A Mathematical Model of Coagulation Factor VIII Kinetics

Noe, Dennis A.

doi:10.1159/000217222

Cited by 27 publications

(22 citation statements)

References 15 publications

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“…In plasma, FVIII is in a dynamic equilibrium with vWF in which approximately 95% of the FVIII molecules have been calculated to be in complex with vWF (44). In complex with vWF, cellular uptake and degradation of FVIII is almost fully 2 ) was examined as described in the legend of Fig.…”

Section: Discussionmentioning

confidence: 99%

The Light Chain of Factor VIII Comprises a Binding Site for Low Density Lipoprotein Receptor-related Protein

Lenting¹,

Neels²,

Berg³

et al. 1999

Journal of Biological Chemistry

201

255

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In the present study, the interaction between the endocytic receptor low density lipoprotein receptor-related protein (LRP) and coagulation factor VIII (FVIII) was investigated. Using purified components, FVIII was found to bind to LRP in a reversible and dose-dependent manner (K d Ϸ 60 nM). The interaction appeared to be specific because the LRP antagonist receptor-associated protein readily inhibited binding of FVIII to LRP (IC 50 ; K d Ϸ 50 nM). Furthermore, experiments using recombinant FVIII C2 domain showed that this domain contributes to the interaction with LRP. In contrast, no association of FVIII heavy chain to LRP could be detected under the same experimental conditions. Collectively, our data demonstrate that in vitro LRP is able to bind FVIII at the cell surface and to mediate its transport to the intracellular degradation pathway. FVIII-LRP interaction involves the FVIII light chain, and FVIII-vWF complex formation plays a regulatory role in LRP binding. Our findings may explain the beneficial effect of vWF on the in vivo survival of FVIII.Low density lipoprotein receptor-related protein (LRP), 1 also known as ␣2-macroglobulin receptor, is a member of the low density lipoprotein receptor family of endocytic receptors (for a review, see Refs. 1 and 2). It consists of a heavy chain and a light chain, which are associated in a noncovalent manner. The 85-kDa light chain comprises the transmembrane and cytoplasmic domains, whereas the ligand binding regions are located within the 515-kDa heavy chain (3). LRP is abundantly present in various tissues such as the liver, placenta, lung, and brain (4) and is expressed in an array of cell types: parenchymal cells, neurons and astrocytes, Leydig cells, smooth muscle cells, monocytes, and fibroblasts (4). Commonly used cell lines such as monkey kidney COS cells and Chinese hamster ovary (CHO) cells also express LRP (5, 6). The function of LRP is to mediate the binding and transport of ligands from the cell surface to the endosomal degradation pathway (1, 2). Binding and internalization of ligands is antagonized by a 39-kDa chaperone protein designated receptor-associated protein (RAP) (7,8). Currently, a wide spectrum of structurally and functionally unrelated ligands involved in a variety of processes such as lipoprotein metabolism, cell growth and migration, and neuronal regeneration (1, 2) has been identified. Furthermore, LRP seems to be linked to the process of blood coagulation. This is apparent from the observations that LRP recognizes thrombin/ antithrombin and factor Xa/␣2-macroglobulin complexes and the Kunitz-type inhibitor tissue factor pathway inhibitor (9 -11). In addition, LRP contributes to down-regulation of tissue factor expression at the surface of monocytes (12). Coagulation factor VIII (FVIII) is the precursor of its activated derivative, which stimulates factor IXa-mediated activation of factor X (for recent reviews, see Refs. 13 and 14). The fact that deficiency or dysfunction of FVIII is associated with severe bleeding tendencies demon...

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Section: Discussionmentioning

confidence: 99%

The Light Chain of Factor VIII Comprises a Binding Site for Low Density Lipoprotein Receptor-related Protein

Lenting¹,

Neels²,

Berg³

et al. 1999

Journal of Biological Chemistry

201

255

View full text Add to dashboard Cite

show abstract

“…Previously, it has been suggested that V2 may reflect the FVIII distribution into extravascular spaces or within an intravascular compartment, more specifically as a reflection of adhesion to the vessel wall, or that it may reflect the process of a rapid initial elimination. 36,37 We hypothesized that an extra intravascular component resulting in a large V2 may be the result of the high affinity and stoichiometry of FVIII to VWF, 38 combined with the significant increase of VWF after surgery due to inflicted endothelial damage and its role in the acute phase reaction. 39 In addition, Deitcher et al have shown that volume of distribution increases after desmopressin administration, which, of course, results in an overall increase in VWF levels.…”

Section: A B C Dmentioning

confidence: 99%

A population pharmacokinetic model for perioperative dosing of factor VIII in hemophilia A patients

et al. 2016

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T he role of pharmacokinetic-guided dosing of factor concentrates in hemophilia is currently a subject of debate and focuses on longterm prophylactic treatment. Few data are available on its impact in the perioperative period. In this study, a population pharmacokinetic model for currently registered factor VIII concentrates was developed for severe and moderate adult and pediatric hemophilia A patients (FVIII levels <0.05 IUmL -1 ) undergoing elective, minor or major surgery. Retrospective data were collected on FVIII treatment, including timing and dosing, time point of FVIII sampling and all FVIII plasma concentrations achieved (trough, peak and steady state), brand of concentrate, as well as patients' and surgical characteristics. Population pharmacokinetic modeling was performed using non-linear mixed-effects modeling. Population pharmacokinetic parameters were estimated in 75 adults undergoing 140 surgeries (median age: 48 years; median weight: 80 kg) and 44 children undergoing 58 surgeries (median age: 4.3 years; median weight: 18.5 kg). Pharmacokinetic profiles were best described by a two-compartment model. Typical values for clearance, inter-compartment clearance, central and peripheral volume were 0.15 L/h/68 kg, 0.16 L/h/68 kg, 2.81 L/68 kg and 1.90 L/68 kg. Interpatient variability in clearance and central volume was 37% and 27%. Clearance decreased with increasing age (P<0.01) and increased in cases with blood group O (26%; P<0.01). In addition, a minor decrease in clearance was observed when a major surgical procedure was performed (7%; P<0.01). The developed population model describes the perioperative pharmacokinetics of various FVIII concentrates, allowing individualization of perioperative FVIII therapy for severe and moderate hemophilia A patients by Bayesian adaptive dosing. ABSTRACT

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“…Levine (1966) was the first to come up with a linear system of first order ODEs to describe this set of enzymatic reactions. Models later emerged for the individual reactions of the coagulation pathway (Nesheim et al, 1984;1992;Nemerson and Gentry, 1986;Gir et al, 1996;Noe, 1996;Panteleev et al, 2002), as the understanding of the coagulation mechanism grew. These models focussed on the factors affecting the kinetics of individual reactions.…”

Section: Literature Survey Of Models For Coagulationmentioning

confidence: 99%

A Model Incorporating Some of the Mechanical and Biochemical Factors Underlying Clot Formation and Dissolution in Flowing Blood

Mohan

Rajagopal

2003

Computational and Mathematical Methods in Medicine

142

121

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Multiple interacting mechanisms control the formation and dissolution of clots to maintain blood in a state of delicate balance. In addition to a myriad of biochemical reactions, rheological factors also play a crucial role in modulating the response of blood to external stimuli. To date, a comprehensive model for clot formation and dissolution, that takes into account the biochemical, medical and rheological factors, has not been put into place, the existing models emphasizing either one or the other of the factors. In this paper, after discussing the various biochemical, physiologic and rheological factors at some length, we develop a model for clot formation and dissolution that incorporates many of the relevant crucial factors that have a bearing on the problem. The model, though just a first step towards understanding a complex phenomenon, goes further than previous models in integrating the biochemical, physiologic and rheological factors that come into play.

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A Mathematical Model of Coagulation Factor VIII Kinetics

Cited by 27 publications

References 15 publications

The Light Chain of Factor VIII Comprises a Binding Site for Low Density Lipoprotein Receptor-related Protein

The Light Chain of Factor VIII Comprises a Binding Site for Low Density Lipoprotein Receptor-related Protein

A population pharmacokinetic model for perioperative dosing of factor VIII in hemophilia A patients

A Model Incorporating Some of the Mechanical and Biochemical Factors Underlying Clot Formation and Dissolution in Flowing Blood

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