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Reduction of early vein graft thrombosis by tissue plasminogen activator gene transfer

Journal: Thrombosis and Haemostasis
ISSN: 0340-6245
DOI: https://doi.org/10.1160/TH08-11-0772
Issue: 2009: 102/1 (July) pp. 1-183
Pages: 145-152

Reduction of early vein graft thrombosis by tissue plasminogen activator gene transfer

Anita C. Thomas 1,2; Marcella J. Wyatt 1; Andrew C. Newby1
1 Bristol Heart Institute, University of Bristol, Bristol, United Kingdom; 2 Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Australia

Keywords

animal model, gene therapy, Tissue plasminogen activator, Vein graft, acute thrombosis

Summary

Vein grafts are used to bypass coronary arterial stenosis, but many grafts thrombose soon after surgery. A model was developed in the pig to allow continuous measurement of blood flow and production of flow-restricting thrombi (cyclic flow reductions; CFRs). Saphenous vein lumen was exposed to adenovirus ex vivo, to over-express human tissue plasminogen activator (h-tPA), with β-galactosidase adenovirus as a control. The vein segments were engrafted into carotid arteries and examined 0, 1 or 3 days later (4–7 animals/group). Untransduced grafts examined on the day of surgery developed repeated CFRs at both normal and restricted flow, but their frequency declined in grafts examined after 3 days. Adenovirus transduction was evident as β-galactosidase or h-tPA expression 1 day after engraftment. Blood flow was increased 1.4-fold in h-tPA transduced grafts after 1 day [control 390 (280–510), h-tPA 550 (450–660) ml/min; p=0.02 (expressed as mean (95% confidence intervals)]. CFRs were less severe (p=0.002) in the h-tPA transduced grafts than β-galactosidase-transduced grafts. CFRs were also less frequent in unstenosed undamaged h-tPA grafts [control 17 (6.1–29), h-tPA 7.6 (1.7–14) CFR/hr; p=0.02], but this difference was reduced after damage or stenosis. CFRs formed faster in h-tPA than in β-galactosidase-transduced grafts [control 14 (11–17), h-tPA 23 (19–27) ml/min2; p<0.001], and resolved twofold faster [control 25 (22–30), h-tPA 48 (39–60) ml/min2; p<0.001]. Hence, in this model, local gene therapy with h-tPA increased graft blood flow and decreased measures of early graft thrombosis, namely quicker CFR resolution and decreased frequency and severity.

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