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)

Abnormal factor IX variant proteins were isolated from the plasmas of three unrelated severe hemophilia-B families that had been previously shown to contain functionally impaired molecules immunologically similar to normal factor IX. The families studied were: (1) a patient with markedly prolonged ox brain prothrombin time, designated factor IX Bm Lake Elsinore (IXBmLE); (b) three patients (brothers) with moderately prolonged ox brain prothrombin time, designated factor IX Long Beach (IXLB); and (c) a patient with normal ox brain prothrombin time designated factor IX Los Angeles (IXLA). Each variant molecule comigrates with normal factor IX (IXN) both in the sodium dodecyl sulfate and in the nondenaturing alkaline gel electrophoresis. All three variant proteins are indistinguishable from IXN in their amino acid compositions, isoelectric points, carbohydrate distributions and number of gamma-carboxyglutamic acid residues. Each variant protein undergoes a similar pattern of cleavage by factor XIa/Ca2+ and by factor VIIa/Ca2+/tissue factor, and is activated at a rate similar to that observed for IXN. All of the three variant proteins also react with an anti-IXN monoclonal antibody that interferes with the binding of activated IXN(IXaN) to thrombin-treated factor VIIIC. However, in contrast to IXaN, the cleaved IXBmLE has negligible activity (approximately 0.2%), and cleaved forms of IXLA and IXLB have significantly reduced activity (approximately 5-6%) in binding to antithrombin-III/heparin, and in activating factor VII (plus Ca2+ and phospholipid) or factor X (plus Ca2+ and phospholipid) +/- factor VIII. These data, taken together, strongly indicate that the defect in these three variant proteins resides near or within the latent catalytic site. This results in virtually a complete loss of catalytic activity of the cleaved IXBmLE molecule and approximately 95% loss of catalytic activity of the cleaved IXLA and IXLB molecules.
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PMID:Characterization of three abnormal factor IX variants (Bm Lake Elsinore, Long Beach, and Los Angeles) of hemophilia-B. Evidence for defects affecting the latent catalytic site. 396 13

A murine hybridoma cell line that produces a monoclonal IgG1 antibody to human factor IX was established to provide a conformational probe for the clotting factor and its genetic variants. The antibody inhibited factor IX procoagulant activity, but did not appreciably interfere with the cleavage of factor IX by factor XIa nor with the binding of antithrombin-III-heparin complex to factor IXa. The antigen-solid-phase-antibody complex could be readily dissociated by relatively low concentrations of guanidine or sodium dodecyl sulfate, but only partially by high concentrations of urea. After gel electrophoresis and blotting of reduced samples of factor IXa, the antibody bound exclusively to the heavy chain. Sensitive immunoradiometric assays were developed using insolubilized monoclonal or polyclonal antibodies. Bovine factor IX had little cross-reactivity with the monoclonal antibody. Of 55 patient samples representing different pedigrees with hemophilia-B, antigen levels by the two assays were in excellent agreement in 49. There were 2 severely affected patients whose levels were too low to quantitate in the monoclonal antibody assay. A third, who had the lowest level of all by polyclonal antibody testing, and 3 less severely affected patients had no detectable antigen in the monoclonal antibody assay system (less than 0.03 U/dl). The latter 3 had at least 100-500 times as much antigen by polyclonal antibody testing. It is proposed that these 3 individuals have structural defects involving the epitope recognized by the monoclonal antibody and that they are due to amino acid substitutions between residues 188 through 359. Furthermore, it is suggested the substitutions lead to abnormal kinetic properties.
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PMID:Monoclonal antibody to an epitope on the heavy chain of factor IX missing in three hemophilia-B patients. 619 35

A prospective cross-over study was carried out on 19 patients with haemophilia B. comparing the pharmacokinetics of a purified factor IX concentrate prepared by metal chelate affinity chromatography (9MC) with a conventional three-factor prothrombin complex concentrate (9A). The highly purified factor IX concentrate was shown to have a half-life comparable to the PCC; the in vivo recovery of the purified concentrate was significantly greater than that of the complex (P < 0.01). The 20% change in the value of the International Standard for Factor IX Concentrate, introduced in 1988, might have been expected to lower the recovery values. However, the in vivo recovery for both concentrates was somewhat higher than reported previously, particularly in the older literature. In nine patients, serial assays for fibrinopeptide A, prothrombin fragment F1+2 and thrombin-antithrombin complexes (TAT) were performed to assess the potential thrombogenicity of the two concentrates. Evidence was obtained that there was significantly less activation of coagulation following administration of purified factor IX (9MC), as compared to the activation that occurred after the PCC.
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PMID:A cross-over pharmacokinetic and thrombogenicity study of a prothrombin complex concentrate and a purified factor IX concentrate. 798 19

The safety and efficacy of recombinant DNA-produced factor VIIa (rFVIIa) was investigated in 15 haemophilic patients in non-bleeding states and during bleeding episodes (mild to moderate joint bleed). Patients with severe haemophilia A without inhibitors (n = 4), haemophilia A with inhibitors (n = 10), and haemophilia B with inhibitor (n = 1) received one or more doses of rFVIIa during 32 non-bleeding study episodes and 23 bleeding episodes. The study was an open, uncontrolled, dose-escalation (17.5 micrograms/kg, 35 micrograms/kg, 70 micrograms/kg) trial. Physical evaluation, laboratory assessment, and immunology testing were conducted at baseline, monthly for 3 months and every 3 months thereafter. The immediate safety of rFVIIa was assessed by monitoring of D-dimer, fibrinogen, platelet count, antithrombin III, thrombin-antithrombin complex, and alpha 2-antiplasmin 5 min before and at multiple times throughout the following 24 h. Prothrombin time (PT) and activated partial thromboplastin time (aPTT) values were also obtained. Pain, swelling, joint circumference, and range of motion were recorded before administration of the initial dose of rFVIIa in bleeding patients and at 6, 12, and 24 h. Haemostatic response to rFVIIa was observed in patients with severe VIII and IX deficiency with and without inhibitors. Therapy with rFVIIa was judged effective in 19 of the 22 evaluable bleeding episodes at one or more time points. The 35 micrograms/kg and 70 micrograms/kg doses were associated with higher response rates at 6 and 12 h compared to the 17.5 micrograms/kg dose level. A second dose of rFVIIa was administered in 20 of the 22 bleeding episodes.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Safety and initial clinical efficacy of three dose levels of recombinant activated factor VII (rFVIIa): results of a phase I study. 821 48

We have looked for evidence of coagulation activation in six subjects with haemophilia B by performing a single-blind active control cross-over study comparing a recently developed factor IX concentrate with a conventional prothrombin complex concentrate (PCC). Samples were obtained before infusion and at 0.25, 0.5, 1, 2, 4, 6, 12, 24, 36 and 48 h for assay of factor IX, prothrombin time, fibrinopeptide A (FPA), prothrombin fragment F1 + 2, D-dimer, thrombin-antithrombin complexes (TAT) and antithrombin III (ATIII). Following administration of the PCC there was evidence of coagulation activation in five of the six recipients for up to 6 h after the infusion. The factor IX concentrate induced a moderate degree of coagulation activation in one subject. There was no significant difference between the two products in respect of either recovery or half-life. This study provides further evidence that the new high purity preparations of factor IX concentrates produce significantly less coagulation activation than currently available PCCs. It remains to be established whether this will result in a corresponding reduction in thromboembolic complications in clinical use.
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PMID:Reduced coagulation activation following infusion of a highly purified factor IX concentrate compared to a prothrombin complex concentrate. 839 31

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

Tissue factor (TF)-induced coagulation was compared in contact pathway suppressed human blood from normal, factor VIII-deficient, and factor XI-deficient donors. The progress of the reaction was analyzed in quenched samples by immunoassay and immunoblotting for fibrinopeptide A (FPA), thrombin-antithrombin (TAT), factor V activation, and osteonectin. In hemophilia A blood (factor VIII:C <1%) treated with 25 pmol/L TF, clotting was significantly delayed versus normal, whereas replacement with recombinant factor VIII (1 U/mL) restored the clot time near normal values. Fibrinopeptide A release was slower over the course of the experiment than in normal blood or hemophilic blood with factor VIII replaced, but significant release was observed by the end of the experiment. Factor V activation was significantly impaired, with both the heavy and light chains presenting more slowly than in the normal or replacement cases. Differences in platelet activation (osteonectin release) between normal and factor VIII-deficient blood were small, with the midpoint of the profiles observed within 1 minute of each other. Thrombin generation during the propagation phase (subsequent to clotting) was greatly impaired in factor VIII deficiency, being depressed to less than 1/29 (<1.9 nmol TAT/L/min) the rate in normal blood (55 nmol TAT/L/min). Replacement with recombinant factor VIII normalized the rate of TAT generation. Thus, coagulation in hemophilia A blood at 25 pmol/L TF is impaired, with significantly slower thrombin generation than normal during the propagation phase; this reduced thrombin appears to affect FPA production and factor V activation more profoundly than platelet activation. At the same level of TF in factor XI-deficient blood (XI:C <2%), only minor differences in clotting or product formation (FPA, osteonectin, and factor Va) were observed. Using reduced levels of initiator (5 pmol/L TF), the reaction was more strongly influenced by factor XI deficiency. Clot formation was delayed from 11.1 to 15.7 minutes, which shortened to 9.7 minutes with factor XI replacement. The maximum thrombin generation rate observed ( approximately 37 nmol TAT/L/min) was approximately one third that for normal (110 nmol/L TAT/min) or with factor XI replacement (119 nmol TAT/L/min). FPA release, factor V activation, and release of platelet osteonectin were slower in factor XI-deficient blood than in normal blood. The data demonstrate that factor XI deficiency results in significantly delayed clot formation only at sufficiently low TF concentrations. However, even at these low TF concentrations, significant thrombin is generated in the propagation phase after formation of the initial clot in hemophilia C blood.
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PMID:Blood coagulation in hemophilia A and hemophilia C. 961 54

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

We report a transient type I factor VIII inhibitor that arose in a 30-year-old hemophilia patient just after staphylococcal septicemia. This situation usually occurs early in the course of substitution therapy with factor VIII concentrate in hemophilia patients. Although disseminated intravascular coagulation and acute respiratory distress syndrome developed after septic shock, the patient recovered following intravenous administration of antibiotics (meropenem and gentamycin), an antithrombin preparation, high-dose methylprednisolone, and recombinant factor VIII concentrate (rFVIII). During this therapy, however, activated partial thromboplastin time gradually lengthened. On the seventh day of hospitalization, intracranial hemorrhage occurred with right hemiplegia, even though the substitution therapy had continued at the same dosage (30 U/kg per day) of rFVIII. At that point, 4 Bethesda units of the type I inhibitor against factor VIII were detected in the plasma. Increased amounts (46 U/kg per day) of rFVIII and prednisolone were administered, and hypothermic therapy was initiated. Following these treatments, the patient's general condition gradually improved, and within 25 days the inhibitor titer dropped to undetectable levels and did not recur during treatment. These clinical findings suggest that the staphylococcal septic shock may have acted as a trigger in the development of transient factor VIII inhibitor in this patient.
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PMID:Transient factor VIII inhibitor in a hemophilia patient after staphylococcal septic shock syndrome. 1119 24

It has been recently suggested that the clinical phenotype of severe hemophilia A (HA) is influenced by co-inheritance with the factor V G1691A mutation. We therefore investigated 124 pediatric PUP patients with hemophilia (A: n = 111) consecutively admitted to German pediatric hemophilia treatment centers. In addition to factor VIII activity, the factor V (FV) G1691A mutation, the prothrombin (PT) G20210A variant, antithrombin, protein C, protein S and antithrombin were investigated. 92 out of 111 HA patients (F VIII activity < 1%) were suffering from severe HA. The prevalence of prothrombotic risk factors in children with severe HA was no different from previously reported data: FV G1691A 6.5%, PT G20201A 3.2%, and protein C type I deficiency 1.1%. No deficiency states of antithrombin or protein S were found in this cohort of hemophilic patients. The first symptomatic bleeding leading to diagnosis of severe hemophilia (< 1%) occurred with a median (range) age of 1.6 years (0.5-7.1) in children carrying defects within the protein C pathway or the PT gene mutation compared with non-carriers of prothrombotic risk factors (0.9 years (0.1-4.0; p = 0.01). The cumulative event-free bleeding survival was significantly prolonged in children carrying additionally prothrombotic defects (log-rank/Mantel-Cox: p = 0.0098). In conclusion, data of this multicenter cohort study clearly demonstrate that the first symptomatic bleeding onset in children with severe HA carrying prothrombotic risk factors is significantly later in life than in non-carriers.
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PMID:Symptomatic onset of severe hemophilia A in childhood is dependent on the presence of prothrombotic risk factors. 1124 35


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