Thrombotic risk factors and liver histologic lesions in non-alcoholic fatty liver disease

Thrombin promotes diet-induced obesity through fibrin-driven inflammation

“…Through gain-and loss-of-function studies targeting thrombin generation and downstream substrates, these studies are, to our knowledge, the first to ascribe thrombin-driven obesity to a function of fibrin(ogen) and not PAR1 signaling. Moreover, to our knowledge, these studies are the first to experimentally demonstrate that procoagulant mutations are capable of exacerbating obesity-associated pathologies, authenticating association studies in humans (16,17,74).…”

“…Total body weights of CD-fed or HFDfed mice were not different between WT and Fibγ Δ5 mice at any time point during the challenge period (see Figure 2, I and J, for representative time points of 9 weeks and 16 weeks, respective-NAFLD, but are associated with the severe form of this disease, nonalcoholic steatohepatitis (NASH), and advanced liver fibrosis (18). Although these association studies are highly intriguing and have serious potential clinical implications, significant knowledge gaps remain, including whether elevated thrombin activity and adipose fibrin deposits are causative factors in obesity and the identification of potential mechanisms linking thrombin and fibrin to obesity sequelae.…”

Is there a rationale for treatment of chronic liver disease with antithrombotic therapy?

“…In other words, PVT may not be the causal factor in cirrhosis progression, but merely the marker of progressive microvascular congestion and it is the "side-effect" of the anticoagulant treatment, the restoration or preservation of blood flow in the hepatic microvasculature, that explains the favorable effects of anticoagulant therapy. This is certainly an appealing hypothesis, especially in relation to multiple epidemiological studies showing a positive correlation between congenital and acquired thrombophilia and liver disease progression, and on the other hand a milder course in female patients and patients with hemophilia [90][91][92][93][94][95][96][97]. In fact, these studies have been complemented using experimental animal models of liver disease, in which was it was demonstrated that thrombophilic gene mutations promote the fibrotic process in the parenchyma, but progression could be attenuated by antithrombotic treatment both in animals carrying the mutations and in wild-type counterparts [98][99][100].…”

Hemostasis and thrombosis in patients with liver disease: The ups and downs

“…Moreover, steatosis has been associated with enhanced PAI-1 and factor VII activity [17]. In addition, altered clot kinetics have recently been described in non-cirrhotic patients with NAFLD and the presence of thrombotic risks has been correlated with the degree of fibrosis in patients with NASH [98,99]. In the setting of these converging risks, we can foresee increasing numbers of patients with both liver disease and cardiovascular diseases.…”