title: The effect of anticoagulation with subcutaneously delivered polyethylene glycol conjugated hirudin and recombinant tissue plasminogen activator on recurrent stenosis in the rabbit double-balloon injury model.
abstract: Myointimal hyperplasia is the condition usually responsible for recurrent stenosis (restenosis) after endarterectomy, bypass grafting and angioplasty. Its cause is still not known. The present study examined whether inhibition of thrombin by tissue plasminogen activator (r-TPA) or polyethylene glycol recombinant hirudin (PEG-hirudin) could reduce restenosis in an animal model. Restenosis was induced in 20 cholesterol-fed rabbits. The right carotid artery underwent a double-balloon injury while left carotid artery acted as a control. Recombinant tissue plasminogen activator (1 mg kg(-1) s.c.) and PEG-hirudin (0.7 mg kg(-1) s.c.) were given subcutaneously with normal saline acting as a control. Blood levels of PEG-hirudin were measured by both ELISA and an Ecarin (activity) assay. Vessel dimensions were measured in histological sections, obtained from perfusion-fixed tissue, using computerised planimetry. The model reproduced many of the histological changes found in human restenosis, such as intramural thrombus, rupture of the elastic lamina, macrophage infiltration and smooth muscle migration. Reinjury caused an almost three-fold reduction in the area of the lumen (median 0.25 mm(2)) compared with uninjured vessels (median 0.72 mm(2)). The mean plasma levels of PEG-hirudin and r-tPA achieved were 291 ng/ml (S.E.M. 28 ng/ml) and 34 IU/ml (S.E.M. 12 IU/ml), respectively. PEG-hirudin significantly inhibited the effect of balloon injury on luminal area compared with saline-treated controls (0.21 versus 0.44 mm(2), respectively, P<0.05). Recombinant tPA also had a similar inhibitory affect, but this did not reach statistical significance (0.16 versus 0.44 mm(2), respectively, P>0.05). The magnitude of luminal narrowing was significantly reduced by subcutaneous injection of PEG-hirudin. Further studies are required to determine whether this effect can be enhanced by other antithrombins or improved methods of delivery.
authors.affiliation: Academic Department of Surgery, GKT School of Medicine and Dentistry, 1st Floor North Wing, St. Thomas' Hospital, Lambeth Palace Road, London SE1 7EH, UK.
authors.forename: Barry
authors.initials: B
authors.lastname: Alexander
authors.forename: Kevin G
authors.initials: KG
authors.lastname: Burnand
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Lattimer
authors.forename: Julia
authors.initials: J
authors.lastname: Humphries
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Gaffney
authors.forename: David
authors.initials: D
authors.lastname: Eastham
authors.forename: Alberto
authors.initials: A
authors.lastname: Smith
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000627:therapeutic use; D002339:Carotid Arteries / Q000187:drug effects / Q000473:pathology; D002340:Carotid Artery Diseases / Q000188:drug therapy / Q000473:pathology; D002404:Catheterization / Q000009:adverse effects*; D003251:Constriction, Pathologic / Q000188:drug therapy* / Q000209:etiology; D004195:Disease Models, Animal; D006629:Hirudins / Q000008:administration & dosage* / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology; D011817:Rabbits; D011994:Recombinant Proteins; D012008:Recurrence; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage* / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D006629:Hirudins; D011994:Recombinant Proteins; C104614:polyethyleneglycol-hirudin; D010959:Tissue Plasminogen Activator