Soluble thrombomodulin antigen as a marker for endothelial damage during liver transplantation

Abstract

RTHOTOPIC liver transplantation (OLT) is now being performed with improved survival rates in a high number of patients suffering from different liver diseases. Despite better control of blood loss, hemorrhages still occur, particularly after reperfusion. Problems arising from defective hemostasis during major abdominal surgery are a major risk for patients with terminal chronic liver disease. 1 Liver transplantation, most often performed in such patients, differs from operations because the recipients start with a diseased liver and end up with a healthy liver, the function of which, however, is compromised by preservation damage. Thrombomodulin (TM), an integral glycoprotein on the surface of endothelial cells, serves as a receptor for thrombin. Thrombin bound to TM greatly reduces procoagulatory and platelet-stimulating effects but activates the zymogen, protein C. 2 Activated protein C together with protein S inactivates two blood coagulation cofactors, factor Va and factor VIIIa, and indirectly stimulates fibrinolysis. Thus, TM plays an important role as an anticoagulant protein on the blood vessel wall. Immunohistochemically, TM has been found to be mainly present on endothelial cell surfaces of blood and lymphatic vessels in all organs except the brain. 3,4 A smaller from of TM, the soluble thrombomodulin (sTM), has been isolated from human blood and urine. 5 The structure of sTM is not known but is thought to be similar to the soluble protein obtained after proteolytic modification of TM with elastase 6 —a cleaved form of tissue TM with loss of part of the transmembrane domain, and the cytoplasmatic tail. 7 Therefore, sTM in plasma appears to be derived from injured endothelial cells or to be proteolytically cleaved from TM by proteases. In vitro, sTM has been shown to be a marker of endothelial damage 8 and several previous clinical studies have shown that plasma levels of sTM are increased in various diseases associated with endothelial cell damage or proteolytic activity on the endothelial cell surface, including DIC, 9,10 adult respiratory distress syndrome (ARDS), 10 thromboembolic disease, 9,10 thrombotic thrombocytopenic purpura, 11,12 diabetes mellitus with microangiopathy, 9,13 systemic lupus erythematosus (SLE), 14 and chronic myelogenous leukemia. 15 Because they are usually associated with vascular endothelium alterations, 10,16 TM plays an important role as an anticoagulant protein on the blood vessel wall. However, in the context of liver transplantation, the understanding of pathophysiology of TM in the coagulation-fibrinolysis equilibrium is still in its infancy. There are only few reports 17,18 on sTM in liver transplantation. In orthotopic liver transplantation, both platelet and leukocyte activation as well as prothrombin activation are suspected of being caused by damaged endothelial cells in the grafted liver. In this study, plasma sTM levels as an endothelial marker were measured in the course of 11 consecutive liver transplantation. Samples were taken at nine different time points perioperatively as well as the perfusate released from the graft outflow vein during the flushing procedure.