Targeting von Willebrand factor in liver diseases: A novel therapeutic strategy?

Abstract

Acute and chronic liver disease are associated with substantial alterations in the hemostatic system. Evidence from both experimental and clinical studies suggests that anticoagulants slow the progression of liver disease. Efficacy of those anticoagulant drugs is, in part, attributed to a reduction of microthrombi formation within the liver. Although anticoagulant drugs show promising results, bleeding risk associated with these drugs is an obvious drawback, particularly in patients with a complex coagulopathy driven by decreased liver function. Identifying therapies that reduce intrahepatic thrombosis with minimal bleeding risk would significantly advance the field. Among the hemostatic alterations observed in patients are substantially increased levels of the platelet-adhesive protein von Willebrand factor (VWF). In contrast, levels of A Disintegrin and Metalloproteinase with Thrombospondin motifs, the enzyme that regulates VWF activity, are significantly reduced in patients with liver disease. Highly elevated VWF levels are proposed to accelerate intrahepatic thrombus formation and thus be a driver of disease progression. Strong clinical evidence suggesting a link between liver disease and changes in VWF is now being matched by emerging mechanistic data showing a detrimental role for VWF in the progression of liver disease. This review focuses on clinical and experimental evidence supporting a connection between VWF function and the progression of acute and chronic liver diseases. Furthermore, with the recent anticipated approval of several novel therapies targeting VWF, we discuss potential strategies and benefits of targeting VWF as an innovative therapy for patients with liver disease.

Keywords: ADAMTS13 protein; blood platelets; fibrosis; liver failure; von Willebrand factor.

Figure 1.. Proposed mechanisms whereby the VWF/ADAMTS13 axis contributes to liver disease.

The liver plays a key role in regulating plasma VWF levels. Hepatic stellate cells release ADAMTS13 into the microcirculation where it regulates plasma VWF multimeric size. VWF is also cleared by liver resident macrophages (i.e., Kupffer cells) and hepatocytes. Acute and chronic liver damage impact VWF regulation. For example, loss of endothelial fenestration impairs fluid exchange between hepatocytes and the sinusoidal blood. Plasma ADAMTS13 levels may be altered by disease-dependent changes in expression, secretion, or consumption. Similarly, increased endothelial secretion of VWF combined with impaired clearance by the diseased liver elevates VWF plasma levels. There is also evidence that HMW VWF multimers can be actively consumed and incorporated into platelet-rich microthrombi in the injured liver. Downstream pathologic effects of these microthrombi include disruption of blood flow, exacerbation of tissue injury and delayed liver repair. In addition, VWF and platelets may contribute to hepatic fibrosis by mechanisms dependent or independent of micro-thrombi by amplifying activation of hepatic stellate cells, the primary cell type responsible for exaggerated collagen deposition in chronic liver diseases. LMW, Low-molecular weight; HMW, High molecular weight, LSEC, liver sinusoidal endothelial cell; HSC, hepatic stellate cell; HPC, hepatocyte. Figure created with BioRender.com