Locally Applied Recombinant Plasmin Results in Effective Thrombolysis in a Porcine Model of Arteriovenous Graft Thrombosis
Received 21 May 2008; received in revised form 23 March 2009; accepted 24 March 2009. published online 28 May 2009.
Purpose
Arteriovenous (AV) graft thrombosis is a frequent complication in patients undergoing hemodialysis. Thrombolytic therapy with tissue plasminogen activator (TPA) is hampered by the risk of bleeding complications. Locally delivered plasmin may have similar thrombolytic efficacy with a superior safety profile, so herein it was compared with TPA in a porcine model of AV graft thrombosis.
Materials and Methods
AV grafts were created bilaterally between the carotid artery and jugular vein. Graft thrombosis was induced by clamping the grafts for 1 hour. On day 3, one graft was treated with a 2-mL local recombinant plasmin injection (10 mg; n = 10) with the contralateral graft being infused with TPA (10 mg, n = 8) or saline solution (n = 2). Thrombolytic efficacy was assessed by weighing the residual clot and released clot fragments.
Results
After saline solution injection, the mean residual clot weight in the graft was 618 mg. Local administration of TPA showed the least residual clot in the graft (69 mg ± 26), with large clot particles reaching the venous outflow (241 mg ± 23). Plasmin treatment significantly reduced the released clot mass versus TPA (52 mg ± 23; P < .05), whereas residual clot weight was greater compared with TPA treatment (140 mg ± 22; P < .05). Overall thrombolytic activity of plasmin (ie, residual clot plus released clot) was significantly better than that of TPA (193 mg ± 25 vs 310 mg ± 35; P < .05).
Conclusions
The thrombolytic efficacy of recombinant plasmin was shown to be superior to that of TPA in this study.
aLaboratory of Experimental Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands
bDepartment of Vascular Medicine, Academic Medical Center Amsterdam, Amsterdam, The Netherlands
cDepartment of Internal Medicine, Academic Medical Center Amsterdam, Amsterdam, The Netherlands
dDepartment of Radiology, Academic Medical Center Amsterdam, Amsterdam, The Netherlands
eDepartment of Vascular Surgery, Erasmus Medical Center, Rotterdam, The Netherlands
fDepartment of Drug Development, Biolex Therapeutics, Pittsboro, North Carolina
Address correspondence to I.E.H., University Medical Center Utrecht, Experimental Cardiology, G02.523, Heidelberglaan 100, NL-3584 CX Utrecht, The Netherlands
From the SIR 2008 Annual Meeting.
None of the authors have identified a conflict of interest.
This work was financially supported by Biolex Therapeutics (Pittsboro, North Carolina). J.E.H. is a paid employee of Biolex Therapeutics. The expanded polytetrafluoroethylene grafts used in the present study were supplied by W.L. Gore and Associates (Flagstaff, Arizona).
ABSTRACT