Localization of ADAMTS13 to the stellate cells of human liver

Uemura, Mamoru; Tatsumi, Kouko; Matsumoto, Masanori; Fujimoto, Masao; Matsuyama, Toyoki; Ishikawa, Masatoshi; Iwamoto, Takaaki; Mori, Toshio; Wanaka, Akio; Fukui, Hiroshi; Fujimura, Yoshihiro

doi:10.1182/blood-2005-01-0152

Cited by 284 publications

(220 citation statements)

References 19 publications

(25 reference statements)

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“…With regard to the site of production, ADAMTS13 mRNA expression was shown exclusively in the liver (7)(8)(9) and then both ADAMTS13 mRNA expression and ADAMTS13 activity were determined primarily in hepatic stellate cells among the liver cells in mice (10). ADAMTS13 expression was also detected in hepatic stellate cells in human and thereby ADAMTS13 is reportedly produced in those cells (11). To elucidate a regulatory mechanism of plasma ADAMTS13 activity, we previously determined that selective hepatic stellate cell damage caused by dimethylnitrosamine in rats leads to decreased plasma ADAMTS13 activity (12).…”

Section: Introductionmentioning

confidence: 89%

Prediction of Hepatocellular Carcinoma Development by Plasma ADAMTS13 in Chronic Hepatitis B and C

Ikeda

Tateishi

Enooku

et al. 2011

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Background: Chronic liver injury evokes a wound healing response, promoting fibrosis and finally hepatocellular carcinoma (HCC), in which hepatic stellate cells play an important role. Although a blood marker of hepatic stellate cells is not known, those cells importantly contribute to the regulation of plasma a disintegrin-like and metalloproteinase with thrombospondin type-1 motifs 13 (ADAMTS13) activity, a defect of which causes thrombotic thrombocytopenic purpura.Methods: Plasma ADAMTS13 was evaluated in chronic hepatitis B or C patients with or without HCC.Results: Plasma ADAMTS13 activity significantly correlated with serum aspartate aminotransferase and alanine aminotransferase, liver stiffness value, and aspartate aminotransferase-to-platelet ratio index, irrespective of the presence of HCC, suggesting that it may reflect hepatocellular damage and subsequent wound healing and fibrosis as a result of hepatic stellate cell action. During the three-year follow-up period for patients without HCC, it developed in 10 among 81 patients. Plasma ADAMTS13 activity was significantly higher in patients with HCC development than in those without and was a significant risk for HCC development by univariate and multivariate analyses. Furthermore, during the one-year follow-up period for patients with HCC treated with radiofrequency ablation, HCC recurred in 55 among 107 patients. Plasma ADAMTS13 activity or antigen level was significantly higher in patients with HCC recurrence than in those without and was retained as a significant risk for HCC recurrence by multivariate analysis.Conclusions: Higher plasma ADAMTS13 activity and antigen level was a risk of HCC development in chronic liver disease.Impact: Plasma ADAMTS13 as a potential marker of hepatic stellate cells may be useful in the prediction of hepatocarcinogenesis. Cancer Epidemiol Biomarkers Prev; 20(10); 2204-11. Ó2011 AACR.

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Section: Introductionmentioning

confidence: 89%

Prediction of Hepatocellular Carcinoma Development by Plasma ADAMTS13 in Chronic Hepatitis B and C

Ikeda

Tateishi

Enooku

et al. 2011

Cancer Epidemiology, Biomarkers &Amp; Prevention

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“…Moreover, although ADAMTS13 levels would be expected to be decreased in cirrhosis, as the principle site of synthesis is presumably the liver, 27 it also may be that either reduced clearance or release of ADAMTS13 from platelets 28 (as a result of platelet activation secondary to DIC) lead to the elevated levels observed in some patients in our study. Alternatively, it might be possible that ADAMTS13 synthesis is induced in liver disease, as ADAMTS13 is synthesized in hepatic stellate cells, 29 which are known to show enhanced protein synthesis in patients with liver cirrhosis. 30 Interestingly, ADAMTS13 antigen levels, and, to a lesser extent, ADAMTS13 activity levels, were negatively correlated with VWF:RCo/VWF:Ag ratio, indicating that the excess of ADAMTS13 in some patients results in excessive VWF proteolysis, resulting in impaired VWF activity.…”

Section: Discussionmentioning

confidence: 99%

“…In accordance, mean MELD scores paralleled the Child classification. The MELD score was 10 [6][7][8][9][10][11][12][13][14][15][16][17][18] (median [range]) in the Child A group, 13 [7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23] in the Child B group, 18 in the Child C group, and 28 [22][23][24][25][26][27][28][29][30][31][32][33][34][35][36] cirrhosis compared with control, P Ͼ .05 for mild cirrhosis compared with control). In the five patients with acute liver failure, the VWF collagen-binding activity was slightly decreased (90% [86-99]), but this difference did not reach statistical significance.…”

Section: Methodsmentioning

confidence: 99%

Elevated levels of von Willebrand Factor in cirrhosis support platelet adhesion despite reduced functional capacity

et al. 2006

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Cirrhosis of the liver is frequently accompanied by complex alterations in the hemostatic system, resulting in a bleeding tendency. Although many hemostatic changes in liver disease promote bleeding, compensatory mechanisms also are found, including high levels of the platelet adhesive protein von Willebrand Factor (VWF). However, conflicting reports on the functional properties of VWF in cirrhosis have appeared in literature. We have measured a panel of VWF parameters in plasma from patients with cirrhosis of varying severity and causes. Furthermore, we assessed the contribution of VWF to platelet adhesion, by measuring the ability of plasma from patients with cirrhosis to support adhesion of normal or patient platelets under flow conditions. VWF antigen levels were strongly increased in patients with cirrhosis. In contrast, the relative collagen binding activity, as well as the relative ristocetin cofactor activity, was significantly lower in patients as compared with controls, indicating loss of function. Accordingly, patients had a reduced fraction of high-molecular-weight VWF multimers. Both strongly elevated and reduced activity and antigen levels of the VWF cleaving protease ADAMTS13 were found in individual patients. Adhesion of either normal or patient platelets to a collagen surface was substantially increased when these platelets were resuspended in plasma of patients with cirrhosis, as compared with control plasma. In conclusion, highly elevated levels of VWF in patients with cirrhosis contribute to the induction of primary hemostasis despite reduced functional properties of the molecule. This phenomenon might compensate for defects in platelet number and function in patients with cirrhosis. (HEPATOLOGY 2006;44:53-61.)

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“…The peptides against which these antibodies were raised were synthesized by Eurogentec, Seraing, Belgium. In addition, one mouse monoclonal antibody, A10 (a gift from Y. Fujimura, Department of Blood Transfusion Medicine, Nara Medical University, Nara and H. Hiura, Japan Clinical Laboratories, Kyoto, Japan) directed against the disintegrin domain [14] was used. The SU19 polyclonal antibody recognizes ADAMTS13…”

Section: Anti-adamts13 Antibodiesmentioning

confidence: 99%

“…ADAMTS13 antigen is present in the plasma of patients with acquired TTP, where it appears to be in complex with auto-antibodies [12], and is absent in congenital TTP [11,13]. The cellular origin of ADAMTS13 in plasma has not been completely elucidated but the protease has been shown to be synthesized in liver stellate cells and in endothelial cells [14,15]. ADAMTS13 mRNA has been detected in a variety of tissues including the kidneys [4,16,17].…”

Section: Introductionmentioning

confidence: 99%