Detection of von Willebrand factor-cleaving protease (ADAMTS-13) in human platelets

Suzuki, Misako; Murata, Mitsuru; Matsubara, Yumiko; Uchida, Toshihiro; Ishiga, Hiroaki; Shibano, Toshiro; Ashida, Shinji; Soejima, Kenji; Okada, Yasunori; Ikeda, Yasuo

doi:10.1016/j.bbrc.2003.11.111

Cited by 101 publications

(73 citation statements)

References 11 publications

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“…26 This is also illustrated by the relatively poor correlation between the two assays used in this study. 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.…”

Section: Discussionmentioning

confidence: 75%

“…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%

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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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Section: Discussionmentioning

confidence: 75%

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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“…In the liver, ADAMTS13 is expressed primarily in the vitamin A-enriched stellate cells [9;10]. ADAMTS13 may also be expressed in platelets and endothelial cells [11][12][13].…”

Section: Adamts13 -Structure and Functionmentioning

confidence: 99%

Thrombotic Thrombocytopenic Purpura: A Thrombotic Disorder Caused by ADAMTS13 Deficiency

Tsai

2007

Hematology/Oncology Clinics of North America

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“…Nevertheless, experiments using RT-PCR detected the presence of ADAMTS13 ADAMTS13 expressed in hepatic stellate cells W Zhou et al transcript in a varieties of tissues, [4][5][6]23 and one study describes the expression of ADAMTS13 in human platelets. 24 However, the RT-PCR studies did not directly compare the levels of expression among the different tissues. In our real-time RT-PCR experiments, we designed the primers to amplify the portion of ADAMTS13 that is present in all the known isoforms, and the results confirm quantitatively that mADAMTS13 is expressed most actively in the liver.…”

Section: Discussionmentioning

confidence: 99%

ADAMTS13 is expressed in hepatic stellate cells

Zhou

Inada

Lee

et al. 2005

Laboratory Investigation

178

126

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ADAMTS13 is a circulating zinc metalloprotease that cleaves the hemostatic glycoprotein von Willebrand factor (VWF) in a shear-dependent manner. Deficiency in ADAMTS13, owing to genetic mutations or autoimmune inhibitors, causes thrombotic thrombocytopenic purpura (TPP). Northern blot analysis has shown that ADAMTS13 is expressed primarily in the liver. By using real-time RT-PCR, we confirmed that in mice the liver had the highest level of the ADAMTS13 transcript. To identify the liver cell-type-specific origin of ADAMTS13, we used in situ hybridization techniques to investigate the pattern of ADAMTS13 expression in the liver; analyzed the ADAMTS13 proteolytic activity in the culture media of fractionated liver cells; and confirmed ADAMTS13 expression with RT-PCR analysis and cloning of the mouse ADAMTS13 gene. The results revealed that ADAMTS13 was expressed primarily in cell fractions enriched in hepatic stellate cells. The mouse ADAMTS13 cloned from primary hepatic stellate cells was similar to its human counterpart in digesting VWF and was susceptible to suppression by EDTA or the IgG inhibitors of patients with TTP. Since hepatic stellate cells are believed to play a major role in the development of hepatic fibrosis and cirrhosis, the identification of the liver cell-type expressing ADAMTS13 will have important implications for understanding pathophysiological mechanisms regulating ADAMTS13 expression. The von Willebrand factor (VWF) is a multimeric glycoprotein that mediates adhesion and aggregation of platelets at sites of vascular injury. A metalloprotease cleaves VWF at the Tyr1605-Met1606 bond, generating homodimers of the 176 and 140 kDa fragments. 1,2 The VWF-cleaving protease is essential for preventing platelet aggregation in the circulation, and deficiency of the protease is associated with thrombotic thrombocytopenic purpura (TTP), a disease characterized by the development of VWF-platelet-rich thrombi in the arterioles and capillaries. 3 Recent studies identified this protease as ADAMTS13, a member of the reprolysin-type zinc metalloprotease family. [4][5][6] The human ADAMTS13 gene, spanning 37 kb on human chromosome 9q34, comprises 29 exons that encode a polypeptide of 1427-amino-acid residues and possibly several splicing isoforms. Although it shares with other members of the ADAMTS family a common domain architecture consisting of metalloprotease, disintegrin-like sequence, thrombospondin type 1 repeat, cysteine-rich and spacer regions, ADAMTS13 exhibits several distinct features, such as an RGDS sequence in the spacer domain and two copies of CUB domains at the carboxyl terminus. Substitution of the D residue in the RGDS sequence does not appear to diminish the proteolytic activity of ADAMTS13. 7 Unlike other ADAMTS proteases, pro-ADAMTS13 is proteolytically active. 8 These unique features of ADAMTS13 are consistent with

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Detection of von Willebrand factor-cleaving protease (ADAMTS-13) in human platelets

Cited by 101 publications

References 11 publications

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

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

Thrombotic Thrombocytopenic Purpura: A Thrombotic Disorder Caused by ADAMTS13 Deficiency

ADAMTS13 is expressed in hepatic stellate cells

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