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)

The FVIII/FIX by-passing agent, rFVIIa, offers an alternative approach to the treatment of hemophilia patients as well as nonhemophiliacs with antibodies against FVIII/FIX. Such treatment can be administered regardless of the inhibitor titer in these patients, and rFVIIa is active hemostatically in hemophilia B patients also. It is easy to administer but seems to need repeated dosing at 2 to 3-hour intervals, at least initially, in patients with severe bleeding, with a dose of 70 to 100 micrograms/kg body weight required to induce hemostasis. Depending on the severity of the bleeding the dose intervals may be prolonged to every 3 hours for 1 to 2 days or until clinical improvement is observed. Thereafter, the dosage interval can be increased to every 4 hours if continued therapy is required.
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PMID:Recombinant activated factor VII in the treatment of bleeding episodes in patients with inherited and acquired bleeding disorders. 848 2

The assessment of carrier state based on the pedigree and laboratory testing in 55 females from 34 Thai hemophilia families (24 affected by hemophilia A, 10 by hemophilia B) was studied. The laboratory testing included phenotypic analysis (FVIII:C/vWF: Ag ratio, FIX:C) and two types of DNA polymorphisms, restriction fragment length polymorphisms (RFLP) and variable number tandem repeats (VNTR) in/and close to the factor VIII genes (Bcl I, Xba I RFLP, St 14 VNTR) and factor IX genes (Mse I, Dde I RFLP). Fifteen out of seventeen (88%) obligate hemophilia A carriers and one out of five (20%) obligate hemophilia B carriers were diagnosed by phenotypic analysis. All hemophilia A carriers were informative for at least one polymorphism (Bcl I, Xba I or St 14) while 42% of hemophilia B carriers were informative for Mse I RFLP only. DNA polymorphism analysis has advantage over phenotypic analysis since it generally gives an absolute diagnosis when informative. Most DNA polymorphism analyses are performed by PCR technique which is a simple, inexpensive and quick procedure. However, it is limited by non-informativeness and high incidence of new mutations.
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PMID:DNA polymorphisms for carrier detection of hemophilia in Thailand. 862 7

A retrospective study was conducted to evaluate the status of hemophilia care in Zimbabwe. Parirenyatwa Hospital in Harare has the only hemophilia clinic in Zimbabwe. This monthly clinic facilitates diagnosis, registration, and long-term management of hemophilia. In mid 1993, there were 190 registered hemophilia cases in Zimbabwe. During 1991-1993, only 70 patients were seen more than once in the clinic. The National Blood Transfusion Service (NTSB) supplies blood products for hemophiliacs. Solvent-detergent treated Factor VIII and IX (FVIII and FIX, respectively) concentrates are imported from South Africa. They are the most common blood products used in Harare. Laboratory staff screen fresh frozen plasma and cryoprecipitate for HIV antibody and hepatitis B surface antigen. Five NTSB branches also distribute blood products. Blood products are expensive. Most hemophiliacs are covered by a social welfare program. 45 hemophiliac cases had been receiving home care since 1987. 67% of 24 home care patients receiving FVIII did not store FVIII packs in a refrigerator. Most home care patients injected blood products 0-6 hours from onset of symptoms (e.g., nosebleed). About 33% did not know how to calculate the dose required. All home care patients were satisfied with treatment. In 1992, Parirenyatwa Hospital registered 3 deaths of hemophiliacs. When considering only the 70 regular clinic attenders, the mortality rate for 1992 was 5.7%. Of the 73 hemophiliac cases tested for HIV infection, 32% tested positive. All HIV-positive hemophiliac cases began treatment for hemophilia before 1986, the year before HIV testing of hemophiliacs started. So far, about 33% of hemophiliacs tested positive for hepatitis C. The only social support system for hemophiliacs is the Zimbabwe Hemophilia Association. None of the 38 hemophiliacs screened for coagulation factor inhibitors had any inhibitors. Hemophilia care in Zimbabwe has a good start and can be used as a model for other developing countries. Expansion and close supervision of the effective home treatment program is advised.
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PMID:Haemophilia care in Zimbabwe. 877 37

Recent studies using assays for surrogate markers of thrombogenicity in man have demonstrated that activation of the coagulation system occurs following infusion of clinical doses of prothrombin complex concentrates (PCC) but not after the same doses of high-purity factor IX concentrates (HP-FIX) in patients with haemophilia B. Here we have investigated the mechanism of such thrombogenesis by applying assays that detect early-through to late-events in coagulation system activation in a pharmacokinetic cross-over study of 50 IU/kg PCC and a new HP-FIX product in haemophilia B patients. Satisfactory recoveries and half-lives were observed for both concentrates. HP-FIX caused no increases in thrombin-antithrombin III complex (TAT), prothrombin activation peptide fragment F1+2 (F1+2), factor X activation peptide (FXAP) or factor VIIa (FVIIa). In contrast the same dose of factor IX in the form of PCC was followed by significant increases over pre-infusion levels of TAT, F1+2 and FXAP, but not FVIIa. Elevations of FIXAP occurred after both HP-FIX and PCC but did not reach normal levels and were attributed to normalisation of the FIX concentration in those patients whose levels of FIXAP were initially low. We conclude that the thrombogenic trigger associated with PCC infusion occurs at the level of factor X activation. In the absence of any increase in FVIIa, we would attribute this to the likely presence of FIXa in the PCC.
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PMID:High purity factor IX and prothrombin complex concentrate (PCC): pharmacokinetics and evidence that factor IXa is the thrombogenic trigger in PCC. 881 46

Hemophilia A (HemA), an X linked genetic disease, is the most common coagulation disorder with an incidence of about 1-2 in 10,000 males and is caused by mutations in the factor VIII (FVIII) coagulation gene. Firstly, some clinical aspects of the HemA are presented: the current methods to assess both the amount and activity of FVIII, the severity range observed and the presence of inhibitor antibodies against the therapeutic FVIII. Follows a discussion of the relationship of the structural domains of the FVIII protein (Figure 1), the aminoacid sequence and their functions. An activation-inactivation model of the successive peptide bonds cleavages of the FVIII is also presented (Figure 2). After the cloning of the FVIII gene in 1984, almost all types of HemA causing mutations have been characterized. However, the size and complexity of this gene prevented a screening of the full range of mutations for an accurate molecular diagnosis. Moreover, most of the patients with moderate and mild disease have missense mutations whereas approximately half of severe patients have nonsense, frameshift, and some missense mutations. There are also less frequently mutations such as deletions and insertions leading to severe phenotype and mutations affecting mRNA splicing and duplications causing both severe and mild HemA. In order to give genetic counselling in HemA families, studies at the DNA level using intragenic and/ or extragenic polymorphism analysis have been used. But this approach is not entirely satisfactory because it fails in several situations. Most of the causing mutations described above are private, and they have been found in only a few unrelated families. Recently, a common molecular inversion of the FVIII gene was identified in 50% of unrelated patients with severe HemA. The copies of a particular DNA sequence (termed F8A gene). One copy is located within intron 22 of the FVIII gene and the other two, 500 kb upstream. An homologous recombination mechanism was proposed for the inversion between an intragenic copy of the F8A gene and either the distal (80% of the inversion) or the proximal copy (20%). Both of these inversions lead to severe HemA because no intact FVIII is produced and can be easily diagnosed by Southern blot analysis. This inversion originates almost exclusively in male germ cells, because pairing Xq with its homologous in female meiosis would probably inhibit the proposed intrachromosome recombination. The molecular analysis of the inversion of intron 22 is now considered as the first line for families with severe HemA patients. In recent years the treatment of patients with hemophilia A and B has been intravenous injection of FVIII or FIX concentrates, respectively. This regimen of regular injection of plasmatic proteins bears a high risk of infection by contaminating viruses (HIV, HBV, etc). Future treatment for patients with hemophilia may include the use of either gene therapy or recombinant coagulation factors. Both strategies would completely avoid the infection risk offering a safe and effective treatment for the disease. Recombinant factors, obtained by genetic engineering methods, provide a renewable and unlimited source of FVIII or FIX. The clinical trials of recombinant factors have already started in mid-1995 giving positive results. On the other hand, gene therapy for hemophilia is now in the pre-clinical stage but offers the prospect of a cure for the disease, thus potentially freeing patients from regular injections of the lacking protein. However, experiments in animal models suggest that it may be difficult to obtain adequate therapeutic levels of factors for long periods of time. Recently, a retroviral-mediated gene delivery of human FVIII in mice has been reported using the ex vivo strategy of gene therapy. Therapeutic levels of FVIII in the circulation were obtained for > 1 week and it was also observed that the capacity of primary cells to deliver FVIII in blood was strongly dependent on
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PMID:[Molecular genetics of hemophilia A]. 923 87

Defects in the genes encoding the human coagulation factor VIII (hFVIII) and IX (hFIX) result in life-threatening haemorrhages and severe arthropathies. While haemophiliacs are currently treated by blood-derived factors or recombinant hFVIII and hFIX, a number of recent technical advances make the prospect of using gene therapy to treat such genetic diseases a realistic goal. Several gene therapy strategies have therefore been developed and evaluated in recent years. Most of the initial protocols were ex vivo gene transfer approaches in which the target cells (fibroblasts, keratinocytes, myoblasts, ...) were expanded and genetically-engineered in the laboratory and then implanted in the host. However, the complexity of most ex vivo gene therapy strategies, together with the disappointing results obtained in various animal models stimulated the development of more direct in vivo gene therapy protocols. In aiming to establish such an in vivo gene transfer protocol for haemophilia B, we constructed and tested in vitro and in vivo various recombinant adenovirus vectors expressing human FIX. Intravenous administration of this vector into various strains of immunocompetent and immunodeficient mice led to an efficient hFIX gene transfer in liver and lung. As a consequence, the hFIX protein was correctly produced and secreted at high levels in the blood of the treated animals. However, expression was transient in all immunocompetent mice, except surprisingly in C57B1/6 animals. A systematic molecular and immunological analysis allowed us to identify the parameters that prevent the long-term in vivo expression of the human molecule and to improve the current adenovirus vectors.
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PMID:[Genetic therapy for hemophiliacs--therapeutic potential and technological limits]. 926 82

The development of anti-factor VIII/IX antibodies (inhibitor-induction) and the transmission of viral infections are the most significant complications of haemophilia treatment. The Humafactor-8 and Humafactor-9 are high-purity pasteurized factor VIII and IX concentrates, which are produced from pooled plasma of Hungarian donors by ion-exchange chromatography. The clinical study has been accomplished in two steps: first we have demonstrated the biological efficacy of the concentrates in a phase IV trial. After that we followed 13 patients with severe haemophilia for 6 months in respect of virus-safety and inhibitor-induction. According to our results the recently developed domestic FVIII/FIX concentrates display appropriate biological activities and they are safe as blood-borne virus-transmission and immunogenicity are concerned.
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PMID:[Clinical evaluation of factors VIII and IX manufactured in Hungary, based on results of the first half year]. 957 3

A novel missense mutation (codon 351, GCT (Ala) --> CCT (Pro)) of the FIX gene was characterised in a young female with mild hemophilia B. She is heterozygous for the FIX mutation inherited from her carrier mother. Analysis of the methyl-sensitive Hpa II sites at the 5' end of the hypoxanthine phosphoribosyltransferase gene showed that skewed inactivation of the X chromosome carrying her normal FIX gene accounted for the hemophilia phenotype.
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PMID:Hemophilia B in a female carrier due to skewed inactivation of the normal X-chromosome. 959 Jan 53

Haemophilia patients developing an inhibitor against factor VIII (FVIII) or FIX require alternative treatment for the management of their bleeding, rather than standard procedures. In patients with low titre inhibitors, increased doses of FVIII or FIX may improve haemostasis. If a higher titre is present, a porcine FVIII concentrate may be efficacious in selected cases. 'Bypassing' agents, such as low purity FIX concentrates, or activated or unactivated concentrates of prothrombin complex may also be useful in inhibitor patients. An activated factor VII molecule (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark), has been produced by recombinant DNA cell technology. In June 1994, we established a home treatment programme with rFVIIa for five inhibitor patients to study its efficacy in the early intervention of bleeding episodes; our results from the first 3 years are presented. Self-treatment in the home took place in 50 instances of acute minor bleeding. A mean of 2.02 doses of rFVIIa (each dose of about 90 microg/kg bodyweight) was required to arrest bleeding (range 1-4 doses). Four bleeding episodes required in-hospital management either because the acute condition was caused by severe trauma, or because treatment had not been instituted in the early phase of bleeding. Here, the range of rFVIIa doses was 4-37. For comparison, we also report 36 minor bleeding episodes managed in-hospital in three of these five patients who participated in the Compassionate Use Study where home treatment was not permitted. These bleeding episodes required considerably more administrations of rFVIIa with a mean consumption of 8 doses in joint bleeds and 9.5 doses in muscle and soft tissue bleeds. In conclusion, we feel that our home treatment results strongly suggest that early intervention by home treatment with rFVIIa in acute minor bleeding is efficacious and cost effective.
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PMID:Home treatment with recombinant activated factor VII: results from one centre. 981 39

We designed a prospective unicentre study to evaluate the safety and efficacy of continuous infusion of different factor VIII (FVIII) and FIX concentrates in haemophilia A (n = 9) and haemophilia B (n = 4) patients undergoing surgical procedures. This study was designed to assess the potential risk of developing thromboembolic complications during different types of surgery and to provide some comparative data with respect to continuous infusion of clotting factor concentrates. Heparin prophylaxis was not used in most cases. As pointed out by others, we did not find any significant changes in prothrombin fragment F1+2 and D-dimers during a pharmacokinetic study using a bolus dose of 50 U/kg of a very high purity clotting factor concentrate. Moreover, prothrombin F1+2 and D-dimer serial assays were also carried out postoperatively, and compared with levels in control non-haemophilic patients who had undergone similar surgery with heparin prophylaxis. In haemophilia patients, despite (in most cases) an absence of heparin prophylaxis, no thrombotic complications occurred, and neither the coagulation cascade nor the fibrinolytic system were significantly over-activated, compared with the control group. From a clinical standpoint, all patients achieved excellent haemostasis without clinical evidence of thrombosis. This study emphasizes the convenient and safe administration of highly-purified FVIII and FIX concentrates in haemophiliacs undergoing surgical procedures, and constitutes a small comparative database for the evaluation of new products.
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PMID:Evaluation of coagulation equilibrium at baseline and during factor VIII and factor IX replacement in haemophiliacs. 981 45


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