Health status and health-related quality of life of children with haemophilia from six West European countries.

A multicentre, international, cross-sectional study was carried out in the frame of field testing of the first haemophilia-specific quality-of-life (QoL) questionnaire (Haemo-QoL). The aim of this paper is to describe health status and health care and their impact on QoL in haemophilic children in Western Europe. Children aged 4-16 years with severe haemophilia without inhibitors were enrolled by 20 centres in France, Germany, Italy, the Netherlands, Spain and the United Kingdom. Clinical information was collected by the physicians with a medical documentation form. Health-related QoL (HRQoL) of children was assessed with Haemo-QoL, available for three age groups. Clinical data were available in 318 patients, 85.5% with haemophilia A. The mean age at first bleeding was 11 months, at first joint bleed 25 months. Functional joint impairments were found in 11.3%. Prophylaxis treatment was given to 66.7% of children in whom breakthrough bleeds occurred 0.4 times a month compared to 1.1 bleeds in children receiving on-demand treatment. A significantly higher factor consumption was found only in the two younger age groups of prophylaxis patients compared to on-demand patients. HRQoL was satisfactory in this cohort: young children were impaired mainly in the dimension 'family' and 'treatment', whereas older children had higher impairments in the so-called 'social' dimensions, such as 'perceived support' and 'friends'. Health care of children in Western Europe is progressively improving with a large diffusion of home treatment and prophylaxis. This provides a high level of health status and HRQoL, being better in haemophilic adolescents on prophylaxis.

[Are the indications and choice of labile blood products adapted? National survey on prescriber's knowledge]. / Les indications et le choix des produits sanguins labiles sont-ils adaptés? Enquête nationale sur les connaissances des prescripteurs.

OBJECTIVE: There is little data available on current practice related to prescription of labile blood products (LBP) by French physicians. The aim of this study was to assess whether prescriptions were conform to Anaes (French Medicine's agency) guidelines, with regard not only to indications but also quality of the products, so as to define the improvements that could be made. METHOD: Thirty-four clinical case reports, classified by specialties were sent to prescribing physicians working in the regional health centers, from 17 different blood banks, from October 1997 to February 1998. The prescribers were requested to answer only the questions that were specific to their particular field of experience. Each case description included multiple choice questions on the indication for transfusion of concentrated of red blood cells (RBC) and/or platelets (CP) and/or plasma, and the possible requirements for specification or modification of the guidelines applicable to these products. The primary end point of analysis was the adequation of the answers to the Anaes recommendations. RESULTS: Answers were obtained regarding 5092 clinical cases from 818 physicians. The participation rate was of 30%. The specialties were as follows: 34% anesthesiologists, 14% oncologists-haematologists, 13% internal medicine specialists, 11% emergency physicians, 10% paediatricians, 8% obstetricians, 7% geriatricians, and 3% transplantation surgeons. Eighty-two percent of the answers came from physicians working in the public health services. The adequation with the indication for transfusion was of 90.3% for RBC, 92.3% for platelets and 93.8% for plasma. The percentages of correct answers regarding the indications for specification or modification of the LBP were as follows: 90.3% were correct for irradiation (of either RBC or platelets); 68.8% and 53.2% respectively for leukocyte depletion from RBC and platelets; 64% for phenotyped RBC; 68.2% for compatibilized RBC; and 57.3% for apheresis platelet concentrates. There was no difference in results depending on the type of center, private or public, and the quality of LBP prescribed. The answers obtained from the anaesthesiologists' clinical cases were less accurate with regard to RBC but more accurate with regard to PC compared with other specialists. CONCLUSION: This study shows the correct management of the indications for transfusion by the prescribing physicians who participated in the study, but the lack of knowledge with regard to the indications for specifications and/or transformations of LBP. The respect of the indications for transfusion is the corner stone of safe transfusion and this phase should be optimized with improved dissemination of information on transfusion and training for the physicians and programs that would improve the quality.

European data of a clinical trial with a sucrose formulated recombinant factor VIII in previously treated haemophilia A patients.

To increase the safety of antihaemophilic treatment, the production process of full-length recombinant factor VIII (FVIII) KOGENATE Bayer (Kogenate FS) has been modified. Human albumin is no longer added as stabilizer during purification and in final formulation. Instead, the new KOGENATE Bayer production process uses sucrose as a stabilizer in the formulation and adds solvent/detergent virus inactivation step. An European clinical trial was carried out in Germany and France in previously treated patients with severe haemophilia A who had more than 100 exposure days to exogenous FVIII. Pharmacokinetic data was analysed according to one-stage and chromogenic assays. Efficacy and safety during home therapy and in surgical procedures were evaluated; inhibitor formation was carefully monitored. Safety and efficacy were evaluated in 33 European patients for 24 months. Patients received more than 13 million IU KOGENATE Bayer. Over 75% of patients accrued more than 100 exposure days with the new product. Of 875 bleeding episodes, 90.7% were treated with 1 or 2 infusions and 75.8% of responses to treatment were rated as 'excellent' or 'good'. Prophylactic treatment was the most common mode of therapy (60.7% of infusions). The product was well-tolerated and FVIII recovery studies were consistent throughout the study period. Only 0.26% of adverse events were reported to be drug related. No evidence of de novo inhibitor formation was observed. Overall, KOGENATE Bayer was efficacious, safe and well-tolerated for the treatment of haemophilia A in multitransfused patients.

Pilot testing of the 'Haemo-QoL' quality of life questionnaire for haemophiliac children in six European countries.

In a multinational working group, an instrument (Haemo-QoL) to assess quality of life in children/adolescents with haemophilia and their parents has been developed. In co-operation with haemophilia treatment centres in six European countries, approximately 10 children/adolescents with haemophilia per country and their parents were asked to participate in the pilot-testing. Both self-reported and parent-reported questionnaires were provided for two age-groups of children (4-16 years). Medical data was collected from physicians from patient files. Answers to open questions from participants (58 children and 57 parents) confirmed the content of 116 of the preliminary items. Cognitive debriefing revealed that the majority of the Haemo-QoL was rated favourably, but 29 questions were recommended to be omitted and several items to be reformulated. Preliminary psychometric testing of the revised 77 item questionnaire in the same sample showed acceptable reliability and validity, which will be examined in a subsequent study with a larger patient sample.

Use of recombinant factor VIIa (NovoSeven) in patients with Glanzmann thrombasthenia.

Recombinant factor VIIa (rFVIIa; NovoSeven, Novo Nordisk, Bagsvaerd, Denmark) appears effective and relatively safe for the treatment of bleeding and for surgical prophylaxis in patients with Glanzmann thrombasthenia as reported to the International Registry on rFVIIa and Congenital Platelet Disorders. One of the shortcomings of the Registry data is the heterogeneity of treatment protocol, including dosage, number of doses used, duration of treatment before declaration of failure, and mode of rFVIIa administration (bolus v continuous infusion). The data are not yet sufficient to define optimal regimens for various indications such as the type of bleeding or the type of procedures. The place of this drug compared to platelet transfusion in the overall management of patients with Glanzmann thrombasthenia will need to be determined in relationship to a number of challenges and unresolved issues in the clinical care of these patients. These issues include: how to improve local measures for patients with mucosal bleeds, optimal management of young women during menarche, optimal platelet transfusion regimens for various indications, the relationship between antiplatelet antibodies detected by monoclonal antibody-specific immobilization of platelet antigens (MAIPA) and effectiveness of platelet transfusion, whether there are other biological tests that may correlate with effectiveness of platelet transfusion, and management of pregnancy and delivery regarding antiplatelet immunization.

[Evaluation of the immediate transfusion reaction incident reporting system at the Brest University Hospital Center]. / Evaluation du système de notification des incidents transfusionnels immédiats au CHU de Brest.

The Haemovigilance Unit of Brest University Hospital has had a reporting system of transfusion reactions since october 1994. Reporting "any unexpected or undesirable effect due or likely to be due to the administering of blood cell components" must be done on an answering machine immediately or in the next eight hours. The main goal of the evaluation of this epidemiological surveillance system was to assess its sensitivity, its positive predictive value, its acceptability, its timeliness and its simplicity, according to the Centers for Disease Control criteria. An exhaustive monitoring of the immediate transfusion reactions (ITR) occurring within the 24 hours following the procedure was conducted from April 1, to June 30, 1998. Two sources of information were used, the spontaneous notification to the Haemovigilance Unit using the answering machine, and a telephone survey of the nurse responsible for the transfusion or post-transfusion follow-up. During the survey, 19 ITR, among which 12 were reported to the Haemovigilance Unit on the answering machine, were recorded. The incidence rate of the I.T.R. was estimated at 5@1000 transfused blood cell components. The sensitivity of the notification system was estimated at 63% (95% confidence interval: 41-85) and the positive predictive value at 70% (95% confidence interval: 48-92). This notification system is operational. The function of sanitary alert is ensured at the primary level of the system surveillance. The undernotification of the ITR (37% of false negative) must be corrected by specific recommendations.

The use of recombinant factor VIIa (NovoSeven) in a patient with a factor XI deficiency and a circulating anticoagulant.

A 75-year-old female known to have a chronic myelomonocytic leukaemia and an acquired FXI deficiency (FXI level, 5%) related to a FXI inhibitor (38 Bethesda units) was admitted to the hospital for acute pneumonia associated with a bulky pleural effusion. A therapeutic puncture was found to be essential for the patient. But, such a procedure is a haemostatic challenge which requires adequate preparation. A first treatment composed of intravenous immunoglobulins and immunosuppressive therapy failed to eradicate the inhibitor and to restore a normal FXI level. In this context, steroids or FXI concentrates were not recommended. Thus, small doses of recombinant activated factor VII were used to achieve haemostasis. The procedure was successful, the tolerance was good and no adverse events occurred.

French previously untreated patients with severe hemophilia A after exposure to recombinant factor VIII : incidence of inhibitor and evaluation of immune tolerance.

Fifty French previously untreated patients with severe hemophilia A (factor VIII < 1%), treated with only one brand of recombinant factor VIII (rFVIII), were evaluated for inhibitor development, assessment of risk factors and outcome of immune tolerance regimen. The median period on study was 32 months (range 9-74) since the first injection of rFVIII. Fourteen patients (28%) developed an inhibitor, four of whom (8%) with a high titer (> or = 10 BU). All inhibitor patients but one continued to receive rFVIII either for on-demand treatment or for immune tolerance regimen (ITR). Among these patients, inhibitor was transient in 2 (4%), became undetectable in 6 and was still present in 6. The prevalence of inhibitor was 12%. Presence of intron 22 inversion was found to be a risk factor for inhibitor development. Immune tolerance was difficult to achieve in our series despite a follow-up period of 16 to 30 months: immune tolerance was complete in only one out of the 3 patients undergoing low dose ITR and in one out of the 5 patients with high dose ITR.

[Feasibility of following up transfused patients]. / Faisabilité d'un suivi de patients transfusés.

The aim of this study was to assess the natural history of patients after transfusion and the acceptability of a standardized biological follow-up. In 1995, during 1 month, in 13 French hospitals, a follow-up at 3 and 6 months after blood transfusion was proposed to all blood recipients who had not received any blood transfusion within the past 6 months (eligible patients): screening for red cell antibodies, alanine aminotransferase (ALT) activity and specific viral markers of hepatitis B (hepatitis B surface antigen and antibody to hepatitis virus core antigen), of hepatitis C (antibodies) and of Human Immunodeficiency Virus (antibodies). At the beginning of the study, 296 patients were followed for 6 months. A complete follow-up was available at 3 months for 183 patients (62%), at 6 months for 168 (57%) and after 6 months, 198 patients (67%) have been once followed. Of eligible patients, 76% were alive at six months. After transfusion, the incidence of red cell alloantibodies and elevated ALT concentration were respectively 4% and 17%. At 6 months, one patient had Hepatitis B surface antigen; the responsibility of blood transfusion was excluded. Within the first 24 hours, 68 patients (23%) required another blood transfusion and 42% of units were transfused to patients with malignant disease. Our study quantifies in real conditions the difficulty of a biological follow-up in a transfused population, mostly composed of patients that could not be followed in the hospital where they were transfused.

[Pilot study of the characteristics of transfused patients and utilized labile blood products]. / Etude pilote des caractéristiques des patients transfusés et des produits sanguins labiles utilisés.

The aim of this study was to describe blood recipients and blood components transfused during the first 24 hours in 13 French hospitals. We included all blood recipients who had not had any blood transfusion within the past six months. Recipients were screened for red cell alloantibodies, the alanine aminotransferase activity and specific viral markers (hepatitis B and C, Human Immunodeficiency Virus). Eligible patients represented 47% of the all transfused. Among the 371 patients included, 57% were males and 71% were transfused in a surgical unit. Alloantibodies, non specific and specific viral markers were detected in 3%, 19% and 2% respectively. Among the patients included, 42 received 172 autologous units. In total, 1056 allogeneic units (an average of 3 units per patient) were transfused; blood products were leucocyte-depleted (49%) or leucocyte-poor (20%); 54% of red cell units were matched for antigens Rh and Kell. Neoplasms were the most frequently reported disease for which patients were transfused. This study provides baseline blood transfusion information on recipients and blood utilization for a specific period in French hospitals. Following this study, a national study will allow the clarification of the characteristics, for instance the surgical procedures requiring transfusion.

[Analysis of transfusion incident reports filed at 15 blood transfusion centers and health facilities during 17 months. Groupe Receveurs de laSFTS]. / Analyse des fiches d'incidents transfusionnels enregistrées par 15 établissements de transfusion sanguine et établissements de santé pendant 17 mois. Groupe Receveurs de la SFTS.

The principal result of the development of hemovigilance since 1994 has been the declaration of undesirable effects likely to be due to transfusions of labile blood products. Using the 1,694 cases of undesirable effects registered, it seemed worthwhile to us to analyze the distribution of the signs noticed, their frequency and the types of blood products responsible. This analysis allowed us to observe that the majority of reactions were shivery-feverish (47%) or allergic (24%). Most of them are linked to platelet concentrate transfusions especially simple donor platelets (with a frequency of ten reactions for thousand apheresis platelet concentrates transfused). In this study the frequency of undesirable effects reported is 2 per 1,000 apheresis platelet concentrate transfusions. Further investigations are necessary to determine the physiological mechanisms of these reactions and to estimate the degree to which transfusions are responsible for their occurrence.

[Importance of flow cytometry in the detection of anti-erythrocyte autoantibodies]. / Intérêt de la cytométrie en flux dans la détection des auto-anticorps anti-érythrocytaires.

Coombs test and flow cytometry have been compared in terms of specificity and sensibility in a population of hospitalized patients, for whom a Coombs test had been required. The Coombs test seems more sensible than flow cytometry to detect red cell-bound IgG. For a given patient and over the time, flow cytometry seems better correlated with the severity of haemolysis if erythrocytes are strongly sensitized by IgG. The results of flow cytometric analysis, in percentage of sensitized erythrocytes, do not allow to define a sensibilization threshold for haemolysis prediction. Flow cytometric analysis would be more sensible than Coombs test in the detection of red cell-bound C3d, but these cases are not associated with autoimmune haemolytic anemia. Direct Coombs test should remain the diagnostic test of autoimmune haemolytic anemia.

Incidence of factor VIII inhibitor development in severe hemophilia A patients treated only with one brand of highly purified plasma-derived concentrate.

The incidence of factor VIII inhibitor was studied in a cohort of 56 previously untreated patients with severe hemophilia A (factor VIII below 1 U/dl). They received only one brand of highly purified factor VIII concentrate (HPSD-VIII) prepared by conventional chromatography with a solvent-detergent step for viral inactivation. Follow-up since the first infusion of HPSD-VIII was from 1 to 76 months (mean = 29) and cumulative exposure days (CED) from 1 to over 100 (median = 26). Five patients (9%) developed an inhibitor after 6 to 19 CED, only one being a high responder (2%), showing a low incidence of inhibitor compared with previous studies using high purity plasma-derived or recombinant products.

[Fresh frozen plasma: a pilot study of the context of utilization and the indications]. / Plasma frais congelé: étude pilote du contexte d'utilisation et des indications.

The aim of this pilot study was to assess the feasibility of a tolerance study of qualified (secured by quarantine or solvent-detergent-treated) fresh frozen plasma (FFP) in real conditions of use. We included all patients receiving qualified FFP during a one-month observation period in three french hospitals (Besançon, Brest, Lyon). The 192 FFP transfusion episodes corresponded to 111 patients. Only two thirds of all prescriptions corresponded to indications mentioned in the ministerial order of december 1991. Forty-two episodes consisted of FFP only; in the 150 remaining episodes, at least one product (mostly labile blood products) had been injected within 24 hours before or after the plasma injection. The free interval between FFP transfusion and the nearest associated product was usually less than three hours. Only one side effect was notified. This pilot study points out the difficulties of a tolerance study of qualified FFP in real conditions of use. It also raises the necessity to clarify current indications of FFP.

Alloimmunization against Iy, a low-frequency antigen on platelet glycoprotein Ib/IX as a cause of severe neonatal alloimmune thrombocytopenic purpura.

Neonatal alloimmune thrombocytopenia (NAIT) is usually induced by platelet-specific antibodies against HPA-1a (Zwa) or HPA-5b (Bra). Recently, low-frequency alloantigens on the platelet glycoprotein (GP) IIb/IIIa complex have been discovered as a cause for NAIT. In this report, a new low-frequency platelet-specific alloantigen, Iy, is described which induced severe NAIT. The corresponding antigen was detected in 1/249 unrelated German blood donors. Antibody binding assays with trypsin-digested platelets (ELISA, immunoprecipitation with biotin-labelled platelets) indicate that the antigen is not localized on the glycocalicin moiety of GP Ib alpha, but may be situated on the remnant moiety of GP Ib alpha, GP IX or GPIb beta. Apparently, Iy is not related to the HPA-2 (Ko) antigen system.

[Immunization against a new, infrequent alloantigen (Iy) on the platelet glycoprotein Ib/IX as a cause of a serious case of neonatal alloimmune thrombocytopenia]. / Immunisierung gegen ein neues, niedrigfrequentes Alloantigen (Iy) auf dem thrombozytären Glykoprotein Ib/IX als Ursache für einen schweren Fall von neonataler Alloimmunthrombozytopenie.

Neonatal alloimmune thrombocytopenia is the consequence of maternal alloimmunization against platelet-specific alloantigens, usually PIA1 or Br(a). The clinical picture is characterized by signs of haemorrhagic diathesis as a result of marked thrombocytopenia. In the last years, rare cases of immunization against 'low-frequency' or 'private' platelet alloantigens on the platelet glycoprotein (GP) complex IIb/IIIa have been found. This is the first report on NAIT due to maternal immunization against a low-frequency platelet alloantigen ('Iy') localized on platelet GP Ib/IX.

[HIV infection among type A and B hemophiliacs]. / Infection VIH chez les hémophiles A et B.

Evolution of HIV infection was studied in 480 hemophiliacs A and 78 hemophiliacs B treated in the "Centre-West" Region. 23.3% hemophiliacs A and 46.1% hemophiliacs B were contaminated by HIV. In this region, HIV seroprevalence in hemophiliacs A was lower than the prevalence noted at the national level (51.2%); this is certainly due to the use of frozen cryoprecipitates in the treatment of a high number of hemophiliacs A. A higher number of hemophiliacs B developed the disease: 12.5% hemophiliacs A versus 22% hemophiliacs B. Moreover hemophilic B patients had a more rapid evolution towards the disease since 6 out of 14 hemophiliacs A and 7 out of 8 hemophiliacs B with AIDS died. The fact that hemophiliacs B were significantly older than hemophiliacs A might be one of the reasons, but it must be noted that the contamination often occurred earlier in hemophiliacs B and was perhaps more important. The more severe evolution in the hemophiliac B group noted in our region is not found in American studies, which may be due to the different ways of preparing Factor IX concentrates in France and the United States.

Impaired fetal erythrocytes' filterability: relationship with cell size, membrane fluidity, and membrane lipid composition.

The lipid composition of erythrocytes (red blood cells [RBCs]) plays a significant role in determining certain membrane biophysical properties. We have found that fetal RBCs showed a dramatically low filterability compared with adult RBCs and questioned whether this could be a consequence of their membrane lipid composition. We therefore studied fetal RBCs at two different gestational ages, neonatal RBCs and adult RBCs. Biophysical parameters were studied using two different techniques, filterability and membrane fluidity. The latter was measured by fluorescence polarization using three different probes. The membrane lipid composition was examined by measuring cholesterol and phospholipids. After extraction of the phospholipids, followed by high performance thin-layer chromatography, the fatty acids in the phospholipid subfractions were analyzed by gas-liquid chromatography. The fetal RBCs' filterability was found to be correlated with both the larger size and the higher hemoglobin content of the cells, but there was no correlation between RBC filterability and fluidity or membrane lipid composition. In adult RBCs, compared with neonatal RBCs, the slight increase of unsaturated fatty acids in phosphatidylcholine and phosphatidylethanolamine should have increased the membrane fluidity. However, in RBCs, no change was observed in the fluidity parameters measured by fluorescence polarization.

[Efficacy in viral inactivation of the concentrates of factor VIII and IX by the solvent/detergent procedure. Evaluation in patients with hemophilia]. / Efficacité de l'inactivation virale des concentrés de facteur VIII et IX par procédé solvant-détergent. Evaluation chez l'hémophile.

Human immunodeficiency virus (HIV) infection and hepatitis virus B or C (HBV, HCV) transmission are major risks following infusion of coagulation factor concentrates. Thus, several methods have been used to achieve viral inactivation of concentrates prepared from plasma collected from a large number of donors. In this study, 32 patients with haemophilia A or B (n = 31) or von Willebrand's disease (n = 1) were treated between 1987 and 1990 only with factor VIII or IX concentrates inactivated by the solvent-detergent procedure. During this period, none of these cases exhibited elevated liver enzymes (alanine amino transferase), and serological tests for HIV, HBV and HCV infections always remained negative. This suggests that the solvent-detergent procedure of concentrate inactivation is an efficient method to prevent not only HIV or HBV transmission but also HCV infection in haemophiliacs.

The antiperinuclear factor. II. Variability of the perinuclear antigen.

Since the antiperinuclear factor (APF) test on human buccal cells is rather unpredictable, we have investigated the possible factors determining the expression of appropriate antigens by the cells. We failed to find any relationship of the expression of perinuclear antigens to the donor's smoking habits, the degree of contamination with saprophytic bacteria, the presence or absence of blood group substances in saliva, or the titers of serum antibodies to Epstein-Barr virus. Family studies were also performed to further elucidate a genetic predisposition to the expression of the APF antigen.