Urokinase, tissue-type plasminogen activator and plasminogen activator inhibitor-1 expression in severely stenosed and occluded vein grafts with thrombosis.
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.
Sirén
Vappu
V
Department of Virology, Haartman Institute, University of Helsinki, Helsinki, Finland. vappu.siren@helsinki.fi
Kauhanen
Petteri
P
Carpén
Olli
O
Luther
Michael
M
Lepäntalo
Mauri
M
Vaheri
Antti
A
Lassila
Riitta
R
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
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