Impact of choice of treatment for bleeding episodes on inhibitor outcome in patients with mild/moderate hemophilia a and inhibitors.

Patients with mild/moderate hemophilia A (MHA) may develop inhibitors to factor VIII (FVIII). In this condition, FVIII clotting activity (FVIII:C) baseline levels may remain stable for some patients, but may be reduced to less than 0.01 U/mL for others. Several risk factors for the development of inhibitors in MHA have been proposed. Genetic factors, such as mutations in the FVIII gene, may play a central role; however, other influences, such as intensive treatment with FVIII products, may also be important. Optimal treatment regimens have yet to be determined, not only for the eradication of inhibitors, but also for the management or surgical prophylaxis of hemorrhages associated with this condition. Several treatment options for the control of bleeding in patients with MHA and inhibitors (MHAI) are currently available, and the choice of therapeutic strategy should be given careful consideration; some treatments may produce an anamnestic response, thus delaying the return to FVIII:C baseline levels and adversely affecting the duration of the severe bleeding phenotype. To increase our knowledge of MHAI, a retrospective collection of data is currently being performed among hemophilia centers in France and Belgium. Based on five examples of patients with MHAI collated from preliminary study data, we illustrate the impact on inhibitor outcome of the therapeutic choices used to treat bleeding episodes in these patients.

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.

Chronic myelogenous leukemia (CML) with translocation (8;22): a new variant.

A case of chronic myelogenous leukemia (CML) in a young woman with a new variant Ph1-translocation--i.e., t(8;22) (q24;q12)--is described. The clinical and biological aspects of the disease did not seem to differ from those of the usual cases of CML.

[Antiprothrombinase and myocardial infarction. Apropos of 2 cases]. / Antiprothrombinase et infarctus du myocarde. A propos de deux observations.

Among the thrombotic events associated with a circulating anticoagulant of the antiprothrombinase type, myocardial infarction is exceptionally reported, which justifies the presentation of two cases. In both patients, myocardial necrosis occurred some time after the antiprothrombinase was discovered, and there was nothing special in its clinical features. No obvious atherosclerotic lesion and no image suggestive of vasculitis were found at coronary arteriography, which suggested that the antiprothrombinase played a predominant role in the genesis of infarction. Relationships between antiprothrombinase, arterial thrombosis (particularly of the coronary arteries) and the presence or absence of systemic lupus erythematosus (SLE) are discussed. As observed in thrombosis of other arteries, it is not certain that the presence of SLE constitutes an additional risk factor, except in cases with unquestionable vasculitis or if the treatment of SLE requires prolonged corticosteroid therapy. On the other hand, the appearance of an antibody directed against phospholipids is not necessarily related to the presence of SLE; in fact, this antibody itself might be a risk factor of myocardial infarction, as has recently been suggested.

[Kinetics of erythropoietin blood levels from D-1 to D-29 in kidney transplantation]. / Cinétique de l'érythropoïétinémie de J-1 à J29 en transplantation rénale.

This study of serum erythropoietin levels and reticulocytes counts in the first month after kidney transplantation shows that the erythropoietin peak is efficient only when serum creatinine level at the time of the peak is under 200 mumol/l.

Prevalence and epitope specificity of non-neutralising antibodies in a large cohort of haemophilia A patients without inhibitors.

Antibodies (inhibitors and non-neutralising antibodies [NNA]) directed against factor VIII (FVIII) remain the main iatrogenic complication in haemophilia A (HA) patients. Inhibitors reduce FVIII pro-coagulant properties, whereas NNA are directed against non-functional epitopes. NNA are poorly studied and their prevalence, epitope specificity and physiopathology inadequately defined. The aim of this study was first to evaluate NNA prevalence in a French retrospective multicentric series of 210 patients without inhibitors, then to determine their epitope specificity (against the heavy chain [HC] or the light chain [LC] of FVIII) and particularly to assess the prevalence of anti-B domain NNA using specifically designed x-MAP assays. NNA occurred in 18.1% of patients (38/210) and their prevalence was not influenced by the severity of the disease. Among the 38 patients with NNA, 73.7% had anti-FVIII Abs against the HC, 13.2% against the LC and 13.2% had anti-FVIII Abs against both chains. There is thus a clear immuno-dominance of the HC of FVIII in the epitope profile of NNA, whatever the severity of HA. The proportion of NNA that recognised the B domain was 18.4% (n=7/38). A multivariate analysis did not highlight differences in NNA occurrence between patients treated with recombinant FVIII or with plasma- derived FVIII (19.6% vs. 14.9%, p=0.53).

[Cytogenetic study of 20 cases of refractory anemia]. / Etude cytogénétique de 20 cas d'anémies réfractaires.

The myelodysplastic syndromes are a group of hematological disorders not yet clearly defined. The authors describe the chromosomal aspects of 20 cases observed in the region of Clermont-Ferrand in comparison with the bibliographical data.

Cost related to replacement therapy during hospitalization in haemophiliacs with or without inhibitors: experience of six French haemophilia centres.

Replacement therapy in haemophiliacs has a major economic impact on health establishments. We assessed in this prospective study the cost of clotting factor concentrate therapy for haemophilia A or B patients. We compared the overall costs of treated patients with or without inhibitors. In six French haemophilia centres, 278 consecutive hospitalizations were collected and analysed between June 97 and June 99. Haemophilia must be considered as the main cost factor during hospitalization. The severity of bleeds and surgical procedures increase the total cost. Furthermore, the daily and total costs are closely linked to the presence or the absence of inhibitors. This study should enable the hospital administration to evaluate the necessary resources to the clotting factor therapy in haemophiliacs with or without inhibitors during hospitalization.

[Action of amsidine on the evolution of lymphocyte cultures and on the structure of human metaphase chromosomes]. / Action de l'amsidine sur l'évolution de cultures lymphocytaires et sur la structure des chromosomes métaphasiques humains.

Chromosomic alterations can be observed after the effect of a antimitotic amsidine on metaphases of cultured human lymphocytes: gaps, breaks, exchange figures, deletions, rings. Moreover we notice, among these cells, particular lines of big sized lymphoplasmocytoid cells, whose rate is abnormally high when compared to reference cultures.

Leukotriene B4 in hemodialysis.

Leukotrienes are eicosanoids arising from arachidonic acid via 5 lipooxygenase, an enzyme essentially present in leukocyte cells. Leukotriene B4 might be an indicator of neutropolymorphonuclear leukocyte activation when there is contact with artificial membranes. The level of plasmatic leukotriene B4 was measured at three different times during the hemodialysis treatment in several patients undergoing dialysis on three different membranes (one cellulosic and two synthetics). A moderate increase of leukotriene B4 was observed early (at 15 min), comparable among the three membranes, but levels returned to baseline at 180 min. Leukotriene B4 production proved leukocyte activation and was probably related to a direct interaction with dialysis membrane. Nevertheless, complement intervention could not be excluded. Leukotriene B4 is one molecule more among the group of inflammatory mediators produced during hemodialysis treatment.

[Evaluation of the biocompatibility of a new cellulose membrane by studying the complement system and histamine liberation]. / Evaluation de la biocompatibilité d'une nouvelle membrane cellulosique par l'étude du système du complément et de l'histaminolibération.

This biocompatibility of the new cellulosic membrane hemophane (HE) is compared to that of cuprophane (CU) in ten maintenance hemodialysis (HD) patients dialyzed on the two types of membranes in randomized order, under otherwise similar technical conditions. Total white blood cell (WBC) and differential counts, blood concentrations of C3a, and C3d and histamine are determined at start of dialysis (TO) and 10, 20 and 180 minutes thereafter. HE is distinct from CU in exerting a minor effect on the generation of C3a, a minor drop of leucocytes during the course of dialysis (P less than 0.01) and also by a lesser increase in blood histamine concentration (P less than 0.05). Histamine liberation is observed on CU together with the generation of anaphylotoxin C3 and with a diminution of circulating basopolymorpho-nuclear cells. According to the variations observed for these three parameters (C3a, leucocytosis and blood histamine concentration), HE appears as being more biocompatible than CU.