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Journal articles on the topic 'FVIII clearance'

Author: Grafiati

Published: 9 March 2023

Last updated: 31 July 2025

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1

Hulshof, Anne-Marije, Lilian Antunes Heck, Ferdows Atiq, et al. "Whole Genome Sequencing to Elucidate Genetic Modifiers of FVIII Clearance Heterogeneity in Patients with Hemophilia a." Blood 144, Supplement 1 (2024): 3958. https://doi.org/10.1182/blood-2024-204546.

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Introduction: Significant inter-individual variation in FVIII clearance has been described in patients with haemophilia A (HA). The mechanisms underlying this heterogeneity remain poorly defined. Importantly, previous GWAS studies in healthy populations have described associations between SNPs and plasma FVIII and VWF levels.Furthermore, specific lectin and scavenger clearance receptors have been shown to regulate FVIII clearance in vivo. Methods: In vivo clearance of rFVIII (Advate) was assessed in 49 adult patients with HA using MyPKFit. Age, ABO blood group, plasma VWF:Ag and VWF propeptide

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2

Swystun, Laura L., Colleen Notley, Kate Sponagle, Paula D. James, and David Lillicrap. "Regulation Of Factor VIII Clearance By Mannose-Binding Lectins." Blood 122, no. 21 (2013): 2340. http://dx.doi.org/10.1182/blood.v122.21.2340.2340.

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Abstract The coagulation factors von Willebrand factor (FVIII) and factor VIII (FVIII) circulate in the plasma in a non-covalent complex. VWF acts as a carrier for FVIII and protects it from proteolysis and accelerated clearance. However, in the absence of VWF, the molecular mechanisms that regulate FVIII clearance are largely uncharacterized. The glycosylation of FVIII may regulate its interaction with lectin clearance receptors such as the asialoglycoprotein receptor and siglec-5. The FVIII polypeptide is modified by the addition of 24 N-linked glycans and 7 O-linked glycans. The majority of

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3

Makogonenko, Evgeny M., Andrey G. Sarafanov, Natalya M. Ananyeva, Klaus-Peter Radtke, Dudley K. Strickland, and Evgueni L. Saenko. "B Domain of Coagulation Factor VIII Regulates Exposure of Its Heparin-Binding Site." Blood 106, no. 11 (2005): 1014. http://dx.doi.org/10.1182/blood.v106.11.1014.1014.

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Abstract B domain of coagulation factor VIII (fVIII) was previously considered to be dispensable for fVIII function. Recently, it was found that the B domain is important for fVIII intracellular interaction with its chaperon and likely involved in fVIII clearance via asialoglycoprotein receptor. At the same time, the major clearance mechanism of fVIII involves initial interaction with heparan sulfate proteoglycans (HSPGs) followed by internalization via low-density lipoprotein receptor-related protein (LRP), member of low-density lipoprotein receptor (LDLR) family (Saenko et al, 1999; Sarafano

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4

Bukkems, Laura H., Jessica M. Heijdra, Nico C. B. de Jager, et al. "Population pharmacokinetics of the von Willebrand factor–factor VIII interaction in patients with von Willebrand disease." Blood Advances 5, no. 5 (2021): 1513–22. http://dx.doi.org/10.1182/bloodadvances.2020003891.

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Abstract Recent studies have reported that patients with von Willebrand disease treated perioperatively with a von Willebrand factor (VWF)/factor VIII (FVIII) concentrate with a ratio of 2.4:1 (Humate P/Haemate P) often present with VWF and/or FVIII levels outside of prespecified target levels necessary to prevent bleeding. Pharmacokinetic (PK)-guided dosing may resolve this problem. As clinical guidelines increasingly recommend aiming for certain target levels of both VWF and FVIII, application of an integrated population PK model describing both VWF activity (VWF:Act) and FVIII levels may im

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5

Pipe, Steven W., Robert R. Montgomery, Kathleen P. Pratt, Peter J. Lenting, and David Lillicrap. "Life in the shadow of a dominant partner: the FVIII-VWF association and its clinical implications for hemophilia A." Blood 128, no. 16 (2016): 2007–16. http://dx.doi.org/10.1182/blood-2016-04-713289.

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Abstract A normal hemostatic response to vascular injury requires both factor VIII (FVIII) and von Willebrand factor (VWF). In plasma, VWF and FVIII normally circulate as a noncovalent complex, and each has a critical function in the maintenance of hemostasis. Furthermore, the interaction between VWF and FVIII plays a crucial role in FVIII function, immunogenicity, and clearance, with VWF essentially serving as a chaperone for FVIII. Several novel recombinant FVIII (rFVIII) therapies for hemophilia A have been in clinical development, which aim to increase the half-life of FVIII (∼12 hours) an

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6

Blasko, Eric, Lilley Leong, Derek S. Sim, et al. "Reduced Polyethylene Glycol-Conjugated B-Domain–Deleted Factor VIII (PEG-BDD-FVIII) Clearance: Selective Peg Steric Modulation without Affecting Potency." Blood 124, no. 21 (2014): 1471. http://dx.doi.org/10.1182/blood.v124.21.1471.1471.

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Abstract Prophylactic factor VIII (FVIII) replacement therapy in hemophilia A requires intravenous administration up to every other day due to the short half-life of FVIII in plasma. Plasma half-life extension of FVIII by polyethylene glycol (PEG) conjugation is thought to be mediated by decreasing hepatic clearance of FVIII. BAY 94-9027 is a rationally designed B-domain–deleted (BDD) FVIII molecule, in which a single 60-kDa PEG molecule was attached to a specific amino acid (1804) to increase its circulating half-life and reduce the exposure to epitopes reported to cause immunogenicity in the

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7

James, Andra H., Peter Kouides, Barbara A. Konkle, and Claire S. Philipp. "Transient Decrease in Factor VIII Following Delivery: Clearance or Consumption?" Blood 118, no. 21 (2011): 2286. http://dx.doi.org/10.1182/blood.v118.21.2286.2286.

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Abstract Abstract 2286 Background: Von Willebrand factor (VWF) and factor VIII (FVIII) levels increase during pregnancy and return to baseline by one month postpartum (PP). Understanding the normal levels during this period has implications for the management of women with bleeding disorders. As part of a larger study of von Willebrand disease (VWD) postpartum, we obtained VWF ristocetin cofactor (VWF:RCo), VWF antigen (VWF:Ag) and FVIII levels on 26 women without a known bleeding disorder to establish normal ranges during the PP period. Methods: Subjects were enrolled during the last trimeste

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8

Ogiwara, Kenichi, Laura L. Swystun, Ilinca Georgescu, et al. "Clearance and Genetic Variability of Von Willebrand Factor Are Major Determinants of the Pharmacokinetic Behavior of Factor VIII Concentrates in the Treatment of Pediatric Hemophilia A." Blood 124, no. 21 (2014): 473. http://dx.doi.org/10.1182/blood.v124.21.473.473.

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Abstract Background: Although Factor VIII (FVIII) concentrates are now routinely used for the prophylactic treatment of hemophilia A (HA), the optimal doses and intervals between administrations are difficult to predict because of variable pharmacokinetics of FVIII (FVIII-PK) between patients. Previous studies in HA have revealed a close relationship between FVIII-PK and the FVIII carrier protein, von Willebrand factor (VWF). A large genome-wide association study from the CHARGE consortium highlighted several novel loci associated with plasma levels of VWF and FVIII in normal subjects, and the

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9

Lenting, Peter J., Vincent Muczynski, Gabriel Aymé, Cecile V. Denis, and Olivier D. Christophe. "Von Willebrand Factor Interaction with FVIII: Development of Long Acting FVIII Therapies." Blood 128, no. 22 (2016): SCI—8—SCI—8. http://dx.doi.org/10.1182/blood.v128.22.sci-8.sci-8.

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Abstract Coagulation factor VIII (FVIII) and von Willebrand factor (VWF) both play a centrol role in hemostasis, illustrated by the severe bleeding disorders associated with their functional absence. Despite their different functionalities in hemostasis and being products from two different genes, both proteins circulate in a tight, non-covalently linked complex. The physiological concequences of complex formation are many, including stabilization of FVIII heterodimeric structure, protection of FVIII from protelytic degradation, and modulation of FVIII immunogenicity. Another relevant issue re

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10

Schambeck, C. M. "Das Janusgesicht der Einzelfaktoren." Hämostaseologie 27, no. 04 (2007): 268–72. http://dx.doi.org/10.1055/s-0037-1617092.

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ZusammenfassungDas Wissen um eine Blutungsneigung infolge Einzelfaktorenmangel ist Allgemeingut. Das Gegenteil – eine Thromboseneigung infolge hoher Einzelfaktorenspiegel – scheint nicht überraschend, doch erst in jüngster Zeit wurde ein Zusammenhang zwischen dem Spiegel von Einzelfaktoren und dem Risiko für venöse Thromboembolien beschrieben. Gut dokumentiert ist die Rolle hoher Faktor- VIII(FVIII)-Spiegel. Das Risiko für ein erstmaliges Thromboseereignis ist ähnlich hoch wie das Risiko infolge einer APC-Resistenz. Ein familiärer Hintergrund wurde für hohe FVIII-Spiegel beschrieben. Veränderu

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11

Garcia-Martínez, Iris, Nina Borràs, Marta Martorell, et al. "Common Genetic Variants in ABO and CLEC4M Modulate the Pharmacokinetics of Recombinant FVIII in Severe Hemophilia A Patients." Thrombosis and Haemostasis 120, no. 10 (2020): 1395–406. http://dx.doi.org/10.1055/s-0040-1714214.

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AbstractThe pharmacokinetic (PK) response of severe hemophilia A (HA) patients to infused factor VIII (FVIII) shows substantial variability. Several environmental and genetic factors are associated with changes in FVIII plasma levels and infused FVIII PK. Based on the hypothesis that factors influencing endogenous FVIII can affect FVIII PK, the contribution of single-nucleotide variants (SNVs) in candidate genes was investigated in 51 severe HA patients. The effects of blood group, F8 variant type, von Willebrand factor antigen and activity levels, age, and weight were also explored. The myPKF

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12

Swystun, Laura L., Kenichi Ogiwara, Orla Rawley, et al. "Genetic determinants of VWF clearance and FVIII binding modify FVIII pharmacokinetics in pediatric hemophilia A patients." Blood 134, no. 11 (2019): 880–91. http://dx.doi.org/10.1182/blood.2019000190.

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Abstract Factor VIII (FVIII) pharmacokinetic (PK) properties show high interpatient variability in hemophilia A patients. Although previous studies have determined that age, body mass index, von Willebrand factor antigen (VWF:Ag) levels, and ABO blood group status can influence FVIII PK, they do not account for all observed variability. In this study, we aim to describe the genetic determinants that modify the FVIII PK profile in a population of 43 pediatric hemophilia A patients. We observed that VWF:Ag and VWF propeptide (VWFpp)/VWF:Ag, but not VWFpp, were associated with FVIII half-life. VW

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13

Yee, Andrew, Austin N. Oleskie, Robert D. Gildersleeve, et al. "Partial in Vivo FVIII Stabilization by VWF Fragments." Blood 120, no. 21 (2012): 15. http://dx.doi.org/10.1182/blood.v120.21.15.15.

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Abstract Abstract 15 Plasma factor VIII (fVIII) circulates in complex with von Willebrand factor (VWF) and is rapidly cleared in the absence of VWF. Previous in vitro studies have 1) localized the fVIII-binding region of VWF to the N-terminus, comprised of the contiguous D' and D3 domains and 2) observed reduced affinity for fVIII upon alterations to the tertiary structure of VWF. To gain insight into the structure-function of VWF for fVIII stabilization, we tested VWF fragments for in vivo fVIII stabilization and investigated the architecture of a VWF fragment in complex with fVIII. For the i

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14

Mertens, Koen, Niels Bovenschen, Louis M. Havekes, and Bart J. M. van Vlijmen. "Role of Low Density Lipoprotein Receptor in the Clearance of Coagulation Factor VIII In Vivo." Blood 104, no. 11 (2004): 1925. http://dx.doi.org/10.1182/blood.v104.11.1925.1925.

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Abstract Low Density Lipoprotein Receptor (LDLR) is the archetype of the family of endocytic receptors that also includes Low-density lipoprotein Receptor-related Protein (LRP), Megalin, and Very Low Density Lipoprotein Receptor (VLDLR). While most of these receptors bind a variety of ligands, LDLR has restricted specifity. Its known ligands are apolipoprotein E (apoE) and apolipoprotein B100 (apoB100). Ligand binding to the LDL-receptor family is inhibited by the Receptor-Associated Protein (RAP). We have previously reported that RAP overexpression elevates plasma levels of factor VIII (FVIII

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15

Bovenschen, Niels, Koen Mertens, Lihui Hu, Louis M. Havekes, and Bart J. M. van Vlijmen. "LDL receptor cooperates with LDL receptor–related protein in regulating plasma levels of coagulation factor VIII in vivo." Blood 106, no. 3 (2005): 906–12. http://dx.doi.org/10.1182/blood-2004-11-4230.

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Abstract Low-density lipoprotein (LDL) receptor (LDLR) and LDLR-related protein (LRP) are members of the LDLR family of endocytic receptors. LRP recognizes a wide spectrum of structurally and functionally unrelated ligands, including coagulation factor VIII (FVIII). In contrast, the ligand specificity of LDLR is restricted to apolipoproteins E and B-100. Ligand binding to the LDLR family is inhibited by receptor-associated protein (RAP). We have previously reported that, apart from LRP, other RAP-sensitive mechanisms contribute to the regulation of FVIII in vivo. In the present study, we showe

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16

Haberichter, Sandra L., Pamela A. Christopherson, Veronica H. Flood, Joan Cox Gill, Kenneth D. Friedman, and Robert R. Montgomery. "Von Willebrand Factor (VWF) Propeptide and Factor VIII (FVIII) Levels Identify the Contribution of Decreased Synthesis and/or Increased Clearance Mechanisms in the Pathogenesis of Type 1 Von Willebrand Disease (VWD) in the Zimmerman Program." Blood 128, no. 22 (2016): 874. http://dx.doi.org/10.1182/blood.v128.22.874.874.

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Abstract Laboratory diagnosis of VWD is challenging, with multiple tests required to obtain an accurate assessment. Plasma VWF level represents a balance between synthesis, secretion, and clearance. Although synthesized together, VWFpp and VWF circulate in plasma independently with differing half-lives. Plasma VWFpp level is used to assess synthesis/secretion, VWFpp/VWF:Ag ratio to indicate clearance of VWF, and FVIII/VWF:Ag ratio to assess VWF synthesis and clearance. We sought to identify the underlying VWD pathophysiology in subjects enrolled in the Zimmerman Program including 245 healthy c

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17

Kurasawa, James H., Svetlana A. Shestopal, Elena Karnaukhova, Evi B. Struble, Timothy K. Lee, and Andrey G. Sarafanov. "Characterization of Molecular Interaction of Blood Coagulation Factor VIII and Its Clearance Receptor, Low-Density Lipoprotein Receptor." Blood 120, no. 21 (2012): 2206. http://dx.doi.org/10.1182/blood.v120.21.2206.2206.

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Abstract Abstract 2206 Background. Clearance of blood coagulation factor VIII (FVIII) is mediated by several receptors (Saenko E. et al, 1999; Lenting P. et al, 1999 and Sarafanov A. et al, 2001) and one of them was proposed to be low-density lipoprotein receptor (LDLR) (Bovenschen N. et al, 2005). Besides FVIII, the major ligands of LDLR are plasma lipoproteins. The ligand-binding portion of LDLR is represented by a cluster of seven complement-type repeats. Each repeat forms a structurally autonomous domain, which are connected with flexible linkers. Two and five adjacent CRs were shown to fo

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18

Batsuli, Glaivy, Wei Deng, John F. Healey, et al. "High-affinity, noninhibitory pathogenic C1 domain antibodies are present in patients with hemophilia A and inhibitors." Blood 128, no. 16 (2016): 2055–67. http://dx.doi.org/10.1182/blood-2016-02-701805.

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Key Points C1 domain antibodies with low inhibitor titers by the Bethesda assay are pathogenic in mice due to increased fVIII clearance. Monoclonal and patient-derived polyclonal anti-fVIII C1 domain antibodies recognize similar B-cell epitopes.

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Planque, Stephanie, Miguel Antonio Escobar, Yasuhiro Nishiyama, and Sudhir Paul. "A Protease Resistant Factor VIII Analog for Blockade of Inhibitory Antibodies." Blood 116, no. 21 (2010): 3361. http://dx.doi.org/10.1182/blood.v116.21.3361.3361.

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Abstract Abstract 3361 High titer inhibitory antibodies (Abs) to Factor VIII (FVIII) generated in response to FVIII replacement therapy can render the therapy ineffective in hemophilia A (HA) patients. Abs to FVIII contain serine protease-like nucleophilic sites that react covalently with electrophilic phosphonate diester groups placed on the Lys side chains of FVIII (E-FVIII), resulting in restoration of the ability of exogenous FVIII to act as a cofactor for blood coagulation (Planque et al, J Biol Chem 2008; 283, p11876-11886). Irreversible inactivation of Abs by E-FVIII could potentially p

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Muczynski, Vincent, Caterina Casari, François Moreau, et al. "A factor VIII–nanobody fusion protein forming an ultrastable complex with VWF: effect on clearance and antibody formation." Blood 132, no. 11 (2018): 1193–97. http://dx.doi.org/10.1182/blood-2018-01-829523.

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Key Points The fusion between FVIII and anti-VWF nanobodies increases affinity for VWF 25-fold without compromising FVIII activity. Stabilized VWF binding results in a twofold enhanced circulatory survival of FVIII and reduced anti-FVIII antibody formation.

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Rottensteiner, Hanspeter, Peter L. Turecek, Rona Pendu, et al. "PEGylation or Polysialylation Reduces FVIII Binding to LRP Resulting in Prolonged Half-Life in Murine Models." Blood 110, no. 11 (2007): 3150. http://dx.doi.org/10.1182/blood.v110.11.3150.3150.

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Abstract The low-density lipoprotein (LDL)-receptor-related protein 1 (LRP1) binds FVIII and is involved in the in vivo clearance and regulation of FVIII plasma levels. The significance of LRP in the regulation of FVIII metabolism has been demonstrated both in conditional LRP1 knock-out mice resulting in increased endogenous levels and prolonged survival of FVIII and by blocking LRP in hemophilic mice leading to prolonged half-life of infused human FVIII. In the current study we investigated whether random chemical modification of lysine residues of recombinant FVIII with branched polyethylene

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van Moort, Iris, Laura H. Bukkems, Jessica M. Heijdra, et al. "von Willebrand Factor and Factor VIII Clearance in Perioperative Hemophilia A Patients." Thrombosis and Haemostasis 120, no. 07 (2020): 1056–65. http://dx.doi.org/10.1055/s-0040-1710591.

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Abstract Background von Willebrand factor (VWF) is crucial for optimal dosing of factor VIII (FVIII) concentrate in hemophilia A patients as it protects FVIII from premature clearance. To date, it is unknown how VWF behaves and what its impact is on FVIII clearance in the perioperative setting. Aim To investigate VWF kinetics (VWF antigen [VWF:Ag]), VWF glycoprotein Ib binding (VWF:GPIbM), and VWF propeptide (VWFpp) in severe and moderate perioperative hemophilia A patients included in the randomized controlled perioperative OPTI-CLOT trial. Methods Linear mixed effects modeling was applied to

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Lunghi, Barbara, Massimo Morfini, Nicola Martinelli, Silvia Linari, Giancarlo Castaman, and Francesco Bernardi. "Combination of CLEC4M rs868875 G-Carriership and ABO O Genotypes May Predict Faster Decay of FVIII Infused in Hemophilia A Patients." Journal of Clinical Medicine 11, no. 3 (2022): 733. http://dx.doi.org/10.3390/jcm11030733.

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The C-type lectin CLEC4M binds and internalizes factor VIII (FVIII). Common CLEC4M variants have been associated with FVIII pharmacokinetic (PK) profiles in hemophilia A (HA) patients. The two-compartment PK analysis of plasma-derived (pd-) and full length recombinant FVIII concentrates was conducted in twenty-six patients (FVIII:C ≤ 2 IU/dL). F8, ABO blood-groups, and the CLEC4M rs868875A/G polymorphism were genotyped. CLEC4M genotype groups differed for the elimination rate constant K 1-0 (p < 0.001), half-life (K 1-0 HL), and the Beta rate constant. Patients treated with pd-FVIII also di

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Seth Chhabra, Ekta, Nancy Moore, Chris Furcht, et al. "Evaluation of Enhanced in Vitro Plasma Stability of a Novel Long Acting Recombinant FVIIIFc-VWF-XTEN Fusion Protein." Blood 126, no. 23 (2015): 2279. http://dx.doi.org/10.1182/blood.v126.23.2279.2279.

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Abstract INTRODUCTION More than 95% of circulating clotting factor VIII (FVIII) exists in a non-covalent complex with von Willebrand Factor (VWF). While VWF stabilizes and protects FVIII from its clearance pathways, it also subjects FVIII to VWF-mediated clearance. Thus, interaction with VWF imposes a limitation on the extent of FVIII half-life extension achieved by current technologies (Fc fusion, PEGylation etc.). Recombinant FVIIIFc-VWF-XTEN (rFVIIIFc-VWF-XTEN) is a novel fusion protein, consisting of the FVIII binding D'D3 domains of VWF fused to a single chain rFVIIIFc (scFVIIIFc). Append

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Chun, Haarin, John R. Pettersson, Svetlana A. Shestopal, et al. "Characterization of Protein Unable to Bind Von Willebrand Factor in Recombinant Factor VIII Products: Can We Reduce Their Immunogenicity?" Blood 136, Supplement 1 (2020): 25–26. http://dx.doi.org/10.1182/blood-2020-133286.

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Introduction Therapeutic products with blood coagulation factor VIII (FVIII) have a wide range of protein contents per activity unit (or IU/mg, specific activity), available from previous studies (Lin et al, 2004; Butenas et al, 2009) and the prescribing information. The wide range of the specific activities seems to be more pronounced in recombinant FVIII products (rFVIII) compared to plasma-derived FVIII, implying presence of protein with altered structure and biochemical properties. In particular, rFVIII products were reported to contain a protein fraction (FVIII*), unable to bind von Wille

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Morfini, M., P. M. Mannucci, P. M. Tenconi, et al. "Pharmacokinetics of Monoclonally-Purified and Recombinant Factor VIII in Patients with Severe von Willebrand Disease." Thrombosis and Haemostasis 70, no. 02 (1993): 270–72. http://dx.doi.org/10.1055/s-0038-1649564.

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SummaryA monoclonally-purified factor VIII (FVIII) concentrate, containing little von Willebrand factor (vWF), was infused to 11 patients with severe von Willebrand disease and unmeasurable levels of plasma vWF. In comparison with the historical data obtained infusing hemophiliacs in the same conditions, monoclonally-purified FVIII had a significantly shorter half-life and faster clearance from plasma but similar in vivo recovery and volume of distribution. Two additional patients with severe von Willebrand disease were also infused with recombinant FVIII totally devoid of vWF. Half-life was v

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Meijer, Alexander B., Sigrid D. Roosendaal, Bas de Laat, et al. "Effective Factor VIII Endocytosis Is under Conformational Control of von Willebrand Factor." Blood 110, no. 11 (2007): 1767. http://dx.doi.org/10.1182/blood.v110.11.1767.1767.

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Abstract Von Willebrand Factor (VWF) protects Factor VIII (FVIII) from rapid clearance of the cofactor from the circulations. This notion may agree with the observation that VWF blocks FVIII binding to LDL receptor (LDLR) and LDL receptor-related protein (LRP) in vitro. In spite of the presence of VWF, however, we have previously demonstrated that LRP and LDLR are involved in the catabolism of FVIII in vivo. This suggests that dissociation of the FVIII-VWF complex in plasma or at the cell surface drives the LRP/LDLR dependent clearance of FVIII. We therefore first assessed the effect of VWF on

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Montgomery, Robert R., Scot A. Fahs, Jeremy G. Mattson, Hartmut Weiler, and Qizhen Shi. "A Murine Model of Type 2N VWD Was Developed By CRISPR/Cas9 Gene Editing and Recapitulates Human Type 2N VWD." Blood 132, Supplement 1 (2018): 221. http://dx.doi.org/10.1182/blood-2018-99-110324.

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Abstract Von Willebrand Disease (VWD) is caused by either an inherited deficiency of von Willebrand factor (VWF) protein or synthesis of a dysfunctional von Willebrand factor (VWF) that is referred to as a type 2 variant. One of the important functions of VWF is to serve as a carrier protein for FVIII - prolonging FVIII's plasma half-life from <2 hrs without VWF to 10-12 hrs with VWF. A variant form of VWF was identified in 1982 in which VWF did not bind FVIII resulting in FVIII's rapid clearance and a phenotype similar to moderate hemophilia and currently referred to as type 2N VWD. Type 2

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Shestopal, Svetlana A., Leonid A. Parunov, Mikhail V. Ovanesov, Timothy K. Lee, and Andrey G. Sarafanov. "Characterization of Interaction of Factor VIII with Engineered Variants of a Single-Chain Variable Antibody Fragment." Blood 132, Supplement 1 (2018): 1170. http://dx.doi.org/10.1182/blood-2018-99-115455.

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Abstract Introduction Replacement therapy for Hemophilia A requires frequent infusions of Factor VIII (FVIII) due to its relatively short half-life of ~12 h in plasma. Previous attempts to extend this half-life by genetic and chemical modification of FVIII met the barrier of ~20 h, which is a half-life of von Willebrand factor (VWF), a carrier of FVIII in plasma. A single-chain variable antibody fragment (scFv) KM33 was shown to inhibit FVIII activity, and interactions with VWF and the low-density lipoprotein receptor-related protein 1 (LRP), the major clearance receptor of FVIII (Bovenschen e

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Landskroner, Kyle A., Zhi-Hua Cui, James Newgren, Michael Fournel, Glenn F. Pierce, and Gary J. Jesmok. "Evaluation of PEG-FVIII Molecules with Prolonged Half-Lives in a Murine FVIII-Dependent Bleeding Model." Blood 108, no. 11 (2006): 1624. http://dx.doi.org/10.1182/blood.v108.11.1624.1624.

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Abstract Current treatment of patients with hemophilia A often requires the frequent infusion of Factor VIII (FVIII) due to its short circulating half-life. A longer-acting FVIII molecule could profoundly impact patients’ lives by extending bleeding protection with a reduced frequency of infusions. Several strategies to prolong plasma concentrations of FVIII have been attempted. In particular, targeting domains on FVIII that bind to LRP, the putative clearance receptor, has been a popular strategy. We have investigated the use of site-directed pegylation of B-domain deleted (BDD) FVIII to eval

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Fijnvandraat, K., E. Berntorp, J. W. ten Cate, et al. "Recombinant, B-domain Deleted Factor VIII (r-VIII SQ): Pharmacokinetics and Initial Safety Aspects in Hemophilia A Patients." Thrombosis and Haemostasis 77, no. 02 (1997): 298–302. http://dx.doi.org/10.1055/s-0038-1655957.

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SummaryThe pharmacokinetics of a second-generation recombinant B-domain deleted factor VIII (FVIII) preparation (r-VIII SQ) were studied in 36 patients with severe hemophilia A. In contrast to full-length recombinant FVIII, no albumin needs to be added to stabilize the final formulation of this B-domain deleted FVIII preparation.The in vivo recovery and half-life of r-VIII SQ were similar to those of plasma-derived (pd) FVIII (mean half-life of r-VIII SQ, 11.7 h). The volume of distribution and clearance were slightly, but significantly, higher for r-VIII SQ than for pdFVIII (p<0.05). Peak

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Mei, Baisong, Clark Pan, Haiyan Jiang, et al. "Rational design of a fully active, long-acting PEGylated factor VIII for hemophilia A treatment." Blood 116, no. 2 (2010): 270–79. http://dx.doi.org/10.1182/blood-2009-11-254755.

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Abstract A long-acting factor VIII (FVIII) as a replacement therapy for hemophilia A would significantly improve treatment options for patients with hemophilia A. To develop a FVIII with an extended circulating half-life, but without a reduction in activity, we have engineered 23 FVIII variants with introduced surface-exposed cysteines to which a polyethylene glycol (PEG) polymer was specifically conjugated. Screening of variant expression level, PEGylation yield, and functional assay identified several conjugates retaining full in vitro coagulation activity and von Willebrand factor (VWF) bin

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Sarafanov, Andrey G. "Plasma Clearance of Coagulation Factor VIII and Extension of Its Half-Life for the Therapy of Hemophilia A: A Critical Review of the Current State of Research and Practice." International Journal of Molecular Sciences 24, no. 10 (2023): 8584. http://dx.doi.org/10.3390/ijms24108584.

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Factor VIII (FVIII) is an important component of blood coagulation as its congenital deficiency results in life-threatening bleeding. Current prophylactic therapy of the disease (hemophilia A) is based on 3–4 intravenous infusions of therapeutic FVIII per week. This poses a burden on patients, demanding reduction of infusion frequency by using FVIII with extended plasma half-life (EHL). Development of these products requires understanding FVIII plasma clearance mechanisms. This paper overviews (i) an up-to-date state of the research in this field and (ii) current EHL FVIII products, including

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Liu, Tongyao, David Lillicrap, Xin Zhang, et al. "Site-Specific PEGylation of Factor VIII (PEG-FVIII) Preserves Full Clotting Activity and Extends Therapeutic Efficacy in HemophiliaA Dogs." Blood 112, no. 11 (2008): 511. http://dx.doi.org/10.1182/blood.v112.11.511.511.

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Abstract To improve the effectiveness of Factor VIII replacement therapy for Hemophilia A, we sought to develop a PEGylated Factor VIII that would effectively treat bleeding episodes, while reducing the frequency of intravenous injections required for prophylaxis. Previously, we found that the site-specific PEGylation of Factor VIII (PEG-FVIII) preserves full clotting activity, prolongs circulating half-life and extends therapeutic efficacy in a number of bleeding models in hemophilic mice. To further characterize its activity, four naïve Hemophilia A dogs were treated with either PEG-FVIII o

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Grossmann, Ralf, Sarah Zonnur, Mario Berger, et al. "High factor VIII (FVIII) levels in venous thromboembolism: role of unbound FVIII." Thrombosis and Haemostasis 92, no. 07 (2004): 42–46. http://dx.doi.org/10.1160/th04-02-0063.

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SummaryTheoretically, von Willebrand factor (VWF) should be capable of binding all factor VIII (FVIII), but an unbound FVIII (uFVIII) plasma fraction remains. In patients’ status post deep-vein thrombosis (DVT), an altered uFVIII fraction and high FVIII levels might be indicative of dysfunctional FVIII regulation. Out of 928 consecutive DVT patients, 321 were found to have high FVIII levels. After excluding 183 patients with known causes for high FVIII levels, plasma samples with unexplainably high FVIII levels were available from 84 patients. To capture the FVIIIVWF-complex, superparamagnetic

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Bovenschen, Niels, Joachim Herz, Jos M. Grimbergen, et al. "Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor–related protein deficiency." Blood 101, no. 10 (2003): 3933–39. http://dx.doi.org/10.1182/blood-2002-07-2081.

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Abstract It has been established that low-density lipoprotein receptor-related protein (LRP) is involved in the cellular uptake and degradation of coagulation factor VIII (FVIII) in vitro. To address the physiologic role of LRP in regulating plasma FVIII in vivo, we used cre/loxP–mediated conditional LRP- deficient mice (MX1cre+LRPflox/flox). Upon inactivation of the LRP gene, MX1cre+LRPflox/flox mice had significantly higher plasma FVIII as compared with control LRPflox/floxmice (3.4 and 2.0 U/mL, respectively; P < .001). Elevated plasma FVIII levels in MX1cre+LRPflox/flox mice coincided w

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37

Swystun, Laura L., Colleen Notley, Ilinca Georgescu, Paula D. James, and David Lillicrap. "The Endothelial Lectin Receptor CLEC4M Internalizes Factor VIII and Von Willebrand Factor Via a Clathrin-Coated Pit-Dependent Mechanism." Blood 122, no. 21 (2013): 1091. http://dx.doi.org/10.1182/blood.v122.21.1091.1091.

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Abstract Regulation of plasma levels of the coagulation factors von Willebrand factor (VWF) and factor VIII (FVIII) involves a dynamic balance between biosynthesis, secretion, and clearance. Clearance of VWF and FVIII occurs through receptor-mediated endocytosis, with both LDL receptor gene family (eg. LRP1), and lectin receptors (eg. asialoglycoprotein receptor, siglec-5) contributing to this process. We have previously characterized the endothelial lectin CLEC4M as an endocytic receptor for FVIII and VWF. These proteins represent the first endogenous glycoprotein ligands indentified for CLEC

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Seth Chhabra, Ekta, Tongyao Liu, John Kulman, et al. "BIVV001, a new class of factor VIII replacement for hemophilia A that is independent of von Willebrand factor in primates and mice." Blood 135, no. 17 (2020): 1484–96. http://dx.doi.org/10.1182/blood.2019001292.

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Abstract Factor VIII (FVIII) replacement products enable comprehensive care in hemophilia A. Treatment goals in severe hemophilia A are expanding beyond low annualized bleed rates to include long-term outcomes associated with high sustained FVIII levels. Endogenous von Willebrand factor (VWF) stabilizes and protects FVIII from degradation and clearance, but it also subjects FVIII to a half-life ceiling of ∼15 to 19 hours. Increasing recombinant FVIII (rFVIII) half-life further is ultimately dependent upon uncoupling rFVIII from endogenous VWF. We have developed a new class of FVIII replacement

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Sarafanov, Andrei G., Natalya M. Ananyeva, Midori Shima, and Evgueni L. Saenko. "Cell Surface Heparan Sulfate Proteoglycans Participate in Factor VIII Catabolism Mediated by Low Density Lipoprotein Receptor-related Protein." Journal of Biological Chemistry 276, no. 15 (2001): 11970–79. http://dx.doi.org/10.1074/jbc.m008046200.

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We have demonstrated previously that catabolism of a coagulation factor VIII (fVIII) from its complex with von Willebrand factor (vWf) is mediated by low density lipoprotein receptor-related protein (LRP) (Saenko, E. L., Yakhyaev, A. V., Mikhailenko, I., Strickland, D. K., and Sarafanov, A. G. (1999)J. Biol. Chem.274, 37685–37692). In the present study, we found that this process is facilitated by cell surface heparan sulfate proteoglycans (HSPGs). This was demonstrated by simultaneous blocking of LRP and HSPGs in model cells, which completely prevented fVIII internalization and degradation fr

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Hoebarth, Gerald, Susan Kubik, Martin Wolfsegger, et al. "Pharmacokinetics of Baxter’s Longer Acting rFVIII (BAX 855) in Factor VIII Ko Mice, Rats and Cynomolgus Monkeys." Blood 118, no. 21 (2011): 4346. http://dx.doi.org/10.1182/blood.v118.21.4346.4346.

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Abstract Abstract 4346 The pharmacokinetic profile of BAX 855, a longer acting PEGylated variant of Baxter’s recombinant FVIII based on the ADVATE™ manufacturing process, was assessed in comparison to ADVATE™ after a single intravenous bolus injection at a target dose of 200 IU/kg BW in mice and rats and 350 IU/kg BW in cynomolgus monkeys. Mean residence time (MRT), terminal half-life (HL), total clearance standardized per kg body mass (Cl), the AUC0-tlast (the area under the concentration vs. time curve from 0 to the last measured time point), the in vivo recovery (IVR) and volume of distribu

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Boross, Peter, Cafer Yildiz, Kamran Bakhtiari, Joost C. M. Meijers, and C. Erik Hack. "Towards Restoring Coagulation in Hemophilia By Antibody-Mediated Inhibition of Antithrombin." Blood 126, no. 23 (2015): 550. http://dx.doi.org/10.1182/blood.v126.23.550.550.

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Abstract Currently hemophilia A is mainly treated with factor VIII (FVIII). However, 20-25% of the hemophiliacs develop inhibiting antibodies (inhibitors) against FVIII. Hemophiliacs with inhibitors are treated with high dose FVIII or with therapies that bypass the need for FVIII such as activated FVII (rFVIIa, NovoSeven) or activated prothrombin concentrate. These have some disadvantages including rapid clearance, price and a risk of thrombo-embolism. In hemophilia, the balance between coagulation and anticoagulation is shifted towards the latter. This balance can be restored by administratio

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Björkman, Sven, MyungShin Oh, Gerald Spotts, et al. "Population pharmacokinetics of recombinant factor VIII: the relationships of pharmacokinetics to age and body weight." Blood 119, no. 2 (2012): 612–18. http://dx.doi.org/10.1182/blood-2011-07-360594.

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Comparison of the pharmacokinetics (PK) of a coagulation factor between groups of patients can be biased by differences in study protocols, in particular between blood sampling schedules. This could affect clinical dose tailoring, especially in children. The aim of this study was to describe the relationships of the PK of factor VIII (FVIII) with age and body weight by a population PK model. The potential to reduce blood sampling was also explored. A model was built for FVIII PK from 236 infusions of recombinant FVIII in 152 patients (1-65 years of age) with severe hemophilia A. The PK of FVII

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van Schooten, Carina J., Shirin Shahbazi, Evelyn Groot, et al. "Macrophages contribute to the cellular uptake of von Willebrand factor and factor VIII in vivo." Blood 112, no. 5 (2008): 1704–12. http://dx.doi.org/10.1182/blood-2008-01-133181.

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Abstract Von Willebrand factor (VWF) and factor VIII (FVIII) circulate in a tight noncovalent complex. At present, the cells that contribute to the removal of FVIII and VWF are of unknown identity. Here, we analyzed spleen and liver tissue sections of VWF-deficient mice infused with recombinant VWF or recombinant FVIII. This analysis revealed that both proteins were targeted to cells of macrophage origin. When applied as a complex, both proteins were codirected to the same macrophages. Chemical inactivation of macrophages using gadolinium chloride resulted in doubling of endogenous FVIII level

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44

Schiviz, Alexandra, Gerald Hoebarth, Martin Wolfsegger, et al. "Pharmacokinetics of BAX 826, a Polysialylated Full-Length rFVIII, in Hemophilia a Mice, Rats, and Cynomolgus Monkeys." Blood 126, no. 23 (2015): 1073. http://dx.doi.org/10.1182/blood.v126.23.1073.1073.

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Abstract Factor VIII (FVIII) is a critical component of the intrinsic coagulation pathway. Plasma-derived or recombinant (r) FVIII concentrates are used in patients with hemophilia A to provide a FVIII level sufficient to treat and prevent bleeding episodes. Prophylactic FVIII levels can only be maintained by administering several infusions per week. Extended FVIII circulation times would reduce the frequency of infusions, increase patient compliance, reduce the number of bleeds, and offer the possibility to achieve higher trough levels of FVIII. Prolonged circulation can be achieved by modify

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45

Bossard, M. J., M. Graninger, H. Gritsch, et al. "BAX 855, a PEGylated rFVIII product with prolonged half-life." Hämostaseologie 32, S 01 (2012): S29—S38. http://dx.doi.org/10.1055/s-0037-1619772.

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SummaryA longer acting recombinant FVIII is expected to serve patients’ demand for a more convenient prophylactic therapy. We have developed BAX 855, a PEGylated form of Baxter’s rFVIII product ADVATE™ based on the ADVATE™ manufacturing process. The conjugation process for preparing BAX 855 uses a novel PEG reagent. The production process was adjusted to yield a rFVIII conjugate with a low PEGylation degree of about 2 moles PEG per FVIII molecule. This optimised modification degree resulted in an improved PK profile for rFVIII without compromising its specific activity. PEGylation sites were i

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Cooke, Esther J., Chanond A. Nasamran, Kathleen M. Fisch, and Annette von Drygalski. "Mechanisms of Iron Clearance from the Joint in FVIII-Deficient Mice after Induced Hemarthrosis." Blood 134, Supplement_1 (2019): 157. http://dx.doi.org/10.1182/blood-2019-131576.

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Introduction Hemarthrosis in hemophilia causes toxic iron accumulation in the joint, which contributes to synovitis. This study aimed to explore mechanisms and timing of iron clearance from the joint space in mouse models of induced hemarthrosis. Methods Hemarthrosis was induced by sub-patellar puncture in FVIII-deficient mice and in hypocoagulable BALB/c (HypoBALB/c) mice treated with 10 µg/ml warfarin for 7 days and 0.25 mg/kg anti-FVIII antibody 2 hours before knee puncture. Warfarin was reversed on day 2 post-injury with 100 IU/Kg 4-factor prothrombinase complex concentrate and the hematoc

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Hoebarth, Gerald, Susan Kubik, Martin Wolfsegger, et al. "Single Dose Pharmacokinetics of a Recombinant FVIIa In Factor VIII KO Mice, Rats, and Cynomolgus Monkeys." Blood 116, no. 21 (2010): 4655. http://dx.doi.org/10.1182/blood.v116.21.4655.4655.

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Abstract Abstract 4655 The purpose of these PK studies was to assess the pharmacokinetic profile of Baxter's rFVIIa in comparison with a commercially available rFVIIa after a single intravenous bolus injection at a target dose of 0.6 mg/kg BW in mice and rats and 2.7 mg/kg BW in cynomolgus monkeys. The AUC0-t last (the area under the concentration vs. time curve from 0 to the last measured time point) was evaluated as primary endpoint. Secondary endpoints were terminal half-life (HL), mean residence time (MRT) and total clearance standardized per kg body mass (Cl) for FVIIa protein and clottin

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48

Holmberg, Heidi L., Marianne Kjalke, Ditte Karpf, et al. "High Affinity Binding of FVIII to VWF Is Not Required for the Haemostatic Effect of FVIII In Vivo." Blood 118, no. 21 (2011): 1182. http://dx.doi.org/10.1182/blood.v118.21.1182.1182.

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Abstract Abstract 1182 VWF protects FVIII from clearance in the circulation and is believed to ensure location of platelets to the site of injury. However, it is unknown if binding of FVIII to VWF has a role in localizing and thereby also facilitating the effect of FVIII in vivo. In the present study, a FVIII variant, FVIII-Y1680F, lacking the high affinity binding to VWF (Leyet et al. JCB 1991; 15; 740) was used to evaluate the binding of FVIII to VWF in clot formation hemophilia A mice in vivo. Binding of the FVIII variant to immobilized VWF was evaluated by surface plasmon resonance showing

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Flier, Arjan van der, Zhan Liu, David R. Light, and Haiyan Jiang. "Immunohistochemical Staining of rFVIIIFc and rFVIII in Liver Cells Differentiates Between a VWF-Dependent and Independent Clearance Pathway in Mice." Blood 122, no. 21 (2013): 2331. http://dx.doi.org/10.1182/blood.v122.21.2331.2331.

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Abstract Introduction rFVIIIFc is a fully recombinant fusion protein consisting of a single B domain-deleted human FVIII covalently attached to the dimeric Fc domain of human IgG1. rFVIIIFc has a 1.5-fold extended half-life and decreased clearance compared to rFVIII in patients with hemophilia A (Powell, Blood 2012). The Fc region of rFVIIIFc binds to the neonatal Fc receptor (FcRn), which is part of a naturally occurring pathway that cycles IgG back into circulation, delaying lysosomal degradation. Our previous studies with FcRn-chimeric mice showed that the decreased clearance of rFVIIIFc is

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50

Atiq, Ferdows, Lisette M. Schütte, Agnes E. M. Looijen, et al. "VWF and FVIII Levels after Desmopressin Are Associated with the Bleeding Phenotype in Type 1 VWD." Blood 134, Supplement_1 (2019): 1116. http://dx.doi.org/10.1182/blood-2019-123634.

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Introduction The bleeding phenotype of type 1 von Willebrand disease (VWD) patients is very heterogeneous. We hypothesized that part of this heterogeneity is explained by variability in response of von Willebrand factor (VWF) and factor VIII (FVIII) levels to stress during hemostatic challenges. Patients who have a strong increase in VWF and FVIII levels during hemostatic challenges, may have less frequent or less severe bleeding episodes compared to patients who have a smaller increase in VWF and FVIII levels. Therefore, we investigated whether VWF and FVIII levels after desmopressin, which m

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