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)

Fifteen previously untreated patients (Pups) with severe haemophilia B (factor IX activity < or = 2 U/dl) only treated with one brand of plasma-derived high purity factor IX concentrate (FIX LFB) were studied. Age at first injection varied from 1 to 137 months and follow-up since this first injection from 21 to 86 months (median: 35). Cumulative exposure days (CED) were from 4 to over 100 (median: 26). Among these 15 Pups only one developed an inhibitor. Mutation analysis performed in all patients showed total gene deletion in the patient with inhibitor, partial gene deletion in another one, and missense mutations in 9 families. Mutation was not found in one patient. Actually, according to the data already published, only two patients were at high risk for inhibitor development in our population. Our study, although rather small, confirms the previously reported low incidence of inhibitors in haemophilia B. Large studies on incidence of FIX inhibitors are indeed difficult to perform, due to both the overall small number of severe haemophilia B patients and the low incidence of FIX inhibitors. Consequently, the impact of bias, such as prevalence of different types of gene defects in a given population, is major. Therefore, any study, dealing with incidence of FIX inhibitors in severe haemophilia B should report, for each patient, the type of gene defect.
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PMID:Incidence of factor IX inhibitor development in severe haemophilia B patients treated with only one brand of high purity plasma derived factor IX concentrate. 1054 7

During the past few years great efforts have been made to construct and to test human factor VIII (hFVIII) and IX (hFIX) vectors suitable for haemophilia gene therapy in vivo. However, little is known about the molecular mechanisms of persistence and shut-off of transgene expression in the target organs after gene transfer using recombinant adenoviral vectors. To evaluate low transgene mRNA levels in different tissues, especially at long times after the gene transfer, the common northern blot method is often not sensitive enough. For this reason we developed a new, highly sensitive and species-specific method for hFIX mRNA quantification and employed it in mice treated with an adenoviral vector (Ad5CMVFIX) expressing human FIX. In addition to its very high sensitivity (lowest detection level=1 fg RNA), the method was shown to be strictly species-specific, since hFIX mRNA signals were never detected in untreated mice. In a long-term study of 18 vector-treated mice we compared the human FIX:Ag levels in the mouse plasma, the human FIX mRNA levels and human FIX vector DNA concentrations in the mouse liver. We found that a slow but continuous decrease of hFIX:Ag levels in mouse plasma was associated with a corresponding decrease of hFIX mRNA levels in the liver. However, the Ad5CMVFIX vector DNA levels did not decrease to a comparable degree, suggesting that the decrease of human FIX:Ag levels in mouse plasma is, to a significant extent, also caused by CMV promotor shut-off and only to a minor degree by loss of vector DNA.
Haemophilia 1999 Sep
PMID:Highly sensitive and species-specific assay for quantification of human transgene expression levels. 1058 15

A method using multiplex PCR followed by cycle-sequencing has been developed to detect mutations in the FIX gene. The procedure was evaluated in 45 severe or mild haemophilia B patients from 45 unrelated families. At least one deleterious mutation was identified in every haemophiliac demonstrating the efficiency of the method. Furthermore the described procedure offers many advantages compared to other screening detection methods: it is fast (less than 48 h), simple (partly automated) and of relatively low cost (it requires only one PCR).
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PMID:Fast and efficient mutation detection method using multiplex PCR and cycle sequencing--application to haemophilia B. 1073 81

Recombinant factor VIIa (rFVIIa) has recently been introduced as a new 'bypassing' agent to improve haemostasis in haemophilia patients with inhibitors to factor (F) VIII or FIX. In noninhibitor patients, levels of circulating FVIII or FIX can be used to assess the quality of substitution therapy. In contrast, laboratory monitoring of haemostatic efficacy in patients treated with rFVIIa has proved more complex. Evaluation of patient samples saved during rFVIIa treatment have revealed some correlation between FVII:C levels and improved haemostasis, while whole blood elasticity, as determined by thromboelastography, has been shown to improve following rFVIIa treatment. The investigation aimed to study the efficacy of rFVIIa in activating FX:C and in shortening the whole blood clotting time (WBCT) using the newly-developed roTEG coagulation instrument. Results indicated a substantial and apparently dose-dependent activation of FX:C by rFVIIa. In addition, the presence of FIX appeared to influence FX:C activation. In-vitro and ex-vivo roTEG thromboelastograph measurements showed that FVIIa shortened WBCT, although normalization did not occur. The results presented here are based on a small number of observations in a few patients and further studies should be planned to test the efficacy of these monitoring principles in clinical treatment practice with rFVIIa.
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PMID:Management and monitoring of recombinant activated factor VII. 1085 May 60

Initiation of haemostasis involves the formation of a complex between tissue factor (TF) and activated factor VII (FVIIa) following injury. TF is found in the deeper layers of the vessel wall, in atherosclerotic plaques and in some types of tumour cell and is only exposed to circulating blood after tissue damage. Likewise, FVII is only enzymatically active when complexed with TF (TF/FVIIa). It has recently been shown that the administration of recombinant activated FVII (rFVIIa) in high doses (approximately 100 microg/kg) can induce haemostasis in the absence of FVIII and FIX. In addition, from in-vitro studies it appears that rFVIIa can bind with low affinity to the activated platelet surface and, independently of TF, induce the thrombin burst needed for haemostasis. The ability of rFVIIa to compensate for FVIII/FIX deficiency has been proven clinically in haemophilia patients with life- and limb-threatening bleeds. In addition, patients with congenital FVII deficiency have been successfully treated for bleeds with rFVIIa. Recombinant FVIIa has been used in patients with platelet disorders; five patients with Glanzmann's thrombasthenia and one with Bernard-Soulier's thrombasthenia have had bleeding episodes managed effectively. Recombinant FVIIa has also been shown to normalize prothrombin time in patients with liver disease and in warfarin-treated individuals.
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PMID:NovoSeven as a universal haemostatic agent. 1085 May 74

The active site of activated Factor IX (FIXa) and related blood-coagulation enzymes is surrounded by a number of highly variable surface loops, which contribute to the characteristic substrate specificity of each individual enzyme. FIX residue Lys(316) is located in one of these loops and mutation of this residue to Glu is associated with haemophilia B. In the present study we investigated the functional role of Lys(316) in human FIXa by analysing the purified and activated FIX mutants FIXa-K316E and FIXa-K316A. FIXa-K316E was indistinguishable from normal FIXa in binding the competitive active-site inhibitor p-aminobenzamidine. In addition, substitution of Glu for Lys(316) had no significant effect on the reactivity towards various synthetic tripeptide substrates. Inhibition by the macromolecular inhibitor antithrombin was only slightly reduced for both FIXa mutants (less than 2-fold). In contrast, proteolytic activity of FIXa-K316E towards the natural substrate Factor X (FX) was virtually lacking, while the Lys(316) to Ala mutation resulted in a more than 10-fold reduction in FX activation. Thus residue Lys(316) plays a key role in FIXa activity towards FX. The requirement for Lys at position 316 for FX activation was also evident in the presence of the cofactor activated Factor VIII, although to a lesser extent than in its absence. These data demonstrate that Lys(316) specifically determines the reactivity of FIXa towards its natural substrate FX, but not to synthetic peptide substrates or antithrombin.
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PMID:Surface-loop residue Lys316 in blood coagulation Factor IX is a major determinant for Factor X but not antithrombin recognition. 1097 Jul 82

The North American Immune Tolerance Registry (NAITR) was initiated with the goal of determining, by questionnaire, immune tolerance (ITT) practices in hemophilia treatment centers in Canada and the United States. Sixty-eight centers (40%) responded. Of the 130 registry subjects with hemophilia A who completed ITT, 93 (72%) achieved tolerance. Of the 11 completed ITT courses in patients with hemophilia B, 4 (36%) were successful. Maintenance therapy was defined as any dotting factor regimen administered subsequent to the patient achieving the treating physician's criteria for successful immune tolerance. Seventy-five (81%) of 93 individuals in the hemophilia A cohort who successfully achieved tolerance were maintained on a regular (prophylactic factor VIII (FVIII) regimen for a variable time period post-ITT. The median dose used was 150 units/kg/week (range: 17-700). Forty-eight (64%) subjects remained tolerant while receiving regular doses of FVIII for a median observation period of 13 months (range 0-129 months). Of 27 patients whose maintenance therapy had been stopped, 17 (68%) remained tolerant over a median period of 19 months (range 1-54 months) and 9 relapsed. Among the relapses, 3 occurred after maintenance therapy was stopped; 6 were noted on prophylactic FVIII at a median time of 11 months (range 2-61 months). The definition of tolerance was reviewed for the 9 subjects who relapsed and was defined by a normal recovery and survival in only 1/9 patients. Among the 11 hemophilia B subjects in the cohort who completed tolerance, 4 had a successful outcome. Four individuals were placed on maintenance regimens of 25-100 units FIX/kg/day and all remained tolerant.
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PMID:The maintenance of tolerance after successful immune tolerance induction in hemophilia A and B: the North American Registry. Factor VIII/IX Subcommittee of the International Society for Thrombosis and Hemostasis. 1118 69

The aims of this study were to investigate possible age-related changes in the disposition of factor IX procoagulant activity (FIX:C) after administration of recombinant factor IX (rFIX) and to translate the pharmacokinetic findings into suggestions for dosing of rFIX during prophylactic treatment of haemophilia B. Pharmacokinetic data were available from a previous study on 56 patients, aged 4-56 years (one of whom was excluded from analysis). FIX:C curves during prophylactic dosing were computer-simulated from the single-dose data. Clearance and volume of distribution at steady state of FIX:C increased linearly with body weight of the patients, consequently increasing during childhood and adolescence but remaining fairly constant during adulthood. The terminal half-life of FIX:C showed no correlation with age, while in vivo recovery (in U dL(-1) per U kg(-1) given) tended to increase. Computer-predicted trough levels of exogenous FIX:C during repeated doses of rFIX (50 U kg(-1)) and, conversely, doses (in U kg(-1)) needed to maintain a 1-U dL(-1) trough level showed little or no dependence on age. There was considerable interindividual variation in disposition and required doses of rFIX, emphasizing the need for individual dose titration. Dosing of rFIX according to lean body mass instead of body weight did not reduce this variability. During prophylaxis a 1-U dL(-1) trough level can normally be maintained by dosing every 2-3 days, the former schedule resulting in, on average, a 45% lower consumption of rFIX.
Haemophilia 2001 Mar
PMID:Pharmacokinetics of recombinant factor IX in relation to age of the patient: implications for dosing in prophylaxis. 1126 Feb 71

The safety and efficacy of adjusted continuous infusion (CI) of recombinant factor IX (FIX; BeneFix) was assessed in vitro and in a clinical study. BeneFix was reconstituted at 100 IU mL-1 with or without unfractionated heparin (4 U mL-1) and stored at either 4 degrees C or room temperature. Reconstituted BeneFix retained at least 90% activity over 14 days if stored at 4 degrees C but stability was reduced at room temperature. BeneFix reconstituted in a sterile pharmacy was free of bacterial contamination. Six patients with haemophilia B received seven CIs of BeneFix to cover routine surgery and severe bleeding episodes. The CIs lasted between 3 and 10 days. In all cases, haemostasis was excellent and the desired therapeutic FIX level was easily maintained. No thrombotic episodes or inhibitor development occurred but two patients developed thrombophlebitis at the infusion site when heparin was not added to the infusion. BeneFix is not currently licensed for CI and we suggest that studies to enable licensing should be established as soon as possible.
Haemophilia 2001 Mar
PMID:Recombinant factor IX (BeneFix) by adjusted continuous infusion: a study of stability, sterility and clinical experience. 1126 Feb 72

Inherited hemophilia dog and other transient hemophilic animal models have been used for evaluation of hemostatic agents for use in treatment of hemophilia. We established the first nonhuman primate hemophilic model by immunizing cynomolgus monkeys with human FIX (hFIX) in adjuvants. FIX activities of all three hFIX-immunized monkeys decreased transiently to less than 10% in accordance with prolongation of activated partial thromboplastin time (APTT). Forty micrograms of human factor VIIa (hFVIIa) per kilogram body weight (that was reported to be clinically effective) was administered to the monkey with the highest inhibitor titer to evaluate its usefulness as a hemophilia inhibitor model. Results of thromboelastography (TEG) after the injection demonstrated that the hemostatic effect of FVIIa in this model would be similar to that in hemophiliacs with inhibitors. The antibodies purified from the monkey's plasma by hFIX-immobilized gel were composed of two types: Ca(2+)-dependent and -independent antibodies, with features of IgG(1) and IgG(4). Both types of antibodies reacted to cynomolgus FIX, and only Ca(2+)-dependent antibodies also expressed inhibitory activity against cynomolgus FIX. Immunoblotting analyses of Ca(2+)-dependent antibodies using hFIX and its derivatives suggested that they recognized the Ca(2+)-dependent conformation related to the gamma-carboxyglutamic acid (Gla) domain. Comparison of FIX cDNA from human, cynomolgus monkey, and other species, and the results of immunization of various animals (goats, beagle dogs, rabbits, and rats) with hFIX in adjuvants strongly suggested that the development of acquired FIX inhibitors in the monkeys might be due to high cross-reactivity of the antibodies to molecular mimic antigens, hFIX, and cynomolgus FIX.
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PMID:Induction of acquired factor IX inhibitors in cynomolgus monkey (Macaca fascicularis): a new primate model of hemophilia B. 1136 29


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