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J Thorac Cardiovasc Surg 2007;133:1362-1363
© 2007 The American Association for Thoracic Surgery
Cardiothoracic Transplantation |
This work has been ongoing for 10 or 15 years, and it strikes me that creating a transgenic knockout swine model is very difficult. You did not mention what it takes to create that. Could you please recap that for us?
Second, I am having some difficulty in trying to put together the accomplishment of a 2-hour survival in two of three pigs. How is two of three an advance?
Finally, you mentioned intravascular coagulation as being the hallmark of the failure of these transplanted lungs, and you mentioned platelet activation and intravascular thrombosis. Could you tease out which is the chicken and which is the egg? Are you activating platelets, which are then causing intravascular coagulation? Are you causing intravascular coagulation, which is then activating platelets? It may help to define your future strategies.
Dr Nguyen. Thank you, Dr Zwischenberger. To answer your first question about how to make the GalT-KO lungs, I wish I knew because then I would be able to make them myself and make them more available. These are very precious animals because they are genetically engineered by only a few groups and we have to share them among many investigators in the field. My understanding is that they can either be cloned or bred naturally. The problem is that they do not breed as well as the other domestic swine and sometimes they have a higher rate of perinatal mortality as well. However, if they survive to adulthood, then they have no other health problems so far as we know.
To answer your second question about whether two of three GalT-KO lungs surviving at 4 hours is an achievement, I think this is phenomenal. If you attach wild-type lungs or even transgenic MCP lungs untreated to a baboon, you do not have any life-supporting function beyond minutes. In the past many other investigators did in vivo transplant. You have to do many treatments to the recipient in terms of antibody absorption before surgery. A lot of manipulation to the recipient sometimes is not beneficial to the recipient. Thus I think two of three lungs beyond 1 hour and 4 hours is significant.
Your third question concerned intravascular thrombosis and whether the coagulation activation starts first or platelet activation starts first. I think it is more of a circle feedback loop. If you perfuse human blood to a pig organ, even in the nonactivated pig endothelial cells, you do see human prothrombin converted to thrombin, because pig thrombomodulin is so ineffective at preventing this process. Human thrombomodulin is very effective in doing this, but not pig thrombomodulin. Thus you have thrombin formation. Even in the absence of complement activation, you have thrombin formation first, and then you could trigger coagulation activation directly from thrombin. However, then thrombin can also activate platelets, and activated platelets can trigger coagulation activation as well. Again, I think it is more like a circle feedback loop. We have to address both platelet activation and coagulation activation together to prevent intravascular thrombosis.
Dr Young Tae Kim (Seoul, South Korea). Did you look at the von Willebrand factor? We have been doing similar experiments, and what we found is that when we deplete the von Willebrand factor by giving vasopressin, the success rate increases. Did you check it?
Dr Nguyen. Do you mean check for the absence of GalT antigen in GalT-KO pigs?
Dr Kim. The von Willebrand factor.
Dr Nguyen. Yes. We did not do this ourselves, but the supplier of the GalT-KO pigs actually confirmed that. Every time they sent us the pigs, they confirmed that this is indeed GalT-KO.
Related Article
J. Thorac. Cardiovasc. Surg. 2007 133: 1354-1363.
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