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 development of rapid procedures for the characterization of mutations is advancing the knowledge of the molecular biology of the haemophilias and transforming the strategies for the diagnoses required for genetic counselling. In haemophilia B more than 300 mutants have been fully characterized. These comprise complete and partial deletions, rare insertions, and 'point' mutations. The latter may impair transcription (promoter mutations), RNA processing (splicing mutations) and translation (frameshifts and stop codons) or cause single amino acid (aa) changes. Eighty-four residues are involved in the 105 presumed detrimental aa substitutions reported so far and these are usually conserved in the factor IX homologues (factors VII, X and protein C) and/or the factor IX of different mammalian species. There are clear correlations between the mutation and clinical features. In addition mutations causing gross physical or functional loss of coding information appear to predispose to the development of antibodies against therapeutic factor IX. Hotspots of mutations have been identified and are usually associated with CpG sequences. In haemophilia A the size and complexity of the factor VIII gene has hindered the analysis of mutants. Most of the studies published so far have analysed only a small fraction of the essential region of the factor VIII gene and this led to the repeated observation of specific types of mutation. The recent development of a rapid method to analyse RNA splicing and the whole coding region of the factor VIII gene should unblock this situation. With regard to genetic counselling, the direct detection of gene defects has increased the proportion of haemophilia B families that can be helped from 60% to virtually 100% and similar expectations may now be formulated for haemophilia A. In the UK a national database of haemophilia B mutations is being constructed to optimize genetic counselling. This should offer a model for a similar development in haemophilia A.
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PMID:Genetics and molecular biology of haemophilias A and B. 176 66

Hemophilia A is caused by a defect in coagulation factor VIII, a protein that undergoes extensive proteolysis during its activation and inactivation. To determine whether some cases of hemophilia are caused by mutations in important cleavage sites, we screened patient DNA samples for mutations in these sites by a two-step process. Regions of interest were amplified from genomic DNA by repeated rounds of primer-directed DNA synthesis. The amplified DNAs were then screened for mutations by discriminant hybridization using oligonucleotide probes. Two cleavage site mutations were found in a survey of 215 patients. A nonsense mutation in the activated protein C cleavage site at amino acid 336 was discovered in a patient with severe hemophilia. In another severely affected patient, a mis-sense mutation results in a substitution of cysteine for arginine in the thrombin activation site at amino acid 1689. This defect is associated with no detectable factor VIII activity, but with normal levels of factor VIII antigen. The severe hemophilia in this patient was sporadic; analysis of the mother suggested that the mutation originated in her gametes or during her embryogenesis. The results demonstrate that this approach can be used to identify factor VIII gene mutations in regions of the molecule known to be important for function.
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PMID:Mutations of factor VIII cleavage sites in hemophilia A. 313 81

Several recent studies have reported conflicting results on the effectiveness of danazol, an attenuated androgen, in raising plasma levels of clotting factors VIII and IX in patients with hemophilia. We undertook a randomized, double-blind cross-over trial using 8 weeks' administration of danazol (D), 600 mg/d, and 8 weeks' administration of placebo (P) separated by 2 weeks of rest in 12 patients with hemophilia A and four patients with hemophilia B. Plasma factor VIII and IX levels, frequency and type of bleeding episodes, amount of factor concentrate infused, fibrinogen, fibrinolysis assays, antithrombin III, liver function, and immune parameters were followed. During the danazol phase a minimal increase was noted in the average clotting factor levels, an increase that, although statistically significant, was of hemostatically marginal magnitude. Significant increases in protein C and plasminogen levels, however, were observed during the danazol period, suggestive of danazol-mediated enhanced fibrinolysis. Clinically, bleeding frequency was significantly increased, and more clotting factor was consumed during the danazol period. Furthermore, eight episodes of hematuria and oral mucosal bleeding was reported during the danazol phase in contrast to only one episode of hematuria during the placebo phase, consistent with an enhancement of fibrinolytic activity with danazol. We conclude that danazol does not have a hemostatically significant effect on plasma levels of factor VIII and IX but may be associated with enhancement of fibrinolytic activity, resulting in increased bleeding frequency and requiring more clotting factor infusions. Therefore, danazol is not a viable alternative in the treatment of hemophilia.
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PMID:Effect of danazol on clotting factor levels, bleeding incidence, factor infusion requirements, and immune parameters in hemophilia. 374 49

The role of Protein C in combined factor V/VIII deficiency was examined by reducing the Protein C concentration using warfarin therapy in a patient with the combined deficiency. The factor VIII deficiency was like Hemophilia-A, with deficiency of VIII:C and VIII:C(Ag), but normal VIIIR:Ag and VIIIR:cof. The factor V deficiency was due to loss of the V antigen. During warfarin therapy the Protein C level was reduced, but concentrations of factors V and VIII did not change. Protein C Inhibitor was normal throughout. Thus combined factor V/VIII deficiency is not related to Protein C levels.
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PMID:Response of protein C and protein C inhibitor to warfarin therapy in patient with combined deficiency of Factors V and VIII. 609 70

Factor VIII (antihemophilic factor) is the protein that is deficient or defective in patients with classical hemophilia and Von Willebrand syndrome. Factor VIII in plasma is thought to be associated in a complex with the highest molecular weight multimers of another glycoprotein, Von Willebrand protein. Highly purified human factor VIII appears to have an Mr of between 200,000 and 300,000 and to consist of several polypeptide chains. The concentration of factor VIII in plasma is around 100-200 ng/ml, equivalent to around 1 nM. The purified proteins retain one or more of the known properties of factor VIII, including the acceleration of factor IXa-mediated activation of factor X, ability to be activated by thrombin and factor Xa, inactivation by activated protein C, and by human antibodies to factor VIII. Among the known clotting factors, factors VIII and V are exceptional in not possessing enzymatic activity. Factors IXa and VIII and X appear to form a functional complex, all of which need to be present and active simultaneously for optimal activation of factor X. The mechanism by which factor VIII promotes activation of factor X by factor IXa is not known, but the major effect is to increase the rate of the reaction. Following treatment of factor VIII with thrombin, a new and smaller polypeptide Mr around 70,000 +/- 5,000 is produced. Factors IXa and Xa also have been reported to activate factor VIII. It is not known whether limited proteolytic cleavage is required absolutely for the expression of factor VIII activity or if it only increases an activity already expressed by the uncleaved protein. Factor VIII is inactivated by thrombin and by activated protein C. Thus, factor VIII can be modulated by at least four of the serine proteases in the clotting system. A major goal for future research is to increase our understanding of the role in blood clotting played by factor VIII, and to apply this information to clinical problems which result from inherited abnormalities of factor VIII.
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PMID:Factor VIII: structure and function in blood clotting. 642 37

Inhibition of activated human protein C was assessed in an amidolytic assay system using normal human plasma and samples from patients with hereditary coagulation abnormalities. In eight experiments normal plasma inhibited 63.5% (+/- 15.6%) protein C activity. Plasma from patients with haemophilia A or isolated factor V deficiency gave results which were not significantly different from normal. However, plasma from patients with combined factor V and factor VIII deficiencies inhibited an average of 24.5% (+/- 13.6%) of the amidolytic activity (P less than 0.01). Two of these plasma samples failed to inhibit any protein C activity. The relationship between the level of inhibitor and those of factor V and factor VII coagulant antigens (VCAg and VIIICAg) in the combined defect was investigated. There was no significant correlation between the level of inhibitor and any of the coagulation immunoassays on these stored samples but there was significant correlation between VCAg and VIIICAg in some assay systems. The levels of VCAg and VII CAg was low in most samples from patients with the combined defect which was in contrast to the results obtained when normal plasma was incubated with activated protein C in vitro. The findings are consistent with the presence of biochemical similarities between factors V and VIIIC molecules, but the role of activated protein C and its inhibitor in hereditary combined factor V/VIII deficiency remains to be firmly established.
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PMID:Quantitation of coagulant antigens and inhibition of activated protein C in combined factor V VIII deficiency. 681 16

The prevalence of inherited thrombophilia in the general population (1 in 2,500) is higher than that of hemophilia and related bleeding disorders. Well established causes of thrombophilia include deficiencies of natural coagulation inhibitors: antithrombin III, protein C and protein S. It is likely that other inherited disorders, such as deficiency of the second cofactor for activated protein C, deficiency of heparin cofactor II, hypo- and dysplasminogenemias, dysfibrinogenemias and homocysteinemia, may predispose to thrombosis. This review discusses clinical and laboratory aspects of these disorders and summarizes the management of individuals with inherited thrombophilia.
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PMID:[Inherited thrombophilia]. 799 73

Patients with hemophilia A and B and factor levels than 1 percent of normal bleed frequently with an average number of spontaneous bleeding episodes of 20-30 or more. However there are patients with equally low levels of factor VIII or factor IX who bleed once or twice per year or not at all. To examine whether the presence of a hereditary defect predisposing to hypercoagulability might play a role in ameliorating the hemorrhagic tendency in these so-called "mild severe" hemophiliacs, we determined the prevalence of prothrombotic defects in 17 patients with hemophilia A and four patients with hemophilia B selected from 295 and 76 individuals with these disorders, respectively, followed at a large Italian hemophilia center. We tested for the presence of the Factor V Leiden mutation by PCR-amplifying a fragment of the factor V gene which contains the mutation site and then digesting the product with the restriction enzyme MnlI. None of the patients with hemophilia A and only one patient with hemophilia B was heterozygous for Factor V Leiden. None of the 21 patients had hereditary deficiencies of antithrombin III, protein C, or protein S. Our results indicate that the milder bleeding diathesis that is occasionally seen among Italian hemophiliacs with factor levels that are less than 1 percent cannot be explained by the concomitant expression of a known prothrombotic defect.
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PMID:Low prevalence of the factor V Leiden mutation among "severe" hemophiliacs with a "milder" bleeding diathesis. 860 5

Several human genetic linkage maps have been constructed as part of the Human Genome Project. These maps show the positional order of closely linked, highly informative AC-repeat polymorphisms on each human chromosome, and are extremely useful in genetic linkage analysis of inheritable diseases. For a candidate gene approach the current linkage maps are less useful, since they consist mainly of anonymous markers rather than of specific genes. This situation also applies for inheritable disorders of blood coagulation. Numerous genes are involved in the blood coagulation cascade and its regulation, and can be considered as candidate genes for unexplained haemophilia and thrombophilia. We have selected 29 candidate genes that seem to be the ones most likely to be involved in thrombophilia. For 19 genes genotype data were already present in the CEPH database (version 7.0). We typed 7 additional genes in the CEPH reference families, i.e. the factor V, factor XII, protein C, protein S, prothrombin, thrombomodulin, and heparin cofactor II gene. The genotype data were used to integrate these 26 genes in the current genetic linkage map, and to identify closely linked AC-repeat polymorphisms. This information will benefit the investigation of inheritable disorders of blood coagulation, especially thrombophilia.
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PMID:Location on the human genetic linkage map of 26 genes involved in blood coagulation. 918 95

The classification of factor VIII deficiency, generally used based on plasma levels of factor VIII, consists of severe (<1% normal factor VIII activity), moderate (1% to 4% factor VIII activity), or mild (5% to 25% factor VIII activity). A recent communication described four individuals bearing identical factor VIII mutations. This resulted in a severe bleeding disorder in two patients who carried a normal factor V gene, whereas the two patients who did not display severe hemophilia were heterozygous for the factor V(LEIDEN) mutation, which leads to the substitution of Arg506 --> Gln mutation in the factor V molecule. Based on the factor VIII level measured using factor VIII-deficient plasma, these two patients were classified as mild/moderate hemophiliacs. We studied the condition of moderate to severe hemophilia A combined with the factor V(LEIDEN) mutation in vitro in a reconstituted model of the tissue factor pathway to thrombin. In the model, thrombin generation was initiated by relipidated tissue factor and factor VIIa in the presence of the coagulation factors X, IX, II, V, and VIII and the inhibitors tissue factor pathway inhibitor, antithrombin-III, and protein C. At 5 pmol/L initiating factor VIIa x tissue factor, a 10-fold higher peak level of thrombin formation (350 nmol/L), was observed in the system in the presence of plasma levels of factor VIII compared with reactions without factor VIII. Significant increase in thrombin formation was observed at factor VIII concentrations less than 42 pmol/L (approximately 6% of the normal factor VIII plasma concentration). In reactions without factor VIII, in which thrombin generation was downregulated by the addition of protein C and thrombomodulin, an increase of thrombin formation was observed with the factor V(LEIDEN) mutation. The level of increase in thrombin generation in the hemophilia A situation was found to be dependent on the factor V(LEIDEN) concentration. When the factor V(LEIDEN) concentration was varied from 50% to 150% of the normal plasma concentration, the increase in thrombin generation ranged from threefold to sevenfold. The data suggested that the analysis of the factor V genotype should be accompanied by a quantitative analysis of the plasma factor V(LEIDEN) level to understand the effect of factor V(LEIDEN) in hemophilia A patients. The presented data support the hypothesis that the factor V(LEIDEN) mutation can increase thrombin formation in severe hemophilia A.
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PMID:An in vitro analysis of the combination of hemophilia A and factor V(LEIDEN). 937 87


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