Warfarin or Low-Molecular-Weight Heparin Therapy does not Prolong Pig-To-Primate Cardiac Xenograft Function

Abstract

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 a -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.

Intravascular Thrombosis in Discordant Xenotransplantation

“…This is supported by the finding of immunoglobulin and C4d deposition in many rejected grafts, Gal KO ( [7,9], our unpublished data; Fig. 1) or otherwise (10) and by the increasingly frequent observation of microvascular thrombosis in association with graft loss (11,12). This "thrombotic microangiopathy" is characterized histologically by microvascular plugging with platelet-rich thrombi, focal ischemia, and fibrinoid necrosis (Fig.…”

“…Therapeutic warfarin or low-molecular-weight heparin anticoagulation had no significant impact on xenograft survival in a CD46 transgenic pig-to-baboon cardiac model, and the levels of fibrin deposition and platelet thrombi were indistinguishable in treated and untreated animals (12). Similarly, the use of a combination of aspirin and clopidogrel to inhibit platelet aggregation neither prolonged cardiac xenograft survival nor prevented the development of microvascular thrombosis (42).…”

Humoral immunity is the dominant barrier for allogeneic bone marrow engraftment in sensitized recipients

“…14,15 Moreover, in xenotransplantation, anti-MHC antibody was recently shown to contribute in a dominant fashion to xenograft rejection. 16,17 This antibody-mediated rejection is not readily controlled with conventional immunosuppressive drugs. Aggressive protocols to decrease the level of sensitization, including plasmapheresis, the administration of immunoglobulin, immunoadsorption, antilymphocyte Abs, and combination therapies using immunosuppression 18,19 have provided limited, short-term success in improving outcomes of organ allografts in sensitized recipients.…”

Increased Immunosuppression, Not Anticoagulation, Extends Cardiac Xenograft Survival

“…To investigate which of these mechanisms may dominate cardiac xenograft rejection, we have reanalyzed a series of heterotopic pig-to-baboon cardiac xenografts (13)(14)(15)(16) comparing graft survival using different levels of maintenance immunosuppression with and without systemic anticoagulation therapies. We find that significant prolongation of xenograft survival is achieved through elevated maintenance immunosuppression and that administration of systemic anticoagulants did not improve graft survival.…”