Thrombin-Activatable Fibrinolysis Inhibitor Is Activated in an Instant Blood-Mediated Inflammatory Reaction After Intraportal Islet Transplant

Abstract

Objectives: Activated thrombin-activatable fibrinolysis inhibitor is a coagulation factor in some thrombotic diseases. However, available data on whether thrombin-activatable fibrinolysis inhibitor is activated in islet transplant are limited. In this study, changes of plasma-activated thrombinactivatable fibrinolysis inhibitor levels in instant blood-mediated inflammatory reaction after islet transplant were assessed. Materials and Methods: Plasma concentrations of thrombin-antithrombin complex, D-dimer, C-peptide, and activated thrombin-activatable fibrinolysis inhibitor were assessed at 0 minutes, 30 minutes, 1 hour, 6 hours, 12 hours, and 24 hours after an intraportal islet transplant using rats via an enzymelinked immunosorbent assay, or solid-phase, 2-site chemiluminescent immunometric assay. We recovered the liver at 1 hour after the transplant for histologic examination. Results: Thrombin-antithrombin complex, C-peptide, and activated thrombin-activatable fibrinolysis inhibitor levels increased immediately after we stopped islet infusion, and their peak levels occurred at 1 hour after islet infusion. D-dimer levels increased continually after islet infusion was stopped, and peaked 24 hours after infusion. Histologic examination of the liver 1 hour after islet infusion revealed frequent portal venous thrombi, with entrapped islets. The entrapped islets showed a disrupted morphology. Conclusions:Activated thrombin-activatable fibrinolysis inhibitor was generated and peaked 1 hour after islet transplant according with activating coagulation, indicating that thrombin-activatable fibrinolysis inhibitor is activated and accumulated at levels in instant blood-mediated inflammatory reaction was sufficient to affect fibrinolysis.

Dual Islet Transplantation Modeling of the Instant Blood-Mediated Inflammatory Reaction

“…Consistent with the studies of others (15,23,(40)(41)(42)(43)(44)(45)(46), IBMIR encompasses a wide spectrum of innate immune components including complement, macrophages, neutrophils and platelet aggregation. We show that some portion of this is in response to portal embolization, but that islet-specific factors contribute substantially to the augmentation of this cascade.…”

Human Recombinant Antithrombin (ATryn®) Administration Improves Survival and Prevents Intravascular Coagulation after Intraportal Islet Transplantation in a Piglet Model

“…This has been attributed to coagulation abnormalities such as IBMIR that results in profound cellular degradation 15,36 , but also to activation of endothelial cells with the appearance of DIC and ischemia by a lack of vascularization 37 . IBMIR is also accompanied by activation of coagulation with decreased fibrinolysis as reflected in the elevation of TAT 38 . Inhibition of thrombin activation by melagatran has already shown efficacy in the reduction of IBMIR 15 .…”

Fibrinolysis-Mediated Pathways in Acute Liver Injury

“…64 While the role of TAFI in ALI has not been thoroughly explored, there is a growing amount of data linking TAFI to other settings of liver injury such as liver transplantation outcome, hepatitis B infection, nonalcoholic steatohepatitis (NASH), and cirrhosis in patients 65 66 67 68 69 and chronic liver injury and inflammation in mice. 70 71 72…”

“…64 While the role of TAFI in ALI has not been thoroughly explored, there is a growing amount of data linking TAFI to other settings of liver injury such as liver transplantation outcome, hepatitis B infection, nonalcoholic steatohepatitis (NASH), and cirrhosis in patients [65][66][67][68][69] and chronic liver injury and inflammation in mice. [70][71][72] One study has specifically examined the impact of TAFI deficiency on acetaminophen-induced ALI. 70 In this study, wild-type and TAFI À/À mice were challenged with a hepatotoxic dose of acetaminophen (300 mg/kg), and liver injury was assessed 2, 6, or 24 hours after acetaminophen challenge.…”