Antithrombotic activity of a monoclonal antibody inducing the substrate form of plasminogen activator inhibitor type 1 in rat models of venous and arterial thrombosis

1 Elevated plasminogen activator inhibitor 1 (PAI‐1) is a risk factor for thrombosis, and inhibitors of the interaction between PAI‐1 and tissue plasminogen activator (t‐PA) have antithrombotic and pro‐thrombolytic activity in animals. We describe the antithrombotic effects in the rat of a monoclonal antibody (MA33H1) which converts PAI‐1 to a non‐inhibitory substrate. 2 The activity of MA33H1 against rat PAI‐1 was confirmed using two‐chain t‐PA and a chromogenic substrate. MA33H1 was evaluated in rat venous (thromboplastin+stasis in the abdominal vena cava) and arterial (electric current applied to a carotid artery) thrombosis models. The effects on tail‐transection bleeding time were studied. 3 MA33H1 at 100 ng ml −1 inhibited both human (44.1%) and rat PAI‐1 (49.7%). This effect was concentration‐dependent. Its effect on human PAI‐1 was not significantly inhibited by 1 μg ml −1 fibrin or a ≈7 fold molar excess of vitronectin (1 n M ). Inhibition of rat PAI‐1 was unchanged by fibrin, but vitronectin reduced inhibition from 0.5 n M . 4 In the venous thrombosis model, MA33H1 significantly reduced thrombus weights by 38 and 58.6% at 50 and 100 μg kg −1 min −1 i.v. respectively. This effect was inhibited by tranexamic acid. In the arterial model, MA33H1 significantly increased the delay to occlusive thrombus formation by 58 and 142% at 50 and 100 μg kg −1  min −1 i.v., and did not affect bleeding time at 300 μg kg −1  min −1 i.v. 5 Thus, a monoclonal antibody which transforms PAI‐1 to a t‐PA substrate prevents thrombus formation in the rat with no effect on bleeding time at a higher dose.British Journal of Pharmacology (1998) 125 , 29–34; doi: 10.1038/sj.bjp.0702030