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PubMed1977

Preparation and properties of a therapeutic factor IX concentrate.

A method for the large-scale preparation of a coagulation factor IX concentrate from human plasma is described. The method includes absorption of the coagulation factors from cryosupernatant plasma to DEAE-Sephadex, extensive washing of the gel and elution of the coagulation factors with 0.5 M phosphate buffer at 6.85, followed by desalting of the eluate in a column of Sephadex G-25, then by lyophilization, dissolving and sterile filtration, and finally by freeze-drying of the final product. Experiments performed with HBsAg-positive plasma demonstrated a decrease in the HBsAg content by a factor of 10(-5) during the process. The product is inactive in a Na-PTT assay. The process yields an about 100-fold purified factor IX concentrate containing also factors II, VII, and X, but in relatively smaller amounts. The average yield relative to factor IX is 60%. The batch size has been from 16 to 150 litres of plasma and about 300 batches of the concentrate have been prepared. About 5,100 bottle (about 4.0 X 10(6) U of factor IX) of the concentrate have been used in the treatment of patients with haemophilia B. The clinical effect has always been good and the in vivo response to factor IX was 1.15 +/- 0.30%/U/kg body weight. Two cases of HBsAg-negative hepatitis that may have been caused by the concentrate, were detected. No thrombotic complications were found.

Factor IX↗
PubMed1993

Accumulation of the recombinant factor VIIa in rat bone: importance of the Gla-domain and relevance to factor IX, another vitamin K-dependent clotting factor.

The vitamin K-dependent clotting factors II, VII, IX, and X are proteins which undergo gamma-carboxylation of specific glutamic acid residues prior to secretion from the liver. These unique Ca2+ binding amino acids allow the interaction of the proteins with cell surface phospholipids, a function that is crucial for expression of full procoagulant activity of the proteins. The N-terminal region of the molecule contains the gamma-carboxylation sites and is termed the Gla-domain. A preliminary observation in rats suggested that mineralized bone accumulated activated recombinant FVII (rFVIIa: NovoSeven) as well as the non-activated, single chain rFVII. The present study investigated the role of the Gla-domain in the accumulation of rFVII in bone, as well as the influence of the activation state of FVII on this phenomenon. Rats were treated with 125I-labelled rFVII, rFVIIa, Gla-domainless rFVIIa, factor IX, iodide, or recombinant human growth hormone (rhGH). Following sacrifice, radioactivity was measured in mineralized bone, among other tissues. Following administration of 125I-radiolabelled rFVII, rFVIIa and factor IX, but not Gla-domainless rFVIIa, iodide or rhGH, extensive sequestration occurred in endochondrally as well as intramenbranously ossified bones. The results indicate that the proteins containing a Gla-domain, and only these, are sequestered in bone. Additionally, the normally occurring form of FVII in the circulation, the single-chain FVII, exhibited similar kinetics in rat bone and plasma, as the two-chain rFVIIa. The half-life of rFVII/rFVIIa in mineralized bone was between 3 and 4 days, implying that significant bone accumulation of the factor will take place at steady state.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2004

Severe factor XI deficiency caused by a Gly555 to Glu mutation (factor XI-Glu555): a cross-reactive material positive variant defective in factor IX activation.

During normal hemostasis, the coagulation protease factor (F)XIa activates FIX. Hereditary deficiency of the FXIa precursor, FXI, is usually associated with reduced FXI protein in plasma, and circulating dysfunctional FXI variants are rare. We identified a patient with < 1% normal plasma FXI activity and normal levels of FXI antigen, who is homozygous for a FXI Gly555 to Glu substitution. Gly555 is two amino acids N-terminal to the protease active site serine residue, and is highly conserved among serine proteases. Recombinant FXI-Glu555 is activated normally by FXIIa and thrombin, and FXIa-Glu555 binds activated factor IX similarly to wild type FXIa (FXIa(WT)). When compared with FXIa(WT), FXIa-Glu555 activates factor IX at a greatly reduced rate ( approximately 400-fold), and is resistant to inhibition by antithrombin. Interestingly, FXIa(WT) and FXIa-Glu555 cleave the small tripeptide substrate S-2366 with comparable k(cat)s. Modeling indicates that the side chain of Glu555 significantly alters the electrostatic charge around the active site, and would sterically interfere with the interaction between the FXIa S2' site and the P2' residues on factor IX and antithrombin. FXI-Glu555 is the first reported example of a naturally occurring FXI variant with a significant defect in FIX activation.

Antithrombin III↗
PubMed1993

Human coagulation factor IX: assessment of thrombogenicity in animal models and viral safety.

Thromboembolic complications associated with prothrombin complex concentrate treatment may be related to the high levels of factors II and X in these products. We report here results from preclinical safety studies with a human coagulation factor IX product (AlphaNine; Alpha Therapeutic Corp., Los Angeles, Calif.) that contains no detectable factor II or VII and less than 10 units of factor X/100 units of factor IX. This product was manufactured from virally inactivated factor IX complex with a barium citrate adsorption step followed by affinity chromatography yielding factor IX concentrate with a specific activity of about 86 factor IX units/mg protein. Electrophoresis and immunoblot analysis indicated that the factor IX represents about 65% of the protein in this product. The virus inactivation step incorporated into the manufacturing process (incubation with n-heptane at 60 degrees C for 20 hours) was shown to inactivate at least 8.6 logs of type 1 human immunodeficiency virus. The barium citrate adsorption and affinity chromatography steps were found to remove 2.0 logs of the marker virus, vaccinia, and the DEAE ion-exchange chromatography used to produce factor IX complex was found to remove 1.4 logs of the marker virus, Sindbis. Analysis of three separate manufacturing lots with the polymerase chain reaction revealed no evidence of hepatitis C virus. The purified factor IX was nonthrombogenic when tested at doses of 450 units/kilogram in a rabbit stasis (Wessler) model, whereas the prothrombin complex concentrates were found to be thrombogenic at doses of less than 50 units/kg. There was no evidence of DIC in a porcine model after infusion of 200 units/kg of coagulation factor IX, as manifested by negative fibrin monomer tests, the absence of fibrin in blood vessels at autopsy, little or no change in prothrombin times and partial thromboplastin times, and only moderate decreases in platelet levels after infusion.

Animals↗
PubMed1997

Persistent and therapeutic concentrations of human factor IX in mice after hepatic gene transfer of recombinant AAV vectors.

Haemophilia B, or factor IX deficiency, is a X-linked recessive disorder that occurs in about one in 25,000 males, and severely affected people are at risk for spontaneous bleeding into numerous organs. Bleeding can be life-threatening or lead to chronic disabilities with haemophilic arthropathy. The severity of the bleeding tendency varies among patients and is related to the concentration of functional plasma factor IX. Patients with 5-30% of the normal factor IX have mild haemophilia that may not be recognized until adulthood or after heavy trauma or surgery. Therapy for acute bleeding consists of the transfusion of clotting-factor concentrates prepared from human blood and recombinant clotting factors that are currently in clinical trials. Both recombinant retroviral and adenoviral vectors have successfully transferred factor IX cDNA into the livers of dogs with haemophilia B. Recombinant retroviral-mediated gene transfer results in persistent yet subtherapeutic concentrations of factor IX and requires the stimulation of hepatocyte replication before vector administration. Recombinant adenoviral vectors can temporarily cure the coagulation defect in the canine haemophilia B model; however, an immune response directed against viral gene products made by the vector results in toxicity and limited gene expression. The use of recombinant adeno-associated virus (rAAV) vectors is promising because the vector contains no viral genes and can transduce non-dividing cells. The efficacy of in vivo transduction of non-dividing cells has been demonstrated in a wide variety of tissues. In this report, we describe the successful transduction of the liver in vivo using r-AAV vectors delivered as a single administration to mice and demonstrate that persistent, curative concentrations of functional human factor IX can be achieved using wild-type-free and adenovirus-free rAAV vectors. This demonstrates the potential of treating haemophilia B by gene therapy at the natural site of factor IX production.

Alanine Transaminase↗
PubMed1987

Effect of propeptide mutations on post-translational processing of factor IX. Evidence that beta-hydroxylation and gamma-carboxylation are independent events.

Post-translational processing of Factor IX includes glycosylation, cleavage of the signal peptide and propeptide, vitamin K-dependent carboxylation of specific glutamic acid residues to form gamma-carboxyglutamic acid, and beta-hydroxylation of aspartic acid at residue 64 to form beta-hydroxyaspartic acid. The human Factor IX cDNA coding sequence was modified in the propeptide region (residue -18 to -1) using oligonucleotide-directed site-specific mutagenesis, and the altered Factor IX cDNA was expressed in Chinese hamster ovary cells. The effects of the mutations on proteolytic processing, gamma-carboxylation, and beta-hydroxylation were assessed by direct structural analysis. After purification, the molecular weight of each of the recombinant Factor IX species and its NH2-terminal amino acid sequence were shown to be identical to those of plasma Factor IX. gamma-Carboxyglutamic acid and beta-hydroxyaspartic acid analyses revealed that recombinant wild-type Factor IX contained 9.2 gamma-carboxyglutamic acid and 0.3 beta-hydroxyaspartic acid residues/molecule compared with 11.4 gamma-carboxyglutamic acid and 0.39 beta-hydroxyaspartic acid residues in plasma Factor IX. When the 18-residue propeptide was deleted or when the cells were grown in the presence of sodium warfarin, secreted Factor IX contained no detectable gamma-carboxyglutamic acid but 0.36 and 0.40 residues of beta-hydroxyaspartic acid, respectively. Point mutations leading to substitution of alanine for phenylalanine at residue -16 or glutamic acid for alanine at residue -10 contained 0.2 and 1.7 gamma-carboxyglutamic acid residues, respectively, and 0.2 residues of beta-hydroxyaspartic acid. These data confirm that the propeptide mutations made do not interfere with proteolytic processing and that the Factor IX propeptide contains a recognition site that designates the adjacent glutamic acid-rich domain for gamma-carboxylation. In contrast, beta-hydroxylation of aspartic acid 64 is an independent process which does not require vitamin K and is mediated through a hydroxylation recognition site in the mature Factor IX, not in the propeptide.

Animals↗
PubMed1997

Modification of the N-terminus of human factor IX by defective propeptide cleavage or acetylation results in a destabilized calcium-induced conformation: effects on phospholipid binding and activation by factor XIa.

The propeptide of human coagulation factor IX (FIX) directs the gamma-carboxylation of the first 12 glutamic acid residues of the mature protein into gamma-carboxyglutamic acid (Gla) residues. The propeptide is normally removed before secretion of FIX into the blood. However, mutation of Arg-4 in the propeptide abolishes propeptide cleavage and results in circulating profactor IX in the blood. We studied three such genetic variants, factor IX Boxtel (Arg-4-->Trp), factor IX Bendorf (Arg-4-->Leu) and factor IX Seattle C (Arg-4-->Gln). These variant profactor IX molecules bind normally to anti-FIX:Mg(II) antibodies, which indicates that the mutations do not seriously affect gamma-carboxylation. Metal ion titration of the binding of variant profactor IX to conformation-specific antibodies demonstrates that the calcium-induced conformation is destabilized in the variant molecules. Also the binding of FIX Boxtel to phospholipids and its activation by factor XIa requires a high (>5 mM) calcium concentration. The three-dimensional structure of the Gla domain of FIX in the presence of calcium indicates that the acylation of the amino-terminus, rather than the presence of the propeptide, was responsible for the destabilization of the calcium-induced conformation. In order to confirm this, the alpha-amino group of Tyr1 of FIX was acetylated. This chemically modified FIX showed a similar destabilization of the calcium-induced conformation to variant profactor IX. Our data imply that the amino-terminus of FIX plays an important role in stabilizing the calcium-induced conformation of the Gla domain of FIX. This conformation is important for the binding to phospholipids as well as for the activation by factor XIa. Our results indicate that mutations in FIX that interfere with propeptide cleavage affect the function of the protein mainly by destabilizing the calcium-induced conformation.

Acetylation↗
PubMed1991

Missense mutations and evolutionary conservation of amino acids: evidence that many of the amino acids in factor IX function as "spacer" elements.

We report 31 point mutations in the factor IX gene and explore the relationship between the level of evolutionary conservation of an amino acid and the probability of a mutation causing hemophilia B. From our total sample of 125 hemophiliacs and from those reported by others, we identify 95 independent missense mutations, 94 of which occur at amino acids that are evolutionarily conserved in the available mammalian factor IX sequences. The likelihood of a missense mutation causing hemophilia B depends on whether the residue is also conserved in the factor IX-related proteases: factor VII, factor X, and protein C. Most of the possible missense mutations in generically conserved residues (i.e., those conserved in factor IX and in all the related proteases) should cause disease. In contrast, missense mutations in factor IX-specific residues (i.e., those conserved in human, cow, dog, and mouse factor IX but not in the related proteases) are sixfold less likely to cause disease. Missense mutations at nonconserved residues are 33-fold less likely to cause disease. At least three models are compatible with these observations. A comparison of sequence alignments from four and nine species of factor IX and an examination of the missense mutations occurring at CpG residues suggest a model in which most residues fall on opposite ends of a spectrum. In about 40% of residues, virtually any missense mutation in a minority of the residues will cause disease, while virtually no missense mutations will cause disease in most of the remaining residues. Thus, many of the residues in factor IX are spacers; that is, the main chains are presumably necessary to keep other amino acid interactions in register, but the nature of the side chain is unimportant.

Amino Acid Sequence↗
PubMed1987

Heterogeneity of the factor IX locus in nine hemophilia B inhibitor patients.

DNA from nine hemophilia B patients who produce anti-factor IX inhibitors (antibodies), including two brothers, was analyzed by the Southern blotting method and hybridization with factor IX cDNA, intragenomic, and 3'-flanking probes. Two inhibitor patients were shown to have total deletions of the factor IX gene. Two other inhibitor patients, the brothers, were shown to have a presumably identical complex rearrangement of the factor IX gene involving two separate deletions. The first deletion is of approximately 5.0 kb and removes exon e. The second deletion is between 9 and 29 kb and removes exons g and h but leaves exon f intact. An abnormal Taq I fragment at one end of the deletion junctions acted as a marker for the inheritance of hemophilia B in the patients' family. Five other inhibitor patients have a structurally intact factor IX gene as detected by this method. Our studies indicate that whereas large structural factor IX gene defects predispose hemophilia B patients to developing an anti-factor IX inhibitor, the development of an inhibitor can be associated with other defects of the factor IX gene.

DNA↗
PubMed1988

Characterisation of two differently processed forms of human recombinant factor IX synthesised in CHO cells transformed with a polycistronic vector.

A stable transformed cell line constitutively expressing human factor IX has been established. Wild-type Chinese hamster ovary cells (CHO cells) were transformed using a polycistronic expression vector carrying a previously isolated factor IX cDNA and a selection gene encoding the Escherichia coli xanthine-guanine phosphoribosyl transferase. One clone, CHO 622.4, contains a high number of genomically integrated plasmids and secretes 1-3 mg factor IX l-1 day-1 into the culture medium with a biological activity ranging from 25% to 40%. The recombinant molecule was purified either by conventional chromatography or by immunoaffinity chromatography using antibodies specific to a calcium-induced factor IX conformer. The purified recombinant protein migrates as a single band with the same mobility as that of natural factor IX on SDS/polyacrylamide gels. N-terminal sequencing shows tow differently processed forms of recombinant factor IX: whereas the majority of the zymogen is correctly processed, approximately 20% of the purified recombinant molecule contains an 18-amino-acid NH2-extension corresponding to the precursor form of factor IX. Analysis of the 4-carboxyglutamic acid content indicates a high but incomplete carboxylation (70%) of the recombinant molecule as compared to natural factor IX. The carbohydrate composition of both the natural and recombinant molecules has been determined. Both molecules have a N-glycan structure of similar complexity, indicating that factor IX contains all the information to direct the same glycosylation pattern in human liver cells and in an unrelated cell line such as CHO-K1.

Amino Acid Sequence↗
PubMed1995

Regulation of the tertiary structure and function of coagulation factor IX by magnesium (II) ions.

The indispensable role of Ca2+ ions in the maintenance of the functional tertiary structures of vitamin K-dependent coagulation factors has been definitively established but the participation of Mg2+ ions, another alkaline-earth metal that is present abundantly in blood plasma, in such a process is not yet understood. We show here that the Ca(2+)-stabilized conformation of coagulation factor IX undergoes a further conformational change upon binding of Mg2+ ions using three independent structural probes. The probes we used were (i) IX/X-bp, a snake venom anticoagulant that recognizes the Gla domains in coagulation factors IX and X, (ii) conformation-specific polyclonal antibodies against bovine factor IX, and (iii) monoclonal antibodies against the Gla domain of human factor IX. The binding of all these probes had an absolute requirement for Ca2+ ions, and Mg2+ ions alone were ineffective. However, when added together with Ca2+ ions, Mg2+ ions at physiological concentrations greatly augmented the binding of these probes to factor IX; the required concentration of Ca2+ ions was much reduced, and the affinity of each probe for factor IX was increased even in the presence of an excess of Ca2+ ions. These results suggest the presence of a Mg(2+)-specific binding site that does not interact with Ca2+ ions in factor IX. Furthermore, Mg2+ ions potentiated the susceptibility of factor IX to activation by factor XIa, concomitant with their effect on the conformation. Similarly, the required Ca2+ concentration was reduced by Mg2+ ions, and the rate of conversion to factor IXa was increased by Mg2+ ions in the presence of an excess of Ca2+ ions. At a saturating concentration of Ca2+ ions (5 mM), addition of 1 mM Mg2+ reduced the apparent Km value for factor IX from 0.31 to 0.18 microM, and in the presence of a physiological concentration of Ca2+ ions (1 mM), the reduction in Km by Mg2+ ions was far more striking (from 0.91 to 0.24 microM). The apparent Vmax values were hardly affected by Mg2+ ions. Our present data reveal a hitherto novel physiological role of the Mg2+ ions in plasma. Not only Ca2+ ions but also Mg2+ ions are important regulators of the stabilization of the native conformation of factor IX as well as of its efficient activation.

Animals↗
PubMed1987

Hemophilia B (factor IXSeattle 2) due to a single nucleotide deletion in the gene for factor IX.

To understand the molecular basis for hemophilia B in patients with little or no circulating Factor IX antigen, a patient who had less than 0.2% circulating Factor IX antigen (Factor IXSeattle 2) was selected for analysis of his Factor IX gene. Genomic DNA fragments from the abnormal gene were cloned into bacteriophage lambda vectors and recombinant phage were identified using radiolabeled genomic probes obtained from the normal Factor IX gene. The exons and flanking regions of the abnormal gene were sequenced by the dideoxy chain-termination method and this sequence was compared with that of the normal gene. Only one significant difference was observed, the deletion of a single adenine nucleotide in exon V. This resulted in a frameshift that converted an aspartic acid at position 85 in the protein to a valine and the formation of a stop signal at position 86. These data indicate that the gene for Factor IXSeattle 2 codes for an 85 residue polypeptide that terminates after the first epidermal growth factor domain. Thus, the putative Factor IXSeattle 2 polypeptide lacks the second epidermal growth factor domain, the activation peptide, and the catalytic domain present in the normal protein. This provides an explanation for the coagulation disorder in this patient and represents the first report of a single nucleotide deletion and frameshift resulting in hemophilia B.

Adenine↗
PubMed1998

Androgen effects on factor IX expression: in-vitro and in-vivo studies in mice.

A role for steroid hormones has been proposed for the post-pubertal factor IX increment of approximately 25% seen in both normal males and females, as well as in the post-pubertal phenotypic recovery seen in haemophilia B Leyden. We have evaluated androgen receptor binding to the factor IX promoter and have assessed transcriptional activation of the factor IX gene in hepatocytes through transient transfection studies and through expression of factor IX in a murine model of androgen insensitivity. Whereas transfection of the androgen receptor alone did not activate expression from the factor IX promoter, co-transfection with the CCAAT enhancer binding protein resulted in a synergistic 17-fold enhancement of transcriptional activity. Using liver nuclear extracts and recombinant androgen receptor protein we have confirmed binding of this protein to the factor IX proximal promoter and disruption of binding with a mutation at nucleotide -26. Finally, studies in normal and testicular feminized male mice showed different developmental patterns of factor IX expression. In normal mice, expression recapitulates that seen in humans, with early post-natal levels being approximately 50% of the adult values and with a post-pubertal increment of approximately 25%. In contrast, testicular feminized animals did not show a significant post-pubertal increment of factor IX. These studies provide further support for the role of androgen receptor binding to the factor IX promoter in regulating the developmental expression of factor IX.

Animals↗
PubMed1995

In vitro characterization of high purity factor IX concentrates for the treatment of hemophilia B.

This study employed sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) analysis and immunoblotting to assess the purity of seven high purity factor IX concentrates: Aimafix (Aima), AlphaNine-SD (Alpha Therapeutic), Factor IX VHP (Biotransfusion), Immunine (Immuno), Mononine (Armour Pharmaceutical), Nanotiv (Kabi Pharmacia), and 9MC (Blood Products Laboratory). The mean specific activity of these products ranged from 68 U factor IX/mg (Aimafix) to 246 U factor IX/mg (Mononine). SDS-PAGE analysis showed that the highest purity product, Mononine, had a single contaminating band under non-reducing conditions. Two additional bands were detected when this product was analyzed under reducing conditions. All other products had multiple contaminating bands that were more apparent under reducing than non-reducing conditions. The immunoblot for factor IX showed a dominant factor IX band for all products. In addition, visible light chain of factor IX was detected for AlphaNine-SD, Factor IX VHP, Immunine, Mononine, Nanotiv, and 9MC, suggesting that the factor IX in these products had undergone partial activation to factor IXa. Another contaminating band was visible at 49,500 for all of the products except 9MC. In addition to this band, high molecular weight contaminants were apparent for some products, most notably AlphaNine-SD. The identity of these bands is unknown. Immunoblotting failed to demonstrate factor VII as a contaminant of any of the high purity products, although factor VIIa could be detected in some lots of Immunine, Nanotiv, and 9MC by a clot-based assay. Factor X contaminated Aimafix, AlphaNine-SD, Factor IX VHP, Immunine, Nanotiv, and 9MC, but activation products of factor X were not detected.(ABSTRACT TRUNCATED AT 250 WORDS)

Drug Contamination↗
PubMed1985

Polymorphism of normal factor IX detected by mouse monoclonal antibodies.

Hemophilia B is an X-chromosomal recessive disease due to deficiency of coagulation factor IX. Three monoclonal antibodies against factor IX were prepared and used to develop immunoradiometric assays (IRMAs) of factor IX antigen (IX-Ag). IX-Ag was measured in 65 normal individuals with one IRMA based on polyclonal anti-IX antibodies and two IRMAs based on three monoclonal anti-IX antibodies. One of the monoclonal antibodies differed in specificity since it neutralized less than 50% of the clotting activity of factor IX (IX-C), whereas the other two monoclonal antibodies neutralized 80-95%. When the former antibody was used as the solid phase in IRMA, two groups of normal individuals were distinguished: group A with measurable IX-Ag, and group B without demonstrable IX-Ag. There were no differences between the groups either in IX-C or in IX-Ag measured with polyclonal antibodies. A subgroup comprising only women could be distinguished in group A, in whom intermediate IX-Ag concentrations were found. Family studies showed the group B variant of normal factor IX to be transmitted according to the pattern of X-linked recessive inheritance. The allelic frequency of group A was 0.66, and that of group B was 0.34.

Adolescent↗
PubMed1990

Clinical experience of a new monoclonal antibody purified factor IX: half-life, recovery, and safety in patients with hemophilia B.

Highly purified factor IX, produced by a monoclonal antibody immunoaffinity technique, contains a high concentration of factor IX with negligible amounts of other vitamin K-dependent coagulation factors. When infused in patients with hemophilia B, monoclonal factor IX concentrate yielded a mean half-life of 34.6 +/- 13.1 (+/- SD) hours and in vivo recovery of 0.67 +/- 0.14 U/dL rise per each U/kg of factor IX infused. Unlike prothrombin complex concentrate (PCC) infusion, monoclonal IX infusion was not associated with rises in factors II, VII, and X, but achieved in vivo recovery and half-life at least comparable to PCC. Long-term use of monoclonal IX as a home-care product provided excellent response in the control of bleeding episodes and was equivalent to previous patient experience with PCC. The results indicate that monoclonal IX concentrate raises factor IX levels effectively, while avoiding extraneous thrombogenic components.

Adult↗
PubMed1989

Comparative efficacy of nonheated and heat-treated factor IX complex concentrate in treatment of hemophiliacs with inhibitors.

To determine if heat-treated factor IX complex concentrate is as effective as nonheated factor IX complex concentrate for treatment of subjects with hemophilia A and antifactor VIII antibodies (inhibitor patients), we have retrospectively reviewed consecutive home treatment records of ten inhibitor patients who had been receiving nonheat-treated factor IX complex concentrate (NHT-Konyne) and subsequently converted to heat-treated factor complex concentrate (Konyne-HT) when it was licensed in late 1984. Overall, 162 of 284 (57%) separate bleeding episodes treated with NHT-Konyne and 53 of 80 (66.3%) separate bleeding episodes treated with Konyne-HT required only one treatment course of approximately 60-75 U/kg. The distribution of bleeding sites and the absolute factor IX unitage required per treatment episode were similar for both preparations. These data suggest that the percentage of hemophilic inhibitor patients responding to factor IX complex concentrate remains at least 50%, as was reported several years ago in a controlled study, and that inhibitor bypass activity has not altered by heat treatment.

Antibodies↗
PubMed1997

Further evidence for the importance of an androgen response element in the factor IX promoter.

Previous work involving the characterizing of a factor IX promoter mutation (-26 G-->C) of a 21-year-old patient with severe haemophilia B suggested that an androgen response element (ARE) was present in the wild-type factor IX promoter but was disrupted in this patient. However, other theories not involving this ARE have been suggested for the mechanism of recovery in the more typical (Leyden) promoter patients, so that the ARE hypothesis requires further evidence if it is to be accepted. We now present a case history and functional data on another 48-year-old severe haemophilia B patient (UK232) with a different (G-->A) mutation at the same position, -26. This mutation impairs transactivation of the minimal factor IX promoter region (-220-->+43) by HNF4 in transient transfection experiments in HepG2 and HeLa cells. It disrupts binding of both androgen receptor (AR) and HNF4 to oligonucleotides spanning this region (-40-->-9) in competition gel mobility shift assays. It impairs AR/testosterone transactivation of these oligonucleotides (-40-->-9) when tetramerized upstream of a CAT reporter gene in cotransfection assays in HeLa cells. And, finally, no clinical recovery has occurred since puberty. These results strengthen the evidence for the importance of nucleotide -26, both for the normal transcription of the gene in response to HNF4 and for the proposed Leyden recovery mechanism in response to AR and testosterone acting directly through the factor IX ARE.

Adult↗