title: Urokinase, tissue-type plasminogen activator and plasminogen activator inhibitor-1 expression in severely stenosed and occluded vein grafts with thrombosis.
abstract: Intimal hyperplasia and subsequent thrombotic occlusions limit the success of vascular reconstructive procedures. Plasminogen activation in situ may be an important factor affecting re-stenosis of the graft. Tissue specimens from eight patients with failing or failed infra-inguinal vein bypasses and three specimens from normal veins were harvested to study urokinase-type plasminogen activator (u-PA), tissue-type plasminogen activator (t-PA) and plasminogen activator inhibitor-1 (PAI-1) by in situ hybridization and immunohistochemistry. The possible presence of thrombi was monitored by platelet and fibrin-specific stainings. In occluded grafts, platelet endothelial cell adhesion molecule (PECAM-1) antibody stained the thrombi but not the endothelial area, indicating the absence of endothelium. Platelet glycoprotein (GP) IIb/IIIa co-localized with PECAM-1 and, furthermore, GP IIb/IIIa staining was positive on the vein walls with thrombi and to some extent in the grafts without thrombi. PAI-1 and u-PA were uniformly upregulated in intimal thickening in grafts without thrombus. In organized thrombi, enhanced u-PA, t-PA and PAI-1 reactivity was detected in the ingrowing subendothelium. In non-occluded grafts with small thrombi, u-PA expression was enriched beneath microthrombi co-localizing with the graft wall injury, while PAI-1 was scattered in the (sub)endothelium. We conclude that fibrinolytic system is upregulated at sites of graft stenosis, and local proteolytic degradation of the graft wall associates with thrombus formation.
authors.affiliation: Department of Virology, Haartman Institute, University of Helsinki, Helsinki, Finland. vappu.siren@helsinki.fi
authors.forename: Vappu
authors.initials: V
authors.lastname: Sirén
authors.forename: Petteri
authors.initials: P
authors.lastname: Kauhanen
authors.forename: Olli
authors.initials: O
authors.lastname: Carpén
authors.forename: Michael
authors.initials: M
authors.lastname: Luther
authors.forename: Mauri
authors.initials: M
authors.lastname: Lepäntalo
authors.forename: Antti
authors.initials: A
authors.lastname: Vaheri
authors.forename: Riitta
authors.initials: R
authors.lastname: Lassila
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D003251:Constriction, Pathologic; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D015870:Gene Expression; D006083:Graft Occlusion, Vascular / Q000150:complications / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D008297:Male; D017395:Plasminogen Activator Inhibitor 1 / Q000032:analysis* / Q000235:genetics; D010960:Plasminogen Activators / Q000032:analysis / Q000235:genetics; D019408:Platelet Endothelial Cell Adhesion Molecule-1 / Q000032:analysis; D012333:RNA, Messenger / Q000032:analysis / Q000235:genetics; D010959:Tissue Plasminogen Activator / Q000032:analysis* / Q000235:genetics; D014568:Urokinase-Type Plasminogen Activator / Q000032:analysis* / Q000235:genetics; D014680:Veins / Q000737:chemistry / Q000378:metabolism / Q000637:transplantation*; D020246:Venous Thrombosis / Q000150:complications* / Q000473:pathology; D014841:von Willebrand Factor / Q000032:analysis; D000097382:CD68 Molecule
chemical_list: D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D017395:Plasminogen Activator Inhibitor 1; D010960:Plasminogen Activators; D019408:Platelet Endothelial Cell Adhesion Molecule-1; D012333:RNA, Messenger; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator; D014841:von Willebrand Factor; C067980:CD68 antigen, human; D000097382:CD68 Molecule