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Presenter: Burcin, Ekser, Pittsburgh, United States
Authors: Burcin EKSER1,2, Chih Che Lin1, Cassandra Long1, Gabriel J. Echeverri1,5, Hidetaka Hara1, Donna B. Stolz3, David Ayares4, David K.C. Cooper1, Bruno Gridelli1,5, Mohamed Ezzelarab1
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Where do platelets go after pig-to-baboon liver xenotransplantation? Evidence for platelet-WBC aggregation
Burcin EKSER1,2, Chih Che Lin1, Cassandra Long1, Gabriel J. Echeverri1,5, Hidetaka Hara1, Donna B. Stolz3, David Ayares4, David K.C. Cooper1, Bruno Gridelli1,5, Mohamed Ezzelarab1
1Thomas E. Starzl Transplantation Institute, University of Pittsburgh Medical Center, Pittsburgh, PA, United States; 2Department of Surgery, Transplantation and Advanced Technologies, Vascular Surgery and Organ Transplant Unit, University Hospital of Catania, Catania, Italy; 3Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA, United States; 4Revivicor, Inc., Blacksburg, VA, United States; 5Mediterranean Institute for Transplantation and Advanced Specialized Therapies, ISMETT, Palermo, Italy
Background: Severe thrombocytopenia occurs after pig-to-baboon orthotopic liver transplantation (LTx), and limits survival to <8 days. The underlying mechanisms causing thrombocytopenia are not fully understood.
Methods: LTx using genetically-engineered pigs (GTKO, n=2; GTKO/CD46, n=8) was carried out with clinically acceptable immunosuppression in baboons. Platelet count, mean platelet volume (MPV), lymphocyte, monocyte, and neutrophil absolute numbers were monitored. In two recipients, platelet-WBC aggregation (CD42+ or CD62+ aggregates) was monitored daily by flow cytometry. Platelet deposition in the liver grafts was assessed by immunohistochemistry and electron microscopy.
Results: Profound thrombocytopenia occurred in all baboons (n=10) within 4h. Mean platelet count (x103/mm3) fell to 63 within 4h, and to 6 by day 3, despite fresh blood or human platelet transfusions. MPV remained normal. Flow cytometry demonstrated platelet and platelet-WBC aggregates in the blood beginning within 4h. Before LTx, lymphocyte, monocyte and neutrophil aggregates with platelets were 1-3%. After LTx, lymphocyte/platelet, monocyte/platelet, and neutrophil/platelet aggregates increased respectively to 24, 8, 6% at 4h, 18, 13, 3% on day 1, and 54, 67, 14% on day 5. Despite immediate thrombocytopenia, bleeding (decrease in Hct and Hb, melena stools, purpura) did not develop before days 2-3. Liver biopsies taken at 2h and at euthanasia showed platelet aggregates within the sinusoids. At euthanasia, platelet aggregates were also present in the native lungs. Despite profound thrombocytopenia, rejection of the liver grafts was not observed.
Conclusions: (1) Platelet activation (increased WBC-platelet aggregation) occurred within 4h after LTx. (2) The platelet count alone may give a misleading impression of the total number of platelets in the circulation, but (3) their presence does not imply adequate function. (4) Clodronate liposomes failed to reduce the early loss of platelets, suggesting that Kupffer cells did not remove them from the circulation. (5) Platelets and platelet-WBCs aggregate in the liver sinusoids and in native lungs, but we cannot exclude phagocytosis by liver endothelial cells.
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