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 swine donors. After LXT, baboons received 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/h, n = 1) or continuous infusion of human recombinant factor VIIa (1 µg/kg per hour, n = 3). The historical control recipient demonstrated persistent thrombocytopenia despite platelet administration after 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 compared with the historical control and bolus hPCC recipients. This effect was most profound with a continuous, escalating dose of factor VIIa. Further studies are warranted because this regimen may allow for prolonged survival following LXT.

Figure 1. Liver Function Tests and Platelet Levels

A) AST, B) Bilirubin and C & D) platelets results for all recipient baboons with respect to the administration of either Octaplex® or NovoSeven®. Octaplex-B denotes bolus Octaplex®, Octaplex-C denotes continuous Octaplex®. Continuous coagulation factor recipients demonstrated resolution of liver function until euthanasia and improvement in circulating platelet counts.

Figure 2. Transfusion Requirements

A) Hematocrit and B) Transfusion requirements for Octaplex® and control recipients and C) Hematocrit and D) Transfusion requirements for NovoSeven® recipients. Overall transfusion requirements were decreased in all recipients when compared to the historical control recipient.

Figure 3. Escalating Doses of NovoSeven® Correlate with an Increase in Circulating Platelets

Escalating doses of NovoSeven® administration, aimed to maintain Factor VII activity >50%, were observed to correlate with increases in circulating platelet counts (B365 shown).

Figure 4. Vitamin-K Dependent Factors

Vitamin K dependent Coagulation factor activity for A) Octaplex® recipients and B) NovoSeven® recipients with the administration of exogenous coagulation factors following transplantation. Octaplex-B denotes bolus Octaplex® and Octaplex-C denotes continuous Octaplex®. Red line indicates pig baseline levels.

Figure 5. Non-Vitamin-K Dependent Factors

Non-vitamin K dependent coagulation factor activity for A) Octaplex® recipients and B) NovoSeven® recipients with the administration of exogenous coagulation factors following transplantation. Octaplex-B denotes bolus Octaplex® and Octaplex-C denotes continuous Octaplex®. Red line indicates pig baseline levels.

Figure 6. Post-Transplant Synthetic Function in Xenolivers

Values for INR in A) Octaplex® and control and recipients and C) NovoSeven® recipients, demonstrating the ability to maintain a stable INR with continuous factor administration until graft failure. Fibrinogen values for B) Octaplex® and control recipients as well as D) NovoSeven® recipients, demonstrating the ability of xenolivers receiving continuous coagulation factors to maintain adequate synthetic function until graft failure. Octaplex-B denotes bolus Octaplex® and Octaplex-C denotes continuous Octaplex®. Red line indicates pig baseline levels. INR, International Normalized Ratio.

Figure 7. Findings on Intra-Operative Biopsy

A) Left, B353; Right, B356, both demonstrating a necrotic, non-viable liver with evidence of vascular thrombosis and TMA during post-operative re-exploration. In comparison, B397, bottom, demonstrates a pink, healthy liver graft without evidence of vascular thrombosis or TMA. B) Top, Middle, Bottom; B368, B365 and B381 respectively, demonstrating a pink, healthy liver without evidence of vascular thrombosis or TMA. TMA, Thrombotic Microangiopathy.