Endothelium Releases More von Willebrand Factor and Tissue-Type Plasminogen Activator upon Venous Occlusion in Patients with Liver Cirrhosis than in Normals

Tornai, István; Hársfalvi, Jolán; Boda, Zoltán; Udvardy, M.; Paragh, György; K, Rák

doi:10.1159/000216853

Cited by 10 publications

(11 citation statements)

References 12 publications

(17 reference statements)

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“…3A), as previously reported (9,10). The marked elevation of plasma VWF:Ag in LC patients may be partly attributable to increased endothelial production induced by endotoxin (9,43) and/or increased synthesis by extrahepatic endothelial cells (44). The VWF:RCo was higher (Fig.…”

Section: Discussionsupporting

confidence: 83%

Comprehensive analysis of ADAMTS13 in patients with liver cirrhosis

Uemura¹,

Fujimura²,

Matsumoto³

et al. 2008

Thromb Haemost

127

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Decreased plasma ADAMTS13 activity (ADAMTS13:AC) results in the accumulation of unusually large von Willebrand factor multimer (UL-VWFM) and the formation of platelet thrombi. It remains controversial whether or not plasma ADAMTS13:AC decreases in patients with liver cirrhosis (LC), and its relationship to clinical features has not been fully investigated. We measured ADAMTS13:AC and its related parameters in plasma in 33 patients with chronic hepatitis (CH) and in 109 patients with LC. ADAMTS13:AC decreased with increasing severity of liver disease (controls means 100%, CH 87%, Child A-LC 79%, Child B-LC 63%, and Child C-LC 31%), and showed severe deficiency (<3% of controls) in five end-stage LC. Activities measured by act-ELISA strongly correlated with those determined by the VWFM assay and ADAMTS13 antigen. Multivariate analysis showed Child-Pugh score and spleen volume independent factors contributing to ADAMTS13:AC. VWFM patterns were normal in 53% of cases, degraded in 31%, and unusually large in 16%. Patients with unusually large VWFM had the lowest ADAMTS13:AC as well as the highest Child-Pugh score, serum creatinine and blood ammonia levels. Plasma inhibitor against ADAMTS13 detected in 83% of patients with severe to moderate ADAMTS13:AC deficiency mostly showed marginal zone between 0.5 and 1.0 BU/ml. The IgG-type autoantibodies specific to plasma derived-ADAMTS13 was detected by Western blot in only five end-stage LC with severe ADAMTS13:AC deficiency. In conclusion, both plasma ADAMTS13 activity and antigen levels decreased with increasing severity of cirrhosis. An imbalance between the decreased ADAMTS13:AC and its increased substrate may reflect the predisposing state for platelet thrombi formation in patients with advanced LC.

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Section: Discussionsupporting

confidence: 83%

Comprehensive analysis of ADAMTS13 in patients with liver cirrhosis

Uemura¹,

Fujimura²,

Matsumoto³

et al. 2008

Thromb Haemost

127

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“…2a) [36], as previously indicated [22,23]. This is presumably attributed to sinusoidal and/or extrahepatic endothelial damage induced by endotoxin and cytokines [22,23,40,41]. The VWF:RCo was higher (Fig.…”

Section: Liver Cirrhosissupporting

confidence: 69%

Pivotal role of ADAMTS13 function in liver diseases

Uemura

Fujimura

et al. 2010

Int J Hematol

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The liver is a major source of clotting and fibrinolytic proteins, and plays a central role in thrombo-regulation. Patients with advanced liver diseases tend to bleed because of reduced plasma levels of several clotting factors and thrombocytopenia, but they do also exhibit thrombotic complications. ADAMTS13 is a metalloproteinase, produced exclusively in hepatic stellate cells, and specifically cleaves highly multimeric von Willebrand factor (VWF). VWF plays a pivotal role in hemostasis and thrombosis, and its function is dependent on its multimeric state. Deficiency of ADAMTS13 results in accumulation of unusually large VWF multimers (UL-VWFM) in plasma, in turn induces platelet clumping or thrombi under high shear stress, followed by microcirculatory disturbances. Considering that UL-VWFM, the substrate of ADAMTS13, is produced in transformed vascular endothelial cells at sites of liver injury, decreased ADAMTS13 activity may be involved in not only sinusoidal microcirculatory disturbances, but also subsequent progression of liver injuries, eventually leading to multiorgan failure. This concept can be applied to the development or aggravation of liver diseases, including liver cirrhosis, alcoholic hepatitis, veno-occlusive disease, and adverse events after liver transplantation. These results promise to bring further understanding of the pathophysiology of liver diseases, and offer new insight for development of therapeutic strategies.

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“…The levels of VWF: Ag, the substrate of ADAMTS13, progressively increased as the functional liver capacity decreased, probably due to the neocapilarization of the hepatic endothelial cells that leads to liver fibrosis, increased endothelial production induced by endotoxin 21,45 and/or increased synthesis by extrahepatic endothelial cells. 46 VWF: RCo relative to ADAMTS13:AC increased as the chronic liver disease progressed, and VWF multimers appeared to shift from a degraded-to normal-VWFM and finally to UL-VWFM as the functional liver capacity and renal function deteriorated, indicating that advanced cirrhosis may predispose the patients to platelet microthrombi formation. 29 The marked impairment in the enzyme to substrate ratio; i.e., decreased ADAMTS13 to increased VWF: Ag, may lead to platelet hyperaggregability with subsequent microcirculatory disturbances not only in the liver but also in other organs, leading to multi-organ failure.…”

Section: Discussionmentioning

confidence: 99%