An unbalance between von Willebrand factor and ADAMTS13 in acute liver failure: Implications for hemostasis and clinical outcome

Abstract

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)

Decreased activity of plasma ADAMTS13 are related to enhanced cytokinemia and endotoxemia in patients with acute liver failure

“…These observations provide an explanation of the deleterious UL-VWFM effects on severe liver injury progression. Conversely, Hugenholtz et al (9) reported that UL-VWFM proportion was reduced in spite of markedly low ADAMTS13:AC in AH and ALF patients. They explained this discrepancy from the action of other proteases on VWF and/or the effect of treatment.…”

“…Hugenholtz et al (9) reported low ADAMTS13:AC and high VWF:Ag in AH and ALF patients. However, they stated that low ADAMTS13:AC, but not high VWF:Ag, was associated with poor outcome.…”

“…The role of ADAMTS13 role in alcoholic hepatitis (7), liver cirrhosis (8) and acute liver failure (ALF) (9) progression is reported by studies, suggesting that ADAMTS13 enzyme-VWF substrate imbalances are related to liver disorders and multiple organ failure (MOF) progression.…”

Coagulopathy in liver disease: Lack of an assessment tool

“…Platelet hyperactivity has also been reported in patients with cholestatic liver disease [12,42] . A prothrombotic state has been reported in acute liver injury based on an imbalance between vWF/ADAMTS13, intact thrombin generation, and high levels of PAI-1 [28,69,70] . Minimal effects on haemostasis are assessed by thromboelastography in these patients [71] , despite the severe derangement shown by standard coagulation tests.…”

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“…1 In addition, chronic and acute liver diseases are characterized by chronic endothelial cell activation resulting in additional hemostatic changes such as substantially elevated plasma levels of von Willebrand factor (VWF). 2,3 Finally, systemic or intrahepatic activation of coagulation results in consumption of platelets and hemostatic proteins. 4,5 These hemostatic changes accompanying liver diseases are among the most complex acquired hemostatic changes, and the net effects of these changes have, therefore, long been unclear.…”