig mesenteric artery thrombosis triggered by laser-induced intimal injury. As the thrombotic response of arteries to such injury is a spontaneous cyclic recurrent process, 5 arteries in each animal were consecutively studied for 15 min each after i.v. bolus injection of 5, 7.5 or 10 mg/kg of ATA, which reduced the number of recurrent thrombi per artery in a dose-dependent manner. The highest dose of 10 mg/kg induced maximal inhibition of thrombus formation (72%, p < 0.001) 5 min after injection. Ex vivo, platelet aggregation was assessed in blood samples taken before and after i.v. bolus injection of 10 or 15 mg/kg ATA. Ten mg/kg significantly inhibited collagen-induced aggregation, and 15 mg/kg, the aggregation induced by ristocetin, ADP, PAF, collagen, I-BOP and arachidonic acid. The results of the in vivo studies confirmed that ATA is an effective antithrombotic agent. In the in vitro and ex vivo studies, ristocetin-induced platelet aggregation confirmed that ATA interacts with the vWF-GPIb axis, and suggests that the final common pathway of the aggregation induced by other agents tested consists of fibrinogen binding to the platelet GPIIb/IIIa receptor. We conclude that ATA interferes with vWF binding to GPIb, that it may interact with fibrinogen binding to GPIIb/IIIa, and that it might possess potent antithrombotic properties in platelet-mediated thrombosis.

Aurintricarboxylic acid prevents acute rethrombosis in a canine model of arterial thrombosis.

Acute rethrombosis following thrombolytic therapy occurs in 5% to 25% of patients. We evaluated the effect of aurintricarboxylic acid (ATA), a triphenyl dye that blocks von Willebrand factor (vWF) binding to platelet glycoprotein Ib, on arterial reperfusion and acute rethrombosis following fibrinolytic therapy. Primary thrombosis was induced in the femoral arteries of anesthetized dogs by application of anodal current and partial arterial constriction. Blood flow was monitored with an electromagnetic flow probe, and primary thrombosis was considered to have occurred when blood flow was reduced to and remained at zero. Reperfusion was induced by intravenous streptokinase 30 minutes after thrombosis. Streptokinase reduced plasma fibrinogen levels from an average of 144 mg/dL to < 5 mg/dL resulting in inhibition of ADP- and epinephrine-induced platelet aggregation ex vivo. Acute rethrombosis following reperfusion occurred within 37 +/- 18 (mean +/- SD) minutes in 89% (16/18) of animals receiving thrombolytic activator treatment. Histological examination of reoccluding thrombi revealed densely aggregated platelets and erythrocytes with no detectable fibrin. In the two other study groups, ATA was infused in conjunction with thrombolytic therapy (10 arteries) or at near completion of acute rethrombosis following fibrinolytic activator treatment (6 arteries). In each case ATA prevented rethrombosis. However, concomitant administration of ATA and thrombolytic therapy delayed restoration of blood flow. ATA had no direct effect on hemodynamics, thrombin time, platelet count, or platelet aggregation response to ADP, epinephrine, or collagen. These data indicate that inhibition of vWF-platelet glycoprotein Ib interaction is effective in preventing acute rethrombosis following thrombolytic therapy.(ABSTRACT TRUNCATED AT 250 WORDS)