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PubMed1985

Intragenic Factor IX restriction site polymorphism in hemophilia B variants.

This study includes 47 normal subjects and 25 hemophilia B patients without inhibitor(s), showing different factor IX coagulant activity and antigen levels. Genomic DNA, digested with various restriction endonucleases, was hybridized with two different factor IX probes, ie, the cDNA and the subgenomic probe for the intragenic TaqI polymorphic site. cDNA restriction patterns suggest absence of gross rearrangements and/or deletions in all hemophilic patients. The frequency of the X chromosome bearing the TaqI polymorphic site is 0.32 +/- 0.09 in hemophilic subjects v 0.36 +/- 0.06 in normal control subjects, the latter value being comparable to that reported for the normal British population. No association between this polymorphism and hemophilia B variants has been observed, thus indicating that a wide spectrum of mutations underlies this blood-clotting disorder and particularly each of its variants.

Cloning, Molecular↗
PubMed1981

Myocardial infarction after factor IX therapy.

A 17-year-old boy with hemophilia A and strong inhibitors for factor VIII suffered a myocardial infarction on the sixth day of treatment with large amounts of human factor IX complex (Konyne). The patient also had had diabetes for one year, for which he was receiving insulin injections, but there was no evidence of vascular disease. Thromboembolic complications that occur after the administration of factor IX concentrates have been reported in patients with hemophilia B or liver disease, but these complications are extremely rare in patients with classic hemophilia.

Adolescent↗
PubMed2000

Assessment of activated partial thromboplastin time and factor IX in subjects attending an anticoagulation clinic.

Very low factor IX (FIX) levels in patients during oral anticoagulant (OA) treatment, due to mutations in the FIX gene, with prolonged activated partial thromboplastin time (aPTT) and associated with bleeding complications have recently been described. We measured aPTT in 595 OA patients while being within therapeutic ranges. Patients were divided into increasing international normalized ratio (INR) classes, and FIX determined in those belonging to the first and fifth quintiles of the aPTT distribution in each INR class. Results obtained in patients of all the first aPTT quintiles were compared with those of all the fifth quintiles. While INR was not different (2.79 versus 2.77 INR), aPTT was longer (1.65 versus 1.21 ratio; P < 0.0001) and FIX lower (0.29 versus 0.44 IU/ml; P < 0.0001) in patients of the fifth quintiles. Only one patient had a markedly reduced FIX (0.03 IU/ml). Bleeding rate was 4.8 and 6.2% patient-years (not significant) in patients of the first and fifth quintiles, respectively. We therefore found that FIX levels vary greatly in spite of similar achieved anticoagulation intensity; very low FIX is, however, a rare condition. In conclusion, screening for the recently identified mutations in FIX gene does not seem justified, and identifying patients with disproportionately prolonged aPTT, to detect those with particularly low FIX levels, is difficult because of the effect of the achieved anticoagulation intensity. Therefore, aPTT measurement is indicated only in patients with increased bleeding during OA.

Adolescent↗
PubMed1995

Retroviral-mediated in vivo gene transfer into muscle cells and synthesis of human factor IX in mice.

Muscle cells, when transduced with a factor IX (FIX) expression vector, are capable of producing FIX protein and secreting it into the blood. These cells can thus serve as appropriate targets for gene transfer in hemophilia B patients. In this work, we studied the potential of retrovirus-mediated in vivo gene transfer of the FIX gene into muscle cells. Producer cells, which produce recombinant retroviruses containing the human FIX cDNA under the transcriptional control of the chicken beta-actin promoter, were treated with the cytostatic drug mitomycin C (MC), and injected into the rectus femoris muscle of 6-week-old CB-17/1cr severe combined immune-deficient (SCID) mice. As a control, SCID mice were injected with NIH 3T3 cells, which were stably transformed by the retroviral vector described above and therefore secreted FIX, but did not produce retroviruses. The injected MC-treated cells did not cause any tumours to develop in the mice, and the amount of human FIX in the plasma of mice injected with the producer cells was significantly higher, at any of the time points measured beyond 10 days postinjection, than the amount of human FIX in the plasma of mice injected with FIX-secreting 3T3 cells. These results indicate that muscle cells transduced by retroviruses produced human FIX and secreted it into the blood. In vivo gene transfer to muscle cells by injection of retrovirus-producing cells, or by direct injection of recombinant retroviruses, could prove to be important for the gene therapy of hemophilia B.

3T3 Cells↗
PubMed2006

Transgene expression levels and kinetics determine risk of humoral immune response modeled in factor IX knockout and missense mutant mice.

Immune responses leading to antibody-mediated elimination of the transgenic protein are a concern in gene replacement for congenital protein deficiencies, for which hemophilia is an important model. Although most hemophilia B patients have circulating non-functional but immunologically crossreactive factor IX (FIX) protein (CRM+ phenotype), inciting factors for FIX neutralizing antibody (inhibitor) development have been studied in crossreactive material-negative (CRM-) animal models. For this study, determinants of FIX inhibitor development were compared in hemophilia B mice, in which circulating FIX protein is absent (CRM- factor IX knockout (FIXKO) model) or present (CRM+ missense R333Q-hFIX model) modeling multiple potential therapies. The investigations compare for the first time different serotypes of adeno-associated virus (AAV) vectors (AAV2 and AAV1), each at multiple doses, in the setting of two different FIX mutations. The comparisons demonstrate in the FIXKO background (CRM- phenotype) that neither vector serotype nor vector particle number independently determine the inhibitor trigger, which is influenced primarily by the level and kinetics of transgene expression. In the CRM+ missense background, inhibitor development was never stimulated by AAV gene therapy or protein therapy, despite the persistence of lymphocytes capable of responding to FIX with non-inhibitory antibodies. This genotype/phenotype is strongly protective against antibody formation in response to FIX therapy.

Animals↗
PubMed2002

Subperiosteal orbital hemorrhage as initial manifestation of Christmas disease (factor IX deficiency).

PURPOSE: To report a case of subperiosteal orbital and subgaleal hemorrhage with optic nerve compromise in a patient with a factor IX deficiency. DESIGN: Interventional case report. METHODS: A 5-year-old male presented 10 days after mild trauma with progressive left-sided scalp swelling, proptosis, and visual loss. RESULTS: The patient had marked proptosis of the left eye, 20/200 visual acuity, and an afferent pupillary defect. Magnetic resonance imaging demonstrated a large subgaleal and left subperiosteal orbital hematoma. Quantitative assays of coagulation proteins identified a factor IX deficiency (Christmas disease). CONCLUSION: Delayed-onset subgaleal and subperiosteal orbital hematoma can rarely be an initial manifestation of Christmas disease.

Child, Preschool↗
PubMed1998

Multidose pharmacokinetics of factor IX: implications for dosing in prophylaxis.

The aim of this study was to investigate the use of single-dose pharmacokinetic data for factor IX (FIX) to predict multidose pharmacokinetics and explore their use for pharmacokinetic dosing in prophylactic treatment of haemophilia B. Eight patients with severe haemophilia B were enrolled. Using single-dose pharmacokinetic data for each patient, plasma factor IX procoagulant activity (FIX:C) curves during prophylactic dosing were computer-simulated. The simulations were verified by repeated blood sampling and measurements of FIX:C. Theoretical dosing regimens to maintain a plasma trough level of 1.0 U dL-1 of FIX:C were calculated. A 2 x 2 week cross-over study on standard dosing according to bodyweight vs. dosing every three days based on individual pharmacokinetics was carried out. FIX:C was measured during each treatment period. FIX:C data from the plasma sampling generally confirmed the single-dose pharmacokinetic data used. Pharmacokinetically tailored dosing of FIX could result in considerable savings of factor concentrate as compared to current standard dosing. The study demonstrates the applicability of individual pharmacokinetics as a tool for cost-effective utilization of FIX concentrates in the prophylactic treatment of haemophilia B.

Adult↗
PubMed1996

A-793 G to A transition in the factor IX gene promoter is polymorphic in the Caucasian population.

We report the incidence of a prevalent polymorphism at position -703 in the promoter region of the factor IX gene in caucasian individuals. This DNA change was originally reported as one of two changes in the factor IX gene of a severely affected haemophilia B patient from Japan. We confirm the neutral nature of this change and demonstrate that, despite showing linkage disequilibrium with the previously reported Msel RFLP < 100 bp distant, the use of these two loci together in a carrier screening strategy significantly increases the level of informativity over the achieved using either polymorphism alone.

Base Sequence↗
PubMed2000

Genetic mechanisms of age regulation of blood coagulation: factor IX model.

Blood coagulation capacity increases with age in healthy individuals, apparently because of increases in the plasma concentration of most procoagulant factors. This phenomenon may play an important role in the advancing age-associated increase of cardiovascular diseases and thrombosis. Through longitudinal analyses of transgenic mice, we recently identified 2 critical age-regulatory elements, AE5' and AE3', which are together essential for age regulation of the normal human factor IX (hFIX) gene. AE5', present in the long interspersed repetitive element-derived sequence of the 5' upstream region, containing polyomavirus enhancer activator-3 or a closely related element, is responsible for age-stable expression of the gene and functions in a position-independent manner. AE3', present in the middle of the 3' untranslated region, is responsible for age-associated elevation of hFIX mRNA levels in the liver. Presence of both AE5' and AE3' is needed to recapitulate normal age regulation of the hFIX gene. Because factor IX clearance from the circulation is not significantly affected by age, age regulation of hFIX levels is achieved primarily by a combination of stabilization of gene transcription and age-dependent increases in the mRNA levels, which are presumably due to increasing mRNA stabilization. The stage is now set for further systematic studies of the genetic and molecular mechanisms of age regulation of other key coagulation and anticoagulation factors in hopes of understanding the overall age regulation of blood coagulation.

Aging↗
PubMed2002

The interaction of factor XIa with activated platelets but not endothelial cells promotes the activation of factor IX in the consolidation phase of blood coagulation.

We have previously shown that the zymogen factor XI (FXI) binds to activated platelets but not to human umbilical vein endothelial cells (HUVEC), a conclusion that is in conflict with previous reports stating that FXI binds to 2.7-13 x 10(6) high affinity sites per HUVEC (Berrettini, M., Schleef, R. R., Heeb, M. J., Hopmeier, P., and Griffin, J. H. (1992) J. Biol. Chem. 267, 19833-19839; Shariat-Madar, Z., Mahdi, F., and Schmaier, A. H. (2001) Thromb. Haemostasis 85, 544-551). It has also been reported that activated FXI (FXIa) binds to 1.5 x 10(6) sites per HUVEC and promotes the activation of factor IX by cell bound FXIa (Berrettini, M., Schleef, R. R., Heeb, M. J., Hopmeier, P., and Griffin, J. H. (1992) J. Biol. Chem. 267, 19833-19839). Therefore, the binding of FXIa to activated platelets was compared with FXIa binding to HUVEC and HEK293 cells immobilized on microcarrier beads. Specific and saturable zinc-dependent FXIa binding was demonstrated to 250 +/- 48 sites per activated platelet (K(D) = 1.7 +/- 0.78 nm) and 6.5 +/- 0.4 x 10(4) sites per HUVEC (K(D) = 2.4 +/- 0.5 nm), whereas no binding to HEK293 cells was detected. A titration with high molecular weight kininogen had no effect on FXIa binding to platelets, but revealed a concentration-dependent decrease in the amount of FXIa bound to HUVEC. The rate of factor IXa generation catalyzed by FXIa was unaffected by the presence of surfaces; however only the activated platelet surface protected FXIa from inhibition by protease nexin 2. The results presented here confirm the conclusion that activated platelets are procoagulant while unstimulated endothelial cells are not.

Amyloid beta-Protein Precursor↗
PubMed2000

Role of vector in activation of T cell subsets in immune responses against the secreted transgene product factor IX.

Defining immune responses against the secreted transgene product in a gene therapy setting is critical for treatment of genetic diseases such as hemophilia B (coagulation factor IX deficiency). We have previously shown that intramuscular administration of an adeno-associated viral (AAV) vector results in stable expression of therapeutic levels of factor IX (F.IX) and may be associated with humoral immune responses against F.IX. This study demonstrates that intramuscular injection of an AAV vector expressing F.IX fails to activate F.IX-specific cytotoxic T lymphocytes (CTLs) in hemostatically normal or in hemophilia B mice, so that there is an absence of cellular immune responses against F.IX. However, transgene-derived F.IX can cause B cell responses characterized by production of T helper cell-dependent antibodies (predominantly IgG1, but also IgG2 subclasses) resulting from activation of CD4+ T helper cells primarily of the Th2 subset. In contrast, administration of an adenoviral vector efficiently activated F.IX-specific CTLs and T helper cells of both Th1 and Th2 subsets, leading to inflammation and destruction of transduced muscle tissue and activation of B cells as well. Therefore, vector sequences fundamentally influence T cell responses against transgene-encoded F.IX. In conclusion, activation of the immune system in AAV-mediated gene transfer is restricted to pathways mediated by F.IX antigen presentation through MHC class II determinants resulting in T and B cell responses that are more comparable to responses in the setting of protein infusion rather than of viral infection/gene transfer.

Adenoviridae↗
PubMed1994

Construction, expression, and properties of a recombinant chimeric human protein C with replacement of its growth factor-like domains by those of human coagulation factor IX.

The cDNA encoding a chimeric human protein C (PC), in which its epidermal growth factor-(EGF) like regions have been replaced with equivalent structures from human factor IX (fIX), was constructed and the gene product was expressed in human 293 cells. A molecular subpopulation of the recombinant chimeric protein (r-[PC/delta EGF-1,2/delta fIXEGF-1,2]) was purified that contained the full complement (9 residues/mol) of gamma-carboxyglutamic acid (Gla). After conversion by thrombin to its activated form (r-[APC/delta EGF-1,2/delta fIXEGF-1,2]), this latter enzyme was found to possess approximately 10% of the activity of wild-type recombinant APC (wtr-APC) in an APTT assay. In assay systems employing purified components, the activity of the mutant enzyme toward prothrombinase cofactor Va (fVa) and tenase cofactor VIII (fVIII) was approximately 30% and < 10%, respectively, of that of wtr-APC. The chimeric protein displayed full reactivity with a Ca(2+)-dependent monoclonal antibody to the Gla domain of PC, yielding a C50 for Ca2+ that was very similar to that obtained with wtr-PC (ca. 3.7 mM). Titrations of the dependency on Ca2+ of the intrinsic fluorescence of r-[PC/delta EGF-1,2/delta fIXEGF-1,2] allowed calculation of a C50 value of 0.34 mM, again very similar to that of wtr-PC. As with wtr-PC, Ca2+ inhibited the thrombin-catalyzed activation of r-[PC/delta EGF-1,2/delta fIXEGF-1,2] with aKi of 148 microM, as compared to a Ki of 125 microM for wtr-PC. At a saturating level of Ca2+, activation of r-[PC/delta EGF-1,2/delta fIXEGF-1,2/] by the thrombin/thrombomodulin (thrombin/TM) complex occurred at approximately 70% of the rate of that of wtr-PC.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acid Sequence↗
PubMed1982

Effect of granulocyte proteases on human coagulation factors IX and X. The protective effect of calcium.

The inactivation of the zymogen and active forms of Factors IX and X by the effect of granulocyte proteases was investigated. As deduced from the apparent first-order inactivation rate constants, Factors IXa and Xa were about ten times as sensitive to proteolytic inactivation as the zymogen factors. In the presence of 2.5mM CaCl2 the rate of inactivation of zymogens decreased to one half. With the active factors, calcium caused complete resistance to proteolysis, prevailing for 15 min. The analysis of resistance to proteolysis, prevailing for 15 min. The analysis of resistance to proteolysis led us to the conclusion that the observed phenomenon was related to the calcium binding ability of the factors studied and can probably be explained by the protection of the active sites of enzymes.

Calcium Chloride↗
PubMed1990

[Coagulation factor IX inhibitor in hemophilia B].

An inhibitor against blood clotting factor IX was observed as a very rare finding in case of an eight year old boy suffering from haemophilia B. By reason of a haemarthros a replacement therapy was successful done using FEIBA (Factor Eight Inhibitor Bypassing Activity). The haemostatic characterization of the inhibitor and its influence by therapy will be presented.

Child↗
PubMed2001

Vitronectin in clotting factor IX concentrates.

Highly purified, plasma-derived factor IX (FIX) concentrates are produced in large part by a combination of anion exchange and heparin affinity chromatography. However, the concentrates still contain some accompanying proteins. The main impurity has turned out to be the adhesive glycoprotein, vitronectin. It occurs in concentrates exclusively in its multimeric form, in contrast to the situation in plasma. The multimeric vitronectin can be removed either by nanofiltration with a crossflow system or by size-exclusion chromatography. When these FIX concentrates are used as therapeutic agents, the fact has to be taken into account that considerable amounts of multimeric vitronectin are given to the patient. The physiological consequences of the dosage of this protein have not yet been investigated. Although no thrombogenicity has been reported in connection with the above-mentioned FIX concentrates, we recommend that the impurity should be removed from the preparation with the methods described here.

Blood Coagulation Factors↗
PubMed1991

CG dinucleotide transitions in the factor IX gene account for about half of the point mutations in hemophilia B patients: a Seattle series.

Hemophilia B is due to multiple molecular defects in the factor IX gene. Over 80% of mutations are single base substitutions. By amplification and direct sequencing, 51 single base substitutions were found in the transcribed sequence of the factor IX genes of patients from 50 distinct families with hemophilia B. These include 30 mutations in 29 families not previously reported by us; of these, 12 are novel, i.e., not previously published in other series. Of the 51 substitutions in our overall series 23 (45%) occurred as C-to-T or G-to-A transitions at 11 sites within CG dinucleotides. It is estimated that CG transitions occur from one to two orders of magnitude more frequently than mutations in nucleotides that are not within a CG pair. More than one family had identical defects for 6 of the CG mutations. At 4 of these sites, most patients had different haplotypes compatible with distinct mutations. Non-CG-type mutations occurred throughout the coding regions with only one mutation in more than one family. The latter included 7 families with a 397 Ile-to-Thr defect that all share a rare haplotype, suggesting a common ancestor.

Amino Acid Sequence↗
PubMed1984

Characterisation and use of an intragenic polymorphic marker for detection of carriers of haemophilia B (factor IX deficiency).

DNA from 33 healthy White subjects was analysed with a 2 X 5 kilobase subgenomic DNA probe derived from the gene for coagulation factor IX, containing the exon "d" region of that gene. Intragenic Taq I restriction-fragment length polymorphism was revealed, with allelic frequencies estimated at 0 X 65 and 0 X 35 (SE = 0 X 06), also detectable by a cDNA probe. The genomic DNA probe is technically superior to the cDNA probe and has been used in three families with haemophilia B (factor IX deficiency). The polymorphic marker segregates with the deleterious mutation, allowing the identification or exclusion of carriers. The allelic frequencies of the Taq I polymorphism are virtually ideal. Therefore, such a polymorphism should be helpful both in genetic counselling of approximately 40% of affected families and in prenatal diagnosis.

Alleles↗