Survival of 125iodine-labeled Factor VIII in normals and patients with classic hemophilia. Observations on the heterogeneity of human Factor VIII.

Over, J; Sixma, Jan J.; Bruïne, M H Doucet-De; Trieschnigg, M C; Vlooswijk, R.A.A.; Beeser‐Visser, Nel H.; Bouma, Bonno N.

doi:10.1172/jci109120

Cited by 100 publications

(56 citation statements)

References 33 publications

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“…7 In the presence of VWF, FVIII half-life varies between 12 and 14 hours in humans 7,36 and about 1 hour in mice. 37 In VWF deficiency, however, FVIII half-life is only to 2 to 3 hours in humans 38 and less than 10 minutes in mice.…”

Section: Discussionmentioning

confidence: 99%

Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor–related protein deficiency

Bovenschen

Herz

Grimbergen

et al. 2003

Blood

108

137

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Section: Discussionmentioning

confidence: 99%

Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor–related protein deficiency

Bovenschen

Herz

Grimbergen

et al. 2003

Blood

108

137

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“…3B; p Ͻ 0.01 and p Ͻ 0.05, respectively). Thus, at IgG concentrations much inferior to that found in normal plasma (11.2 and 1 g/ml for IgG from patients Wal and B1, respectively), half of the FVIII available in the assay was inactivated after 7 and 16 h, respectively, values inferior or equal to the normal half-life of therapeutic FVIII in circulation (22)(23)(24). Importantly, the assays were performed in the presence of 1 mg/ml HSA, thus making the experimental conditions close to physiological ones.…”

Section: Fviii-hydrolyzing Igg Neutralize Fviii Procoagulant Activitymentioning

confidence: 99%

Catalytic IgG from Patients with Hemophilia A Inactivate Therapeutic Factor VIII

Lacroix‐Desmazes

Wootla

Dasgupta

et al. 2006

The Journal of Immunology

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Factor VIII (FVIII) inhibitors are anti-FVIII IgG that arise in up to 50% of the patients with hemophilia A, upon therapeutic administration of exogenous FVIII. Factor VIII inhibitors neutralize the activity of the administered FVIII by sterically hindering its interaction with molecules of the coagulation cascade, or by forming immune complexes with FVIII and accelerating its clearance from the circulation. We have shown previously that a subset of anti-factor VIII IgG hydrolyzes FVIII. FVIII-hydrolyzing IgG are detected in over 50% of inhibitor-positive patients with severe hemophilia A, and are not found in inhibitor-negative patients. Although human proficient catalytic Abs have been described in a number of inflammatory and autoimmune disorders, their pathological relevance remains elusive. We demonstrate here that the kinetics of FVIII degradation by FVIII-hydrolyzing IgG are compatible with a pathogenic role for IgG catalysts. We also report that FVIII-hydrolyzing IgG from each patient exhibit multiple cleavage sites on FVIII and that, while the specificity of cleavage varies from one patient to another, catalytic IgG preferentially hydrolyze peptide bonds containing basic amino acids.

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“…The physiological significance of complex formation between FVIII and vWF is particularly apparent in patients having von Willebrand disease type 3, who have no detectable vWF protein. Not only do these patients have a secondary deficiency of FVIII, but they also have a considerably reduced half-life of intravenously administered FVIII (26,27). It is tempting to speculate that the decreased levels of FVIII in these patients are associated with increased binding and internalization of FVIII by LRP due to the absence of vWF.…”

Section: Fig 5 Binding Of Fviii or Its C2 Domain To Lrp In The Presmentioning

confidence: 99%

“…vWF prevents the FVIII precursor from binding to components of the factor X-activating complex (14,24,25). Furthermore, the halflife of FVIII is considerably reduced in the absence of vWF (26,27), indicating that vWF prevents FVIII from premature clearance. However, the mechanism by which FVIII is removed from the circulation has remained unidentified.…”

mentioning

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

199

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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Survival of 125iodine-labeled Factor VIII in normals and patients with classic hemophilia. Observations on the heterogeneity of human Factor VIII.

Cited by 100 publications

References 33 publications

Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor–related protein deficiency

Elevated plasma factor VIII in a mouse model of low-density lipoprotein receptor–related protein deficiency

Catalytic IgG from Patients with Hemophilia A Inactivate Therapeutic Factor VIII

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

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