ABSTRACT
INTRODUCTION: There exists variation regarding the approach to anticoagulation and variceal hemorrhage (VH) prophylaxis among patients with cirrhosis and portal vein thrombosis (PVT). METHODS: A survey was distributed to gastroenterology and hepatology providers to assess the approach to anticoagulation and VH prophylaxis among patients with PVT in cirrhotic patients. RESULTS: Providers were more likely to start anticoagulation if the patient was listed for liver transplantation, was symptomatic, or had superior mesenteric vein thrombosis. For prevention of first VH, many providers opt for combination therapy with both nonselective beta blockers and variceal ligation. DISCUSSION: Although providers agree on the clinical scenarios that merit initiation of anticoagulation, practice variation was identified in the means of preventing first VH.
Subject(s)
Esophageal and Gastric Varices , Liver Diseases , Varicose Veins , Venous Thrombosis , Humans , Esophageal and Gastric Varices/etiology , Esophageal and Gastric Varices/therapy , Portal Vein , Gastrointestinal Hemorrhage/etiology , Gastrointestinal Hemorrhage/therapy , Gastrointestinal Hemorrhage/pathology , Liver Diseases/pathology , Liver Cirrhosis/complications , Liver Cirrhosis/pathology , Venous Thrombosis/etiology , Anticoagulants/therapeutic use , North AmericaABSTRACT
The innate immune system plays a critical role in allograft rejection. Alloresponses involve numerous cytokines, chemokines, and receptors that cause tissue injury during rejection. To dissect these inflammatory mechanisms, we developed cell transplantation models in dipeptidylpeptidase-deficient F344 rats using mycophenolate mofetil and tacrolimus for partial lymphocyte-directed immunosuppression. Syngeneic hepatocytes engrafted in liver, whereas allogeneic hepatocytes were rejected but engrafted after immunosuppression. These transplants induced mRNAs for >40 to 50 cytokines, chemokines, and receptors. In allografts, innate cell type-related regulatory networks extended to granulocytes, monocytes, and macrophages. Activation of Tnfa and its receptors or major chemokine receptor-ligand subsets persisted in the long term. An examination of the contribution of Tnfa in allograft response revealed that it was prospectively antagonized by etanercept or thalidomide, which resolved cytokine, chemokine, and receptor cascades. In bioinformatics analysis of upstream regulator networks, the Cxcl8 pathway exhibited dominance despite immunosuppression. Significantly, Tnfa antagonism silenced the Cxcl8 pathway and decreased neutrophil and Kupffer cell recruitment, resulting in multifold greater engraftment of allogeneic hepatocytes and substantially increased liver repopulation in retrorsine/partial hepatectomy model. We conclude that Tnfa is a major driver for persistent innate immune responses after allogeneic cells. Neutralizing Tnfa should help in avoiding rejection and associated tissue injury in the allograft setting.