Coagulation Dysfunctions in Non-Alcoholic Fatty Liver Disease-Oxidative Stress and Inflammation Relevance

Abstract

Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases. Its incidence is progressively rising and it is possibly becoming a worldwide epidemic. NAFLD encompasses a spectrum of diseases accounting for the chronic accumulation of fat within the hepatocytes due to various causes, excluding excessive alcohol consumption. In this study, we aimed to focus on finding evidence regarding the implications of oxidative stress and inflammatory processes that form the multifaceted pathophysiological tableau in relation to thrombotic events that co-occur in NAFLD and associated chronic liver diseases. Recent evidence on the pathophysiology of NAFLD suggests that a complex pattern of multidirectional components, such as prooxidative, proinflammatory, and prothrombotic components, better explains the multiple factors that promote the mechanisms underlying the fatty acid excess and subsequent processes. As there is extensive evidence on the multi-component nature of NAFLD pathophysiology, further studies could address the complex interactions that underlie the development and progression of the disease. Therefore, this study aimed to describe possible pathophysiological mechanisms connecting the molecular impairments with the various clinical manifestations, focusing especially on the interactions among oxidative stress, inflammation, and coagulation dysfunctions. Thus, we described the possible bidirectional modulation among coagulation homeostasis, oxidative stress, and inflammation that occurs in the various stages of NAFLD.

Keywords: adipokines; endoplasmic reticulum; foamy cells; hepatic steatosis; hypercoagulability; lipid peroxidation; macrophages; mitochondria; reactive oxygen species; steatohepatitis; thrombosis.

Figure 1

The stages of NAFLD pathophysiology and its progression in HCC, and subsequent prooxidative, proinflammatory and prothrombotic events. (NASH: nonalcoholic steatohepatitis, ROS: reactive oxygen species, HC: hepatocellular, HCC: hepatocellular carcinoma, ↑––increased; ↓––decreased).

Figure 2

Schematic representation of the interaction established between NAFLD and coagulation dysfunctions. (FVIII: factor VIII; ROS: reactive oxygen species; VWF: Von Willebrand factor).

Figure 3

Schematic representation of several alterations that occur in the coagulation cascade associated with NAFLD and oxidative stress. The failure of liver leads to the release of more CK in response to necrotic tissue, which triggers the synthesis of FVIII. When FVIII, which is known to be implicated in thrombin generation, exceeds normal levels, it provokes the appearance of extracellular matrix protein deposition and fibrosis. In the same context of liver injury, a low level of the enzyme ADAMTS13 generates the formation of platelet microthrombi and impacts the sinusoidal microcirculation. In addition, changes in the activity of coagulation factors can damage the coagulation balance. Coagulation balance refers to the interaction between the procoagulant pathways specific for clot formation and those mechanisms included under the name of the fibrinolysis system. In addition, HSCs are activated in the presence of free radicals, initiating the proliferative and fibrogenic “behavior” that sustains the progression of liver disease. Consequently, oxidative stress is able to perturb the homeostasis maintenance by inducing the appearance of thrombotic and hemorrhagic events. (CK: cytokines; DVT: deep vein thrombosis; FVIII: factor VIII; HSCs: hepatic stellate cells; KCs: Kupffer cells; OS: oxidative stress; PE: pulmonary embolism; PVT: portal vein thrombosis; VWF: Von Willebrand factor).