Effects of bivalirudin on instant blood-mediated inflammatory reaction after intraportal islet transplantation

The instant blood-mediated inflammatory reaction (IBMIR) is a major barrier to successful intraportal islet engraftment. Bivalirudin, a direct thrombin inhibitor, could mitigate IBMIR by suppressing thrombin activity and platelet activation, yet its role in islet transplantation remains insufficiently defined. Using a portal vein islet transplantation model with rat islets, we compared bivalirudin treatment (BT) with heparin treatment (HT). In recipient Wistar rats, both BT and HT increased circulating antithrombin and prolonged activated partial thromboplastin time (APTT) versus saline. BT more effectively reduced serum β-thromboglobulin (β-TG) and thrombin-antithrombin (TAT) complexes, and it decreased peri-graft fibrin deposition to a greater extent than HT. BT and HT also attenuated hepatic NF-κB activation, lowered serum TNF-α, and diminished inflammatory-cell infiltration within grafts, with more pronounced effects under BT. In BALB/c-nu recipient mice, BT and HT similarly reduced graft inflammatory infiltration. Functionally, a higher proportion of diabetic recipients achieved normoglycemia after BT or HT than after saline, and BT yielded a greater normoglycemia rate with a shorter time-to-normoglycemia than HT. Collectively, BT and HT alleviate coagulation activation and inflammatory infiltration characteristic of IBMIR, thereby improving post-transplant islet survival. BT demonstrated greater anti-thrombotic and anti-inflammatory activity than HT in this setting, supporting bivalirudin as a promising adjunct anticoagulant strategy for intraportal islet transplantation and potentially other cell-therapy applications.