Portal vein thrombosis and chronic liver disease progression: The closer you look the more you see
Authors: Edoardo G. Giannini, R. Todd Stravitz, Stephen H. Caldwell
Journal: Hepatology (2015)

Potential conflict of interest: Nothing to report. To the Editor: We read with great interest the article by Nery et al. recently published in Hepatology.1 The authors should be commended for the great effort in performing this study, which prospectively assessed the incidence of portal vein thrombosis (PVT) in patients with compensated and mildly decompensated cirrhosis, the risk factors for its occurrence, and its impact on disease history. The primary conclusion of this study is that the development of PVT and cirrhosis progression are not associated in a cause‐and‐effect relationship, but rather represent two independent phenomena along the course of disease, that nevertheless may share some pathophysiological mechanisms.1 The authors note that their results are consistent with observations within a 48‐week, randomized study that evaluated the potential benefit of enoxaparin, in which anticoagulation decreased cirrhosis disease progression far more markedly than the decreased incidence of PVT.2 Together, the results of these studies suggest common, but not identical, mechanisms underlying the progression of liver disease and PVT occurrence and imply that activation of hemostasis within the microcirculation of the liver, rather than occlusion of larger portal vessels, is the primary driver of disease progression. These results suggest that enoxaparin prevented both PVT‐independent progression of cirrhosis and PVT itself, but that PVT may occur within the natural history of disease—without necessarily determining progression of cirrhosis. Thus, activation of the coagulation cascade and thrombosis are likely the principal determinants of both disease progression and macrovascular thrombosis. Indeed, it has been shown that intrahepatic microvascular thrombosis—in the absence of portal vein occlusion—is responsible for parenchymal extinction and enhanced fibrogenesis and therefore progressive loss of functioning hepatic mass and worsening stage of disease.3 Concurrently, activation of the coagulation cascade and a shift toward the procoagulant side of the hemostatic balance of patients with cirrhosis may also lead to the occurrence of macrovascular thrombosis, such as PVT. Furthermore, infection and inflammation may represent a common denominator for the occurrence of both intrahepatic microvascular thrombosis and intra‐/extrahepatic macrovascular thrombosis. In fact, the study by Villa et al. showed that the positive effect of enoxaparin was associated with decreased rates of bacterial infections, lower levels of markers of intestinal bacterial translocation, and lower levels of potent inflammatory mediators, such as intereleukin‐6.2 It is well known that, in patients with cirrhosis, systemic clotting activation mediated by endothelial perturbation can be triggered by intestinal bacterial translocation secondary to portal hypertension and low‐grade endotoxemia, and that endothelial perturbation is associated with very high von Willebrand factor levels, which, in turn, promote platelet adhesion.5 Thus, we propose a model (Fig. 1) describing a cascade of events where a chronic, procoagulant activity secondary to subclinical infection and inflammation may determine both intrahepatic microvascular thrombosis, thus leading to loss of functioning hepatic mass, and PVT. Sometimes these two processes are evident together in a single patient, but often they proceed independently despite their relationship. Such a relationship but lack of one‐to‐one correlation likely explains the conflicting literature and clinical impressions that attend questions on how best to address PVT in a given patient. Potential therapeutic strategies—for the time being—can only be hypothesized and need to be tested in future clinical studies.Figure 1: Proposed model for the occurrence of microvascular and macrovascular thrombosis in patients with cirrhosis.