Increased Plasma VWF Antigen over Decreased ADAMTS13 Activity in Patients with Liver Cirrhosis: Relationship to Degree of Liver Disturbance and Clinical Features.
Authors: Uemura Masahito , Kato Seiji , Matsumoto Masanori , Ishizashi Hiromichi , Isonishi Ayami , Hiura Hisahide , Matsuyama Tomomi , Yagi Hideo , Ishikawa Masatoshi , Fujimoto Masao , Kojima Hideyuki , Yoshiji Hitoshi , Fujimura Yoshihiro , Fukui Hiroshi 
Published: October 2019

Abstract
Background/aims: Deficiency of plasma ADAMTS13 activity (:act) accumulates unusually large von Willebrand factor multimer (UL-VWFM) in circulation that might induce platelet thrombi formation. We demonstrated that hepatic stellate cells are major ADAMTS13-producing cells in human liver using in situ hybridization and immunohistochemistry (Blood, 2005, 106:922), and a decreased plasma ADAMTS13:act in patients with cirrhotic biliary atresia can be fully restored after living-related liver transplantation (Blood2000, 96:636a). Taken these findings together, ADAMTS13 may play a role on the regulation of sinusoidal microcirculation in the liver. We, therefore, investigated the relationship of ADAMTS13 and its substrate (UL-VWFM) to clinical features in patients with chronic liver diseases.
Methods: Plasma levels of ADAMTS13:act, ADAMTS13 antigen (:ag) and VWF antigen (VWF:ag) were determined in 33 patients with chronic hepatitis (CH) and 109 liver cirrhosis (LC). ADAMTS13:act was measured by both the classic VWFM assay and the novel monoclonal antibody-based ELISA (Transfusion2006, 46:1444). The ADAMTS13:ag was quantified by a sandwich ELISA using two anti-ADAMTS13 murine monoclonal Abs (A10 and C7), and the UL-VWFM was analyzed by a SDS−0.9% agarose gel electrophoresis.
Results: ADAMTS13:act in LC progressively decreased from the highest in Child A (mean 79%), to Child B (63%), to the lowest in Child C (30%), compared with CH (87%) and normal healthy subjects (N, 102%). The activity measured by VWFM assay highly correlated with that assayed by ELISA (r=0.75, p<0.001), which was also correlated with ADAMTS13:ag (r=0.79, p<0.001). Markedly decreased ADAMTS13 :act was noted in cirrhotics with hepatic encephalopathy (28%), refractory ascites (25%), and hepatorenal syndrome (13%). The multivariate analysis showed Child-Pugh score and spleen volume as independent factors contributing to the activity (r=0.69, p<0.001). VWF:ag was remarkably high with the progression of liver disturbance (N 100%, CH 245%, Child A LC 320%, Child B LC 436%, Child C LC 486%, respectively), resulting in extremely increased ratio of VWF:ag to ADAMTS13 activity in advanced cirrhotics (N 1.0, CH 2.9, Child A LC 4.3, Child B LC 13.3, Child C LC 43.2, respectively). The cirrhotics with UL-VWFM showed higher Child-Pugh score (10.8 vs. 7.7, p<0.001), lower hemoglobin levels (9.6 g/dl vs. 11.3 g/dl, p<0.005), severe thrombocytopenia (6.2 x104/mm3 vs. 9.2 x104/mm3, p<0.05), higher C-reactive protein (3.8 mg/dl vs. 0.9 mg/dl, p<0.001), and higher serum creatinine (1.5 mg/dl vs. 0,9 mg/dl, p<0.005) than those without.
Conclusions: Both the activity and antigen of plasma ADAMTS13 decrease with increasing severity of cirrhotics. The imbalance of a larger amount of UL-VWFM over the decreased plasma level of ADAMTS13 may reflect the predisposing state for the development of microcirculatory disturbance in advanced cirrhotics.