Nonalcoholic Fatty Liver Disease, Portal Vein Thrombosis and Coagulation: More Questions Than Answers?

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Portal vein thrombosis (PVT) remains a controversial area of study without consensus opinion on clinical importance. PVT has been described both as a precipitant of hepatic decompensation with increased morbidity and mortality as well as a reflection of more advanced liver disease without clinical implication. We read with great interest the report by Ghabril et al,1 in which the authors examined both risk factors for the development of PVT as well as patient-centered pre and posttransplantation outcomes. The authors concluded that PVT at the time of liver transplantation was associated with early mortality and graft failure and that cryptogenic cirrhosis, diabetes, and obesity were associated with the highest odds of PVT. We have recently reported results on this topic analyzing the same nationwide US-based database, and also found this association to hold true for recipients with cirrhosis secondary to nonalcoholic steatohepatitis (NASH) as well as in those recipients who were obese, despite several differences in methodology.2 We did not analyze diabetes as a separate covariate, rather, we accounted for the codependency between diabetes and NASH as well as diabetes and obesity with interaction terms in our model.
Making the distinction between NASH and being overweight or obese and the impact of each on clinically relevant hemostatic events is important given recent conflicting reports on hemostatic profiles in these patient populations.3,4 Tripodi et al3 argue that nonalcoholic fatty liver disease (NAFLD) is the main prohemostatic factor as supported by a progressive procoagulation imbalance from steatosis to cirrhosis in which both the endogenous thrombin potential (ETP) ratio and Factor VIII:Protein C ratio increase. On the other hand, based on analysis of not only coagulation but also primary hemostasis and fibrinolysis, Potze et al4 concluded that overall, hemostasis remains rebalanced in patients with NAFLD and that being overweight conferred a much greater prohemostatic profile. Nonetheless, Potze et al4 identified several individual prohemostatic features in patients with NAFLD or NASH cirrhosis including elevated levels of plasminogen activator inhibitor 1, fibrinogen, factor VIII and decreased levels of antithrombin. Furthermore, NAFLD subjects were found to have both evidence of hypofibrinolysis as well as a prohemostatic structure to the fibrinclot with increased clot density and decreased clot permeability, the latter of which was also seen in overweight patients without NAFLD.
Given these opposite conclusions about the complex interplay between NAFLD, obesity and clotting risk, the hemostatic environment in patients with NAFLD and NASH cirrhosis remains controversial and offers avenue for future mechanistic study. What does appear to hold true based on large-scale epidemiologic data is that patients with NAFLD are at increased risk for clinically important thrombotic events including PVT, as well as pulmonary embolism and deep vein thrombosis.1,2,5 The hemostatic environment remains relatively unexplored in this patient population, and we would suggest this as an avenue for future provocative study and ultimately the possibility of intervention with anticoagulation pretransplantation and posttransplantation in this high-risk population where PVT may be more of a disease modifier rather than downstream effect.

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