Emerging evidence supports the concept of a rebalanced hemostatic state in liver disease as a result of a commensurate decline in prohemostatic and antihemostatic drivers. In the present study, we assessed levels and functionality of the platelet-adhesive protein von Willebrand factor (VWF) and its cleaving protease ADAMTS13 in the plasma of patients with acute liver injury and acute liver failure (ALI/ALF). Furthermore, we explored possible associations between VWF, ADAMTS13, and disease outcome. We analyzed the plasma of 50 patients taken on the day of admission for ALI/ALF. The plasma of 40 healthy volunteers served as controls. VWF antigen levels were highly elevated in patients with ALI/ALF. In contrast, the collagen-binding activity and the ratio of the VWF ristocetin cofactor activity and VWF antigen was significantly decreased when compared with healthy controls. Also, the proportion of high molecular weight VWF multimers was reduced, despite severely decreased ADAMTS13 levels. In spite of these functional defects, platelet adhesion and aggregation were better supported by plasma of patients with ALI/ALF when compared with control plasma. Low ADAMTS13 activity, but not high VWF antigen, was associated with poor outcome in patients with ALI/ALF as evidenced by higher grades of encephalopathy, higher transplantation rates, and lower survival. VWF or ADAMTS13 levels were not associated with bleeding or thrombotic complications. Conclusion: Highly elevated levels of VWF in plasma of patients with ALI/ALF support platelet adhesion, despite a relative loss of function of the molecule. Furthermore, low ADAMTS13 activity is associated with progressive liver failure in the patient cohort, which might be attributed to platelet-induced microthrombus formation in the diseased liver resulting from a substantially unbalanced VWF/ ADAMTS13 ratio. (HEPATOLOGY 2013;58:752-761)

To cite this article: Hugenholtz GCG, Macrae F, Adelmeijer J, Dulfer S, Porte RJ, Lisman T, Ari€ ens RAS. Procoagulant changes in fibrin clot structure in patients with cirrhosis are associated with oxidative modifications of fibrinogen. J Thromb Haemost 2016; 14: 1054-66. Essentials Patients with cirrhosis have hemostatic changes, which may contribute to a risk of thrombosis. This in vitro study compares clot formation and structure between patients and healthy subjects. Clot formation is delayed in patients; ultimately, however , clot permeability is decreased. The thrombogenic structure of fibrin clots may contribute to the thrombotic risk in cirrhosis. Abstract. Background and Objectives: Patients with cirrho-sis can be at risk of thrombotic complications due to an imbalance between hemostatic components. However, little is known on how the disease affects clot generation or how alterations in the structure of fibrin clots may affect the hemostatic function of these patients. Methods: We investigated the formation and structure of clots generated with plasma and purified fibrinogen of 42 patients with cirrhosis. Clots generated with plasma and fibrino-gen of 29 healthy volunteers were studied for comparison. Clot formation and structure were assessed by turbidity, permeation studies, confocal laser and scanning electron microscopy (SEM). The extent of fibrinogen oxidation was assessed by measuring the carbonyl content of purified fibrinogen samples. Results: Tissue factor and throm-bin-induced clotting of plasma was delayed in patients. The clotting rate was also decreased, but change in tur-bidity, fibrin density and fiber thickness were largely comparable to healthy volunteers. Conversely, clot perme-ability was significantly decreased in patients. When clots were generated with purified fibrinogen, differences in clot formation and structure similar to those in plasma were found. The carbonyl content was increased in patient fibrinogen and correlated with disease severity and clot permeability. Conclusions: Delayed clot formation in cir-rhosis ultimately results in decreased clot permeability. Similar alterations in clots generated with purified fibrino-gen suggest that modifications of the molecule are (partly) responsible. Taken together, these findings are indicative of hypercoagulable features of clots of patients with cirrhosis, which may explain the increased risk of thrombosis associated with this condition.

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