The Fab-fragment of a PAI-1 inhibiting antibody reduces thrombus size and restores blood flow in a rat model of arterial thrombosis.
The effect of PRAP-1, a Fab-fragment of a PAI-1-inhibiting polyclonal antibody, on thrombus size and arterial blood flow was studied in a rat model of arterial thrombosis. It was shown that exposure of the carotid artery to FeCl3 led to the rapid formation of an occlusive thrombus with a morphology similar to that of arterial thrombi found in humans. Tranexamic acid (50 mg/kg), an inhibitor of fibrinolysis, increased thrombus size (p = 0.014) when given intravenously (i.v.) prior to the FeCl3-exposure. Heparin (1000 U), when given i.v. after FeCl3, did not affect the thrombus size per se, but caused a reduction in the interindividual variation of the size of the thrombus (p < 0.05). Thus, heparin was included in all the subsequent experiments. An i.v. infusion of t-PA (1 mg/kg/h), starting before thrombus formation, induced a 3.3 fold increase in the perfusion rate (p = 0.006) and a 67% reduction in the thrombus size (P < 0.001). PRAP-1, an inhibitor of rat PAI-1 activity, was given i.v. as a bolus followed by an infusion. Two doses of PRAP-1 were studied (7.5 and 15 mg/kg/h), and the administration of the PAI-1 inhibitor was started 10 min before FeCl3. The lower PRAP-1 dose caused a 3.8 fold increase in perfusion rate (p = 0.036), a 1.44 fold increase in the time to occlusion (p = 0.034), and the thrombus size was decreased by 18% (p = 0.104). The corresponding effects of the high PRAP-1 dose were a 6.5 fold increase in perfusion rate (p < 0.001), a 1.6 fold increase in time to occlusion (p = 0.038) and a 32% reduction in thrombus size (p = 0.016). It is concluded that an inhibitor of PAI-1 activity, PRAP-1, caused a moderate decrease in thrombus size and partly restores blood flow in a rat model of arterial thrombus. This finding suggests a potential role for an inhibitor of PAI-1 in the treatment of arterial thrombosis.
van Giezen
J J
JJ
Department of Pharmacology CV, Astra Hässle AB, Mölndal, Sweden.
Wahlund
G
G
Nerme
Abrahamsson
T
T
D000818:Animals; D000933:Antifibrinolytic Agents / Q000494:pharmacology; D001783:Blood Flow Velocity; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology / Q000503:physiopathology; D002341:Carotid Artery Thrombosis / Q000473:pathology / Q000503:physiopathology* / Q000628:therapy*; D002712:Chlorides; D004334:Drug Administration Schedule; D005290:Ferric Compounds; D007140:Immunoglobulin Fab Fragments / Q000627:therapeutic use*; D017395:Plasminogen Activator Inhibitor 1 / Q000276:immunology* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use*; D014148:Tranexamic Acid / Q000494:pharmacology
D000933:Antifibrinolytic Agents; D002712:Chlorides; D005290:Ferric Compounds; D007140:Immunoglobulin Fab Fragments; D017395:Plasminogen Activator Inhibitor 1; D014148:Tranexamic Acid; D010959:Tissue Plasminogen Activator; C024555:ferric chloride