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)

Hemophilia Bm, a variant of hemophilia B, results in a marked increase in the ox brain prothrombin time. Mutations known to cause hemophilia Bm occur at residue 180, 181, or 182 near the amino terminus of the heavy chain and at residue 311, 364, 368, 390, 396, or 397 near the activation site of factor IX (Giannelli et al., 1990). In this study we replaced factor IX residues 181, 182, and 390 in separate experiments by site-directed mutgenesis. Valine 181 was replaced by isoleucine or alanine, and valine 182 was replaced by alanine or glycine. Alanine 390 was replaced by valine or aspartic acid. Recombinant factor IXs were expressed in human kidney 293 cells and purified by absorption and elution from a conformational specific monoclonal antibody column. The results show that factor IX Bm is a function not only of the position of the mutated amino acid but also of the particular amino acid substituted. For example, when valine 181 or 182 was replaced by small hydrophobic amino acids (alanine and glycine), factor IXs were found to have significantly decreased clotting activity. Unlike the naturally occurring mutations (Val181 --> Phe181 or Val182 --> Leu182), however, the small amino acid replacements did not result in prolonged ox brain prothrombin times. Surprisingly, the Ala390 --> Asp390 exchange did not affect clotting activity or binding to the macromolecular inhibitor antithrombin III. The Ala390 --> Val390 exchange resulted in loss of both clotting activity and binding to antithrombin III. These results suggest that residue 390 is not directly involved in binding to antithrombin III.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Mutations in the catalytic domain of factor IX that are related to the subclass hemophilia Bm. 851 77

The aftermath of the HIV catastrophe and hepatitis virus transmission to hemophiliacs has been characterized by continuous efforts to improve the purity of factor VIII and factor IX concentrates, increasing sophistication of the virucidal methods used, and the introduction of recombinant factor VIII. The cost of hemophilia care is substantial and there is a large price difference between products depending on their purity; generally, the purer the concentrate, the higher the price. The use of expensive highly purified concentrates may be questioned if these products are not superior in terms of safety, efficacy or convenience. The properties of concentrates used in hemophilia care are discussed in this review, as are their safety and side effects. The available data do not clearly reveal any clinical difference between factor VIII concentrates, although the highly purified products may be of theoretical benefit. With regard to factor IX, purified products do not seem to carry any risk of the well-known thromboembolic complications which occur in certain situations after treatment with prothrombin complex concentrates.
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PMID:Why prescribe highly purified factor VIII and IX concentrates? 880 65

Recent studies using assays for surrogate markers of thrombogenicity in man have demonstrated that activation of the coagulation system occurs following infusion of clinical doses of prothrombin complex concentrates (PCC) but not after the same doses of high-purity factor IX concentrates (HP-FIX) in patients with haemophilia B. Here we have investigated the mechanism of such thrombogenesis by applying assays that detect early-through to late-events in coagulation system activation in a pharmacokinetic cross-over study of 50 IU/kg PCC and a new HP-FIX product in haemophilia B patients. Satisfactory recoveries and half-lives were observed for both concentrates. HP-FIX caused no increases in thrombin-antithrombin III complex (TAT), prothrombin activation peptide fragment F1+2 (F1+2), factor X activation peptide (FXAP) or factor VIIa (FVIIa). In contrast the same dose of factor IX in the form of PCC was followed by significant increases over pre-infusion levels of TAT, F1+2 and FXAP, but not FVIIa. Elevations of FIXAP occurred after both HP-FIX and PCC but did not reach normal levels and were attributed to normalisation of the FIX concentration in those patients whose levels of FIXAP were initially low. We conclude that the thrombogenic trigger associated with PCC infusion occurs at the level of factor X activation. In the absence of any increase in FVIIa, we would attribute this to the likely presence of FIXa in the PCC.
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PMID:High purity factor IX and prothrombin complex concentrate (PCC): pharmacokinetics and evidence that factor IXa is the thrombogenic trigger in PCC. 881 46

In the haemophilic patient, development of antibodies that inhibit the function of the missing coagulation factor causes several delicate problems. Most importantly, antibodies will block the function of the specific coagulation factor, and often the antibody activity is so fierce that effective substitution therapy is outruled. In consequence, alternative measures must be adopted to control bleeding. Amongst those most commonly employed, like factor IX concentrates, activated prothrombin complex concentrates, and factor VIII of porcine origin, a new recombinant activated factor VII molecule has been evaluated clinically for some years with promising results. The aim of the present paper was to present a series of patients suffering from haemophilia A or B in whom inhibitors have complicated the clinical picture, and in whom a surgical procedure was indicated. As part of a compassionate use program devised by the producer of this genetically engineered factor VIIa, 12 patients underwent life-saving or essential surgery where the recombinant factor VIIa product was used to promote haemostasis in 13 surgical procedures. Due to a short in vivo half-life of activated factor VIIa, frequent administration was scheduled, injecting factor VIIa every 2-3 h for up to 2 days after which dosage intervals were prolonged. In one case, a global evaluation of the end treatment result was not reported, but in all of the other 12 cases the end result were considered excellent (n = 11) or efficient (n = 1). In none of the cases was other types of coagulation factor treatment modalities necessary. In conclusion, recombinant factor VIIa seems a tempting alternative to traditional treatment of the haemophilic patient with inhibitors, in whom surgery is called for. With other types of haemostatic agents, surgery in haemophilic inhibitor patients has only been studied rarely, and operations have generally been restricted to life-threatening situations.
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PMID:Major surgery in haemophilic patients with inhibitors using recombinant factor VIIa. 890 85

In our patients, haemophilia A was observed in German shepherd dogs and Siberian huskies. Frequently occurring clinical symptoms were excessive bleeding from the gums, when getting adult teeth, and haematomas in the regions of the proximal hindleg, the knee joint as well as the chest or abdominal wall, respectively. The activated partial thromboplastin time (aPTT) as a screening test of the intrinsic coagulation system reflects sensitively also a mildly reduced factor VIII:C activity which may be present for example during substitution therapy. Therefore, the aPTT is well suited for screening for haemophilia A. In haemophilic dogs suffering from hypovolaemic shock due to a considerable acute blood loss, besides the aPTT also the prothrombin time and partly the platelet number were beyond the respective reference range due to loss and consumption of coagulation factors and thrombocytes. For substitution therapy, fresh frozen plasma was used in the first line. Administered at a dose of 15 or 20 ml/kg BW, it caused an increase of factor VIII:C activity by 20 or 33%, respectively. 24 hours after the end of infusion the mean of the remaining activity increase in comparison with the value measured immediately after substitution was 27%. The fast, biphasic elimination of factor VIII:C in some cases required a repeated application until clinical recovery. Desmopressin acetate given at a dose of 1 microgram/kg KGW intravenously or subcutaneously to two dogs each did not cause a distinct increase of the factor VIII:C activity, and is, therefore, not an efficacious supplementary therapy to substitution therapy in haemophilic dogs.
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PMID:[Hemophilia A in the dog: symptoms, blood coagulation analysis and treatment]. 900 37

The finding of a prolonged partial thromboplastin time and a normal prothrombin time localized the coagulation defect to the intrinsic or contact activation limb of the coagulation cascade. Because the situation is a source of hemorrhage, a rational and rapid approach is necessary with measure of factors of intrinsic limb of coagulation (especially factors VIII and IX, for the diagnosis of classic hemophilia), study of von Willebrand factor and search of coagulation factor inhibitors. We report the case of a 25-year old woman with high titer postpartum antibody against factor VIII for illustrating the diagnosis approach.
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PMID:[Acquired autoantibodies against human factor VIII: a new case]. 902 52

Three small animal models of bleeding are described and used to evaluate the effects of preparations intended for therapy of human bleeding disorders. We modified techniques for the assessment of bleeding to be able to reproducibly quantify blood loss and rate of blood flow in addition to the measurement of bleeding time. Temporary hemophilia was induced in a rabbit model by injection of high titer human inhibitor plasma [> or = 1000 Bethesda units (BU)/ml]. A decrease in rabbit FVIII from normal values to below the limit of detection was observed within 30 min, cuticle bleeding time changed from normal (approx. 10 min) to steady state bleeding (> 30 min), and the rate of blood flow increased from 4 to > 30 microliters blood/min. Infusion of an activated prothrombin complex concentrate, (FEIBA STIM4, Immuno) at doses between 75 and 150 U/kg normalized the rate of blood flow, while infusion of FVIII/vWF concentrate resulted in partial correction. Administration of FVIIa, both recombinant and plasma-derived, failed to correct bleeding, however. In an analogous murine model, FVIII/ vWF inhibitor plasma was obtained by immunizing goats with a purified human FVIII/vWF complex. This plasma cross-reacted with mouse vWF in vitro. Injection of the anti-FVIII/vWF inhibitor plasma into mice caused a decrease in vWF antigen, in some animals with a complete loss of vWF multimers comparable to severe von Willebrand disease. A specific anti-vWF inhibitor plasma obtained by immunization of goats with recombinant vWF was used in a further murine model, resulting in a gradual but substantial decrease in FVIII as well as in intensive bleeding. The infusion of a FVIII/vWF concentrate (IMMUNATE, IMMUNO) normalized the rate of blood flow in both murine models. The same assessment methods were used to characterize bleeding in a natural mouse model of von Willebrand disease (strain RIIIS/J). The use of quantitative techniques of assessment of blood loss and rate of blood flow appears to be a helpful tool for characterizing hemorrhagic situations and evaluating the capacity of therapeutic preparations to correct hemostatic defects.
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PMID:Assessment of bleeding for the evaluation of therapeutic preparations in small animal models of antibody-induced hemophilia and von Willebrand disease. 906 15

In patients with hemophilia, prothrombin complex concentrates (PCCs) have been successfully used to bypass inhibitors to factor VIII during bleeding episodes. The use of PCCS, including FEIBA (factor eight inhibitor bypassing activity), has been associated with thromboembolic complications. Myocardial infarction (MI) is a rare but serious complication, reported in 13 previous cases, six in the pediatric age group. In all four patients who died during the acute MI, autopsy revealed extensive myocardial hemorrhage. The hearts of three other patients examined at least 5 months after the acute MI showed no evidence of prior hemorrhage. Magnetic resonance (MR) imaging has been shown to be able to evaluate the sequelae of myocardial infarction in adults with coronary artery disease and in children with Kawasaki syndrome. We report the first case of the use of MR imaging in the evaluation of myocardial damage during the acute stage of a FEIBA-associated MI in a 10-year-old boy.
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PMID:Magnetic resonance imaging of myocardial infarction during prothrombin complex concentrate therapy of hemophilia A. 912 91

Several human genetic linkage maps have been constructed as part of the Human Genome Project. These maps show the positional order of closely linked, highly informative AC-repeat polymorphisms on each human chromosome, and are extremely useful in genetic linkage analysis of inheritable diseases. For a candidate gene approach the current linkage maps are less useful, since they consist mainly of anonymous markers rather than of specific genes. This situation also applies for inheritable disorders of blood coagulation. Numerous genes are involved in the blood coagulation cascade and its regulation, and can be considered as candidate genes for unexplained haemophilia and thrombophilia. We have selected 29 candidate genes that seem to be the ones most likely to be involved in thrombophilia. For 19 genes genotype data were already present in the CEPH database (version 7.0). We typed 7 additional genes in the CEPH reference families, i.e. the factor V, factor XII, protein C, protein S, prothrombin, thrombomodulin, and heparin cofactor II gene. The genotype data were used to integrate these 26 genes in the current genetic linkage map, and to identify closely linked AC-repeat polymorphisms. This information will benefit the investigation of inheritable disorders of blood coagulation, especially thrombophilia.
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PMID:Location on the human genetic linkage map of 26 genes involved in blood coagulation. 918 95

Factor VIII or factor IX replacement is frequently impossible in inhibitor-developing hemophiliacs, because of the level of the inhibitor titer. Activated prothrombin complex concentrates are one of the available options to treat the bleeding episodes in such patients. However, the efficacy of these products and the associated thrombogenic risk, particularly in prolonged administration such as employed during surgeries, are important concerns for hemophilia care providers. We performed a multicenter retrospective study to evaluate the use of FEIBA (Factor Eight Bypassing Activity) in France, and data is presented on 433 bleeding episodes, including surgical procedures, concerning 60 patients from 15 hemophilia centers. The efficacy was judged as good or excellent in 352 episodes (81.3%), poor in 73 episodes (16.9%) and non-existent in 8 episodes (1.8%). Minor and major surgical procedures were successfully performed using FEIBA as a second-line therapy after human or porcine factor VIII, and in some occasions FEIBA was utilized as the only substitution product. The tolerance was assessed as good in 428 episodes (98.8%), but in 5 cases adverse effects were reported. Only 3 patients out of 52 regularly evaluated (5.8%) were HIV-seropositive, and for two of them the seroconversion occurred prior to the first use of FEIBA. In contrast, 80.4% of the patients were HCV-seropositive. An anamnestic response after the administration of FEIBA was noted in 31.5% of cases. This study points out the main features of the use of FEIBA in France, and particularly the low HIV seroprevalence in the patients treated. The good efficacy and the excellent tolerance still confer to this product a place to consider in the therapeutic options for the treatment of inhibitor-developing hemophiliacs or in acquired hemophilia.
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PMID:Multicenter retrospective study on the utilization of FEIBA in France in patients with factor VIII and factor IX inhibitors. French FEIBA Study Group. Factor Eight Bypassing Activity. 924 42


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