Prevention of arterial reocclusion after thrombolysis with recombinant lipoprotein-associated coagulation inhibitor.

Abstract

BACKGROUND This study was designed to determine whether arterial reocclusion after thrombolysis can be prevented by lipoprotein-associated coagulation inhibitor (LACI), a physiological inhibitor of tissue factor-induced coagulation mediated by the extrinsic pathway. METHODS AND RESULTS Thrombosis was induced in femoral arteries of anesthetized dogs with the use of anodal current to elicit extensive vascular injury and formation of platelet-rich thrombi in one artery and with thrombogenic copper wire to elicit fibrin-rich thrombi without appreciable vascular injury in the contralateral artery. Recanalization of both vessels was induced with t-PA (1.7 mg/kg i.v. over 1 hour) and verified with Doppler flow probes. Reocclusion occurred within 2 hours in seven of seven arteries with electrical injury-induced thrombosis and in four of seven arteries with copper wire-induced thrombosis in the absence of LACI. In dogs given infusions of recombinant DNA-produced LACI (225 micrograms/kg over 15 minutes, followed by 4 micrograms/kg/min i.v.) after completion of the infusion of t-PA, no reocclusion occurred during the 2-hour interval of observation in any of the five arteries subjected to electrical injury (p less than 0.001), and cyclic partial occlusions were nearly abolished (0.4 +/- 0.4/hr in LACI-treated dogs compared with 13.7 +/- 5.5/hr in saline-treated dogs, p less than 0.0001). In contrast, reocclusion occurred in two of five arteries with indwelling copper wires, and cyclic partial occlusions were unaffected despite LACI. LACI prolonged the partial thromboplastin time modestly (1.7 +/- 0.2 x baseline) but did not affect platelet counts or aggregation assessed ex vivo. CONCLUSIONS Inhibition of the extrinsic pathway of coagulation with LACI prevents thrombotic arterial reocclusion after thrombolysis in vessels subjected to extensive vascular injury. Our results demonstrate that activation of the extrinsic pathway plays a critical role in thrombotic reocclusion and that LACI provides a highly targeted approach to facilitate sustained recanalization without directly inhibiting platelets.

Tissue factor and tissue factor pathway inhibitor

“…TFPI that is concentrated from plasma inhibits fibrin formation in a flow model on endothelial cell matrix [90]. In a dog model (where dog femoral artery was injured leading to thrombosis) treatment with tissue plasminogen activator and TFPI prevented reocclusion of the femoral artery [91]. As re-stenosis is a major problem after coronary artery thrombosis with or without balloon angioplasty or stenting, and aspirin and heparin only partially prevent re-stenosis, the potential benefits of TFPI in these patients may be envisaged.…”

Thromboresistance of Balloon-Injured Porcine Carotid Arteries After Local Gene Transfer of Human Tissue Factor Pathway Inhibitor

“…7 Although attractive in principle, it is uncertain whether shortterm administration of rTFPI will achieve lasting vasoprotection after percutaneous revascularization, particularly at sites of increased tissue factor burden. 4,8 Moreover, the systemic doses of recombinant TFPI capable of preventing arterial thrombosis and potentially restenosis are substantial (100 g ⅐ kg Ϫ1 ⅐ min Ϫ1 in Reference 6) and may entail significant hemorrhagic risks.…”

Intravascular Free Tissue Factor Pathway Inhibitor Is Inversely Correlated With HDL Cholesterol and Postheparin Lipoprotein Lipase but Proportional to Apolipoprotein A-II

“…3 The free form includes 2 subfractions except in platelets, 4 ie, a circulating free TFPI fraction without carrier in preheparin plasma and a heparin-releasable TFPI fraction from endothelial cells. 5 Exogenous administration of recombinant TFPI to experimental animals prevents thrombosis, 6 whereas increased TFPI levels have been observed in patients with acute myocardial infarction. 7 Although the alteration of serum lipids by cholesterol-lowering therapy influences Lpbound TFPI profiles, 8 -11 little is known about the clinical implications of the TFPI level and its regulation in relation to lipid risk profiles.…”