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Query: UMLS:C0684275 (haemophilia)
 10,958 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Haemophilia is an ideal condition for gene therapy because of its monogenetic character and the fact that it requires only a small amount of the expressed protein to achieve palliation. To date, research in the field of gene therapy for haemophilia has largely relied on retroviruses, adenoviruses and adeno-associated viruses as transfer vectors and the major aims will be to achieve stable longlasting in vivo expression of factors VIII or IX (FVIII or FIX) at therapeutic levels. Two clinical trials have been approved by the US Food and Drug Administration (FDA), using miniadenovirus FVIII and the intrahepatic and intramuscular delivery of adeno-associated virus FIX. In the third millennium, haemophilia treatment should encompass more ambitious goals through gene replacement, to result in permanent and safe haemophilia 'eradication', making haemophilia a part of the history of medicine.
Haemophilia 2001 Sep
PMID:Gene therapy for haemophilia: the end of a 'royal pathology' in the third millennium? 1155 29

Hemophilia is a genetically inherited bleeding disorder caused by a deficiency of the blood clotting factors VIII (hemophilia A) or IX (hemophilia B). Hemophiliacs suffer prolonged bleeding which can be life threatening and often leads to chronic disabilities. Current hemophilia treatment involves infusions of plasma-derived or recombinant clotting factor in response to bleeding crises. Prophylactic treatment is not available and current treatments remain problematic. The development of a gene therapy for hemophilia has been under investigation for the past decade. An overview is presented of the initial efforts using retroviral and adenoviral vectors for ex vivo and in vivo gene delivery strategies, respectively. Recent progress in developing FIX and FVIII adeno-associated virus vectors is reviewed. Sustained expression of therapeutic levels of FIX and FVIII have been demonstrated in mice. Phenotypic correction of hemophilia B has been shown in the murine and dog models of disease. A phase I human clinical trial has been initiated involving intramuscular injection of FIX. Prospectsfor hemophilia gene therapy look bright and the hopefor a cure has now moved from the realm of the possible to the probable.
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PMID:Gene therapy for hemophilia. 1171 65

Human parvovirus B19 (B19) has been transmitted by some brands of virally attenuated plasma-derived factor VIII (FVIII) or IX (FIX) concentrates. To quantify the differences of human parvovirus B19 risk transmission between albumin-stabilized recombinant factor and plasma-derived factor, we studied the prevalence of IgG antibodies to B19 (anti-B19) in 193 haemophiliac children between 1 and 6-years of age who had previously been treated with albumin-stabilized recombinant FVIII only (n = 104), and in children previously treated with solvent/detergent high-purity non-immunopurified and non-nanofiltered FVIII or IX concentrates (n = 89). Association between the prevalence of anti-B19 and the treatment group was analysed using multivariate logistic regression. Age, severity and type of haemophilia, number of cumulative days of exposure to factor VIII or IX, previous history of red blood cells or plasma transfusion were considered as potential confounding variables. A higher prevalence of anti-B19 was found in children previously treated with solvent/detergent high-purity non-immunopurified and non-nanofiltered FVIII or IX concentrates than in children treated with albumin- stabilized recombinant FVIII only (OR: 22.3; CI: 7.9-62.8), independently of the other factors studied.
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PMID:Prevalence of IgG antibodies to human parvovirus B19 in haemophilia children treated with recombinant factor (F)VIII only or with at least one plasma-derived FVIII or FIX concentrate: results from the French haemophilia cohort. 1184 42

Recombinant human FIX (rFIX) was evaluated in 28 subjects, including 26 with mild, moderate, or severe haemophilia B and two haemophilia B carriers undergoing 36 surgical procedures. Preoperative rFIX dose was highly correlated with postinfusion FIX activity, r=0.61, P=0.0158. Peri- and post-operative estimated blood loss was similar to that expected in non-haemophilic individuals, and haemostasis was rated as excellent or good in 34 of 35 (97.1%) of the operative procedures. Transfusions were required in five of 36 (13.9%) procedures, including one liver transplantation, and three knee and one hip arthroplasties. Adverse events occurred in 15 of 28 (53.6%) subjects, but there were no perioperative haemorrhages, thromboembolic events, coagulation activation, viral transmission, or inhibitor formation. A transient low-responding FIX inhibitor developed in one subject preoperatively, but required no change in treatment and resolved 15 months later. Thus, rFIX was found to be safe and effective in achieving haemostasis in subjects with FIX deficiency undergoing surgery.
Haemophilia 2002 Mar
PMID:Use of recombinant factor IX in subjects with haemophilia B undergoing surgery. 1195 43

The development of inhibitors to therapeutic factor concentrates in children with haemophilia A or B is a troublesome complication of factor replacement therapy. Immune tolerance protocols have been developed to eliminate the inhibitors, and these are successful in approximately 80% of children. However, acute bleeding episodes require treatment with a factor (F)VIII or FIX bypassing agent to prevent an anamnestic rise in the inhibitor level before starting immune tolerance. In addition, central venous access is necessary to help parents administer frequent, high dose factor concentrate. In view of the benefits of rFVIIa seen in adults, a study has been carried out on the use of this agent as haemostatic cover in children with severe FVIII or FIX deficiency with high responding inhibitors. Information was obtained retrospectively from the National Children's Hospital, Dublin and Great Ormond Street Hospital, London. Twelve children aged 1-16 years were treated successfully with rFVIIa to prevent surgical bleeding in 20 surgical procedures. Minor post-operative haematomata developed in 2 of 20 cases after regular rFVIIa therapy had been discontinued. In both cases, resolution of bleeding occurred after a short course of rFVIIa. Three children experienced a total of six life- or limb-threatening bleeds. All bleeding episodes resolved with regular rFVIIa treatment, although topical fibrin glue was needed in one child with a frenulum tear. The rFVIIa therapy was well tolerated and there was no evidence of any treatment-related complications. In conclusion, rFVIIa is the treatment of choice for the management of surgery and acute life- or limb-threatening bleeding in children with haemophilia and high responding inhibitors.
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PMID:Recombinant factor VIIa in the management of surgery and acute bleeding episodes in children with haemophilia and high-responding inhibitors. 1221 42

Haemophilia is the most serious bleeding model that nature has provided us with, indicating the importance of factor FVIII and FIX in haemostasis. According to current knowledge, haemostasis is initiated by the formation of a complex between tissue factor (TF), exposed as a result of a vessel wall injury, and activated FVII (FVIIa) that is normally present in circulating blood. The TF-FVIIa complexes convert FX into FXa on the TF-bearing cell. FXa then activates prothrombin into thrombin. This limited amount of thrombin activates FVIII, FV, FXI and platelets. Thrombin-activated platelets change shape, resulting in exposure of negatively-charged phospholipids, which form the perfect template for full thrombin generation involving FVIII and FIX. In patients with haemophilia FVIII or FIX is missing. These individuals generate only initial limited amounts of thrombin as its generation is dependent on the presence of FVIII and FIX. Full thrombin generation is necessary for complete activation of FXIII and thrombin activatable fibrinolytic inhibitor to occur. Furthermore, full thrombin generation is important for the fibrin structure of the haemostatic plug. In the case of impaired thrombin generation, fibrin plugs will be loose and highly permeable. Such fibrin plugs are easily dissolved by normal fibrinolytic activity and thus prevent full and maintained haemostasis from occurring. The addition of rFVIIa to FVIII- or FIX-deficient plasma has been shown to increase thrombin generation in a cell-based in vitro model. Furthermore, extra rFVIIa was found to normalise fibrin clot permeability in vitro and to tighten the fibrin structure as studied by three-dimensional confocal microscopy. These findings indicate that administration of rFVIIa is capable of compensating for the lack of FVIII and FIX. Accordingly, the administration of exogenous rFVIIa has been found to stop bleedings in haemophilia patients and, provided it is given in doses high enough, to allow major surgery to be performed in severe haemophiliacs with inhibitors. As rFVIIa enhances thrombin generation on already activated platelets, it has been suggested that rFVIIa may also help to improve haemostasis in other situations involving impaired thrombin generation, such as platelet disorders (thrombocytopenia and functional platelet defects). Preliminary clinical data appear to support this. Patients with profuse bleeding due to extensive surgery or trauma often develop a complex coagulation pattern which includes reduced plasma levels of fibrinogen, FVIII and FV, and decreased platelet counts. These patients may well have an impaired capacity to generate thrombin. Consequently, they may benefit from one or two doses of rFVIIa in order to assist in the generation of a thrombin peak sufficient to form a firm, stable fibrin haemostatic plug and thereby reduce bleeding. This would facilitate any mechanical repair necessary for full haemostasis. Preliminary results in a few patients may support such an effect for rFVIIa. As thrombin has such a crucial role in providing haemostasis, any agent that enhances the thrombin generation in situations with an impaired thrombin formation may be characterised as a 'general haemostatic agent'. Let us look forward to more 'facts' through the 'evidence-based route'.
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PMID:General haemostatic agents--fact or fiction? 1221 45

Recombinant activated factor VII (rFVIIa, 'NovoSeven') is indicated for the treatment of spontaneous and surgical bleeding in patients with haemophilia A or B with antibodies to factors VIII or IX (FVIII or FIX) worldwide, and in patients with acquired haemophilia in Europe. In vitro cell models have demonstrated that rFVIIa can bind to activated platelets and generate small amounts of Fxa, independent of the presence of tissue factor. The amount of platelet-surface Fxa formed increases with rising concentrations of FVIIa and, at levels of rFVII a that are effective in patients, sufficient platelet surface Fxa is generated partially to restore platelet surface thrombin generation. Acquired haemophilia is a rare but potentially life-threatening condition, caused by the autoimmune reduction of clotting factor levels as a result of the spontaneous development of auto-antibodies directed against the deficient factor. Bleeding into the skin or muscles is common in acquired haemophilia and the associated mortality rate is approximately 20%. rFVIIa has reported efficacy in the treatment of major bleeding episodes in patients with acquired haemophilia, which may be explained by its distinct mechanism of action that induces haemostasis at the site of injury, independent of the presence of FVIII or FIX. Also, the localisation of the action of rFVIIa at the site of injury may explain why it is well tolerated in these patients.
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PMID:NovoSeven: mode of action and use in acquired haemophilia. 1240 90

Because peculiar profiles for some genetic haematological diseases have been described among Basques, we aimed to investigate the distribution of haemophilia among this specific population. Hence, we retrospectively assessed all the cases of factor (F) VIII and FIX deficiencies seen in the French Basque country during a 16-year period. Data on 41 patients with haemophilia (FVIII or FIX = 25%) were compiled. Incidence and prevalence for the whole population ranged within the classical limits (but with an unusually high A : B ratio) and tended to be slightly lower in autochthonous Basques (P = n.s.). Our data did not support significant differences in the distribution of this disease among French Basques.
Haemophilia 2002 Nov
PMID:Distribution of haemophilia in the French Basque country. 1241 Jun 40

A comprehensive survey concerning the Shiraz Hemophilia Society and the associated haemophilia treatment centre was undertaken in April 2002 to collect data on demographics, signs and symptoms in the southern Iranian population with haemophilia and allied disorders. The total number of patients with coagulation disorders was 367. Haemophilia A (factor [F] VIII deficiency) was found in 271, 39 had haemophilia B (FIX deficiency) and 24 had von Willebrand disease. The rare coagulation disorders (n = 33) included 11 patients with FX deficiency; 10 with FVII; six with FXIII; two with afibrinogenaemia; two with FXI; one with combined FVIII and FV; and one with combined FVII, FVIII and FIX deficiency. The prevalence was 6.64 per 100,000 inhabitants. The most common symptoms were haemarthrosis, haematomas and epistaxis. None of the patients were human immunodeficiency virus positive but 47 (15%) were hepatitis C virus positive and two (0.7%) were hepatitis B positive, so that the rate of transfusion-transmitted infections was lower compared with other populations.
Haemophilia 2002 Nov
PMID:Inherited coagulation disorders in southern Iran. 1241 Jun 41

Recombinant activated factor VII (rFVIIa, NovoSeven, Novo Nordisk A/S, Denmark) is a treatment used to prevent and arrest intra- and postoperative bleeding in patients with haemophilia A or B complicated by circulating anticoagulants (inhibitors of FVIII and FIX) and in patients without haemophilia who spontaneously develop inhibitors of FVIII, i.e. in acquired haemophilia. Patients who qualify for liver transplantation due to liver dysfunction may have varying degrees of coagulation impairment and thus carry an elevated risk of massive bleeding and have worse prognosis. The authors administered recombinant activated factor VII to two patients with coagulation abnormalities in the course of Wilson's disease during liver transplantation.
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PMID:Application of recombinant activated factor VII for treatment of impaired haemostasis during liver transplantation in recipients with Wilson's disease--a report of two cases. 1246 34


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