Good dental care.
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Creutzfeldt-Jakob Syndrome↗
Biomedical subjects
P L F Giangrande
Publications and source records attributed to P L F Giangrande.
The incidence of factor VIII and factor IX inhibitors in the hemophilia population of the UK and their effect on subsequent mortality, 1977-99.
BACKGROUND: Previous studies of the development of inhibitors and their impact on mortality have been small. OBJECTIVES: To examine the development of inhibitors in people with hemophilia in the UK and their effect on subsequent mortality. PATIENTS: 6078 males with hemophilia A and 1172 males with hemophilia B registered in the UK Haemophilia Centre Doctors' Organisation database, 1977-98. RESULTS: In severe hemophilia A inhibitors developed at rates of 34.4, 5.2 and 3.8 per 1000 years at ages <5, 5-14 and 15+years; cumulative risks at ages 5 and 75 were 16% and 36%. In hemophilia A the rate of inhibitor development decreased during 1977-90, but increased during the 1990s. In severe hemophilia B inhibitors developed at rates of 13.3 and 0.2 per 1000 years at ages <5 and 5+ and cumulative risks at ages 5 and 75 were 6% and 8%. With HIV, inhibitor development did not increase mortality. In severe hemophilia without HIV, inhibitor development doubled mortality during 1977-92, but during 1993-99 mortality was identical with and without inhibitors. In severe hemophilia without HIV but with inhibitors, mortality from causes involving bleeding decreased during 1977-99 (P = 0.001) as did mortality involving intracranial hemorrhage (P = 0.007). CONCLUSIONS: These data provide estimates of the rate of inhibitor development in hemophilia A and hemophilia B, and they show that the rate of inhibitor development has varied over time, although the reasons for this remain unclear. They also show that in severe hemophilia the substantial increase in mortality previously associated with inhibitors is no longer present.
Adolescent↗
Pharmacokinetics of activated recombinant coagulation factor VII (NovoSeven) in children vs. adults with haemophilia A.
To establish the pharmacokinetic profile of activated recombinant coagulation factor VII (rFVIIa; NovoSeven in children with haemophilia A, and to compare it with the pharmacokinetic profile in adults with haemophilia A. Twelve children (2-12 years) received one single dose of rFVIIa 90 and 180 micrograms kg(-1) in randomized order separated by a washout period of 48 h to 1 month. Six adults (18-55 years) received a single dose of rFVIIa 90 micrograms kg(-1). The pharmacokinetic analyses were based on a non-compartmental method. In children, the plasma level of FVII increased proportionally with the dose. The total body clearance normalized for body weight was significantly faster in children than in adults (FVII:C, 58 vs. 39 mL kg(-1) h(-1) and FVIIa, 78 vs. 53 mL kg(-1) h(-1), P < 0.05). A trend towards a larger volume of distribution at steady-state in children than in adults was observed (P > 0.05). Dose proportionality was established for plasma concentrations of FVII in children with haemophilia A at the dose levels investigated (90 and 180 micrograms kg(-1) rFVIIa). Following administration of rFVIIa 90 micrograms kg(-1), significantly faster clearance was observed in children compared with adults, suggesting that higher doses of rFVIIa may be needed to achieve the same plasma levels as in adults.
Child↗
Gene therapy for hemophilia? No.
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Bioethics↗
Treatment of patients with haemophilia and inhibitory antibodies.
The development of inhibitory antibodies is a complication which arise in approximately 10% of patients with haemophilia A. The underlying genetic mutation is the single most important predisposing cause, although other risk factors have been identified. Periodic screening for inhibitors is a vital aspect of haemophilia care. The consequences of inhibitor development are very significant in terms of morbidity and cost. Several agents are now available for control of bleeding, but these are often very expensive. The most useful agents include recombinant activated factor VII, prothrombin complex concentrates and porcine factor VIII. It is possible to suppress antibody production with immune tolerance, which is successful in approximately 85% of cases and relapse is rare.
Blood Coagulation Factor Inhibitors↗
Ethnic variation in von Willebrand factor levels can influence the diagnosis of von Willebrand disease.
The amount and function of von Willebrand factor (VWF), measured against a panel of laboratory tests, is the normal basis for the diagnosis of von Willebrand's disease (VWD). The normal range for each test is usually obtained by assaying samples from a cross section of the local population or from a manufacturer's kit insert. While collecting normal controls for another study, population from Durban in South Africa, with its distinct ethnic mix of Africans, Indians and Caucasians were also studied. Previously, Indians from their subcontinent have not been looked at separately and compared with Africans and Caucasians. It is confirmed in a previous study (Miller, Dilley, Richardson, Craig, Evatt. (2001) American Journal of Hematology 67, 125) that African Americans had significantly higher VWF:Ag and FVIII levels when compared with Caucasians. In addition, it was found that there was a significant difference in VWF:Ag levels between Indians and Africans, and between Caucasians and Africans, whereas no significant difference between Indians and Caucasians. Africans, Indians and Caucasians with blood group O showed significantly lower VWF:Ag and FVIII than the other ABO blood groups. Normal ranges of VWF for different blood groups are well established and this information should be utilized while considering a diagnosis of VWD. It is proposed here that the influence of racial origin should also be considered in the clinical and laboratory evaluation of VWD.
ABO Blood-Group System↗
The WFH Haemophilia Centre Twinning Programme: 10 years of growth, 1993-2003.
The World Federation of Haemophilia (WFH) Twinning Programme celebrates its tenth anniversary this year. Twinning is one of several international WFH programmes designed to improve haemophilia care at a global level. There are two types of twinning, and the haemophilia treatment centre twinning programme should be distinguished from the WFH haemophilia organization twinning involving national member organizations. The WFH Haemophilia Treatment Centre Twinning Programme helps emerging haemophilia treatment centres develop partnerships with well-established and experienced centres. Twinning can improve diagnosis and clinical care through coaching, training and transfer of expertise, ultimately leading to improved quality of life for patients. Twinning can also enhance the profile and recognition of treatment centres in emerging countries, which can be valuable in raising awareness among politicians and the media. Examples of activities include consultation on the management of specific cases, clinical and laboratory training, donation of equipment and publications as well as research projects. The centre twinning programme also benefits centres in developed countries by giving them the opportunity to gain exposure to clinical problems no longer encountered in their own countries, as well as experience of new cultures. Currently, a total of 23 treatment centres around the world are linked through the twinning programme and applications for new partnerships are welcome. Twinning links are not permanent, but are reviewed on an annual basis and typically remain in place for periods of 3-5 years. Limited financial support from WFH is available to twinned centres in the form of money for an initial assessment visit, as well as regular annual grants to established partners and the possibility of applying for additional funding to support specific projects. In addition, continuing support and advice are available from the WFH regional programme officers.
Developing Countries↗
Consensus perspectives on prophylactic therapy for haemophilia: summary statement.
Participants in an international conference on prophylactic therapy for severe haemophilia developed a consensus summary of the findings and conclusions of the conference. In the consensus, participants agreed upon revised definitions for primary and secondary prophylaxis and also made recommendations concerning the need for an international system of pharmacovigilance. Considerations on starting prophylaxis, monitoring outcomes, and individualizing treatment regimens were discussed. Several research questions were identified as needing further investigation, including when to start and when to stop prophylaxis, optimal dosing and dose interval, and methods for assessment of long-term treatment effects. Such studies should include carefully defined cohorts, validated orthopaedic and quality-of-life assessment instruments, and cost-benefit analyses.
Consensus Statements as Topic↗
Adverse events in the prophylaxis of haemophilia.
Whilst prophylaxis undoubtedly offers many advantages, the potential for adverse effects must also be borne in mind. Modern plasma-derived products have an extremely good safety record with regard to transmission of pathogens, although continuous vigilance is required as new pathogens continue to emerge, eg new variant Creutzfeldt-Jakob disease. There is no evidence that prophylactic treatment is associated with an increased incidence of inhibitors, and it is now recognized that genetic factors are the most significant in conferring susceptibility. Although subtle immunological abnormalities have also been observed in patients with haemophilia, there is no evidence that these are of any clinical significance. There has been a growing trend to use indwelling venous catheters for prophylaxis. The risk of infection has been appreciated for some time, although it has only recently been possible to quantify this with more precision. The risk of catheter-associated thrombosis is now recognized to be higher than hitherto appreciated. Whilst sporting activities are to be encouraged, there is a potential for significant trauma in children with prophylaxis, as plasma coagulation factor levels remain far below normal with the usual regimens.
Blood Coagulation Factors↗
Treatment of hemophilia: recombinant factors only? Yes.
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Blood Coagulation Factors↗
Choice of replacement therapy for hemophilia-a rebuttal.
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Blood Coagulation Factors↗
Safety and efficacy of KOGENATE Bayer in previously untreated patients (PUPs) and minimally treated patients (MTPs).
Safety and efficacy of KOGENATE Bayer (Kogenate FS), a second-generation full-length recombinant factor VIII formulated with sucrose as stabilizer and produced without the addition of human albumin during purification and the final formulation, was assessed in a prospective, international clinical trial including 31 previously untreated patients (PUPs) and minimally treated patients (MTPs) with severe haemophilia A in home therapy and surgery. Factor VIII inhibitor development was monitored and mutation type profiles were analysed. As of 30 June 2000, the patients received a total of 2.729 infusions (mean 88; range 6-274) for bleeding episodes, surgery or prophylactic treatment. No unexpected drug-related adverse events were observed. Four patients developed an inhibitor after 3-12 exposure days (EDs). One patient successfully underwent immune tolerance treatment; inhibitors in two patients disappeared spontaneously with on-demand treatment, while the inhibitor titre remains low in one patient. Twenty-nine patients (93%) with more than 20 EDs can be regarded as at low risk for inhibitor development. In conclusion, KOGENATE Bayer is efficacious and well-tolerated for treatment of children with severe haemophilia A. The incidence of inhibitor formation is not different to that observed with other recombinant or plasma-derived products.
Adolescent↗
Viral pharmacovigilance study of haemophiliacs receiving porcine factor VIII.
Porcine factor VIII (FVIII; Hyate:C; Speywood Biopharm Ltd, UK) has been used since 1980 for the treatment both of patients with acquired haemophilia and those with congenital haemophilia and inhibitory antibodies. Each batch is extensively screened using cell-culture techniques to confirm the absence of viruses. The production process does not incorporate specific virucidal treatment steps, such as heat treatment or the addition of a solvent/detergent mixture. Low levels of porcine parvovirus were detected in some batches of the product in late 1996 and supply was suspended. In this retrospective study, sera from 81 recipients of porcine FVIII and 125 other volunteers were screened for evidence of antibodies against a range of porcine viruses: porcine parvovirus (PPV), encephalomyocarditis virus (EMCV), and porcine respiratory and reproductive syndrome virus (PRRSV). The 125 volunteer controls included subjects from six categories: healthy control subjects, pig abattoir personnel, personnel involved in the manufacture of porcine FVIII, recipients of porcine heparin, recipients of porcine insulin, and haemophiliacs treated only with human FVIII. No antibodies to PPV or PRRSV were detected in any subject. Four patients and two volunteers were found to have antibodies to EMCV, but this incidence is similar to that observed in the general population. In conclusion, there was no evidence of transmission of PPR or other marker porcine virus associated with the use of porcine FVIII concentrate (Hyate: C).
Animals↗
Complications in HIV-infected and non-HIV-infected haemophiliacs and other patients after oral surgery.
Dental extractions and other oral surgical procedures, including local analgesic injections, potentially can cause problems in haemophiliac and HIV infected persons. There are few data on treatment results in HIV-infected haemophiliacs compared with non-HIV-infected haemophiliacs. The oral surgery treatment results in 48 patients with special needs, including HIV-infected haemophiliacs, non-HIV-infected haemophiliacs, HIV-infected non-haemophiliacs, and a group with other medical problems were therefore studied. Around 20% of the haemophiliacs developed post-oral surgical complications, which was not significantly different whether or not they were HIV-infected. However, complications were less frequent (8%) in HIV-infected non-haemophiliacs or other patients with special needs. Although the patient groups are not large, it would appear that haemophiliacs had more postoperative complications but that the presence of HIV infection had no notable influence on treatment outcome.
Adult↗
Fondaparinux (Arixtra): a new anticoagulant.
Fondaparinux is a promising new antithrombotic agent. This pentasaccharide selectively and specifically inhibits coagulation factor Xa, and requires antithrombin as co-factor It is entirely synthetic, in contrast to conventional heparin and low molecular heparins which are derived from animal tissues. Fondaparinux exhibits a high bioavailability and is convenient to use as it only needs to be given once daily by subcutaneous injection. Peak plasma levels are achieved within two hours of dosing and the plasma half-life of fondaparinux is approximately 17 hours. There is no specific antidote for fondaparinux: it is not neutralised by protamine sulphate. Fondaparinux shows no cross-reactivity with antibodies associated with heparin-induced thrombocytopenia. Several randomised, double-blind studies have demonstrated superiority with respect to a low molecular weight heparin (enoxaparin) in preventing venous thromboembolism in the setting of orthopaedic surgery. The results of clinical trials of fondaparinux in the treatment of deep vein thrombosis and acute coronary syndrome are also presented.
Anticoagulants↗