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

Abstract

Human islet transplantation is a viable treatment option for type 1 diabetes mellitus (T1DM). However, pancreatic islet inflammation after transplantation induced by innate immune responses is likely to hinder graft function. This is mediated by incompatibility between islets and the blood interface, known as instant blood-mediated inflammatory reaction (IBMIR). Herein we hypothesized that portal venous administration of islet cells with human recombinant antithrombin (ATryn®), a serine protease inhibitor (serpin), which plays a central role in the physiological regulation of coagulation and exerts indirect anti-inflammatory activities, may offset coagulation abnormalities such as disseminated intravascular coagulation (DIC) and IBMIR. The current prospective, randomized experiment was conducted using an established preclinical pig model. Three groups were constituted for digested pancreatic tissue transplantation (0.15 ml/kg): control, NaCl 0.9% (n = 7); gold standard, heparin (25 UI/kg) (n = 7); and human recombinant ATryn® (500 UI/kg) (n = 7). Blood samples were collected over time (T0 to 24 h), and biochemical, coagulation, and inflammatory parameters were evaluated. In both the control and heparin groups, one animal died after a portal thrombosis, while no deaths occurred in the ATryn®-treated group. As expected, islet transplantation was associated with an increase in plasma IL-6 or TNF-α levels in all three groups. However, DIC was only observed in the control group, an effect that was suppressed after ATryn® administration. ATryn® administration increased antithrombin activity by 800%, which remained at 200% for the remaining period of the study, without any hemorrhagic complications. These studies suggest that coadministration of ATryn® and pancreatic islets via intraportal transplantation may be a valuable therapeutic approach for DIC without risk for islets and subjects.

Point Mutation of a Non-Elastase-Binding Site in Human α1-Antitrypsin Alters Its Anti-Inflammatory Properties

“…Collectively, the findings suggest that the effect of hAAT on the production and shedding of TNFα from leukocytes may involve multiple structural domains on hAAT, altogether irrespective of the RCL, affecting both intra- and extracellular elements in TNFα levels. In support of this possibility, antithrombin III, which shares structural homology to hAAT outside the RCL, has been shown to produce several overlapping outcomes to some of those obtained using hAAT ( 87 , 88 ), including reduced LPS-stimulated TNFα release in monocytes ( 89 ).…”

Polymeric Approaches to Reduce Tissue Responses Against Devices Applied for Islet-Cell Encapsulation

“…However, its clinical application was and is limited by high risks for thrombosis and infections, and the demand for major surgery for implantation. Although some groups still publish novel approaches for intravascular devices that are associated with less risks (Prochorov et al, 2008; Gmyr et al, 2017), the majority of research papers in the past decade focus on extravascular devices. Extravascular devices are therefore the major focus of this review.…”

Chemical Strategies for Improving Islet Transplant Outcomes

“…The prevention of coagulation is another mechanistic approach to improving islet transplantation success, due to links between coagulation and IBMIR [128]. Antithrombin has been explored for this application [128][129][130].…”

“…The prevention of coagulation is another mechanistic approach to improving islet transplantation success, due to links between coagulation and IBMIR [128]. Antithrombin has been explored for this application [128][129][130]. While alternative thrombin inhibitors such as heparin and hirudin are available, these drugs are limited in terms of efficacy and safety in transplantation [131,132].…”