Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684275 (haemophilia)
 10,958 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Haemophilia B is an X-linked recessively inherited bleeding disorder caused by heterogeneous mutations spanning the entire factor IX gene. As spontaneous germ-line mutations are known to occur mostly at CpG dinucleotides in the FIX gene, control of the disease would require continuous carrier detection and mutation screening. Identification of point mutations, the most common type of mutation in FIX gene, is more challenging compared with deletion and insertion mutations. We examined the haemophilia B database to identify specific nucleotides in the FIX gene that are mutated in relatively large number of patients and the variability (if any) in the mutational hotspots at CpG dinucleotides. It was found that while mutations responsible to account for all 2348 haemophilia B patients covered 20% of the FIX cDNA, only 1% of the cDNA involving mostly CpG dinucleotides accounted for mutation in 42.41% of the patient pool. Thus, only 27 nucleotides need to be investigated to identify the common point mutations, among which 15 are predicted to undergo change in restriction sites on mutation. It is interesting to note that seven nucleotides occurring in CpG dinucleotides do not have any reported mutation despite each of those being predicted to harbour mutation as a result of transition and having mutations recorded in the database for the neighbouring nucleotides. Strikingly large number of mutation in codon 296 causing T to M change in catalytic domain originally proposed to be the result of the founder effect also contains largest number of haplotype suggesting recurrence of de novo mutation.
Haemophilia 2003 Mar
PMID:Analysis of haemophilia B database and strategies for identification of common point mutations in the factor IX gene. 1261 70

The development of inhibitory antibodies to factor (F) VIII and FIX continues to be a major challenge in the treatment of patients with hemophilia. In patients with low-responding inhibitors, it is usually possible to saturate the inhibitor with the deficient factor and to achieve hemostasis, but in patients with high-responding inhibitors, two major tasks have to be considered. One is how to treat the acute bleedings and the other is how to permanently eliminate the immune response, in other words, to induce tolerance. There are several hemostatic agents available for bleeding patients with high-responding inhibitors. Nonactivated and activated prothrombin complex concentrates (PCCs) have been used for almost 30 years, and since the beginning of the 1980s, porcine FVIII has also been used. In more recent years, recombinant FVIIa has been added to the therapeutic armamentarium and has been shown to control hemostasis in most patients. Immunoadsorption may temporarily reduce the inhibitor, enabling replacement therapy for several days. Available data on these alternative regimens will be discussed with a focus on the mechanisms of action, pharmacokinetics, safety, monitoring, and clinical experience.
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PMID:Treatment of the bleeding inhibitor patient. 1264 May 69

Gene therapy is a novel area of therapeutics in which the active agent is a nucleic acid sequence rather than a protein or small molecule. Successful clinical applications of gene transfer have been limited to date because of shortcomings in the available gene delivery vehicles. The goal of gene transfer for hemophilia is to achieve sustained expression of factor (F) VIII or FIX at levels high enough to improve the symptoms of the disease. Hemophilia has proved to be an attractive model for those interested in gene transfer, and multiple gene transfer strategies are currently being investigated. So far, five different trials, three for hemophilia A and two for hemophilia B, have enrolled approximately 40 patients with severe hemophilia. This article summarizes the gene transfer strategies being investigated, the available preclinical data, and the early clinical results. In the past year, several groups have demonstrated sustained expression of clotting factors at levels of 5 to 10% of normal in large animal models of hemophilia. The goal of the ongoing clinical studies is to determine whether these results can safely be extended to humans.
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PMID:Gene transfer as an approach to treating hemophilia. 1264 May 73

The classical model of the coagulation cascade is to be replaced by a new, cell based model of coagulation emphasizing the interaction of coagulation proteins with cell surfaces of platelets subendothelial cells and the endothelium. According to current knowledge hemostasis is initiated by the formation of a complex between tissue factor (TF) exposed as a result of a vessel wall injury, and already activated factor (F) VII (FVIIa) normally present in the circulating blood. The TF-FVIIa complexes convert FX into FXa on the TF bearing cell. FXa then activates prothrombin (FII) into thrombin (FIIa). This limited amount of thrombin activates FVIII, FV, FXI and platelets. Thrombin-activated platelets change shape and as a result will expose negatively charged phospholipids, which form the perfect template for full thrombin generation involving FVIIIa and FIXa. Thrombin also converts fibrinogen into fibrin, it activates the fibrin stabilizing FXIII, as well as the thrombin activatable fibrinolysis inhibitor (TAFI). The fibrin structure has been found to be dependent on the amount of thrombin formed and the rate of thrombin generation. Full thrombin generation is necessary for the formation of a tight, stable fibrin hemostatic plug resistant to premature fibrinolysis which is required for full and sustained hemostasis. Since thrombin has such a crucial role in providing hemostasis, any agent that enhances thrombin generation in situations with impaired thrombin formation may be characterized as a 'general hemostatic agent' - a term that has been applied to recombinant activated FVII. Recombinant coagulation factor VIIa (rFVIIa; NovoSeven(R)) was originally developed and approved for the treatment of bleeding episodes and the prevention of bleeding during surgery in hemophilia patients with inhibitors and in patients with auto-antibodies against FVIII or FIX (acquired hemophilia). As rFVIIa in pharmacological doses enhances thrombin generation on activated platelets, it has been suggested that rFVIIa may also help to improve hemostasis in other situations involving impaired thrombin generation. This is substantiated by the accumulation of published data indicating that rFVIIa is able to control bleeding in patients with thrombocytopenia or platelet function deficiencies as well as in patients without pre-existing coagulopathies.
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PMID:New insights into the coagulation system and implications for new therapeutic options with recombinant factor VIIa. 1267 84

The aim of this retrospective review was to assess the overall effectiveness of prophylaxis when compared with on-demand treatment of haemophilic patients. Twenty-five children (22 with severe haemophilia A and three with severe haemophilia B) were evaluated. Five haemophilia A patients received primary prophylaxis (instituted before the onset of any joint bleed) while the other 17 haemophilia A and all three haemophilia B patients were on secondary prophylaxis. We compared factor usage, number of bleeding episodes, emergency room (ER) visits and hospitalizations while on prophylaxis to those while on demand therapy. All subjects were male, the median age at time of review was 11.4 years and at start of prophylaxis was 4.5 years. Thirteen of the 25 patients (52%) required indwelling venous catheters for access, seven of these had one or more (one-six) episodes of line sepsis. Haemophilia A patients received an average of 23.8 U kg(-1) (20-30 U kg(-1)) of recombinant factor VIII three times a week while haemophilia B patients received 50 U kg(-1) recombinant FIX twice weekly. There was a significant reduction in the mean number of major bleeds on prophylaxis from 15.5 to 1.9 per year and a significant decrease in target joints, ER visits and hospitalizations. Although factor usage per year was higher on prophylaxis, there was an overall reduction in number of bleeds and resultant decrease in hospitalizations and ER visits. By preventing new target joints, prophylaxis can lead to reduction in long-term morbidity and a better quality of life despite increased central lines and higher factor usage.
Haemophilia 2003 May
PMID:The overall effectiveness of prophylaxis in severe haemophilia. 1269 17

Severe factor IX deficiency is an X-linked disorder which gives rise to spontaneous and often life-threatening bleeds. The major source of morbidity worldwide is recurrent haemarthroses, giving rise to joint destruction and deformity. However, the incidence of spontaneous haemarthroses has decreased since the advent of prophylactic home-based, on-demand, early replacement therapy. We present the case of a non-ambulant, 13-year-old boy from Chernobyl, who did not have access to this type of treatment, and whose deformity was managed using the Ilizarov external fixator. An external fixator was applied under general anaesthetic in theatre. Haemostasis was achieved by maintaining his FIX levels at 1.0 IU mL(-1) pre- and post-operatively. Three months later, the fixed flexion deformity had been reduced from 50 to 5 degrees. Four months postsurgery, this boy was walking freely without pain. There was no peri- or post-operative bleeding or joint swelling.
Haemophilia 2003 May
PMID:The treatment of flexion contracture of the knee using the Ilizarov technique in a child with haemophilia B. 1269 27

We describe successful induction of immune tolerance (IT) in a 10-month-old boy with severe haemophilia B. Urticaria developed soon after starting prophylactic treatment and was associated with an inhibitor at 7 Bethesda units mL(-1). Initially, we tried low dose factor IX therapy to induce IT with only a transient effect. The patient experienced an intracranial haemorrhage. A simple bolus dose of FIX eradicated the inhibitor. Thereafter he has been free from inhibitor and nephrotic syndrome for more than 5 years, although he receives FIX three times a week.
Haemophilia 2003 May
PMID:Successful induction of immune tolerance in a patient with haemophilia B with inhibitor. 1269 28

Some of the major issues related to the development and control of antibodies that occur during treatment of haemophilia with replacement factors (Factor VIII and Factor IX) are reviewed. Information on analytical issues, immunogenicity, and immune tolerance may be applicable to the study of other therapeutic proteins. Conversely, new information obtained from evaluation of other therapeutic protein products may address issues that remain unresolved for Factor VIII and FIX replacement therapy.
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PMID:Immunogenicity and immune tolerance coagulation Factors VIII and IX. 1276 4

Many approaches for treating hemophilia via gene transfer have been attempted in large animal models but all have potential drawbacks. Recombinant adenoviral vectors offer high-efficiency transfer of an episomal vector but have been plagued by the cytotoxicity/immunogenicity of early-generation vectors that contain viral genes. In our current study, we have used a nonintegrating helper-dependent (HD) adenoviral vector for liver-directed gene transfer to achieve hemostatic correction in a dog with hemophilia B. We measured plasma canine factor IX (cFIX) concentrations at a therapeutic range for up to 2.5 months and normalization of the whole blood clotting time (WBCT) for about a month. This was followed by a decrease and stabilized partial correction for 4.5 months. Hepatic gene transfer of a slightly lower dose of the HD vector resulted in WBCTs that were close to normal for 2 weeks, suggesting a dose threshold effect in dogs. In sharp contrast to other studies using first- or second-generation adenoviral vectors, we observed no vector-related elevation of liver enzymes, no fall in platelet counts, and normal liver histology. Taken together, this study demonstrates that injection of an adenoviral HD vector results in complete but transient phenotypic correction of FIX deficiency in canine models with no detectable toxicity.
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PMID:A gene-deleted adenoviral vector results in phenotypic correction of canine hemophilia B without liver toxicity or thrombocytopenia. 1280 62

Significant progress has recently been made in the development of gene therapy for the treatment of hemophilia A and B. These advances parallel the development of improved gene delivery systems. Long-term therapeutic levels of factor (F) VIII and FIX can be achieved in adult FVIII- and FIX-deficient mice and in adult hemophiliac dogs using adeno-associated viral (AAV) vectors, high-capacity adenoviral vectors (HC-Ad) and lentiviral vectors. In mouse models, some of the highest FVIII or FIX expression levels were achieved using HC-Ad vectors with no or only limited adverse effects. Encouraging preclinical data have been obtained using AAV vectors, yielding long-term FIX levels above 10% in primates and in hemophilia B dogs, which prevented spontaneous bleeding. Non-viral ex vivo gene therapy approaches have also led to long-term therapeutic levels of coagulation factors in animal models. Nevertheless, the induction of neutralizing antibodies (inhibitors) to FVIII or FIX sometimes precludes stable phenotypic correction following gene therapy. The risk of inhibitor formation varies depending on the type of vector, vector serotype, vector dose, expression levels and promoter used, route of administration, transduced cell type and the underlying mutation in the hemophilia model. Some studies suggest that continuous expression of clotting factors may induce immune tolerance, particularly when expressed by the liver. Several gene therapy phase I clinical trials have been initiated in patients suffering from severe hemophilia A or B. Some subjects report fewer bleeding episodes and occasionally have low levels of clotting factor activity detected. Further improvement of the various gene delivery systems is warranted to bring a permanent cure for hemophilia one step closer to reality.
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PMID:Gene therapy for the hemophilias. 1287 Dec 90


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