Early Loss of Thrombomodulin Expression Impairs Vein Graft Thromboresistance: Implications for Vein Graft Failure

• Published in: Circulation research Vol. 90; no. 2; pp. 205 - 212
• Main Authors: Kim, Antony Y, Walinsky, Peter L, Kolodgie, Frank D, Bian, Ce, Sperry, Jason L, Deming, Clayton B, Peck, Eric A, Shake, Jay G, Ang, Gregory B, Sohn, Richard H, Esmon, Charles T, Virmani, Renu, Stuart, R Scott, Rade, Jeffrey J
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Heart Association, Inc 08.02.2002; Lippincott; Lippincott Williams & Wilkins Ovid Technologies
• Subjects: Animals; Biological and medical sciences; Biotechnology; Blood Coagulation Factors; Blotting, Western; Carotid Arteries - surgery; Disease Models, Animal; Fibrinolytic Agents - pharmacology; Fundamental and applied biological sciences. Psychology; Gene therapy; Genetic Vectors - genetics; Genetic Vectors - metabolism; Health. Pharmaceutical industry; Immunohistochemistry; Industrial applications and implications. Economical aspects; Jugular Veins - drug effects; Jugular Veins - metabolism; Jugular Veins - pathology; Jugular Veins - transplantation; Male; Medical sciences; Protein C - metabolism; Rabbits; Receptors, Cell Surface - metabolism; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; Thrombin - antagonists & inhibitors; Thrombin - metabolism; Thrombomodulin - deficiency; Thrombomodulin - genetics; Thrombomodulin - metabolism; Transduction, Genetic; Transplantation, Autologous - adverse effects; Tunica Intima - drug effects; Tunica Intima - pathology; Vascular surgery: aorta, extremities, vena cava. Surgery of the lymphatic vessels; Vascular Surgical Procedures - adverse effects; Venous Thrombosis - etiology; Venous Thrombosis - metabolism; Venous Thrombosis - pathology; Graft(material); Endothelial cell; Rabbit; Cardiovascular disease; Protein C; Lagomorpha; Gene expression; Thrombosis; Genetic transfer; Vascular disease; Vertebrata; Mammalia; Sensitivity resistance; Blood vessel; Animal; Surgery; Circulatory system; Thrombomodulin; Gene therapy; Vein; Biological receptor
• ISSN: 0009-7330; 1524-4571
• DOI: 10.1161/hh0202.105097

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 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, 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.