Effects of Long-term Administration of High-dose Recombinant Human Antithrombin in Immunosuppressed Primate Recipients of Porcine Xenografts

Abstract

These results suggest that a high daily dose of rhAT fails to influence survival or prevent fibrin formation and deposition in the graft in our pig-to-primate model. However, the potential role of rhAT administered in combination with heparins or other clotting inhibitor concentrates in this model remains to be determined.

Increased Immunosuppression, Not Anticoagulation, Extends Cardiac Xenograft Survival

“…Consistent with this anticoagulation has been shown to block acute thrombotic microangiopathy associated with cellular xenotransplantation (20) and Kuwaki et al (21) using chronic costimulation blockage have suggested based on a limited number of recipients that postoperative heparin and aspirin may prolong graft survival. Our work and similar work by Cozzi (22) using prospectively defined transplant protocols demonstrate that the beneficial effects of a variety of systemic anticoagulants are at best modest when the recipient is immunosuppressed. Furthermore, in this work and in all reported instances that we are aware of, using very different immunosuppressive strategies and with variable xenograft survival, it appears that anticoagulant therapy does not appreciably alter the histology of xenograft rejection which remains dominated by vascular antibody staining and microvascular thrombosis.…”

Antiinflammatory and Anticoagulant Effects of Transgenic Expression of Human Thrombomodulin in Mice

“…Although these genetic modifications of the pig donor have largely prevented HAR, there has been little progress in preventing graft loss due to acute vascular rejection (AVR) (also known as delayed xenograft rejection and acute humoral xenograft rejection) and failure of these grafts is inevitable within 6 months. Our group has demonstrated marked attenuation of consumptive coagulopathy and thrombosis and a near doubling of survival of nonimmunosuppressed pig to baboon kidney grafts with antithrombin III treatment (1), indicating the importance of thrombosis in this model, however others have been unsuccessful in obtaining lasting benefit with a variety of anticoagulants in immunosuppressed xenograft recipients (2,3). …”

In Vivo Anti-HIV Activity of the Heparin-Activated Serine Protease Inhibitor Antithrombin III Encapsulated in Lymph-Targeting Immunoliposomes

“…We based our dosing regimen for non-activated ATIII on a baboon model of sepsis, in which ATIII administration between 10 to 20-fold the physiological level (2.4 µM) was required to initiate an anti-inflammatory response to prevent disseminated intravascular coagulation [34]. A comparable dose had also been shown to be non-cytotoxic in primates [35]. Based on this, 0.8 µmol/kg ATIII was injected daily for 4 days during a loading phase and then applied every 3 rd day for a 14-day period.…”