Inclusion of Human Tissue Factor Pathway Inhibitor or Thrombomodulin Transgenes Attenuates Critical Consumptive Thrombocytopenia in Cardiac Xenotransplantation.
1Cardiothoracic Surgery Research Program/National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD
2Division of Veterinary Resources, National Institutes of Health, Bethesda, MD
3Revivicor Inc., Blacksburg, VA.
Meeting: 2016 American Transplant Congress
Abstract number: 361
Keywords: Gene expression, Heart/lung transplantation, Thrombocytopenia, Xenotransplantation
Session Information
Session Name: Concurrent Session: Xenotransplantation: Animal Models
Session Type: Concurrent Session
Date: Monday, June 13, 2016
Session Time: 4:30pm-6:00pm
Presentation Time: 4:42pm-4:54pm
Location: Room 102
Objective
A major obstacle in the success of cardiac xenotransplantation has been the development of significant consumptive thrombocytopenia, frequently limiting recipient survival. Advances in genetic engineering have allowed expression of multiple humanized genes in order to achieve greater xenograft acceptance. We now detail the incorporation of human tissue factor pathway inhibitor (hTFPI) and thrombomodulin (hTBM) transgenes to attenuate critical consumptive thrombocytopenia.
Methods
Heterotopic cardiac xenotransplantations were performed on baboons (7-15 kg) using grafts from genetically-modified swine (α-galactosidase transferase knockout with hCD46, endothelial protein C receptor [EPCR], and decay accelerating factor [DAF] transgenes). Either hTFPI or hTBM was also included. Subjects were maintained on conventional and targeted immunosuppression.
Results
All heterotopic heart transplants were completed without perioperative complications. Compared to historical controls, where a significant decrease in platelets was observed within one week of transplantation, baboons receiving hTFPI or hTBM-expressed xenografts maintained superior platelet counts (210K vs 337K, p=0.002). Non-hTFPI/hTBM subjects were associated with a greater initial reduction of platelets postoperatively (35.92% decrease vs 7.43% decrease, p=0.01) and were found to have thrombocytopenia-related complications including DIC, GI bleeding, anemia requiring multiple transfusions, and decreased survival. Hemorrhagic episodes remain absent in the hTFPI and hTBM cohorts; platelet counts recovered back to baseline levels within seven days following transplantation and none have experienced critical thrombocytopenia (platelet counts <100,000). No difference in platelet levels were found between hTFPI and hTBM groups at 14 days (374K vs 385K, p=0.93).
Conclusion
The inclusion of hTFPI or hTBM transgenes appears to mitigate the presence of severe consumptive thrombocytopenia and resultant critical hemorrhagic-associated complications. Implementation of these additional humanized genes is a significant development toward improving cardiac xenograft outcomes.
CITATION INFORMATION: Chan J, Singh A, Corcoran P, Thomas III M, Lewis B, Ayares D, Horvath K, Mohiuddin M. Inclusion of Human Tissue Factor Pathway Inhibitor or Thrombomodulin Transgenes Attenuates Critical Consumptive Thrombocytopenia in Cardiac Xenotransplantation. Am J Transplant. 2016;16 (suppl 3).
To cite this abstract in AMA style:
Chan J, Singh A, Corcoran P, III MThomas, Lewis B, Ayares D, Horvath K, Mohiuddin M. Inclusion of Human Tissue Factor Pathway Inhibitor or Thrombomodulin Transgenes Attenuates Critical Consumptive Thrombocytopenia in Cardiac Xenotransplantation. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/inclusion-of-human-tissue-factor-pathway-inhibitor-or-thrombomodulin-transgenes-attenuates-critical-consumptive-thrombocytopenia-in-cardiac-xenotransplantation/. Accessed May 21, 2025.« Back to 2016 American Transplant Congress