Summary
Bay U3405 is a thromboxane A2 (TxA2)-receptor antagonist that inhibits the binding of TxA2 to its target cells. The aim of this study was to determine if Bay U3405 could be
used to inhibit arterial thrombosis. A thrombogenic de vice, consisting of uncrimped
Dacron vascular graft material (0.5 cm2) built into the wall of silicone rubber tubing with 4 mm inside diameter, was exposed
to native flowing blood under arterial blood flow conditions (100-140 ml/min) by interposing
the devices as extension segments into permanent femoral arteriovenous shunts implanted
in baboons. Thrombus formation was quantified in vivo by measuring the deposition
of 111In-labelled platelets onto the graft material with a scintillation camera. In six
baboons, a bolus injection of Bay U3405, calculated to attain an initial plasma concentration
of 300 ng/ml, reduced the maximum thrombus formation measured over a 2 h study period.
Platelet deposition was reduced by 33 ± 14% (SD) at 2 h as compared to control studies
done in the same baboons. The accumulation of additional platelets onto a thrombus
that was allowed to form for 1 h, was reduced by 58 ± 28% at 2 h. Ex vivo platelet
aggregation in response to ADP, activated partial thromboplastin time (APTT), prothrombin
time (PT), and thrombin time (TT) were not affected by the treatment. Ex vivo platelet
aggregation in response to collagen was markedly inhibited for 2 h after treatment.
The results demonstrated that selective blocking of the TxA2-receptor on platelets reduced platelet-dependent thrombus formation and the accumulation
of additional platelets in a freshly formed thrombus. This may provide a viable approach
for preventing excessive thrombus formation in patients undergoing arterial reconstructive
surgery.
