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.

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.

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.

Monoclonal gammopathies in the adult population of Finistère, France.

Three hundred and thirty-four monoclonal gammopathies were detected in the sera of 30 279 adults from Finistère. Monoclonal gammopathies (MG) are more common in Finistère than in Paris and their distribution is not homogeneous. IgG paraproteins are particularly common in the northeast of Finistère whereas IgM paraproteins are more common in the southwest. Family studies and the high degree of inbreeding would support the hypothesis that there is a genetic predisposition to develop MG but the occurrence of paraproteins among three non-consanguineous couples seems to favour the existence of an environmental factor.

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.

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.

[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.

[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.

[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.

[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.

[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.

[Effect of in vitro carbamylation of erythrocytes on their rheological properties]. / Effet de la carbamylation "in vitro" des érythrocytes sur leurs propriétés rhéologiques.

In order to assess the role of carbamylation of erythrocyte proteins in the modification of rheological parameters of red blood cells observed in uremic patients, and in vitro carbamylation of erythrocytes and hemoglobin was carried out using sodium cyanate. The carbamylation of hemoglobin was determined by observation of the increase of HbA1 fraction. The deformability of erythrocytes and the viscosity of erythrocyte suspensions and of hemolysate were measured. The results showed an increase in the deformability of red blood cells and a decrease in the viscosity of hemoglobin as the carbamylation increased. This is attributed to a decrease of hemoglobin viscosity and to a modification of the electric charge of the membrane. These results show that the reduced erythrocyte deformability observed in patients with renal failure is not due to erythrocyte protein carbamylation.

[Drug-induced thrombopenias and neutropenias. An in vitro study by the indirect immunofluorescence test]. / Thrombopénies et neutropénies induites par des médicaments. Etude in vitro par le test d'immunofluorescence indirecte.

The sera from 38 patients with suspected drug-induced thrombocytopenia (22) or neutropenia (16) were tested with the indirect immunofluorescence test on platelets or granulocytes for the presence of drug-dependent antibodies. Three drug-induced antibodies with reactivity against platelets and 5 with reactivity against granulocytes were detected. In 3 sera antibodies were found which reacted already with target cells without adding the drug to the test system. These data show that drug-induced blood dyscrasias often have an immunological cause and that in vitro tests can be helpful in detecting the responsible drug. Different mechanisms can be involved. In many sera circulating antibodies were not found, but an immunological mechanism is likely to be involved in some of these cytopenias: the antibody could be entirely absorbed by the target cells, a metabolite of the drug could be the immunogen and finally the test may not be sensitive enough.

[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.

[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.

[Autotransfusion and hemodilution in orthopedic surgery in children]. / Auto-transfusion et hémodilution en chirurgie orthopédique pédiatrique.

The risk of transmitting viral diseases is a constant worry for those who perform blood transfusions. In the last three years several techniques were used to avoid homologous blood transfusions. Four series of patients were evaluated: 1st series: Only homologous blood transfusions (27 cases); 2nd series: Acute normovolaemic haemodilution during surgery (20 cases); 3rd series: Autologous blood storage prior to surgery and haemodilution during surgery (20 cases); 4th series: Blood storage prior to surgery + haemodilution + Trinitine perfusion during surgery (44 cases). 111 patients having undergone vertebral arthrodesis and 13 children having undergone orthopaedic or repair surgical procedures are reported. In the first series, 98 per cent of blood loss was replaced by homologous transfusions, in the second series, 46 per cent, in the third series, 19 per cent, in the fourth series, less than 5 per cent. This study provides confirmation that in cases of major pediatric orthopaedic surgery, it is possible to use the various techniques demonstrated to avoid homologous transfusions.

[Transfusional malaria in France (1960-1979) (author's transl)]. / Paludisme transfusionnel en France de 1960 à 1979.

Transfusional Malaria is not a rare condition in France: in the past 20 years, 110 cases were cited in the literature and/or reported to us in answers to a recent questionnaire. Of these, 24 cases occurred between 1960 and 1969 and 78 between 1970 and 1979. This apparent increase in occurrence in the past decade is most probably due to the increase in the number of transfusions of whole blood or fresh fractions containing infected erythrocytes, although population exchanges with inter-tropical Africa may also play a preponderant role. Our study confirms that Plasmodium falciparum is the most prevalent pathogen responsible for this condition in France; it caused 84% of cases in the past five years. We think this point must be taken in account by the legislator.

[Anti-leuko-platelet allo-immunization in blood replacements. Do transfusions of platelets from single donors present an advantage over platelets from multiple donors?]. / Allo-immunisation anti-leuco-plaquettaire en réanimation hématologique. Les transfusions de plaquettes de donneurs uniques prêsentent-elles un avantage sur les plaquettes de donneurs multiples?

42 patients with acute leukaemia, treated with cytotoxic drugs, have been evaluated retrospectively: --group I: 11 patients received packed red blood cells and platelets from single donors; --group II: 6 patients received packed red blood cells and platelets from multiple donors; --group III: 25 patients received packed red blood cells and platelets from single or multiple donors and granulocytes transfusions. There was no difference in age, sex, time of follow up, number of transfusions, in the three groups. The rate of alloimmunization defined as lymphocytotoxicity against more than 20% of a panel of 24 lymphocytes, was 33% (36% group I--33% group II--32% group III). This study shows that platelets from single donors are of no use in preventing or delaying alloimmunization. On the other hand, their major interest is to provide alloimmunized patients with compatible platelets.