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At least 217 records · Page 12Linked to original sources
PubMed1990

Disruption of a C/EBP binding site in the factor IX promoter is associated with haemophilia B.

Haemophilia B (or Christmas disease) is an inherited, X-linked bleeding disorder caused by mutations in the gene for clotting factor IX. There is a rare class of patients, exemplified by haemophilia B Leyden, who suffer from haemophilia B as children but improve after puberty. In these patients, plasma factor IX concentrations are less than 10% of normal during childhood, but after puberty they gradually rise to between 40 and 80% of normal. Mutations clustered around the main transcription start point (defined as +1 (ref.2)) have been reported in seven of these patients (at -20 (refs 1, 3, 4); -6 (refs 5, 6) and +13 (refs 7, 8)). To determine how these mutations interfere with factor IX expression, we have assayed for transcription factors binding to this area and have identified a nuclear factor-1 liver (NF1-L) binding site (-99 to -76) and a binding site for the CCAAT/enhancer binding protein (C/EBP) (+1 to +18). We show that the A----G mutation at +13 prevents the binding of C/EBP to this site. Furthermore, we show that C/EBP is capable of transactivating a cotransfected normal factor IX promoter but not the mutant promoter. This is the first natural mutation to be reported which disrupts a C/EBP binding site and is an illustration of the importance of this transcription factor in humans.

Age Factors↗
PubMed2002

Management of splenic trauma in the pediatric hemophiliac patient: Case series and review of the literature.

In July and August 1998, 3 patients who attend the Hemophilia Treatment Center required emergency admission to the authors' hospital for management of hemorrhagic shock caused by splenic injury. Computed tomography was used to diagnose and grade the splenic injuries, which ranged from II to IV on the organ injury scale. Two patients had Christmas disease (Factor IX deficiency) and were treated with splenorrhaphy and factor IX replacement. One patient who has severe von Willebrand disease (Type 3) had grade II splenic injury that required splenectomy to secure hemostasis. The coagulopathic deficiency was aggressively treated in each patient. All patients required operative intervention with attempted splenorrhaphy. All patients survived their operative experience, and none suffered a rebleeding episode. With correction of the coagulopathy throughout the perioperative period and local hemostatic control by operative techniques, salvage procedures for splenic injury were successful for 2 of these 3 patients.

Adolescent↗
PubMed1990

Expression of human factor IX in rabbit hepatocytes by retrovirus-mediated gene transfer: potential for gene therapy of hemophilia B.

Hemophilia B (Christmas disease) is a chromosome X-linked blood clotting disorder which results when factor IX is deficient or functionally defective. The enzyme is synthesized in the liver, and the existence of animal models for this genetic disease will permit the development of somatic gene therapy protocols aimed at transfer of the functional gene into the liver. We report the construction of an N2-based recombinant retroviral vector, NCMVFIX, for efficient transfer and expression of human factor IX cDNA in primary rabbit hepatocytes. In this construct the human cytomegalovirus immediate early promoter directs the expression of factor IX. Hepatocytes were isolated from 3-week-old New Zealand White rabbits, infected with the recombinant virus, and analyzed for secretion of active factor IX. The infected rabbit hepatocytes produced human factor IX that is indistinguishable from enzyme derived from normal human plasma. The recombinant protein is sufficiently gamma-carboxylated and is functionally active in clotting assays. These results establish the feasibility of using infected hepatocytes for the expression of this protein and are a step toward the goal of correcting hemophilia B by hepatic gene transfer.

Animals↗
PubMed1991

Somatic mosaicism and female-to-female transmission in a kindred with hemophilia B (factor IX deficiency).

Studies have shown that hemophilia B (Christmas disease; factor IX deficiency) results from many different mutations in the factor IX gene, of which greater than 95% are single nucleotide substitutions. This study has identified a previously unreported form of hemophilia B in a patient who was a somatic mosaic for a guanine-to-cytosine transversion at nucleotide 31,170 in the factor IX gene. This point mutation changes the codon for residue 350 in the catalytic domain of factor IX from a cysteine to a serine. We used differential termination of primer extension to confirm and measure the degree of mosaicism. Our study shows that a varying proportion of cells from hepatic, renal, smooth muscle, and hematopoietic populations possessed normal as well as mutant factor IX sequences. These results indicate that the mutation in this patient occurred either as an uncorrected half-chromatid mutation in the female gamete or as a replication or postreplication error in the initial mitotic divisions of the zygote preceding implantation. In addition, this kindred also contains two females in successive generations who have moderately severe factor IX deficiency. The molecular pathogenesis of this latter phenomenon has been studied and seems to relate to the unaccompanied expression of the mutant factor IX gene consequent upon a second, as yet undefined, genetic event that has prevented inactivation of sequences including the mutant factor IX gene on the X chromosome inherited from the affected male.

Base Sequence↗
PubMed1988

High-dose intravenous immunoglobulin and splenectomy for the treatment of HIV-related immune thrombocytopenia in patients with severe haemophilia.

Four patients with severe haemophilia A and one patient with severe Christmas disease developed severe immune thrombocytopenia (platelet count less than 20 x 10(9)/l). All five patients were HIV-antibody positive and one was HIV-antigen positive. Four patients were treated initially with prednisolone, but with only a transient platelet response in three and no response in the fourth. All patients were treated with high dose intravenous immunoglobulin (0.4 g/kg daily for 5 d) resulting in a rise in platelet count in all cases (range 138-300 x 10(9)/l) and then proceeded to splenectomy. Three remain in complete remission after 6-14 months, and one showed a good response with platelet counts ranging from 103 to 187 x 10(9)/l. The fifth patients achieved a normal platelet count for 3 months post-splenectomy, but suffered a relapse with platelet counts ranging from 25 to 108 x 10(9)/l over the next 3 years. However, following a severe Varicella infection 10 months ago, during which he developed a marked transient thrombocytosis, he has also maintained a normal platelet count.

Adolescent↗
PubMed1984

Abnormal T-cell subpopulations in hemophilic patients receiving factor VIII concentrates from voluntary donors.

Recently, Acquired Immune Deficiency Syndrome (AIDS) has been reported in hemophiliacs in the USA, Canada and Spain, and this has caused considerable concern amongst hemophiliacs regarding the use of factor VIII concentrates. The aim of this study was to determine whether hemophiliacs in Australia have T-lymphocyte subpopulation changes similar to those observed in patients with AIDS. Factor VIII produced in Australia is derived from a totally volunteer blood donor system and none of the hemophiliacs in this study had received commercial blood products. For the hemophiliacs, the T-helper cell to T-suppressor cell ratio was 1.1 +/- 0.6 (mean +/- SD) which was significantly less (p less than 0.001) than that of the normal age and sex-matched controls. There was a significant relative (p less than 0.001) and absolute (p less than 0.05) reduction of the helper cell subsets and a significant relative (p less than 0.001) and absolute (p less than 0.05) increase of the suppressor cell subsets, in the hemophiliacs compared to the normal controls. There appears to be no correlation between the amount of factor VIII therapy received during the last three years and the T-cell subset changes. All patients with Christmas disease had T-cell subsets within the normal range. All patients were negative for the hepatitis B virus antigen, but all were positive for the antibody, indicating that there had been exposure to the hepatitis virus in all cases. Cytomegalovirus titres were uniformly low and immunoglobulin levels were normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1975

The therapeutic role of epsilon-aminocaproic acid (EACA) for dental extractions in hemophiliacs.

The results of a double-blind controlled trial, previously reported, showed that EACA is a useful adjunct to preoperative therapeutic concentrates of factor VIII or IX for dental extractions in hemophilia and Christmas disease. To estimate the amount of factor VIII and IX conserved in hemophiliacs receiving EACA for dental surgery compared with those not receiving EACA we have surveyed the usage of therapeutic materials in ten hemophilia centers in the U.S. and at Oxford. The amount of postoperative factor-VIII containing materials given to 20 U.S. hemophiliacs not receiving EACA averaged 11 062 units of factor-VIII activity per patient; 4,146 units for each of 22 U.S. patients receiving EACA; and 717 units for each of 56 patients at Oxford receiving EACA. Conservation of factor-IX-containing material was not as great. At Oxford 62.5% of patients receiving preoperative factor-VIII or -IX concentrates sufficient to raise the deficient factor to 50% of normal together with EACA, 24 g per day for ten days, required no postoperative therapeutic materials to control bleeding. The remainder required an average of two postoperative doses to control bleeding.

Adult↗
PubMed1986

Liver dysfunction in haemophilia.

Liver function was studied in 139 of 291 haemophiliacs known to a single Regional Haemophilia Centre including patients with classical haemophilia, Christmas disease and von Willebrand's disease. In 57 patients, six-monthly liver function tests over a five year period were also available. Thirty-nine of the 139 patients had had jaundice or hepatitis and 56 had a positive test for HBsAb in the blood although few of these had had an identifiable clinical illness. Fifty-eight haemophiliacs had elevated serum aminotransferases at the time of study, but the five year review revealed only six patients who had had persistently abnormal results, although none had clinically evident liver disease. Liver dysfunction was unrelated to a history of hepatitis, to a positive HBsAb test, or to age, type of haemophilia, factor level or frequency of factor replacement treatment. Abnormalities of liver function in haemophilia appear to be unrelated to past or present hepatitis B infection in most cases and may not be related to any single transmitted infectious agent.

Adult↗
PubMed2004

Permanent phenotypic correction of hemophilia B in immunocompetent mice by prenatal gene therapy.

Hemophilia B, also known as Christmas disease, arises from mutations in the factor IX (F9) gene. Its treatment in humans, by recombinant protein substitution, is expensive, thus limiting its application to intermittent treatment in bleeding episodes and prophylaxis during surgery; development of inhibitory antibodies is an associated hazard. This study demonstrates permanent therapeutic correction of his disease without development of immune reactions by introduction of an HIV-based lentiviral vector encoding the human factor IX protein into the fetal circulation of immunocompetent hemophiliac and normal outbred mice. Plasma factor IX antigen remained at around 9%, 13%, and 16% of normal in the 3 hemophilia B mice, respectively, until the last measurement at 14 months. Substantial improvement in blood coagulability as measured by coagulation assay was seen in all 3 mice and they rapidly stopped bleeding after venipuncture. No humoral or cellular immunity against the protein, elevation of serum liver enzymes, or vector spread to the germline or maternal circulation were detected.

Animals↗
PubMed1976

Failure of immunosuppression in a severe haemophilia B patient with specific antibody.

Prevention of a secondary response to factor IX by cyclophosphamide was attempted in an 11 year old patient with severe Christmas disease. An antibody to factor IX had been present for 4 years before immunosuppressive therapy was tried. Despite profound lymphopenia, synthesis of factor IX antibody was not depressed. The difficulties of modifying the anamnestic response to factor IX by chemical immunosuppression may be as real as has been reported for factor VIII in classical haemophilia.

Antibodies↗
PubMed1975

Pregnancy and delivery in a woman with hemophilia B.

Hemophilia B (Factor IX deficiency, Christmas disease) may cause excessive bleeding in women. The obstetric and hematologic management of the pregnancy and delivery of a woman with a Factor IX level of 4% is presented and discussed.

Adult↗
PubMed1975

Serial changes in the coagulation system following clotting factor concentrate infusion.

Various parameters of the coagulation system have been monitored in patients with Christmas disease following the infusion of clotting factor concentrates. Significant reduction of clotting factor VIII and serum antithrombin III were observed in each of the five studies, whilst the plasma fibrinogen level fell in four subjects. The induced abnormalities were shortlived and there were no clinical sequelae. Further studies are required to assess the effects of similar concentrates in patients with liver disease.

Antithrombins↗
PubMed1992

An unusual complication in a gravida with factor IX deficiency: case report with review of the literature.

Factor IX deficiency (hemophilia B, Christmas disease) is an X-linked recessive coagulation disorder. It occurs in one out of every 25,000-30,000 male births and requires even rarer genetic circumstances for phenotypic expression in females. We report the occurrence of a large, late-trimester subchorionic hematoma in a gravida with factor IX deficiency and with laboratory evidence of consumptive coagulopathy during treatment. The patient was managed conservatively and had a successful outcome at term. The only four reported cases of antepartum management of factor IX deficiency in the English literature are reviewed.

Adolescent↗
PubMed2005

Hemophilia B and free tissue transfer: medical and surgical management.

Hemophilia B (Christmas disease) is a rare, X-linked bleeding diathesis, which may present with life-threatening hemorrhage. Management of the coagulopathy in the setting of free tissue transfer may be particularly challenging. The authors present the first case in the English literature of a male with hemophilia B undergoing microvascular free flap reconstruction, as well as a review of the current surgical and medical management of hemophilia B. Based upon this experience, perioperative specific factor replacement is recommended. Given physiologic trough levels of the replaced factor, routine antiplatelet therapy appears appropriate. Management of free tissue transfer in the setting of severe hemophilia is significantly more challenging and should benefit from multidisciplinary coordination.

Aged↗
PubMed1990

Haemophilia in Zimbabwe.

Of the 120 haemophiliacs diagnosed in Zimbabwe in 8 years, haemophilia A and Christmas disease accounted for 90% and 10% respectively (i.e. a ratio of 9:1). Although the clinical and laboratory parameters were essentially similar to those previously described in Caucasian, African and other populations in the World, sub-haemophiliac cases are probably still being missed particularly in very busy health centres where the index of suspicion is low and malnutrition and infectious disease predominate and therefore readily attract the attention of most health workers. However, with the steadily improving socio-economic status and decentralization of health care facilities, more of these cases are likely to be diagnosed. Major constraints in the diagnosis and management of haemophilia in an African setting are succinctly discussed; including home therapy; and the implications of recent findings of HIV sero-positivity. The study serves as evidence that haemophilia is common in Zimbabwe contrary to earlier published literature.

Adolescent↗
PubMed1987

The molecular pathology of haemophilia.

The great success of recombinant DNA technology in unravelling the pathology of the thalassaemias at a molecular level has encouraged the application of these methods to other single gene disorders of man in the hope of gaining a deeper insight into the biochemical defects underlying them. An example of this approach is provided by the sex-linked recessive disorders of blood clotting: haemophilia and Christmas disease. These clinically indistinguishable, life-long disorders result from the deficiency or abnormality of the clotting proteins factor VIII and factor IX, respectively, which both participate in the activation of factor X in the intrinsic pathway of blood coagulation. This paper looks at the information concerning the molecular biology and pathology of the haemophilias which has recently been forthcoming. The genes for factor VIII and factor IX have both been successfully cloned within the past five years, with that of factor VIII, achieved in 1984, being a particular tour de force. It encompasses 0.1 per cent of the human X chromosome and is the largest gene yet characterised. Gene cloning is the starting point from which gene probes can be designed to elucidate the molecular pathology of the haemophilias. The implications of these discoveries for the practice of clinical medicine are reviewed, with special emphasis on prenatal diagnosis and carrier detection by means of restriction fragment length polymorphisms, and replacement therapy with recombinant factor VIII.

Genetic Engineering↗
PubMed1985

AIDS and haemophilia.

Approximately 1% of all AIDS cases are haemophiliacs. LAV/HTLV-III is transmitted by blood and in factor VIII concentrates. Since 1981, increasing numbers of haemophiliacs have been infected, as indicated by detection of antibodies to LAV/HTLV-III. Up to 90% of haemophiliacs in some populations are now seropositive, but to date less than 1% have progressed to clinical AIDS. Immunological abnormalities, in particular reduced T-lymphocyte helper/suppressor ratios, are common in haemophiliacs treated with factor VIII. Such abnormalities do not necessarily indicate past infection by the AIDS virus, but they may predispose to infection following exposure to the virus. Blood Transfusion agencies are introducing screening tests for antibodies to LAV/HTLV-III to help prevent the spread of AIDS by blood products. Heat treated factor VIII concentrate is now available and appears not to transmit AIDS. Factor IX concentrate may also transmit LAV/HTLV-III, but less frequently. A few cases of AIDS have occurred in Haemophilia B (Christmas Disease) patients.

Acquired Immunodeficiency Syndrome↗