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

Abstract

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 prothrombolytic 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 microg ml(-1) fibrin or a approximately 7 fold molar excess of vitronectin (1 nM). Inhibition of rat PAI-1 was unchanged by fibrin, but vitronectin reduced inhibition from 0.5 nM. 4. In the venous thrombosis model, MA33H1 significantly reduced thrombus weights by 38 and 58.6% at 50 and 100 microg 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 microg kg(-1) min(-1) i.v., and did not affect bleeding time at 300 microg 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.

• Authors: C N Berry, C Lunven, I Lechaire, C Girardot, S E O'Connor
• Journal: British journal of pharmacology (Br J Pharmacol) Vol. 125 Issue 1 Pg. 29-34 (Sep 1998) ISSN: 0007-1188 [Print] England
• PMID: 9776340 (Publication Type: Journal Article)

Chemical References

• Antibodies, Monoclonal
• Anticoagulants
• Fibrinolytic Agents
• Pipecolic Acids
• Plasminogen Activator Inhibitor 1
• Platelet Aggregation Inhibitors
• Sulfonamides
• Heparin
• Arginine
• argatroban

Topics

• Animals
• Antibodies, Monoclonal (therapeutic use)
• Anticoagulants (pharmacology)
• Arginine (analogs & derivatives)
• Bleeding Time
• Cross Reactions
• Fibrinolytic Agents (therapeutic use)
• Heparin (pharmacology)
• Humans
• Male
• Pipecolic Acids (pharmacology)
• Plasminogen Activator Inhibitor 1 (metabolism)
• Platelet Aggregation Inhibitors (pharmacology)
• Rats
• Sulfonamides
• Thrombosis (therapy)
• Venous Thrombosis (immunology, therapy)