Factor VIIa binding to endothelial cell protein C receptor

Rao, L. Vijaya Mohan; Pendurthi, Usha R.

doi:10.1016/s0049-3848(08)70009-4

Cited by 4 publications

(3 citation statements)

References 19 publications

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“…In addition, EPCR functions as a receptor for coagulation factors VIIa (68,(71)(72)(73) and Xa (74). EPCR-FVIIa interactions may sequester FVIIa from procoagulant phosphatidylserine-rich membrane domains, thereby exerting a FVIIa-dependent anticoagulant activity (73,75), and modulate the bioavailability of therapeutically administered recombinant FVIIa (76).…”

Section: Epcrmentioning

confidence: 99%

Multiple receptor-mediated functions of activated protein C

Weiler¹

2011

Hamostaseologie

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The central effector protease of the protein C pathway, activated protein C (APC), interacts with the endothelial cell protein C receptor, with protease activated receptors (PAR), the apolipoprotein E2 receptor, and integrins to exert multiple effects on haemostasis and immune cell function. Such receptor interactions modify the activation of PC and determine the biological response to endogenous and therapeutically administered APC. This review summarizes the current knowledge about interactions of APC with cell surface-associated receptors, novel substrates such as histones and tissue factor pathway inhibitor, and their implications for the biologic function of APC in the control of coagulation and inflammation.

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Section: Epcrmentioning

confidence: 99%

Multiple receptor-mediated functions of activated protein C

Weiler¹

2011

Hamostaseologie

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“…Also in rats, histopathological examinations of the liver suggest that rFVIIa is cleared by hepatocytes and kuppfer cells via clathrin-mediated endocytosis [11]. Recent data suggest that rFVIIa associates with the vascular endothelium, specifically with the endothelial cell protein C receptor (EPCR) [12], and perhaps enters into the extravascular space [13]; however, the clinical significance of these findings is not clear as the amount and the activity status is unknown.…”

Section: Introductionmentioning

confidence: 99%

Recombinant human factor VIIa (rFVIIa) cleared principally by antithrombin following intravenous administration in hemophilia patients

Agersø

Brophy

Pelzer

et al. 2011

Journal of Thrombosis and Haemostasis

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Summary. Objective: The objective of the present study was to evaluate the pharmacokinetics and the clearance pathways of rFVIIa after intravenous administration to hemophilia patients. Methods: Ten severe hemophilia patients were included in the study; all patients were intravenously administered a clinically relevant dose of 90 μg kg−1 (1.8 nmol kg−1) rFVIIa. Blood samples were collected consecutively to describe the pharmacokinetics of rFVIIa. All samples were analyzed using three different assays: a clot assay to measure the activity (FVIIa:C), an enzyme immunoassay (EIA) to measure the antigen levels (FVII:Ag), and an EIA (FVIIa‐AT) to measure the FVIIa antithrombin III (AT) complex. Pharmacokinetic parameters were evaluated both by use of standard non‐compartmental methods and by use of mixed effects methods. A population pharmacokinetic model was used to simultaneously model all three datasets. The total body clearance of rFVIIa:C was estimated to be 38 mL h−1 kg−1. The rFVII‐AT complex formation was responsible for 65% of the total rFVIIa:C clearance. The initial and the terminal half‐life of rFVIIa:C was estimated to be 0.6 and 2.6 h, respectively. The formation of rFVII‐AT complex was able to explain the difference observed between the rFVIIa:C and the rFVII:Ag concentration. The non‐compartmental analysis resulted in almost identical parameters.

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“…Although many cellular studies have investigated the fate of rFVIIa both in the presence and absence of TF (5)(6)(7)(8)(9), the mechanisms of rFVIIa clearance and metabolism following intravenous (iv) administration have not been extensively studied. Whole body autoradiography and tissue distribution studies in which radioiodinated rFVIIa ( 125 I-rFVIIa) was administered intravenously to rats showed that radioactivity was associated with a few highly perfused organs, including the liver (10,11).…”

Section: Introductionmentioning

confidence: 99%

Investigating clearance mechanisms for recombinant activated factor VII in a perfused liver model

Appa

Theill²,

Hansen³

et al. 2010

Thromb Haemost

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Clearance mechanisms for recombinant activated human FVII (rFVIIa; NovoSeven), a heterogeneously glycosylated protein, have yet to be fully elucidated, but may involve the liver. The effects of the gamma-carboxy glutamic acid (Gla) domain and the sialic acid content of the protein on rFVIIa clearance were investigated following intravenous administration of rFVIIa lacking the Gla domain, des(1-44) rFVIIa and asialo-rFVIIa in pharmacokinetic (PK) studies and perfused rat livers. PK parameters for both rFVIIa and des(1-44) rFVIIa had similar biphasic clearance profiles, as well as half-lives ([t(1/2)]=80 and 88 minutes, respectively), while asialo-rFVIIa was cleared quickly (t(1/2)=21 minutes) with a linear clearance profile. Perfused liver studies with all proteins (10 nM) mirrored the trends in profiles observed in the PK study. rFVIIa and des(1-44) rFVIIa were cleared to a similar extent, 41% and 35%, respectively, after 1 h, whereas plasma-derived FVII from humans (which has a higher sialylation content than rFVIIa) was cleared to a lesser extent (21%). Asialo-rFVIIa, on the other hand, was almost totally cleared and when an excess of asialo-orosomucoid was added to the perfusate, its clearance was significantly reduced (by 34%) and also for rFVIIa, albeit to a lesser extent (by 14%). Together these data suggest that carbohydrate receptor(s) (e.g. the asialoglycoprotein receptor, ASGPR) play a role in asialo-rFVIIa and rFVIIa clearance. In vivo and liver clearance data correlated well showing similar trends and indicated that rFVIIa clearance is not affected by the Gla domain, but rather by a subpopulation of N-glycosylated structures on rFVIIa.

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Factor VIIa binding to endothelial cell protein C receptor

Cited by 4 publications

References 19 publications

Multiple receptor-mediated functions of activated protein C

Multiple receptor-mediated functions of activated protein C

Recombinant human factor VIIa (rFVIIa) cleared principally by antithrombin following intravenous administration in hemophilia patients

Investigating clearance mechanisms for recombinant activated factor VII in a perfused liver model

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