Advanced liver disease is characterized by profound hemostatic alterations that can lead both to bleeding or to thrombotic complications. While pro-hemorrhagic alterations are present including thrombocytopenia and reduced plasmatic levels of coagulation factors, pro-thrombotic abnormalities such as decrease in anti-coagulant proteins antithrombin, Proteins C and S, increase in prothrombotic Factor VIII, and von Willebrand factor are also present.
The most frequent site of thrombosis in cirrhotic patients is the portal vein, consequence of an interplay of factors including altered hemostasis and venous stasis. The endothelium, the third component of the thrombosis triad, however, probably plays an important role in the genesis of in situ thrombosis within the portal vein. In the present study, endothelium form portal and cava veins were analyzed in cirrhotic patients, and compared to that of non-cirrhotic subjects, in order to determine the possible role of local alterations in the development of thrombosis. The immunofluorescence study of the main endothelial anticoagulant protein, thrombomodulin, revealed decreased presence of this component in the endothelium of the portal vein with respect to the vena cava in cirrhosis patients. On the other hand, the immunohistochemical analysis of pro-coagulant Factor VIII revealed that this endothelial protein is present uninterruptedly lining the lumen of portal vein and vena cava of both cirrhosis patients and non-cirrhotic subjects, without showing any differences between them. Diminished thrombomodulin may hamper the endothelium’s anticoagulant properties, which, in the presence of conserved Factor VIII, may lead to the development of thrombosis.
The thrombosis of the portal vein represents an important milestone in the natural history of patients with cirrhosis, often increasing morbidity before and mortality after liver transplantation. Obtainment of recanalization through anticoagulation is therefore paramount, and in the present study, an analysis was performed regarding factors that may have an impact on efficacy of anticoagulation with low molecular weight heparin in cirrhotic patients with this complication. Anticoagulation with low molecular weight heparin was demonstrated to be a valid strategy for achieving portal vein recanalization, with a response rate of 65.2%, including complete recanalization in 24 of the 46 treated patients, after a mean of 4.5 months (±3.1 months) of anticoagulation. Whereas the hemostatic status of patients did not correlate with the response to anticoagulation, the interval between thrombus onset and start of therapy was the only predictive factor of therapeutic efficacy. Specifically, thrombus age at diagnosis (1.9 ± 1.2 months vs 6.3 ± 4.5 months in the recanalization group and in the non-recanalization group, respectively, p<.001), and the interval between thrombus onset and start of anticoagulation (3.2 ± 1.7 months vs 7.78 ± 4.5 months in the recanalization group and in the non-recanalization group, respectively, p<.002) were the principal determinants of therapeutic efficacy. This underlines the importance of prompt diagnosis and start of therapy to increase the probability of successful anticoagulant therapy.
Although in cirrhosis the low levels of antithrombin, which is necessary for the action of heparins, could theoretically hamper the anticoagulant effect, the clinical efficacy of anticoagulant therapy with low molecular weight heparin has been herein demonstrated.
The anticoagulant effect of low molecular weight heparin was then tested in vitro using the thrombin generation assay, and concentrations within the therapeutic range achieved reduction of endogenous thrombin potential notwithstanding the marked reduction in antithrombin levels that were present in plasma from cirrhotic patients and the low plasma anti-Xa activity determined in vitro. In particular, patients with Child Pugh C cirrhosis were characterized by antithrombin levels which were as low as those of subjects with the prothrombotic condition of genetic antithrombin deficit (42±14% versus 52±4%, respectively, p=.06). At low molecular weight heparin 0.35 UI/mL concentration in vitro, anti-Xa activity was significantly lower in Child Pugh B and Child Pugh C patients as compared to controls (p<0.001), as well as in patients with congenital AT defect as compared to controls (p<0.001). Despite low levels of antithrombin and anti-Xa activity, patients with cirrhosis showed a greater anticoagulant effect of low molecular weight heparin, with a mean endogenous thrombin potential reduction of 72.6±11% (p=0.02 versus controls). This increased susceptibility of cirrhosis patients with advanced stages of the disease may therefore actually warrant dose reduction of anticoagulation
