Warfarin or Low-Molecular-Weight Heparin Therapy Does Not Prolong Pig-To-Primate Cardiac Xenograft Function

Microvascular thrombosis is a prominent feature in cardiac delayed xenograft rejection (DXR). We investigated the impact of warfarin or low- molecular- weight heparin (LMWH) anti- coagulation on xenograft function using a heterotopic pig- to- primate model. Donor hearts were from CD46 transgenic pigs and baboon immunosuppression included tacrolimus, sirolimus, anti-CD20 and TPC, an alpha-galactosyl-polyethylene glycol conjugate. Three groups of animals were studied. Group 1 (n = 9) was treated with warfarin, Group 2 (n = 13) with LMWH and Group 3, received no anticoagulant drugs. The median duration of xenograft function was 20 days (range 3 - 62 days), 18 days (range 5 - 109 days) and 15 days (range 4 - 53 days) in Groups 1 to 3 respectively. Anti- coagulation achieved the targeted international normalized prothrombin ratio (INR) and anti- factor Xa levels consistent with effective in vivo therapy yet, no significant impact on median xenograft function was observed. At rejection, a similar histology of thrombosis and ischemia was apparent in each group and the levels of fibrin deposition and platelet thrombi in rejected tissue was the same. Anti- coagulation with warfarin or LMWH did not have a significant impact on the onset of DXR and microvascular thrombosis. However, a role for specific anticoagulant strategies to achieve long- term xenograft function cannot be excluded.