[Aregenerative anemia and erythrocytes hemighosts: a case report]. / Anémie non régénérative et hématies fantômes : à propos d'un cas.

An 11 year old African boy without previous history was hospitalised for fever and a severe anaemia (haemoglobin = 55 g/L) with low reticulocyte count. Blood smear showed more than 35% of ghost red blood cells which allows the diagnosis of G6PD deficiency (< 1% of normal level). Anaemia was demonstrated as haemolytic and was associated with a drepanocytosis trait. Aspect of red blood cells on blood smear remains important for the diagnosis of congenital or acquired red blood cell diseases, even abnormalities are often of low specificity.

Detection of 95 novel mutations in coagulation factor VIII gene F8 responsible for hemophilia A: results from a single institution.

Hemophilia A (HA) is an X-linked hereditary bleeding disorder defined by a qualitative and/or quantitative factor VIII (FVIII) deficiency. The molecular diagnosis of HA is challenging because of the high number of different causative mutations that are distributed throughout the large F8 gene. The putative role of the novel mutations, especially missense mutations, may be difficult to interpret as causing HA. We identified 95 novel mutations out of 180 different mutations responsible for HA in 515 patients from 406 unrelated families followed up at a single hemophilia treatment center of the Bicêtre university hospital (Assistance Publique-Hôpitaux de Paris [AP-HP], Le Kremlin-Bicêtre). These 95 novel mutations comprised 55 missense mutations, 12 nonsense mutations, 11 splice site mutations, and 17 small insertions/deletions. We therefore developed a mutation analysis based on a body of proof that combines the familial segregation of the mutation, the resulting biological and clinical HA phenotype, and the molecular consequences of the amino acid (AA) substitution. For the latter, we studied the putative biochemical modifications: its conservation status with cross-species FVIII and homologous proteins, its putative location in known FVIII functional regions, and its spatial position in the available FVIII 3D structures. The usefulness of such a strategy in interpreting the causality of novel F8 mutations is emphasized.

Glanzmann's thrombasthenia treatment: a prospective observational registry on the use of recombinant human activated factor VII and other hemostatic agents.

Glanzmann's thrombasthenia (GT) is a rare congenital bleeding disorder caused by deficiency or dysfunction of platelet surface glycoprotein (GP) IIb/IIIa receptor. Platelet transfusion is the standard treatment for bleeding that remains non-responsive to conservative measures, and for surgical coverage. Platelet transfusions, however, may result in the development of antibodies to GPIIb/IIIa and/or human leukocyte antigen (HLA), rendering further transfusions ineffective. Recombinant human activated factor VII (rFVIIa; NovoSeven/Niastase [Canada], Novo Nordisk, Bagsvaerd, Denmark) has documented efficacy in GT patients, and is approved in the European Union for the treatment of GT patients with platelet antibodies and platelet refractoriness. However, there are insufficient data to determine the optimal rFVIIa regimen (eg, for major surgery) or to allow thorough safety evaluation (eg, thrombotic risk). A post-marketing, prospective, observational, multinational registry has been developed to collect data on the efficacy and safety of rFVIIa in the treatment and prevention of bleeding in GT patients with platelet antibodies or platelet refractoriness. Patients treated with other hemostatic agents or rFVIIa to avoid the development of antibodies against GPIIb/IIIa will also be reported. Standardized data will be collected using a customized internet-based (www.glanzmann-reg.org) data collection tool. Data collection will begin in 2005 and continue for up to 6 years. Patients of all ages from any country are eligible for inclusion.

Risk of inhibitors in haemophilia and the type of factor replacement.

PURPOSE OF REVIEW: Inhibitors in haemophilia are a serious complication that may render usual replacement therapy ineffective. The risk is greatest in previously untreated children with severe haemophilia A. The role of replacement factor VIII in this group is an important issue. RECENT FINDINGS: Until now, few clinical studies have correctly taken into account the variety of cofactors involved in inhibitor development: genetic (familial antecedents, ethnicity, F8 and immune response genotypes), and environmental cofactors (age at first infusion, prophylaxis and intensity of treatment). This is a prerequisite to correctly evaluating the putative role of the type of factor replacement. Prospective cohort studies are therefore urgently needed. Depending on the expected inhibitor risk in the reference group, the intensity of the relationship between risk factor and endpoint, the duration of patient follow up, and the design of the study (balanced or unbalanced groups), cohorts including 200-500 previously untreated children should be sufficient to demonstrate an increased intensity of risk of about 2 or more with one product compared with another. SUMMARY: Aside from clinical studies, fundamental research is essential to test the multiple hypotheses that could explain a difference in inhibitor risk between the currently available factor VIII concentrates in order to develop less immunogenic factor VIII.

Influence of the type of factor VIII concentrate on the incidence of factor VIII inhibitors in previously untreated patients with severe hemophilia A.

Inhibitor development is the major treatment complication in children with severe hemophilia A. It is not clear whether the risk of inhibitors is higher with recombinant factor VIII or with plasma-derived factor VIII. We used multivariate analysis to compare 2 cohorts of previously untreated patients (PUPs) with severe hemophilia A: 62 patients treated with the same brand of high-purity plasma-derived FVIII (pFVIII) containing von Willebrand factor (VWF) and 86 patients treated with full-length recombinant FVIII (rFVIII). In addition to the usual end points (all inhibitors, high inhibitors), we also examined a third end point (high inhibitors and/or immune tolerance induction). The risk of inhibitor development was higher in patients treated with rFVIII than in patients treated with pFVIII, regardless of other risk factors (F8 genotype; nonwhite origin; history of inhibitors in patients with a family history of hemophilia; age at first FVIII infusion). The adjusted relative risk (RRa) for inhibitor development with rFVIII versus pFVIII was 2.4 (all inhibitors), 2.6 (high inhibitors), and 3.2 (high inhibitors and/or immune tolerance induction), respectively, depending on the end point (above). The pathophysiology of this large effect must be understood in order to improve the characteristics of recombinant products and to reduce the incidence of inhibitors to FVIII.

Treatment of bleeding in patients with platelet disorders: is there a place for recombinant factor VIIa?

The mechanism of action of recombinant factor VIIa (rFVIIa), i.e. increased thrombin generation on the membrane of activated platelets, as well as the results from in vitro and ex vivo models of thrombocytopenia or inherited thrombocytopathia may support some potential of rFVIIa in thrombocytopenia/thrombocytopathia. rFVIIa was reported as effective to stop or to decrease bleeding in few patients with severe thrombocytopenia resistant to platelet transfusions; however data are still scarce and clinical studies are really needed to define efficacy/safety ratio as well as optimal treatment regimen in this potential indication. Some data in patients with Glanzmann thrombasthenia (GT) may support the use of rFVIIa outside its primary indication in the cases in which there is no real treatment alternative (GT patients with antibodies to GP IIb-IIIa or with platelet refractoriness).