Recombinant Factor VIII Concentrates

Franchini, Massimo; Lippi, Giuseppe

doi:10.1055/s-0030-1255443

Cited by 30 publications

(10 citation statements)

References 42 publications

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“…Human and porcine FVIII expressed in mammalian cells with or without parts of the B domain27 have very similar biochemical and hemostatic properties to plasma derived (pd) FVIII and a similar pharmacokinetic profile2 when used for treatment of Hemophilia A. Human FVIII lacking the B domain (hFVIII) shows much less structural heterogeneity than pdFVIII and is more suitable for biochemical, biophysical and structural studies28.…”

mentioning

confidence: 99%

Dimeric Organization of Blood Coagulation Factor VIII bound to Lipid Nanotubes

Dalm

Galaz-Montoya

Miller

et al. 2015

Sci Rep

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Membrane-bound Factor VIII (FVIII) has a critical function in blood coagulation as the pro-cofactor to the serine-protease Factor IXa (FIXa) in the FVIIIa-FIXa complex assembled on the activated platelet membrane. Defects or deficiency of FVIII cause Hemophilia A, a mild to severe bleeding disorder. Despite existing crystal structures for FVIII, its membrane-bound organization has not been resolved. Here we present the dimeric FVIII membrane-bound structure when bound to lipid nanotubes, as determined by cryo-electron microscopy. By combining the structural information obtained from helical reconstruction and single particle subtomogram averaging at intermediate resolution (15-20 Å), we show unambiguously that FVIII forms dimers on lipid nanotubes. We also demonstrate that the organization of the FVIII membrane-bound domains is consistently different from the crystal structure in solution. The presented results are a critical step towards understanding the mechanism of the FVIIIa-FIXa complex assembly on the activated platelet surface in the propagation phase of blood coagulation.

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confidence: 99%

Dimeric Organization of Blood Coagulation Factor VIII bound to Lipid Nanotubes

Dalm

Galaz-Montoya

Miller

et al. 2015

Sci Rep

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“…Despite advances that have led to the availability of purified plasma-derived and recombinant FVIII 5 and FIX, 6 infusions of replacement coagulation factors require intravenous access, must be given repeatedly and frequently due to defined terminal half-lives of the replacement protein, and are associated with the development of inhibitory antibodies in 25%-30% of patients with hemophilia A 7 and to a lesser extent in patients with hemophilia B. 6 Patients who develop inhibitory antibodies to FVIII or FIX that do not respond to immune tolerance induction incur severe morbidity due to repeated episodes of joint and soft tissue bleeding.…”

Section: Bioengineering Of Therapeutic Coagulation Proteinsmentioning

confidence: 99%

Biological Rationale for New Drugs in the Bleeding Disorders Pipeline

Fogarty

2011

Hematology

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Since the introduction of replacement coagulation factor infusions for the treatment of hemophilia in the 1970s and subsequent improvements in the safety profile of available factor VIII (FVIII) and factor IX (FIX) concentrates, mortality among patients with hemophilia has improved considerably and now parallels that of the noncoagulopathic population in developed countries. Substantial morbidity, however, continues from the development of inhibitory antibodies, a recognized complication of clotting factor replacement; from infections and thrombosis complicating placement of central venous catheters, which are required in children with hemophilia due to frequent prophylactic infusions of coagulation factors with defined half-lives; and from disabling joint disease in individuals without access to costly prophylaxis regimens. In response to the need for long-acting, more potent, less immunogenic, and more easily administered therapies, an impressive array of novel agents is nearly ready for use in the clinical setting. These therapeutics derive from rational bioengineering of recombinant coagulation factors or from the discovery of nonpeptide molecules that have the potential to support hemostasis through alternative pathways. The number of novel agents in clinical trials is increasing, and many of the initial results are promising. In addition to advancing treatment of bleeding episodes or enabling adherence to prophylactic infusions of clotting factor concentrate, newer therapeutics may also lead to improvements in joint health, quality of life, and tolerability of iatrogenic or comorbidity-associated bleeding challenges.

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“…Since recombinant FVIII (rFVIII) was first used in the 1980s, continuing efforts to improve the safety of replacement therapy have led to the latest generation of recombinant products being devoid of animal-or human-derived proteins in the cell culture or formulation processes [5]. Despite these advances, which have provided a normal or nearnormal life expectancy for most people with haemophilia, key challenges remain [6].…”

Section: Introductionmentioning

confidence: 99%