The Effects of Exogenous Administration of Human Coagulation Factors Following Pig-to-Baboon Liver Xenotransplantation

Abstract

We sought to determine the effects of exogenous administration of human coagulation factors following pig-to-baboon liver xenotransplantation (LXT) using GalT-KO donors. Post-LXT, baboons received either: no coagulation factors (historical control, n=1), bolus administration of a human prothrombin concentrate complex (hPCC) (2.5 mL/kg, n = 2), continuous infusion of hPCC (1.0 ml/hr, n=1) or a continuous infusion of human recombinant Factor VIIa (1 mcg/kg/hr, n=3). The historical control recipient demonstrated persistent thrombocytopenia despite platelet administration post-transplant along with widespread thrombotic microangiopathy (TMA). In contrast, platelet levels were maintained in bolus hPCC recipients, however these animals quickly developed large vessel thrombosis and TMA leading to graft failure with shortened survival. Recipients of continuous coagulation factor administration experienced either stabilization or an increase in their circulating platelets with escalating doses. Furthermore, transfusion requirements were decreased and hepatic TMA was noticeably absent in recipients of continuous coagulation factor infusions when compared to the historical control and bolus hPCC recipients. This effect was most profound with a continuous, escalating dose of Factor VIIa. Further studies are warranted as this regimen may allow for prolonged survival following LXT.

A Bridge to Somewhere

“…2 Based upon our observation of marginal coagulation factor production in baboon recipients of porcine livers, we recently developed a novel approach utilizing the continuous administration of exogenous human coagulation factors after LXT. 3 This demonstrated the ability to control coagulopathy, maintain circulating platelets, and prevent thrombotic microangiopathy (TMA) in our pig-to-baboon model of orthotopic LXT. On the basis of these findings, we have now further extended our study of continuous coagulation factor administration by adding measures to minimize infectious risks, and utilize costimulation blockade.…”

“…2 More recently, we experienced similar infectious complications in 2 of 6 recipients, leading to survival of only 5 and 6 days. 3 This increased susceptibility to infectious complications, especially at the time of re-exploration, led to a concerted effort to avoid re-exploration in the early postoperative period in the current experimentas evidenced by the empiric treatment of rejection on POD 7 when the LFT's began to rise, rather than pursuing exploration and an open liver biopsy. This effort to avoid re-exploration was facilitated by the absence of coagulopathy and bleeding, the effects of which were likely attributable to the administration of continuous, exogenous coagulation factors.…”

“…3 The alpha-1,3-galactosyltransferase knock out miniature swine donor (male, 9.4 kg) was porcine cytomegalovirus (CMV) (pCMV)-negative and underwent hepatectomy in a standard fashion with in situ cold perfusion using UW solution (Barr Pharmaceuticals, Pomona, NY). Six hours post-LXT continuous administration of human prothrombin concentrate complex (Octaplex, Octapharma, Lachen, CH) was initiated at 1.0 mL/h and then titrated to maintain an INR below 2.0.…”

“…3 The interplay between coagulation factor administration, platelet count recovery, and TMA prevention has yet to be elucidated and warrants further investigation, as does the role of coagulation factor supplementation in potentially lending to a prosurvival state (2) Infection control:…”

New Hope for Liver Xenotransplantation

“…6 Recently, developed xenoantigen knockout pigs reduce this barrier and will allow for the transplantation of pig livers into NHPs without using Cobra Venom Factor, a drug unsuitable for clinical usage. 7 The path forward for liver xenotransplantation can now be pursued with the optimism that prolonged survival of a pig liver has been achieved.…”