Transgenic Expression of Human Thrombomodulin in Donor Pigs Reduces the Incidence of Coagulopathies in a Pig to Baboon Cardiac Xenotransplantation Model
NHLBI /NIH, Bethesda
ORS/NIH, Bethesda
Revivicor Inc., Blacksburgh
Beth israel Deaconess Medical Center, Boston
Meeting: 2013 American Transplant Congress
Abstract number: B1152
Introduction: For cardiac xenograft to become clinical reality, many genetic modifications are required in the donor pigs. We have shown that significant graft survival can be achieved after knocking out the alpha 1-3 Gal transferase enzyme (GalKO) and introducing anti complement human transgene CD46 in donor pigs (CD46Tg). Despite of longest reported survival by us, many baboons in this experimental group suffered from serious coagulation disorders. Therefore in this study we have hypothesized that further addition of human thrombomodulin gene (TM) in GalKO CD46Tg pigs may prevent platelet consumption and may also avert consumptive coagulopathy (CC). Methods: Specific pathogen free baboons weighing 8-12 Kg were used as recipients of hearts from weight matched GalKO CD46Tg pigs also expressing human TM gene. Immunosuppressive regimen included induction with thymoglobulin, anti CD20 antibody, cobra venom factor (CVF) and maintenance with anti CD40 antibody, MMF and steroids. Heart function was evaluated with continuous telemetry monitoring and weekly echocardiography. Results: Significant prolongation of graft survival was achieved in two out of three animals. One animal was euthanized after GI bleeding 14 days post transplant, possibly due to aspirin / NSAID toxicity after septicemia and in remaining two baboons, heart xenografts were still functioning until the day of submission of this abstract at days 60 and 54 post transplant respectively. None of the baboons demonstrated a reduction in platelet number and had no signs of consumptive coagulopathy. The hematocrit and hemoglobin was also maintained at the normal level. Both the surviving baboons are are active, healthy and without any complications. Conclusion: Transgenic expression of human thrombomodulin effectively prevented platelet consumption and resulting CC. This molecule has proven to be an important component of genetic modifications required in donor pigs to bring xenotransplantation close to clinical reality.
Ayares, D.: Employee, Transgenic Pigs.
To cite this abstract in AMA style:
Mohiuddin M, Singh A, Corcoran P, Mayhew C, Hoyt R, Thomas M, Lewis B, Clark T, Eckhaus M, Reimann K, Ayares D, Horvath K. Transgenic Expression of Human Thrombomodulin in Donor Pigs Reduces the Incidence of Coagulopathies in a Pig to Baboon Cardiac Xenotransplantation Model [abstract]. Am J Transplant. 2013; 13 (suppl 5). https://atcmeetingabstracts.com/abstract/transgenic-expression-of-human-thrombomodulin-in-donor-pigs-reduces-the-incidence-of-coagulopathies-in-a-pig-to-baboon-cardiac-xenotransplantation-model/. Accessed May 14, 2025.« Back to 2013 American Transplant Congress