Hepatic stellate cell activation leads to impaired ADAMTS13 secretion and VWF/ADAMTS13 imbalance in liver cirrhosis

Abstract Background: The coagulopathy of liver cirrhosis remains incompletely understood. Intrahepatic microthrombi formation is integral to the progression of liver fibrosis while macrovascular complications—such as hepatic artery and portal vein thrombosis—frequently complicate orthotopic liver transplantation and contribute to early graft failure. Pro-thrombotic ultralarge multimers of von Willebrand Factor (VWF) have been identified in patients with liver cirrhosis. Deficiency of ADAMTS13, the VWF-cleaving protease, is also observed in cirrhotic patients and is associated with thrombotic events and shortened overall survival. Despite its prognostic significance, the mechanistic basis of ADAMTS13 deficiency in this patient population remains poorly defined. Furthermore, there are no established strategies to enhance physiological VWF cleavage, reduce thrombotic risk, or improve microvascular perfusion in patients with liver cirrhosis. Methods: VWF and ADAMTS13 function were characterized in a cohort of patients with liver cirrhosis (n = 12) in a clinically stable state. Primary human hepatic stellate cells and whole liver lysates were obtained from healthy controls and patients with liver cirrhosis to investigate the biogenesis of ADAMTS13. Hepatic stellate cells were activated in vitro to model a fibrotic phenotype and analyzed alongside primary human endothelial cells. The relationship between intracellular proteolysis of ADAMTS13 and its secretion was further examined using ADAMTS13-expressing cell lines. Results: In patients with liver cirrhosis, VWF activity was elevated (mean: 599% of control, P < 0.001), while ADAMTS13 activity (mean: 61%) and antigen levels (mean: 43%) were both significantly reduced (P < 0.001). A strong correlation was observed between the level of ADAMTS13 antigen and activity (r = 0.91), whereas ADAMTS13 autoantibody levels in plasma showed no correlation with ADAMTS13 activity (r = - 0.14). Activated hepatic stellate cells exhibited markedly impaired secretion of ADAMTS13 when compared to endothelial cells, despite similar intracellular expression levels. Proteolysis of the ADAMTS13 metalloprotease domain was detected in activated hepatic stellate cells and in whole liver lysates of patients with chronic hepatitis and cirrhosis. In model cell lines, intracellular proteolysis of ADAMTS13 was similarly associated with impaired cellular secretion. Conclusions: Patients with liver cirrhosis consistently exhibit elevated VWF levels and reduced plasma ADAMTS13 activity, resulting in hemostatic imbalance. Activation of hepatic stellate cells during liver fibrogenesis impairs ADAMTS13 secretion, likely due to intracellular proteolysis of its metalloprotease domain. These findings provide mechanistic insight into ADAMTS13 deficiency observed in cirrhosis, which contributes to VWF:ADAMTS13 imbalance, promotes microvascular thrombosis, and may drive the progression of liver fibrosis.