title: Early loss of thrombomodulin expression impairs vein graft thromboresistance: implications for vein graft failure.
abstract: Thrombosis is the major cause of early vein graft failure. Our aim was to determine whether alterations in the expression of the anticoagulant proteins, thrombomodulin (TM) and the endothelial cell protein C receptor (EPCR), impair endothelial thromboresistance that may contribute to vein graft failure. Immunohistochemical staining of autologous rabbit vein graft sections revealed that the expression of TM, but not EPCR, was reduced significantly early after graft implantation. Western blot analysis revealed that TM expression was reduced by >95% during the first 2 weeks after implantation, with gradual but incomplete recovery by 42 days. This resulted in up to a 95% reduction in the capacity of the grafts to activate protein C and was associated with an increase in bound thrombin activity, which peaked on day 7 at 28.7 +/- 3.8 mU/cm(2) and remained elevated for more than 14 days. Restoration of TM expression using adenovirus vector-mediated gene transfer significantly enhanced the capacity of grafts to activate protein C and reduced bound thrombin activity on day 7 to levels comparable to that of normal veins (5.7 +/- 0.4 versus 5.2 +/- 1.1 mU/cm(2), respectively, P=0.74). Surprisingly, neointima formation was not affected by this inhibition of local thrombin activity. These data suggest that the early loss of TM expression significantly impairs vein graft thromboresistance and results in enhanced local thrombin generation. Although enhanced local thrombin generation may predispose to early vein graft failure due to thrombosis, it does not seem to contribute significantly to late vein graft failure due to neointimal hyperplasia.
authors.affiliation: Divisions of Cardiology, The Johns Hopkins School of Medicine, Baltimore, MD 21287, USA.
authors.forename: Antony Y
authors.initials: AY
authors.lastname: Kim
authors.forename: Peter L
authors.initials: PL
authors.lastname: Walinsky
authors.forename: Frank D
authors.initials: FD
authors.lastname: Kolodgie
authors.forename: Ce
authors.initials: C
authors.lastname: Bian
authors.forename: Jason L
authors.initials: JL
authors.lastname: Sperry
authors.forename: Clayton B
authors.initials: CB
authors.lastname: Deming
authors.forename: Eric A
authors.initials: EA
authors.lastname: Peck
authors.forename: Jay G
authors.initials: JG
authors.lastname: Shake
authors.forename: Gregory B
authors.initials: GB
authors.lastname: Ang
authors.forename: Richard H
authors.initials: RH
authors.lastname: Sohn
authors.forename: Charles T
authors.initials: CT
authors.lastname: Esmon
authors.forename: Renu
authors.initials: R
authors.lastname: Virmani
authors.forename: R Scott
authors.initials: RS
authors.lastname: Stuart
authors.forename: Jeffrey J
authors.initials: JJ
authors.lastname: Rade
mesh_terms: D000818:Animals; D001779:Blood Coagulation Factors; D015153:Blotting, Western; D002339:Carotid Arteries / Q000601:surgery; D004195:Disease Models, Animal; D005343:Fibrinolytic Agents / Q000494:pharmacology; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D007601:Jugular Veins / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000637:transplantation; D008297:Male; D011486:Protein C / Q000378:metabolism; D011817:Rabbits; D011956:Receptors, Cell Surface / Q000378:metabolism*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism; D018180:Thrombomodulin / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic; D014182:Transplantation, Autologous / Q000009:adverse effects; D017539:Tunica Intima / Q000187:drug effects / Q000473:pathology; D014656:Vascular Surgical Procedures / Q000009:adverse effects; D020246:Venous Thrombosis / Q000209:etiology / Q000378:metabolism* / Q000473:pathology
chemical_list: D001779:Blood Coagulation Factors; D005343:Fibrinolytic Agents; D011486:Protein C; D011956:Receptors, Cell Surface; D018180:Thrombomodulin; C091963:activated protein C receptor; D013917:Thrombin