Abstract:
:Recombinant activated factor VII (rFVIIa; NovoSeven®) is a heterogeneously glycosylated serine protease used for treatment of haemophiliacs with inhibitors. The drug substance contains a subpopulation consisting of ~20% of rFVIIa molecules which are unsialylated and consists of carbohydrate moieties with terminally exposed galactose and N-acetyl-D-galactosamine (GalNAc). Recently, data from an in situ perfused liver model showed that a subpopulation of rFVIIa, appearing to be unsialylated rFVIIa, was cleared by the liver, thus suggesting a carbohydrate-moiety mediated mechanism. The parenchymal cells of the liver, hepatocytes, are known to abundantly express functional carbohydrate-specific receptors and in this study we therefore used primary rat hepatocytes to study binding and intracellular fate of rFVIIa at a cellular level. Immunofluorescence microscopy showed that rFVIIa was distributed into distinct intracellular vesicles and electron microscopic autoradiography revealed that radioiodinated rFVIIa distributed only into cytoplasmic free vesicles resembling endosomes and lysosomes. These findings suggest that endocytosis of rFVIIa in hepatocytes could be partly mediated via initial membrane binding to a receptor. Quantitative binding studies showed that the presence of excess unlabelled asialo-orosomucoid, asialo-rFVIIa and GalNAc significantly decreased binding of 125I-rFVIIa. An antibody which specifically binds to the carbohydrate recognition domain of the asialoglycoprotein receptor (ASGPR) significantly decreased binding of asialo-rFVIIa by ~36% and rFVIIa by ~19%. Together our data showed that a receptor-mediated mechanism involving the ASGPR is able to bind a subpopulation of unsialylated rFVIIa, while a hepatic mechanism for binding and clearing sialylated rFVIIa is still unknown.
journal_name
Thromb Haemostjournal_title
Thrombosis and haemostasisauthors
Seested T,Nielsen HM,Christensen EI,Appa RSdoi
10.1160/TH10-06-0356subject
Has Abstractpub_date
2010-12-01 00:00:00pages
1166-73issue
6eissn
0340-6245issn
2567-689Xpii
10-06-0356journal_volume
104pub_type
杂志文章abstract::We studied human platelet aggregation and beta-TG/PF4 release induced by heparin and related GAGs in vitro both in normal PRP and in PRP after aspirin. In our experimental conditions, heparin and related GAGs always caused PF4 release in vitro from normal platelets, whether or not there was measurable platelet aggrega...
journal_title:Thrombosis and haemostasis
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doi:10.1160/TH10-04-0216
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journal_title:Thrombosis and haemostasis
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更新日期:2001-08-01 00:00:00
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journal_title:Thrombosis and haemostasis
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
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journal_title:Thrombosis and haemostasis
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journal_title:Thrombosis and haemostasis
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doi:
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pub_type: 杂志文章
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1987-08-04 00:00:00
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journal_title:Thrombosis and haemostasis
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1994-12-01 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1987-02-03 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
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journal_title:Thrombosis and haemostasis
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journal_title:Thrombosis and haemostasis
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doi:
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:2006-05-01 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1981-08-28 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1986-06-30 00:00:00
abstract::Cysteinyl leukotrienes (i.e. LTC4, LTD4), produced by activated leukocytes or by transcellular metabolism may act at different levels on vascular smooth muscle cells (VSMC) during inflammatory process or atherosclerosis. We studied the effect of LTC4, LTD4, and LTE4 on the in vitro proliferation of rat VSMC, measured ...
journal_title:Thrombosis and haemostasis
pub_type: 杂志文章
doi:
更新日期:1996-07-01 00:00:00
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journal_title:Thrombosis and haemostasis
pub_type: 临床试验,杂志文章,随机对照试验
doi:
更新日期:1996-01-01 00:00:00
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