Inhibition of factor XIIIa in a canine model of coronary thrombosis: effect on reperfusion and acute reocclusion after recombinant tissue- type plasminogen activator

Abstract

The effect of inhibition of factor XIIIa with 2-(l-acetonylthio)-5- methylthiazolo[2,3-b]1,3,4-thiadiazo lium perchlorate (L-722,151) on coronary thrombolysis and reocclusion was studied in an acute dog model of electrically induced coronary thrombosis. L-722,151 (0.1 mg/kg/min intravenously [IV] or placebo was administered 15 minutes before current initiation (150 microA) and for the duration of the experiment (270 minutes). Fifteen minutes after thrombus formation, heparin (300 U/kg, IV) was administered, followed 45 minutes later by recombinant tissue-type plasminogen activator (tPA) (10 micrograms/kg/min, IV for 90 minutes). Placebo-treated animals thrombosed at 48.9 +/- 8.1 minutes (mean +/- SEM) and reperfused in response to tPA at 49.1 +/- 9.3 minutes. L-722,151 pretreated animals thrombosed at 44.4 +/- 9.7 minutes and reperfused in response to tPA at 16.4 +/- 2.8 minutes (P less than .05 v vehicle). Furthermore, residual thrombus mass was reduced by L-722,151 from 6.9 +/- 1.9 mg in placebo-treated animals to 1.7 +/- 0.6 mg (P less than .05 v vehicle). Acute reocclusion occurred in 86% of placebo and in 75% of L-722,151-treated animals. The incidence of tPA-induced reperfusion in L-722,151-treated dogs was 100% (8 of 8), whereas only 70% (7 of 10) of placebo-treated dogs reperfused. These results demonstrate that pretreatment with L-722,151 hastens reperfusion time threefold and reduces residual thrombus mass. These effects occurred with no change in systemic blood pressure in response to L-722,151. When L-722,151 was administered 15 minutes after thrombus formation in a separate group of dogs (n = 5), no beneficial effect on thrombolysis time or thrombus mass was observed. Thus, the specific factor XIIIa catalyzed crosslinking reaction(s), which may determine(s) resistance to plasmin-mediated fibrin degradation, occur(s) rapidly. Inhibition of this crosslinking by pretreatment with L-722,151 promotes tPA-induced thrombolysis.

Factor XIII deficiency does not prevent FeCl3‐induced carotid artery thrombus formation in mice

“…Previous studies in rabbits and dogs showed that pharmacologic FXIII inhibition accelerates thrombolysis in response to administration of therapeutic lytic agents, suggesting that prophylactic FXIII inhibition may facilitate thrombus dissolution. Notably, however, in both the pharmacologic and now genetically engineered animal models, FXIII reduction failed to alter the events leading to the formation of occlusive thrombi.…”

“…Previous studies in rabbits and dogs showed that pharmacologic FXIII inhibition accelerates thrombolysis in response to administration of therapeutic lytic agents, suggesting that prophylactic FXIII inhibition may facilitate thrombus dissolution. Notably, however, in both the pharmacologic and now genetically engineered animal models, FXIII reduction failed to alter the events leading to the formation of occlusive thrombi. Collectively, these data from multiple, independent experimental models of arterial thrombosis suggest FXIIIa does not contribute prominently to the molecular events that promote artery occlusion, and that inhibiting FXIIIa, alone, would not prevent the initial formation of arterial thrombi or associated tissue ischemia.…”

“…The role of FXIII in arterial thrombosis is less established. In experimental models of thrombosis in rabbit femoral and dog coronary arteries, administration of the nonpeptidyl active site‐directed FXIIIa inhibitor L‐722‐151 prior to thrombus induction increases thrombus susceptibility to tissue plasminogen activator–driven thrombolysis. Surprisingly, however, in spite of observations that FXIII facilitates platelet recruitment and adhesion under flow, FXIIIa inhibition with L‐722‐151 failed to independently prolong the time to vessel occlusion or reduce thrombus mass .…”

Newly-Recognized Roles of Factor XIII in Thrombosis

“…101 Similarly, in a canine model of coronary artery thrombosis, FXIIIa inhibition accelerated reperfusion and reduced residual thrombus mass following tPA administration. 102 Notably, in both models, this effect was limited to animals pretreated with the FXIIIa inhibitor, and was not observed in animals infused with FXIIIa inhibitor after thrombus induction. 101,102 This finding suggests that FXIII activation and cross-linking activity occur early during thrombogenesis.…”

“…102 Notably, in both models, this effect was limited to animals pretreated with the FXIIIa inhibitor, and was not observed in animals infused with FXIIIa inhibitor after thrombus induction. 101,102 This finding suggests that FXIII activation and cross-linking activity occur early during thrombogenesis. Accordingly, using a fluorescent peptide derived from α 2 -antiplasmin to probe for FXIIIa activity in mice, Jaffer et al 103 detected signal enhancement within 30 minutes of thrombus induction, indicating early generation of FXIIIa activity during thrombogenesis.…”