Early loss of thrombomodulin expression impairs vein graft thromboresistance

Implications for vein graft failure

Antony Y. Kim, Peter L. Walinsky, Frank D. Kolodgie, Ce Bian, Jason L. Sperry, Clayton B. Deming, Eric A. Peck, Jay G. Shake, Gregory B. Ang, Richard H. Sohn, Charles T. Esmon, Renu Virmani, R. Scott Stuart, Jeffrey J. Rade

Research output: Contribution to journalArticle

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/cm2 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/cm2, 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.

Original languageEnglish (US)
Pages (from-to)205-212
Number of pages8
JournalCirculation Research
Volume90
Issue number2
DOIs
StatePublished - Feb 8 2002

Fingerprint

Thrombomodulin
Veins
Transplants
Thrombin
Protein C
Thrombosis
Neointima
Adenoviridae
Anticoagulants
Hyperplasia
Western Blotting
Staining and Labeling
Rabbits

Keywords

  • Gene therapy
  • Thrombomodulin
  • Thrombosis
  • Vein grafts

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

Cite this

Kim, A. Y., Walinsky, P. L., Kolodgie, F. D., Bian, C., Sperry, J. L., Deming, C. B., ... Rade, J. J. (2002). Early loss of thrombomodulin expression impairs vein graft thromboresistance: Implications for vein graft failure. Circulation Research, 90(2), 205-212. https://doi.org/10.1161/hh0202.105097

Early loss of thrombomodulin expression impairs vein graft thromboresistance : Implications for vein graft failure. / 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.

In: Circulation Research, Vol. 90, No. 2, 08.02.2002, p. 205-212.

Research output: Contribution to journalArticle

Kim, AY, Walinsky, PL, Kolodgie, FD, Bian, C, Sperry, JL, Deming, CB, Peck, EA, Shake, JG, Ang, GB, Sohn, RH, Esmon, CT, Virmani, R, Stuart, RS & Rade, JJ 2002, 'Early loss of thrombomodulin expression impairs vein graft thromboresistance: Implications for vein graft failure', Circulation Research, vol. 90, no. 2, pp. 205-212. https://doi.org/10.1161/hh0202.105097
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. / Early loss of thrombomodulin expression impairs vein graft thromboresistance : Implications for vein graft failure. In: Circulation Research. 2002 ; Vol. 90, No. 2. pp. 205-212.
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AU - Bian, Ce

AU - Sperry, Jason L.

AU - Deming, Clayton B.

AU - Peck, Eric A.

AU - Shake, Jay G.

AU - Ang, Gregory B.

AU - Sohn, Richard H.

AU - Esmon, Charles T.

AU - Virmani, Renu

AU - Stuart, R. Scott

AU - Rade, Jeffrey J.

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N2 - 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/cm2 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/cm2, 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.

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