Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0684275 (haemophilia)
 10,958 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In our clinic, five patients with haemophilia A and one patient with haemophilia B and inhibitors have been treated with immune tolerance induction (ITI) since 1995. Bleeding symptoms during this period have been treated with recombinant activated factor VII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark). Four of the six patients did not need rFVIIa during ITI other than for port-a-cath insertions, but two have been treated intensively because of repeated bleeding problems. The first of these developed inhibitors at the age of 2 years after 11 days of exposure to factor VIII (FVIII). He was treated for 40 bleeding episodes before ITI started, and during ITI he was treated another 24 times, including eight treatments for joint bleeds. Treatment was effective for the different types of bleeding episode. However, in spite of repeated treatment for these joint bleeds, he developed two target joints with synovitis (right knee and left elbow). The synovitis only showed signs of regression when inhibitor levels were reduced due to the ITI regimen. The second patient, now 5 years old, has severe haemophilia B. He developed inhibitors and anaphylaxia having received prophylactic treatment from the age of 1 year. He has now received ITI with 120 units/kg body weight per day of FIX for 68 weeks. In the event of trauma and bleeding he is treated promptly with rFVIIa by his parents at home. Treatment is started with 160-180 microg/kg body weight and, if needed, another dose of 90 microg/kg is given after 3 h. During 1996, 35 bleeds or traumas were treated. The total amount of rFVIIa administered to this child was 211.2 mg. All but one joint bleed and all muscle bleeds needed more than one injection. The need for another injection is judged by the parents and the child from clinical signs, such as pain and swelling. Neither of these two boys have shown any signs of thrombosis or disseminated intravascular coagulation. In summary, rFVIIa is a well tolerated and effective therapy for acute bleeding episodes during ITI. Dosing and intervals can be the same as for patients not on ITI therapy. Early intervention at home can minimize the risk of synovitis.
 ...
PMID:Treatment of acute bleeds with recombinant activated factor VII during immune tolerance therapy. 981 46

The problems with management of haemophilia in developing countries are poor awareness, inadequate diagnostic facilities and scarce factor concentrates for therapy. The priorities in establishing services for haemophilia include training care providers, setting up care centres, initiating a registry, educating affected people and their families about the condition, providing low-cost factor concentrates, improving social awareness and developing a comprehensive care team. A coagulation laboratory capable of reliably performing clotting times with correction studies using normal pooled, FVIII and FIX deficient patient plasma and factor assay is most essential for diagnosis. More advanced centralized laboratories are also needed. Molecular biology techniques for mutation detection and gene tracking should be established in each country for accurate carrier detection and antenatal diagnosis. Different models of haemophilia care exists. In India, there is no support from the government. Services, including import of factor concentrates, are organized by the Haemophilia Federation of India, with support from other institutions. Haemophilia is managed with minimal replacement therapy (about 2000 i.u./PWH/year). In Malaysia, where the system is fully supported by the government, facilities are available at all public hospitals and moderate levels of factor concentrates are available 'on-demand' (about 11,000 i.u./PWH/year) at the hospitals. Haemophilia care in South Africa is provided through major public hospitals. Intermediate purity factor concentrates are locally produced (about 12,000 i.u./PWH/year) at low cost. The combined experience in the developing world in providing haemophilia services should be used to define standards for care and set achievable goals.
Haemophilia 1998 Jul
PMID:Management of haemophilia in the developing world. 987 77

The development of factor VIII (FVIII) and FIX inhibitors is one of the most serious complications of repeated transfusions in patients with haemophilia. Management of patients with haemophilia with inhibitors must be separated into 2 concepts: the control of acute bleeding episodes and, in the long term, the treatment of the inhibitor itself. This paper will discuss both aspects of the management of these patients, focusing in particular on the therapeutic options available for the treatment of bleeding episodes during immune tolerance induction (ITI) therapy. The second part of the paper will review the management and outcomes of 10 patients with severe haemophilia in whom recombinant activated FVII (rFVIIa: NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) has been used to treat bleeding episodes in the Haemophilia Centre at Bonn University; 6 patients were treated with rFVIIa for bleeding episodes while undergoing ITI. The results obtained demonstrate that rFVIIa is a safe and effective treatment for bleeding episodes and haemostatic cover for surgical procedures in patients with inhibitors. Inhibitor titres were not boosted in patients with haemophilia and inhibitors on treatment with rFVIIa. Therefore, rFVIIa is also a suitable treatment for bleeding episodes or control of haemostasis during surgery in patients prior to initiation of ITI therapy.
 ...
PMID:Immune tolerance induction: a role for recombinant activated factor VII (rFVIIa)? 988 28

The management of bleeding episodes and surgery in haemophilia patients who develop inhibitors is especially difficult. Haemostasis is typically achieved using high doses of factor VIII (FVIII) or FIX to overcome the inhibitor, or by using activated products, or by inhibitor eradication by immune tolerance induction. We assessed the costs of coagulation factors for non-inhibitor haemophilia A and B patients (ACneg; n = 104), patients with low responding inhibitors (LR; n = 24) and patients with high responding inhibitors (HR; n = 17) in our centre between 1988 and 1995. In ACneg and LR patients, > 90% of costs were attributed to home treatment, compared with 54% for HR patients. The costs of treatment were $US 36.8 m total, $US 41,000 mean per patient for ACneg patients; $US 10 m total, $US 46,000 mean per patient for LR patients; and $US 7.6 m total, $US 59,000 mean per patient for HR patients. The mean cost of hospital treatment per HR patient was more than 10 times that for ACneg or LR patients and this was influenced by the occurrence of 4 very severe bleeding episodes in these patients. This analysis highlights the different costs and treatment patterns for inhibitor patients and should enable us to evaluate the impact of new treatments such as recombinant activated rFVII (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) on treatment at our centre in the future.
 ...
PMID:Pharmaco-economic aspects of inhibitor treatment. 988 29

Recommendations for factor replacement therapy for postoperative haemostasis in haemophilia are often empirical and based on the physiological understanding of haemostatic requirements. This report describes the haemostatic management of patients with severe haemophilia undergoing major surgery using lower than usually recommended levels of factor replacement therapy. Eighteen adults (11 with FVIII and seven with FIX deficiency) with an average weight of 52 kg (range: 27-69) underwent 20 major surgical procedures. Factor concentrates were administered by intermittent bolus infusions. The dose of FVIII infused before surgery was 76 mu kg-1 (range: 51-113) and that of FIX was 77 mu kg-1 (range: 50-104). The preoperative levels achieved were 107% (range: 80-180) and 73% (range: 60-90), respectively. Between days 1 and 3 after surgery, an average of 29 mu kg-1 day-1 (range: 20-46) of FVIII and 23 mu kg-1 day-1 (range: 12-42) of FIX was used resulting in mean trough levels of 36% (range: 12-62) and 34% (range: 11-52), respectively. After day 4, an average of 19 mu kg-1 day-1 (range: 15-25) of FVIII and 18 mu kg-1 day-1 (range: 10-37) of FIX was administered until wound healing. The average duration of factor replacement was 11 days (range: 8-16). The mean dose of factor concentrate per patient was 260 mu kg-1 (range: 179-338) of FVIII and 300 mu kg-1 (range: 183-524) of FIX. The total amount of factor used per patient ranged from 12,380 to 19,980 units of FVIII and 8000 to 23,600 units of FIX. Only one patient had post-operative bleeding which was due to a surgical cause. It is concluded that it may be possible to use much lower than recommended levels of factor replacement therapy for postoperative haemostasis in severe haemophilia.
Haemophilia 1998 Nov
PMID:Low-dose intermittent factor replacement for post-operative haemostasis in haemophilia. 1002

Pharmacokinetic studies in haemophilia B have found in vivo recovery of FIX (FIX) to be uniformly lower than the factor VIII recovery in haemophilia A. We hypothesized that this lower recovery could result from rapid binding to high-affinity receptors on platelets and endothelium. To test this hypothesis, we evaluated the kinetics of FIX activity and protein in haemophilia B patients. Twelve patients were enrolled in a double dosing, crossover study with two high-purity FIX concentrates, AlphaNine SD and MonoNine. Subjects were given 40 U kg-1 of FIX concentrate and blood samples were taken at 15, 30, and 60 min. A second infusion of 40 U kg-1 was given after the 60 min blood sample and further blood samples removed at 15, 60, 120, and 360 min after the second dose. Patients were infused with the alternate concentrate at least 7 days later. Plasma samples were assayed for FIX activity by coagulation assay and antigen by RIA. FIX antigen in the infused concentrates was measured and quantified as microg U-1. There was no difference between the two FIX concentrates (AlphaNine vs. MonoNine) in the initial (15 min) activity (57% +/-1 19% vs. 53% +/-1 12%) and antigen (62% +/-1 16% vs. 55% +/-1 19%) recoveries. Recoveries after the second FIX dose were not statistically different than those observed after the first FIX dose. In one patient, a doubling of the initial infusion dose did not increase FIX recovery after the second FIX dose. However, the recovery of FIX antigen was significantly greater than the recovery of FIX activity and the differences became more significant in the post-15 min samples. We calculated a ratio of plasma FIX antigen to FIX activity in microg U-1. Average antigen to activity ratio increased from 5.8 +/-1 1.9 microg U-1 at 15 min to 7.1 +/-1 2.2 microg U-1 at 60 min. At 420 min the ratio increased to 9.3 +/-1 2.4 microg U-1. Although these studies failed to demonstrate a significant FIX receptor pool, they did demonstrate a phenomenon of progressive loss of biologic activity of the FIX protein after infusion of FIX concentrates.
Haemophilia 1999 May
PMID:Kinetics of factor IX activity differ from that of factor IX antigen in patients with haemophilia B receiving high-purity factor IX replacement. 1044 84

Haemophilia B, an X-linked recessive bleeding disorder characterized by lack or deficiency of factor IX, has been shown to be caused by any of a variety of DNA abnormalities (partial or total deletions, nonsense or missense mutations). Since in most countries carrier detection is based on factor IX coagulant activity (FIX:C) assay, this study was designed to determine whether carriers' FIX:C values are dependent on the severity of haemophilia (mild, moderate or severe) or on the genetic anomaly in the family. FIX:C concentrations were studied in 28 obligate carriers, 39 women known to carry the mutation and 33 verified noncarriers subgrouped by severity of disorder or genetic anomaly. No significant subgroup differences in FIX:C values were found, thus suggesting the level of FIX:C concentrations in carriers to be unaffected by the severity of haemophilia, or by its expression (i.e. deficient or dysfunctional factor IX). The specificity and sensitivity of FIX:C analysis for the purpose of carrier diagnosis was judged by receiver operating characteristic curve analysis, where an FIX:C cut-off level of 75 IU dL-1 was found to be optimal (sensitivity 93% and specificity 88%).
Haemophilia 1999 Jul
PMID:Haemophilia B carrier detection by factor IX:C analysis; no impact of the type of mutation or severity of disorder. 1046 76

Inhibitors to factor VIII (FVIII) or IX (FIX) in patients with haemophilia A or B create a challenging problem for the treatment of these patients. Recombinant FVIIa (rFVIIa; NovoSeven, Novo Nordisk A/S, Bagsvaerd, Denmark) is a realistic treatment option, owing to its specific mode of action and lack of immunogenicity. This was a multicentre, open-label, compassionate-use trial in patients with severe haemophilia A (FVIII:C < 1%) or B (FIX:C < 1%) with inhibitors, acquired antibodies to FVIII or FIX, or FVII deficiency (FVII:C < 5%), for whom alternative therapies had failed or were contraindicated. Patients received rFVIIa treatment for life- or limb-threatening bleeding episodes or for coverage during essential surgery. The mean rFVIIa dose was approximately 90 microg kg-1 for haemophilia A/B and acquired inhibitor patients, and 25 microg kg-1 for FVII-deficient patients. Efficacy data for 67 treatment episodes (45 bleeding episodes, 22 surgical procedures) are presented; seven patients were treated for a concurrent serious bleeding episode and surgical procedure. At the end of treatment, rFVIIa was effective or partially effective in 85% of serious bleeding episodes. During surgery, bleeding was assessed as none or less than or equivalent to normal in 91% of surgical procedures; postoperatively, 91% of procedures were associated with no or minimal oozing. During 60 separate treatment episodes, 26 adverse events (22 nonserious, four serious) were reported in 15 patients, during 17 bleeding episodes or surgical procedures. Only 10 were considered as having a possible, probable, or unknown relationship with rFVIIa; of these, fever (n=2) and thrombophlebitis (n=3) were the most common. There was no evidence of disseminated intravascular coagulation. In conclusion, rFVIIa is an effective, well-tolerated treatment for serious bleeding episodes and bleeding associated with surgical procedures in patients with severe haemophilia A/B with inhibitors, acquired inhibitors, or FVII deficiency.
Haemophilia 1999 Jul
PMID:Recombinant factor VIIa for patients with inhibitors to factor VIII or IX or factor VII deficiency. 1046 79

An overview is given on APCCs and recombinant FVIIa for the treatment of bleeding episodes in hemophiliacs with FVIII or FIX inhibitors or in patients with acquired hemophilia. The initial dose of activated plasma-derived PPCs, mainly FEIBA, is up to 100 U/kg body weight, and the maintenance dosage is up to 100 U/kg body weight twice daily. The single dosage of recombinant FVIIa is about 60-90 microg/kg body weight, which has to be repeated every 2 to 6 hours depending on the bleeding situation.
 ...
PMID:Clinical efficacy of prothrombin complex concentrates and recombinant factor VIIa in the treatment of bleeding episodes in patients with factor VII and IX inhibitors. 1049 7

Prevalence of FIX inhibitor is ten times lower than factor VIII inhibitor. FIX inhibitor patients pose major challenges for treatment because of the simultaneous occurrence of severe allergy to FIX at the time of inhibitor development. Immune tolerance induction in haemophilia B inhibitor patients with allergy to FIX is complicated due to the development of nephrotic syndrome. Moreover, response to ITI usually is poor.
 ...
PMID:Factor IX antibody and immune tolerance. 1052 93


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>