BACKGROUND Hemophilia A (HA) is an X-linked inherited bleeding disorder, resulting from a qualitative or quantitative deficiency of clotting factor VIII (FVIII). Antibodies against FVIII, also called inhibitors, block the procoagulant activity of FVIII; thus, impairing hemostatic activity in patients with HA. The exact mechanism underlying the immunological events behind the development of inhi...

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(+)LRP(flox/flox)). Upon inactivation of the LRP gene, MX1cre(+)LRP(flox/flox...

Current treatment of hemophilia A (HemA) patients with repeated infusions of factor VIII (FVIII; abbreviated as F8 in constructs) is costly, inconvenient, and incompletely effective. In addition, approximately 25 % of treated patients develop anti-factor VIII immune responses. Gene therapy that can achieve long-term phenotypic correction without the complication of anti-factor VIII antibody for...

BACKGROUND Point mutations resulting in reduced factor VIII (FVIII) binding to von Willebrand factor (VWF) are an important cause of mild/moderate hemophilia A. Treatment includes desmopressin infusion, which concomitantly increases VWF and FVIII plasma levels, apparently from storage pools containing both proteins. The source of these VWF/FVIII co-storage pools and the mechanism of granule bio...

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

Treatment of von Willebrand disease typically requires multiple infusions of von Willebrand factor (VWF)/factor VIII (FVIII) concentrate. Accumulation of FVIII is a clinical concern due to potential risk for thromboembolism. This study sought to determine whether VWF/FVIII concentrate of high VWF:FVIII ratio can prevent FVIII accumulation. VWF-deficient knockout mice received four 150 IU/kg VWF...

Human and porcine coagulation factor VIII (fVIII) display a biosynthetic efficiency differential that is being exploited for the development of new protein and gene transfer-based therapies for hemophilia A. The cellular and/or molecular mechanism(s) responsible for this phenomenon have yet to be uncovered, although it has been temporally localized to post-translational biosynthetic steps. The ...

Introducción: la hemofilia A severa (HAS) es una enfermedad hemorrágica hereditaria causada por un déficit de factor VIII (FVIII) menor al 1%. Se presenta principalmente con sangrados articulares, los cuales provocan artropatía hemofílica que afecta su independencia funcional. El uso profilaxis terciaria FVIII ofrece beneficios en adultos disminuyendo tasa anual sangrado (TAS) y mejorando funci...

Low density lipoprotein receptor (LDLR) was shown to mediate clearance of blood coagulation factor VIII (FVIII) from the circulation. To elucidate the mechanism of interaction of LDLR and FVIII, our objective was to identify the region of the receptor necessary for binding FVIII. Using surface plasmon resonance, we found that LDLR exodomain and its cluster of complement-type repeats (CRs) bind ...

We have localized the binding region of a previously described monoclonal anti-factor VIII (FVIII) inhibitory antibody (C5) to amino acid residues Thr351-Ser '5 ofthe thrombin-generated 54-kD fragment of the heavy chain of FVIII. Synthetic FVIII peptides were examined for the ability to competitively inhibit the binding of C5 to FVIII in an ELISA system. The synthetic FV1lI peptide Thr35'-Ser36...