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Acta Biochimica Polonica 2016Factor VIII (FVIII), an essential blood coagulation protein, is a key component of the fluid phase blood coagulation system. Human factor VIII is a single chain of about... (Review)
Review
Factor VIII (FVIII), an essential blood coagulation protein, is a key component of the fluid phase blood coagulation system. Human factor VIII is a single chain of about 300 kDa consisting of domains described as A1-A2-B-A3-C1-C2. The protein undergoes processing prior to secretion into blood resulting in a heavy chain of 200 kDa (A1-A2-B) and a light chain of 80 kDa (A3-C1-C2) linked by metal ions. The role of factor VIII is to increase the catalytic efficiency of factor IXa in the activation of factor X. Variants of these factors lead frequently also to severe bleeding disorders.
Topics: Factor VIII; Hemophilia A; Humans; Models, Molecular
PubMed: 26824291
DOI: 10.18388/abp.2015_1056 -
Frontiers in Immunology 2020
Topics: Antibodies, Neutralizing; Blood Coagulation Factor Inhibitors; Factor VIII; Hemophilia A; Humans; Immune Tolerance
PubMed: 33569066
DOI: 10.3389/fimmu.2020.639386 -
British Journal of Anaesthesia Dec 2014Cryoprecipitate, originally developed as a therapy for patients with antihaemophilic factor deficiency, or haemophilia A, has been in use for almost 50 yr. However,... (Review)
Review
Cryoprecipitate, originally developed as a therapy for patients with antihaemophilic factor deficiency, or haemophilia A, has been in use for almost 50 yr. However, cryoprecipitate is no longer administered according to its original purpose, and is now most commonly used to replenish fibrinogen levels in patients with acquired coagulopathy, such as in clinical settings with haemorrhage including cardiac surgery, trauma, liver transplantation (LT), or obstetric haemorrhage. Cryoprecipitate is a pooled product that does not undergo pathogen inactivation, and its administration has been associated with a number of adverse events, particularly transmission of blood-borne pathogens and transfusion-related acute lung injury. As a result of these safety concerns, along with emerging availability of alternative fibrinogen preparations, cryoprecipitate has been withdrawn from use in a number of European countries. Compared with the plasma from which it is prepared, cryoprecipitate contains a high concentration of coagulation factor VIII, coagulation factor XIII, and fibrinogen. Cryoprecipitate is usually licensed by regulatory authorities for the treatment of hypofibrinogenaemia, and recommended for supplementation when plasma fibrinogen levels decrease below 1 g litre(-1); however, this threshold is empiric and is not based on solid clinical evidence. Consequently, there is uncertainty over the appropriate dosing and optimal administration of cryoprecipitate, with some guidelines from professional societies to guide clinical practice. Randomized, controlled trials are needed to determine the clinical efficacy of cryoprecipitate, compared with the efficacy of alternative preparations. These trials will allow the development of evidence-based guidelines in order to inform physicians and guide clinical practice.
Topics: Blood Coagulation Disorders; Coagulants; Drug Administration Schedule; Drug Approval; Drug Costs; Drug Monitoring; Factor VIII; Fibrinogen; Humans; Practice Guidelines as Topic
PubMed: 24972790
DOI: 10.1093/bja/aeu158 -
Blood Aug 2015In this issue of Blood, back-to-back (dos-à-dos) papers by Chiu et al and Yee et al present complementary findings of structural investigations into the interaction...
In this issue of Blood, back-to-back (dos-à-dos) papers by Chiu et al and Yee et al present complementary findings of structural investigations into the interaction between factor VIII (FVIII) and von Willebrand factor (VWF). The binding of FVIII to VWF contributes in a major way to the regulation of hemostasis.
Topics: Factor VIII; Humans; Models, Molecular; von Willebrand Factor
PubMed: 26294711
DOI: 10.1182/blood-2015-06-652073 -
Journal of Thrombosis and Haemostasis :... Mar 2022Trousseau sign was the first demonstration of a close relationship between cancer and thrombosis. Currently, venous thromboembolism (VTE) is five to six times more...
BACKGROUND
Trousseau sign was the first demonstration of a close relationship between cancer and thrombosis. Currently, venous thromboembolism (VTE) is five to six times more likely to occur in cancer patients, whereas there is a greater risk of cancer diagnoses following thromboses. In considering novel players, factor VIII (FVIII), an essential coagulation cofactor with emerging extracoagulative functions, has been identified as an independent VTE risk factor in cancer; however, the basis of this increase is unknown.
OBJECTIVE
To investigate the possible direct expression and secretion of FVIII by cancer cells.
METHODS
Bladder cancer, with a high VTE risk, and normal bladder tissue and epithelium, were used to investigate FVIII. Factor VIII protein and secretion were examined in bladder cancer cell lines. Expanding to other cancers, the Cancer Cell line Encyclopedia database was used to analyze FVIII, tissue factor, FV, FVII, FIX, FX, and von Willebrand factor (VWF) mRNA in 811 cell lines subdivided according to origin. Factor VIII protein synthesis, secretion, and bioactivity were investigated in a profile of cancer cell lines of differing origins.
RESULTS AND CONCLUSIONS
Although expressed in the normal bladder epithelium, FVIII mRNA and protein were higher in matched bladder neoplasms, with synthesis and secretion of bioactive FVIII evident in bladder cancer cells. This can be extended to other cancer cell lines, with a pattern reflecting the tumor origin, and that is independent of VWF and other relevant players in the coagulation cascade. Here, evidence is provided of a possible independent role for FVIII in cancer-related pathophysiology.
Topics: Blood Coagulation; Factor VIII; Hemostatics; Humans; Neoplasms; von Willebrand Factor
PubMed: 34847278
DOI: 10.1111/jth.15611 -
British Journal of Haematology Jun 2015Treatment of congenital haemophilia with factor VIII and IX concentrates often requires frequent infusions. This has obvious implications in establishing effective... (Review)
Review
Treatment of congenital haemophilia with factor VIII and IX concentrates often requires frequent infusions. This has obvious implications in establishing effective administration strategies and, in turn, adherence. To overcome these issues, three main technologies--polyethylene-glycol, Fc-neonatal IgG1 and albumin fusion products--have emerged into various stages of clinical development. Published data indicates an approximately 1·5- and fivefold increase in half-life of factor VIII and IX, respectively, compared to standard recombinant concentrates. Studies into efficacy and safety are starting to be published. Monitoring and optimal use of these new concentrates remains unknown. Weekly factor IX prophylaxis appears to be a feasible prophylactic regimen in haemophilia B patients. Weekly longer-acting FVIII is unlikely to provide adequate prophylaxis in most patients with haemophilia A but may reduce the frequency of infusions. Ongoing clinical trials and real life experience will help shape how these products can be used in practice and their cost effectiveness. The drive for convenience however should not overshadow the ultimate goal of prophylaxis, namely, preventing bleeding and arthropathy.
Topics: Drug Monitoring; Factor IX; Factor VIII; Half-Life; Hemophilia A; Hemophilia B; Humans; Medication Adherence; Treatment Outcome
PubMed: 25754016
DOI: 10.1111/bjh.13360 -
The Journal of Biological Chemistry 2021Von Willebrand factor (VWF) is a plasma glycoprotein that circulates noncovalently bound to blood coagulation factor VIII (fVIII). VWF is a population of multimers...
Von Willebrand factor (VWF) is a plasma glycoprotein that circulates noncovalently bound to blood coagulation factor VIII (fVIII). VWF is a population of multimers composed of a variable number of ∼280 kDa monomers that is activated in shear flow to bind collagen and platelet glycoprotein Ibα. Electron microscopy, atomic force microscopy, small-angle neutron scattering, and theoretical studies have produced a model in which the conformation of VWF under static conditions is a compact, globular "ball-of-yarn," implying strong, attractive forces between monomers. We performed sedimentation velocity (SV) analytical ultracentrifugation measurements on unfractionated VWF/fVIII complexes. There was a 20% per mg/ml decrease in the weight-average sedimentation coefficient, s, in contrast to the ∼1% per mg/ml decrease observed for compact globular proteins. SV and dynamic light scattering measurements were performed on VWF/fVIII complexes fractionated by size-exclusion chromatography to obtain s values and z-average diffusion coefficients, D. Molecular weights estimated using these values in the Svedberg equation ranged from 1.7 to 4.1 MDa. Frictional ratios calculated from D and molecular weights ranged from 2.9 to 3.4, in contrast to values of 1.1-1.3 observed for globular proteins. The Mark-Houwink-Kuhn-Sakurada scaling relationships between s, D and molecular weight, [Formula: see text] and [Formula: see text] , yielded estimates of 0.51 and -0.49 for a and a, respectively, consistent with a random coil, in contrast to the a value of 0.65 observed for globular proteins. These results indicate that interactions between monomers are weak or nonexistent and that activation of VWF is intramonomeric.
Topics: Blood Platelets; Collagen; Drug Combinations; Factor VIII; Humans; Molecular Conformation; Molecular Weight; Plasma; Scattering, Small Angle; Ultracentrifugation; von Willebrand Factor
PubMed: 33600794
DOI: 10.1016/j.jbc.2021.100420 -
Blood Jun 2017In hemophilia A, the most severe complication of factor VIII (FVIII) replacement therapy involves the formation of FVIII neutralizing antibodies, also known as... (Review)
Review
In hemophilia A, the most severe complication of factor VIII (FVIII) replacement therapy involves the formation of FVIII neutralizing antibodies, also known as inhibitors, in 25% to 30% of patients. This adverse event is associated with a significant increase in morbidity and economic burden, thus highlighting the need to identify methods to limit FVIII immunogenicity. Inhibitor development is regulated by a complex balance of genetic factors, such as FVIII genotype, and environmental variables, such as coexistent inflammation. One of the hypothesized risk factors of inhibitor development is the source of the FVIII concentrate, which could be either recombinant or plasma derived. Differential immunogenicity of these concentrates has been documented in several recent epidemiologic studies, thus generating significant debate within the hemophilia treatment community. To date, these discussions have been unable to reach a consensus regarding how these outcomes might be integrated into enhancing clinical care. Moreover, the biological mechanistic explanations for the observed differences are poorly understood. In this article, we complement the existing epidemiologic investigations with an overview of the range of possible biochemical and immunologic mechanisms that may contribute to the different immune outcomes observed with plasma-derived and recombinant FVIII products.
Topics: Blood Coagulation Factor Inhibitors; Factor VIII; Hemophilia A; Humans; Plasma; Recombinant Proteins
PubMed: 28432221
DOI: 10.1182/blood-2016-11-750885 -
BMJ (Clinical Research Ed.) Aug 1995
Topics: Factor VIII; Hemophilia A; Humans; Recombinant Proteins
PubMed: 7647632
DOI: 10.1136/bmj.311.7003.465 -
Cellular Immunology Mar 2016Replacement therapy for patients with hemophilia A using plasma-derived or recombinant factor VIII (FVIII) is complicated by the short half-life of the FVIII products... (Review)
Review
Replacement therapy for patients with hemophilia A using plasma-derived or recombinant factor VIII (FVIII) is complicated by the short half-life of the FVIII products and by the occurrence of neutralizing antibodies in a substantial number of patients. In the recent years, enormous efforts have been invested to develop new generations of coagulation factors with extended half-lives. Presumably, the use of long-lasting FVIII products should reduce the frequency of administration to the patients and drastically improve their quality of life. The question of their immunogenicity remains however unanswered as yet. The present review proposes a summary of the different strategies developed to enhance the half-life of FVIII, including fusion of FVIII to the Fc fragment of the human IgG1 or to human serum albumin, or attachment of polyethylene glycol. Based on the available literature, we hypothesize on the potential benefits or risks associated with each of the latter strategies in terms of immunogenicity of the newly derived hemostatic drugs.
Topics: Factor VIII; Half-Life; Hemophilia A; Humans; Recombinant Fusion Proteins
PubMed: 26723503
DOI: 10.1016/j.cellimm.2015.12.006