Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:Q00604 (X-linked)
 16,883 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Haemophilia A (HA) and B (HB) are X-linked congenital disorders caused by deficiencies of Factor VIII and FIX. Being the world's most populous country, China potentially has a large population of haemophilia patients. During the last decade, no studies have been published regarding the clinical information of haemophilia in China. A retrospective study was conducted in patients with HA and HB referred to Tianjin Haemophilia Centre between 2002 and 2012. We identified 1,226 males with haemophilia (1,019 HA and 207 HB). The results revealed that activate partial thromboplastin time was negatively correlated plasma factor level of person with haemophilia. Our data did not offer sufficient evidence of any relationship existed between disease severity and risk or site of haemorrhage. There was a trend toward a higher inhibitor incidence induced by plasma-derived factor VIII products, than by recombinant FVIII (rFVIII) alone. It seemed that second generation of rFVIII more likely developed inhibitor, and first generation of rFVIII was nevertheless more closely connected to high-titer inhibitor. We found that delay in diagnosis and blood-borne infections were significantly reduced, while the joint deformity rate did not decrease despite the wide variety of products to choose from in this decade. The development of inhibitor still remains a major challenge in replacement therapy in haemophilia.
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PMID:Retrospective analysis of 1,226 Chinese patients with haemophilia in a single medical centre. 2419 52

Hemophilia A is a congenital, recessive, X-linked bleeding disorder that is managed with infusions of plasma-derived or recombinant factor (F) VIII. The primary considerations in FVIII replacement therapy today are the: 1) immunogenicity of FVIII concentrates, 2) role of longer-acting FVIII products, 3) prophylactic use of FVIII in children and adults with severe hemophilia A, and 4) affordability and availability of FVIII products. Improving patient outcomes by increasing the use of FVIII prophylaxis, preventing or eliminating FVIII inhibitors, and expanding access to FVIII concentrates in developing countries are the major challenges confronting clinicians who care for patients with hemophilia A.
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PMID:Factor VIII therapy for hemophilia A: current and future issues. 2471 90

Haemophilia is an X-linked inherited clotting disorder with a prevalence of 1 per 5000 men. A deficiency of clotting factor VIII (FVIII; haemophilia A) or IX (FIX; haemophilia B) causes haemophilia patients to suffer from spontaneous bleeding and excessive blood-loss following surgery or trauma. Prophylactic administration of a factor VIII- or factor IX-concentrate is the standard treatment for children with severe haemophilia. Women who are carriers of the F8 or F9 gene mutation can have a lowered plasma concentration of factor VIII or IX, and thus suffer from a mild form of haemophilia. Drugs that have a negative influence on blood clotting, such as NSAIDs, can lead to life-threatening bleeding in haemophilia patients. One of the main complications of haemophilia treatment is the formation of inhibiting antibodies that inactivate FVIII or FIX. Haemophilia patients should be treated by a multidisciplinary team in a hospital with a haemophilia treatment centre.
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PMID:[Haemophilia]. 2535 81

Hemophilia A is an X-linked disorder affecting 1 in 10,000 males. The disease is caused by a defect or mutation of factor 8 or 9. Human factor 8 gene (hFVIII) is a relatively large gene consisting of 26 exons and approximately 2,351 amino acids with a length of 9 Kb mRNA. Expression of hFVIII in mammalian milk is becoming a widespread strategy for high-level production of hFVIII because of the most complex post-translational modifications. The aim of this study was the cloning and expression of hFVIII in mammary glands of two transgenic mice. To obtain a recombinant plasmid, first a plasmid carrying an FVIII gene fragment (pCMV6-hFVIII) was digested by EcoRI-SalI restriction enzymes and then the fragment was purified from agarose gel and inserted into a pUCWAP7 vector carrying a tissue-specific promoter (mWAP 4.1 kbp). After that, it was isolated by agarose gel and transferred into the murine zygotes by standard microinjection methods. Methods for expression of recombinant FVIII RT-PCR and ELISA were studied. The results show the successful expression of factor FVIII gene and its product in the mouse mammary glands.
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PMID:Investigation of hFVIII production in mammary glands of transgenic mice. 2535

Hemophilia A is a hereditary disorder caused by various mutations in factor VIII gene resulting in either a severe deficit or total lack of the corresponding activity. Recent success in gene therapy of a related disease, hemophilia B, gives new hope that similar success can be achieved for hemophilia A as well. To develop a gene therapy strategy for the latter, a variety of model systems are needed to evaluate molecular engineering of the factor VIII gene, vector delivery efficacy and safety-related issues. Typically, a tissue culture cell line is the most convenient way to get a preliminary glimpse of the potential of a vector delivery strategy. It is then followed by extensive testing in hemophilia A mouse and dog models. Newly developed hemophilia A sheep may provide yet another tool for evaluation of factor VIII gene delivery vectors. Hemophilia models based on other species may also be developed since hemophiliac animals have been identified or generated in rat, pig, cattle and horse. Although a genetic nonhuman primate hemophilia A model has yet to be developed, the non-genetic hemophilia A model can also be used for special purposes when specific questions need to be addressed that cannot not be answered in other model systems. Hemophilia A is caused by a functional deficiency in the factor VIII gene. This X-linked, recessive bleeding disorder affects approximately 1 in 5000 males [1-3]. Clinically, it is characterized by frequent and spontaneous joint hemorrhages, easy bruising and prolonged bleeding time. The coagulation activity of FVIII dictates severity of the clinical symptoms. Approximately 50% of all cases are classified as severe with less than 1% of normal levels of factor VIII detected [4]. This deficiency may lead to spontaneous joint hemorrhages or life-threatening bleeding. In contrast, patients with 5-30% of normal factor VIII activity exhibit mild clinical manifestations.
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PMID:In vitro and In vivo Model Systems for Hemophilia A Gene Therapy. 2540 Oct 41

Hemophilia A is an X-linked bleeding disorder caused by widespread mutations in the factor VIII gene. In the course of a screening to research some hemophilia A mutations, our team has identified and posted a previously unreported nucleotide change in intron 10 in 20 patients with hemophilia A. We tried to identify a possible blood relationship between the people with this mutation, performing a backwards study of every family tree. First, we interviewed the patients and, if possible, parents and grandparents. When direct memory was no longer available, we consulted Registries of Births, Marriages and Deaths, and if these data were not sufficient, going backwards in time, we consulted registries of parish churches where newborns were baptized. The studied mutation was present in 33 hemophilic patients living in Calabria, 28 of them related. Three patients, carriers of this mutation, developed an FVIII inhibitor. In all the cases, the inhibitor development followed intensive treatments, after many days of exposure. Our study displayed the presence of a responsible moderate hemophilia A mutation, limited apparently to our country, probably because of a single ancestral event, and connected with FVIII inhibitor development.
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PMID:Prevalence of IVS10nt-18G/A in Calabrian patients with moderate/mild hemophilia A and relation with Factor VIII inhibitor antibodies. 2618 42

Current therapy for the X-linked coagulation disorder hemophilia is based on intravenous infusion of the specifically deficient coagulation factor. However, 20-30% of hemophilia A patients (factor VIII, FVIII, deficiency) generate inhibitory antibodies against FVIII. While formation of inhibitors directed against factor IX, FIX, resulting from hemophilia B treatment is comparatively rare, a serious complication that is often associated with additional immunotoxicities, e.g. anaphylaxis, occurs. Current immune tolerance protocols to eradiate inhibitors are lengthy, expensive, not effective in all patients, and there are no prophylactic tolerance regimens to prevent inhibitor formation. The outcomes of recent experiments in animal models of hemophilia demonstrate that regulatory CD4(+) T cells (Treg) are of paramount importance in controlling B cell responses to FVIII and FIX. This article reviews several novel strategies designed to in vivo induce coagulation factor-specific Treg cells and discusses the subsets of Treg that may promote immune tolerance in hemophilia. Among others, drug- and gene transfer-based protocols, lymphocyte transplant, and oral tolerance are reviewed.
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PMID:In vivo induction of regulatory T cells for immune tolerance in hemophilia. 2645 43

Severe hemophilia A is an X-linked bleeding disorder. Immune tolerance induction (ITI) is the best strategy of treatment when patients develop inhibitors. The objective is to illustrate the benefit of a high-purity human factor VIII/von Willebrand factor (VWF) concentrate (Octanate) in the management of ITI. We also wanted to raise the potential interest of laboratory assays such as thrombin-generation test (TGT) and epitope mapping. Two patients were treated during ITI, first with a recombinant FVIII and then with plasma-derived factor VIII without success, and, finally, with Octanate. Bypassing agents were used based on the results of TGT. Epitope mapping was performed during ITI therapy. These observations suggest the potential contribution of Octanate in the management of ITI in difficult cases. The use of bypassing agents can be necessary in prophylaxis or to treat bleedings, and may be guided by TGT results. Epitope mapping is used to describe the inhibitor. This article shows a decrease of the inhibitor directed against the C2 domain after initiation of Octanate. A high-purity human factor VIII/von Willebrand factor concentrate (Octanate) may be a valuable therapeutical option for ITI therapy. TGT and epitope mapping could be of help in the management of ITI.
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PMID:Challenges of the management of severe hemophilia A with inhibitors: two case reports emphasizing the potential interest of a high-purity human Factor VIII/von Willebrand factor concentrate and individually tailored prophylaxis guided by thrombin-generation test. 2651 64

Hemophilia A is an X-linked rescessive bleeding disorder that results from F8 gene aberrations. Previously, we established embryonic stem (ES) cells (tet-226aa/N6-Ainv18) that secrete human factor VIII (hFVIII) by introducing the human F8 gene in mouse Ainv18 ES cells. Here, we explored the potential of cell transplantation therapy for hemophilia A using the ES cells. Transplant tet-226aa/N6-Ainv18 ES cells were injected into the spleens of severe combined immunodeficiency (SCID) mice, carbon tetrachloride (CCl4)-pretreated wild-type mice, and CCl4-pretreated hemophilia A mice. F8 expression was induced by doxycycline in drinking water, and hFVIII-antigen production was assessed in all cell transplantation experiments. Injecting the ES cells into SCID mice resulted in an enhanced expression of the hFVIII antigen; however, teratoma generation was confirmed in the spleen. Transplantation of ES cells into wild-type mice after CCl4-induced liver injury facilitated survival and engraftment of transplanted cells without teratoma formation, resulting in hFVIII production in the plasma. Although CCl4 was lethal to most hemophilia A mice, therapeutic levels of FVIII activity, as well as the hFVIII antigen, were detected in surviving hemophilia A mice after cell transplantation. Immunolocalization results for hFVIII suggested that transplanted ES cells might be engrafted at the periportal area in the liver. Although the development of a safer induction method for liver regeneration is required, our results suggested the potential for developing an effective ES-cell transplantation therapeutic model for treating hemophilia A in the future.
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PMID:Therapeutic approaches for treating hemophilia A using embryonic stem cells. 2713 Dec 24

Hemophilia A, a deficiency in the activity of coagulation factor (F) VIII, is an X-linked bleeding disorder with an approximate incidence of one in 5,000 male infants. Bleeding-related complications often result in greater severity of disease, poor quality of life, surgical interventions for severe joint destruction, and shortened life span. With the availability of plasma-derived and recombinant FVIII products, the benefits of primary prophylaxis were demonstrated and is now the standard of care for patients with severe factor deficiencies. Current hemophilia research is focusing on the creation of new factor replacement therapies with longer half-lives; accessing alternative mechanisms to achieve desired hemostasis and enhance bypassing activity; and limiting the immunogenicity of the protein. PEGylation involves the covalent attachment of polyethylene glycol (PEG) to a protein, peptide, or a small molecule drug. PEG effectively increases the molecular weight and size of the protein by creating a hydrophilic cloud around the molecule. This molecular change may reduce susceptibility of the molecule to proteolytic activity and degradation. It is also believed that PEGylation changes the surface charge of the protein that ultimately interferes with some receptor-mediated clearance processes. The half-life of PEGylated factor is more prolonged when compared to non-PEGylated full-length recombinant FVIII. The dawn of a new era in the care of hemophilia patients is upon us with the release of recombinant FVIII products with extended half-lives, and products with even more extended half-life will become available in a very short time. With all the promise of these new agents, many questions still remain.
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PMID:Potential role of a new PEGylated recombinant factor VIII for hemophilia A. 2738 47


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