[Dental and oral surgical treatment of a B haemophilic patient with high inhibitor level. Case report]. / Magas inhibitor titeru B-haemophiliás beteg fogorvosi-szájsebészeti ellátása. Esetismertetés.

More than 1000 hemophilic male patients are registered in Hungary, from which only a trace number suffers from factor IX inhibitory hemophilia. For correct dental and oral surgical treatment of these patients mandatory cooperation is required among medical specialties, exerting multi-staged haemostatic principles. Authors represent in this case report the dental and oral surgical treatment of a B hemophilic patient with high inhibitor level and describe possible local haemostatic measures.

Prolonged half-life and preserved enzymatic properties of factor IX selectively PEGylated on native N-glycans in the activation peptide.

Current management of hemophilia B entails multiple weekly infusions of factor IX (FIX) to prevent bleeding episodes. In an attempt to make a longer acting recombinant FIX (rFIX), we have explored a new releasable protraction concept using the native N-glycans in the activation peptide as sites for attachment of polyethylene glycol (PEG). Release of the activation peptide by physiologic activators converted glycoPEGylated rFIX (N9-GP) to native rFIXa and proceeded with normal kinetics for FXIa, while the K(m) for activation by FVIIa-tissue factor (TF) was increased by 2-fold. Consistent with minimal perturbation of rFIX by the attached PEG, N9-GP retained 73%-100% specific activity in plasma and whole-blood-based assays and showed efficacy comparable with rFIX in stopping acute bleeds in hemophilia B mice. In animal models N9-GP exhibited up to 2-fold increased in vivo recovery and a markedly prolonged half-life in mini-pig (76 hours) and hemophilia B dog (113 hours) compared with rFIX (16 hours). The extended circulation time of N9-GP was reflected in prolonged correction of coagulation parameters in hemophilia B dog and duration of effect in hemophilia B mice. Collectively, these results suggest that N9-GP has the potential to offer efficacious prophylactic and acute treatment of hemophilia B patients at a reduced dosing frequency.

Sustained release of transgenic human factor IX: preparation, characterization, and in vivo efficacy.

The current regimen of factor IX (FIX) injection is of an episodic format, which leads to limited efficacy. A sustained release dosage form is beneficial in terms of reducing the injection frequency and improving the therapeutic effectiveness. The aim of this study was to formulate a new microsphere form of a FIX-containing preparation to diminish these shortcomings. Using the water-in-oil-in-water (W/O/W) double emulsion technique, injectable long-acting FIX microspheres were prepared with transgenic recombinant human FIX (rhFIX) and poly(lactic-co-glycolic acid) (PLGA) polymer. The rhFIX microspheres prepared had diameters ranging between 25-350 µm and easily passed through a small-gauge-number needle for subcutaneous injection. In in vitro release testing, the microspheres had a sustained release profile featuring an initial burst and sustained release spanning a 5-day period. In in vivo pharmacodynamic testing, normalization of the bleeding of hemophilic mice was maintained for 5 days with microsphere injection as compared with 2 days with native rhFIX. Taken together, these results indicated that long-acting FIX microspheres were successfully prepared for potential use in hemophilic prophylaxis.

Long-Term Safety and Efficacy of Nonacog Beta Pegol (N9-GP) Administered for at Least 5 Years in Previously Treated Children with Hemophilia B.

Long-term safety and efficacy data of extended half-life factor IX (FIX) prophylaxis in children with hemophilia B (HB) are sparse. paradigm 5 is a multinational, open-label, single-arm, phase III trial assessing once-weekly (40 IU/kg) prophylactic nonacog beta pegol (N9-GP) in previously treated patients (PTPs) aged ≤ 12 years with HB (FIX activity ≤ 2%). Primary endpoint: incidence of anti-FIX inhibitory antibodies (≥ 0.6 Bethesda Units). We present a 5-year analysis (N = 25, including remaining patients with ≥ 5 years' follow-up) and compare with a 1-year analysis (≥ 52 weeks' exposure). The main phase enrolled 25 children; 22 entered the extension phase; 17 remained in trial at data cutoff. Median treatment period: 5.6 years/patient; median total number of N9-GP exposure days: 290.0/patient. No patients developed anti-FIX inhibitory antibodies. No other safety concerns, including thromboembolic events, were reported. Neurological examinations have not revealed any new abnormal findings. Sixteen (64.0%) patients remained free from spontaneous bleeds; all bleeds were mild/moderate in severity; 93.0% were controlled with 1 to 2 N9-GP injections. No intracranial hemorrhages were reported. Annualized bleeding rates (ABRs) were very low at 5 years (median/Poisson-estimated mean overall ABR: 0.66/0.99), having decreased from the 1-year analysis (1.00/1.44). Median/Poisson-estimated mean spontaneous ABRs for the 1- and 5-year analyses: 0.00/0.45 and 0.00/0.33. Mean FIX trough activity at 5 years: 17.9%. Mean polyethylene glycol plasma concentration reached steady state at 6 months, increasing slightly over time, in line with increased FIX trough activity. N9-GP administered for ≥ 5 years shows favorable long-term safety and efficacy in PTPs with HB (FIX activity ≤ 2%).

Variability in bleeding phenotype in Amish carriers of haemophilia B with the 31008 C-->T mutation.

The aim of this study was to characterize the variability of bleeding phenotype and its association with plasma factor IX coagulant activity (FIX:C) in haemophilia B carriers in a large Amish pedigree with a unifying genetic mutation, C-to-T transition at base 31008 of the factor IX gene (Xq27.1-27.2). A cross-sectional survey of haemophilia B carriers included a multiple choice questionnaire evaluating symptoms of mucocutaneous bleeding, joint bleeding and bleeding after haemostatic stress [menstruation, postpartum haemorrhage (PPH), dental extractions and invasive surgeries]. Severity of bleeding was graded as 0 to 4, 0 being no bleeding whereas 4 being severe bleeding. Association between total bleeding scores and the FIX:C was evaluated. Sixty-four haemophilia B carriers participated in this study. Median age: 18 years (range 1-70 years); median bleeding score: 1 (range 0-8). Besides PPH, isolated symptoms of bruising, epistaxis, menorrhagia and postsurgical bleeding including dental extraction were not associated with lower FIX:C. Bleeding score >/=3 was associated with involvement of at least two bleeding sites and a lower mean FIX:C of 42 +/- 10.3% (95% CI 36.4-47.7) while a score >3 had involvement of /=3. Phenotypic variability existed among the carriers of haemophilia B who belonged to a single pedigree carrying a single unifying mutation. The utility of bleeding scores to define bleeding phenotype precisely in haemophilia B carriers needs further evaluation.

Pharmacokinetic and safety considerations when switching from standard to extended half-life clotting factor concentrates in hemophilia.

Introduction: Plenty of new FVIII/IX concentrates have been developed and entered the market of hemophilia treatment. Others are going to end the long/demanding procedures for approval. Changes of the FVIII molecule (single chain), pegylation of B-domain deleted FVIII, and fusion with Fc succeeded to improve the FVIII half-life, about 4 hours. Pegylation and fusion with albumin or Fc of rFIX caused a substantial increase of half-life, approximately 3-4 times that of FIX standard concentrates. Area covered: Extended Half-life concentrates may allow a longer time interval between the prophylaxis bolus, a feature very well accepted by young patients. Also, adherence of adolescents can be improved by these new, less demanding, concentrates. The immunogenicity of these new molecules is so far under post-marketing evaluation. The incidence of neutralizing antibodies is very low in previously treated patients, but the data on previously untreated patients are not yet assessed. The cost of some Extended Half-Life concentrates is higher than that of standard ones, and some concerns have been raised about the cost for public or private health care institutions. Expert opinion: An accurate evaluation of patients' needs, individual pharmacokinetics, and cost/effectiveness might allow a more appropriate usage of these new and expensive concentrates.

Nonacog beta pegol in previously treated children with hemophilia B: results from an international open-label phase 3 trial.

UNLABELLED: Essentials Nonacog beta pegol is a recombinant glycoPEGylated factor IX with an extended half-life. This phase 3 trial investigated its safety/efficacy in previously treated hemophilia B boys ≤ 12 years. A 40 IU kg(-1) dose provided effective once-weekly prophylaxis and hemostasis when used to treat bleeds. Nonacog beta pegol was well tolerated in previously treated boys ≤ 12 years with hemophilia B. SUMMARY: Background Nonacog beta pegol is a recombinant glycoPEGylated factor IX with an extended half-life, developed to improve care for patients with hemophilia B. Objectives To investigate the safety, efficacy and pharmacokinetics of nonacog beta pegol for the prophylaxis and treatment of bleeds in previously treated children with hemophilia B. Patients/Methods This phase 3 trial, paradigm(™) 5, enrolled and treated 25 children (aged ≤ 12 years) with hemophilia B (FIX ≤ 2%). Patients were stratified by age (0-6 years and 7-12 years), and received once-weekly prophylaxis with 40 IU kg(-1) nonacog beta pegol for 50 exposure days. Results No patient developed inhibitors, and no safety concerns were identified. Forty-two bleeds in 15 patients were reported to have been treated; the overall success rate was 92.9%, and most bleeds (85.7%) resolved after one dose. The median annualized bleeding rates (ABRs; bleeds per patient per year) were 1.0 in the total population, 0.0 in the 0-6-year group, and 2.0 in the 7-12-year group; the estimated mean ABRs were 1.44 in the total population, 0.87 in the 0-6-year group, and 1.88 in the 7-12-year group. For 22 patients who had previously been receiving prophylaxis, the estimated mean ABR was 1.38 versus a historical ABR of 2.51. Estimated mean steady-state FIX trough levels were 0.153 IU mL(-1) (0-6 years) and 0.190 IU mL(-1) (7-12 years). Conclusion Nonacog beta pegol was well tolerated in previously treated children with hemophilia B; a 40 IU kg(-1) dose provided effective once-weekly prophylaxis and hemostasis when bleeds were treated.

Measuring factor IX activity of nonacog beta pegol with commercially available one-stage clotting and chromogenic assay kits: a two-center study.

UNLABELLED: Essentials Validated assays are required to precisely measure factor IX (FIX) activity in FIX products. N9-GP and two other FIX products were assessed in various coagulation assay systems at two sites. Large variations in FIX activity measurements were observed for N9-GP using some assays. One-stage and chromogenic assays accurately measuring FIX activity for N9-GP were identified. SUMMARY: Background Measurement of factor IX activity (FIX:C) with activated partial thromboplastin time-based one-stage clotting assays is associated with a large degree of interlaboratory variation in samples containing glycoPEGylated recombinant FIX (rFIX), i.e. nonacog beta pegol (N9-GP). Validation and qualification of specific assays and conditions are necessary for the accurate assessment of FIX:C in samples containing N9-GP. Objectives To assess the accuracy of various one-stage clotting and chromogenic assays for measuring FIX:C in samples containing N9-GP as compared with samples containing rFIX or plasma-derived FIX (pdFIX) across two laboratory sites. Methods FIX:C, in severe hemophilia B plasma spiked with a range of concentrations (from very low, i.e. 0.03 IU mL(-1) , to high, i.e. 0.90 IU mL(-1) ) of N9-GP, rFIX (BeneFIX), and pdFIX (Mononine), was determined at two laboratory sites with 10 commercially available one-stage clotting assays and two chromogenic FIX:C assays. Assays were performed with a plasma calibrator and different analyzers. Results A high degree of variation in FIX:C measurement was observed for one-stage clotting assays for N9-GP as compared with rFIX or pdFIX. Acceptable N9-GP recovery was observed in the low-concentration to high-concentration samples tested with one-stage clotting assays using SynthAFax or DG Synth, or with chromogenic FIX:C assays. Similar patterns of FIX:C measurement were observed at both laboratory sites, with minor differences probably being attributable to the use of different analyzers. Conclusions These results suggest that, of the reagents tested, FIX:C in N9-GP-containing plasma samples can be most accurately measured with one-stage clotting assays using SynthAFax or DG Synth, or with chromogenic FIX:C assays.

Overestimation of N-glycoPEGylated factor IX activity in a one-stage factor IX clotting assay owing to silica-mediated premature conversion to activated factor IX.

UNLABELLED: Essentials Nonacog beta pegol (N9-GP) activity is overestimated in clot method using silica-based reagents. Mimicking contact activation phase with silica reveals N9-GP activation before recalcification. Localization of N9-GP to silica facilitates activation by factor XIa and plasma kallikrein. Silica-based reagents to be used with caution when monitoring N9-GP therapy using clot method. SUMMARY: Background Clinical laboratories routinely quantify factor IX (FIX) activity by measurement of the activated partial thromboplastin time (APTT) in a one-stage (OS) clotting assay. This assay can be performed with any of a plethora of differently composed APTT reagents, giving variable recovery when applied to nonacog beta pegol (N9-GP), an N-glycoPEGylated recombinant FIX. Objective To identify the cause of observed overestimations of N9-GP activity in an OS FIX clotting assay when most APTT reagents containing silica are used as the contact activator, and to elucidate the underlying mechanism. Methods Experiments mimicking the contact activation and clotting phases of the OS assay, combined with the use of plasmas with various deficiencies, were employed to shed light on the unique behavior of N9-GP. Confirmatory activations of N9-GP with purified enzymes and physical adsorption to silica particles were studied, and the influence of free polyethylene glycol (PEG) on these processes was investigated. Results N9-GP, but not native FIX, added to FIX-deficient plasma was prematurely converted to activated FIX (FIXa) during the contact activation phase of the clotting assay. Activated FXI (FXIa) and plasma kallikrein (PK) were responsible for the activation of N9-GP, an event that appeared to require the presence of a silica-containing APTT reagent. PEG-dependent adsorption of N9-GP to silica particles could be demonstrated. Conclusions The PEG moiety mediates colocalization of N9-GP with its activators FXIa and PK on silica surfaces, thereby facilitating premature conversion of N9-GP to FIXa during the contact activation phase, and leading to overestimation of the FIX activity in the OS clotting assay.

Hemophilia in Iran.

BACKGROUND: Hemophilia A (HA) and B (HB) are common bleeding disorders, Iran having the ninth largest such population in the world. A considerable number of studies have been performed on different aspects of their disorder. OBJECTIVE: The aim of the study was to gather all obtainable data about Iranian patients with HA and HB, including molecular studies, clinical presentations and treatment, and development and management of patients with inhibitor, to help better understand the disease and its management in other parts of the world. METHODS: For this review study, we searched MEDLINE and Scientific Information Database for English and Persian sources until 2015. RESULTS AND DISCUSSION: There are 5369 patients with HA and HB in Iran among which 4438 patients have HA. About one-fifth of HA patients' genes were analyzed and their underlying defects detected. Hemarthrosis, epistaxis, ecchymosis, and post-dental extraction bleeding are the most common clinical presentations. Bleeding was mainly managed by on-demand replacement therapy with factor VIII/factor IX (FVIII/FIX) concentrates or cryoprecipitate in HA, and fresh frozen plasma in HB in the absence of factor concentrate. Mean per capita for FVIII in HA patients is 1.56 IU, which is higher than the global per capita mean. However, mean per capita for FIX (0.24 IU) is lower than the global mean but highest among eastern Mediterranean countries. Replacement with plasma-derived components has led to infection in a large number of patients as well as inhibitor development against exogenous infusion of coagulation factors. According to a World Federation of Hemophilia survey, 223 HA and 6 HB patients in Iran have developed inhibitor and have been mainly managed by recombinant FVII (rFVIIa) and activated prothrombin-complex concentrate. CONCLUSION: Although this study was performed in Iranian patients, the large number thereof gives confidence that the results can be used more widely for other countries, especially in the developing world.

Hemophilia A and B are associated with abnormal spatial dynamics of clot growth.

To gain greater insight into the nature of the bleeding tendency in hemophilia, we compared the spatial dynamics of clotting in platelet-free plasma from healthy donors and from patients with severe hemophilia A or B (factor VIII:C or IX:C<1%). Clotting was initiated via the intrinsic or extrinsic pathway in a thin layer of nonstirred plasma by bringing it in contact with the glass or fibroblast monolayer surface. The results suggest that clot growth is a process consisting of two distinct phases, initiation and elongation. The clotting events on the activator surface and the preceding period free of visible signs of clotting are the initiation phase. In experiments with and without stirring alike, this phase is prolonged in hemophilic plasma activated by the intrinsic, but not the extrinsic pathway. Strikingly, both hemophilia A and B are associated with a significant deterioration in the elongation phase (clot thickening), irrespective of the activation pathway. The rate of clot growth in hemophilic plasma is significantly lower than normal and declines quickly. The resulting clots are thin, which may account for the bleeding disorder.

Liposome-encapsulated DNA-mediated gene transfer and synthesis of human factor IX in mice.

Hemophilia B is an X-chromosome-linked recessive disorder that is caused by a deficiency of biologically active clotting factor IX (FIX). In this work, liposomes (Lip) were used for non-viral, in vivo gene transfer of the human FIX gene into mouse organs. Plasmid DNA, containing the human FIX cDNA under the control of the Moloney murine leukemia virus (MoMLV) long terminal repeat (LTR), was encapsulated in 1-2-microns multilamellar Lip composed of egg phosphatidylcholine (EPC). The percentage of Lip-associated DNA was 47%, and 72% of the Lip DNA was protected from DNase I digestion. The Lip-encapsulated (Len) DNA was injected intravenously into Balb/c mice, and at various times post-injection, various tissues were examined for the presence of the exogenous DNA. Plasmid DNA was detected by Southern blot analysis mainly in the liver and spleen, but small amounts were also detected in the lungs, heart and kidneys. The plasmid DNA was retained in mouse liver cells for at least 7 days post-injection, and remained in an episomal state. The levels of human FIX protein in the mouse plasma were 190-650 pg per ml for 2 to 7 days post-injection. Treatment of mice with chloroquine (Cq) and colchicine (Cc) prior to Lip injection significantly increased the amount of plasmid DNA found in the liver cells, as well as the level of human FIX in the plasma. These results demonstrate the potential use of Len DNA for gene transfer into liver and spleen, and for gene therapy of inherited and acquired disorders.

[Treatment of the patient with a coagulation defect in oral and maxillofacial surgery. III. The management of patients in a hypocoagulative state because of a hemophilic-type primary pathology]. / Il trattamento del paziente con difetto di coagulazione in chirurgia orale e maxillo-facciale. Nota III: Il management dei pazienti in stato ipocoagulativo a causa di una patologia primaria di tipo emofilico.

Hemophilia plays a particularly important role among the diseases caused by abnormal coagulation. Defective blood-clotting factor diseases have a particular importance between coagulopathies: hemophilia, among these hematic disorders, plays a principal role. In this paper the authors present the results of scientific research on hemophilic disease carried out to obtain a correct clinical and therapeutic approach for clinical and surgical Odontostomatology. The authors, after having presented in short the physiopathologic function of coagulation factors, illustrate the clinical and therapeutic aspects of Hemophilia A and Hemophilia B. The correct Odontostomatological and Maxillo-Facial Surgical approach is presented as the result of the authors' research. Also von Willebrand's disease is illustrated even if it is not exactly a hemophilic disease. This is because all hemophilias must produce a gynephoric inheritance pattern. Nevertheless clinical, therapeutic and molecular biology appearance suggests the illustration of von Willebrand's disease together with hemophilias. Von Willebrand's disease can be divided into three nosologic groups and to each one corresponds a particular clinical and therapeutic management. Such cases are illustrated and examined from an Odontostomatologic point of view. The results obtained suggest the necessity of keeping to the management that was described. Actually a low percentage of accidents occurred only when the above-mentioned clinical processes were completely performed.

Bleeding in carriers of hemophilia.

A wide range of factor VIII and IX levels is observed in heterozygous carriers of hemophilia as well as in noncarriers. In female carriers, extreme lyonization may lead to low clotting factor levels. We studied the effect of heterozygous hemophilia carriership on the occurrence of bleeding symptoms. A postal survey was performed among most of the women who were tested for carriership of hemophilia in the Netherlands before 2001. The questionnaire included items on personal characteristics, characteristics of hemophilia in the affected family members, and carrier testing and history of bleeding problems such as bleeding after tooth extraction, bleeding after tonsillectomy, and other operations. Information on clotting factor levels was obtained from the hospital charts. Logistic regression was used to assess the relation of carrier status and clotting factor levels with the occurrence of hemorrhagic events. In 2004, 766 questionnaires were sent, and 546 women responded (80%). Of these, 274 were carriers of hemophilia A or B. The median clotting factor level of carriers was 0.60 IU/mL (range, 0.05-2.19 IU/mL) compared with 1.02 IU/mL (range, 0.45-3.28 IU/mL) in noncarriers. Clotting factor levels from 0.60 to 0.05 IU/mL were increasingly associated with prolonged bleeding from small wounds and prolonged bleeding after tooth extraction, tonsillectomy, and operations. Carriers of hemophilia bleed more than other women, especially after medical interventions. Our findings suggest that not only clotting factor levels at the extreme of the distribution, resembling mild hemophilia, but also mildly reduced clotting factor levels between 0.41 and 0.60 IU/mL are associated with bleeding.

Reabilitação odontológica multidisciplinar em paciente pediátrico com hemofilia: relato de caso / Multidisciplinary rehabilitation of pediatric dentistry in patients with hemophilia: case report

A hemofilia é uma coagulopatia congênita autossômica recessiva ligada ao cromossomo X, isso é devido à deficiência do fator VIII (hemofilia A) ou do fator IX (hemofilia B) afetando apenas os homens.Os transtornos hemorrágicos constituem um dos problemas de maior interesse a serem considerados pelo cirurgião-dentista na prática odontológica. O tratamento odontológico de pacientes com hemofilia deve ser realizado sob cuidados especiais com uma equipe multidisciplinar, nos quais os profissionais da saúde devem ter experiência médica e apoio hematológico adequados. O Objetivo deste trabalho foi relatar a reabilitação odontológica de maneira multidisciplinar de um paciente pediátrico com diagnóstico de hemofilia B grave, a qual é tratada e controlada por médicos hematologos do Hospital Geral de Zona (HGZ). O diagnóstico odontológico foi de acúmulo de placa bacteriana nas superfícies dentais por má higiene bucal, lesões de cárie e hipoplasia de esmalte. Para reabilitação bucal foram realizadas extrações de alguns elementos dentais, profilaxia, flúor terapia, orientação emotivação de higiene bucal, remoção de tecido cariado com auxílio de ultrassom, restaurações com resina composta, ionômero de vidro e restaurações indiretas cerômeros. Concluiu-se que para um adequado manejo odontológico é imprescindível o conhecimento de diversas patologias sistêmicas como a hemofilia, o atendimento multidisciplinar, além do conhecimento de técnicas de mínima intervenção em Odontopediatria para assim poder oferecer ao paciente melhores alternativas de tratamento com a mínima invasão e resultados favoráveis.

Hemophilia is an autosomal recessive congenital blood coagulation desorder to X chromosome, this is due to deficiency of factor VIII (hemophilia A) or factor IX (hemophilia B) affects only men. Bleeding disorders are one of the issues of greatest interest to be considered by the dentist in the dental practice. Dental treatment of patients with hemophilia should be done under special care bya multidisciplinary team in which health professionals must have medical experience and adequate hematologic support. The objective of this study was to report the dental rehabilitation in a multidisciplinary team to a pediatric patient with severe haemophilia B, which is treated and controlled by medical hematologists in Zone General Hospital (HGZ). The dental diagnosis was accumulation ofplaque on dental surfaces by poor oral hygiene, dental caries and enamel hypoplasia. For oral rehabilitation extractions were performed in some dental elements, prophylaxis, fluoride therapy, guidance and motivation of oral hygiene, caries removal with ultrasound assistance restorations with compositeres in, glass ionomer and indirect restorations with cerômics. It was concluded that for properdental management is essential knowledge of various systemic diseases such as hemophilia, multidisciplinary care, in addition to knowledge of minimal intervention techniques in pediatric dentistry so as to offer the best treatment alternatives patient with minimal invasion and favorable results.

Reactions of blood with nonbiologic surfaces. Ultrastructural and clotting studies with normal and coagulation factor deficient bloods.

Interaction of normal and coagulation factor deficient bloods with glass, Teflon and silicone-coated glass surfaces have been studied. The morphology of the blood-surface interaction was observed by scanning electron microscopy. Activation of the intrinsic coagulation system and progression of these changes, monitored by use of the partial thromboplastin time test, were influenced by both the type of surface to which blood was exposed and the deficiencies of coagulation Factors I, VIII, IX, or XII. Deficiency of fibrinogen appears to enhance, minimally, activation of the coagulation sequences by test materials. However, deficiency of fibrinogen markedly reduces adhesion of platelets to foreign surfaces. Deficiency of Factor XII, but not of Factors VIII or IX, decreases platelet adhesion to nonbiologic surfaces but to a lesser extent than does deficiency of fibrinogen. Roughness of test surfaces appears to encourage cellular deposition from blood. An ex vivo model designed for screening materials for their compatibility with blood is described.

A retrospective survey on the safety of Replenine, a high-purity factor IX concentrate.

PURPOSE: To assess the safety of a plasma-derived highly purified factor IX concentrate (Replenine) in routine clinical use. METHODS: Following guidelines entitled Safety Assessment of Marketed Medicines (SAMM), safety data were collected in the UK by retrospective review of the hospital notes of 114 patients who received an estimated 14.8 million IU of Replenine. Included were 40 patients undergoing 44 surgical procedures or dental extractions [corrected]. RESULTS: The study detected a total of nine adverse events (AEs), four of which were possibly product-related, four that were unrelated to the product and one whose causality was unknown. None of these cases had been notified to the manufacturer through conventional spontaneous reporting procedures. One patient was switched from Replenine because of infusion site irritation, but no unexpected adverse reactions were noted. There were no reports of virus transmission or new factor IX inhibitor development. The mean factor IX recovery value was 1.44 IU/dl per IU/kg (95%CI: 1.31-1.57 IU/dl per IU/kg). CONCLUSIONS: The study was a practical application of the SAMM guidelines to the collection of pharmacovigilance data on patients with Haemophilia B. Replenine is well tolerated in routine clinical practice.