Roberto Musso

MYH9-related disease: May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but represent a variable expression of a single illness

May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are autosomal dominant macrothrombocytopenias distinguished by different combinations of clinical and laboratory signs, such as sensorineural hearing loss, cataract, nephritis, and polymorphonuclear Döhle-like bodies. Mutations in the MYH9 gene encoding for the nonmuscle myosin heavy chain IIA (NMMHC-IIA) have been identified in all these syndromes. To understand the role of the MYH9 mutations, we report the molecular defects in 12 new cases, which together with our previous works represent a cohort of 19 families. Since no genotype-phenotype correlation was established, we performed an accurate clinical and biochemical re-evaluation of patients. In addition to macrothrombocytopenia, an abnormal distribution of NMMHC-IIA within leukocytes was observed in all individuals, including those without Döhle-like bodies. Selective, high-tone hearing deficiency and cataract was diagnosed in 83% and 23%, respectively, of patients initially referred as having May-Hegglin anomaly or Sebastian syndrome. Kidney abnormalities, such as hematuria and proteinuria, affected not only patients referred as Fechtner syndrome and Epstein syndrome but also those referred as May-Hegglin anomaly and Sebastian syndrome. These findings allowed us to conclude that May-Hegglin anomaly, Sebastian syndrome, Fechtner syndrome, and Epstein syndrome are not distinct entities but rather a single disorder with a continuous clinical spectrum varying from mild macrothrombocytopenia with leukocyte inclusions to a severe form complicated by hearing loss, cataracts, and renal failure. For this new nosologic entity, we propose the term “MHY9-related disease,” which better interprets the recent knowledge in this field and identifies all patients at risk of developing renal, hearing, or visual defects.

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.

Antithrombin III Concentrate for Treatment of Chronic Leg Ulcers in Sickle Cell-Beta Thalassemia: A Pilot Study

Excerpt Chronic leg ulcers are a common distressing complication in patients with sickle cell-beta thalassemia and are difficult to heal. The pathogenic mechanism of this complication is not known ...

A prospective registry of European haemophilia B patients receiving nonacog alfa, recombinant human factor IX, for usual use.

Summary.  Nonacog alfa, a recombinant factor IX (FIX) used for the treatment of haemophilia B, was approved in Europe in 1998. In accordance with European Medicines Agency requirements, a registry study was conducted from 2002 to 2009. A reformulated iso‐osmotic version was approved for European use in 2007. This study was conducted to evaluate the safety of nonacog alfa in a usual care setting, and provide clinical trial and postmarketing surveillance data support. This open‐label, non‐interventional, prospective observational cohort study (registry) comprised 52 sites in nine European countries. Patients with haemophilia B receiving nonacog alfa in either formulation for prevention or treatment were followed on a usual care schedule. A total of 218 patients were enrolled, of whom 66 (30.3%) were <18 years of age. Haemophilia severity was evenly distributed, with baseline FIX activity of <1%, 1–5% and >5% in 33.3%, 36.6% and 30.1% of patients, respectively. One hundred thirty‐eight patients received the original formulation alone; 80 switched to or received only the new formulation. There was a low incidence of events of special interest (ESIs), with less‐than‐expected therapeutic effect in five patients (2.2%), inhibitor development in two (0.9%), thrombosis in one (0.5%) and allergic events in eight (3.7%). These accounted for the majority of the 15 serious AEs reported in six patients. Six patients discontinued because of AEs, primarily related to hypersensitivity. Nonacog alfa was shown to be safe for the treatment of haemophilia B, with a low incidence of serious AEs and ESIs.

Haemostatic abnormalities and lupus anticoagulant activity in patients with Gaucher disease type I.

Gaucher disease (GD) type I (McKusick 230800), the most prevalent lysosomal storage disorder, is due to β-glucocerebrosidase (EC 3.2.1.45) deficiency. It is characterized by the storage of uncleaved β-glucocerebroside in the cells of the reticuloendothelial system, leading to bone marrow infiltration, hepatosplenomegaly and skeletal lesions. Other clinical features include haematological changes with anaemia and thrombocytopenia (Beutler and Grabowski 1995). Enzyme replacement therapy has become available and is effective in reversing hepatosplenomegaly and haematological abnormalities (Charrow et al 1998). Patients with GD type I have a bleeding tendency partially due to thrombocytopenia; a combined deficiency of clotting factors and inhibitors has also been reported (Billet et al 1996; Hollak et al 1997). We undertook this study to gain further insight into the pathophysiology of haemostatic abnormalities associated with Gaucher disease. The effect of enzyme replacement therapy on haemostasis was also monitored in comparison with changes of other laboratory parameters reflecting the status of the disease.

Acute Respiratory Distress During Sclerotherapy for Esophageal Varices

Excerpt To the editor: Connors and coworkers (1) report that the adult respiratory distress syndrome, which may occur after endoscopic variceal sclerotherapy using sodium morrhuate, was not depende...

The Correlation Between Fatty Acids and Platelet Function

It is well known that fatty acids (FA) show in vitro the capability to induce platelet aggregation when employed at optimal concentrations (1–4). On the other hand, there is evidence that among FA the arachidonic acid (AA) plays a key role in platelet metabolic pathway leading to the synthesis of strongly aggregating agents, such as prostaglandins (PG) and thromboxanes (TXA) (5–9). Moreover, it has been documented that some inducers can activate platelet membrane lipases (10–11), so that their aggregating effect would also be mediated by a lipometabolic activation (11–12). Such data, therefore, would demonstrate that a correlation between platelet membrane phospholipids (13–14) and aggregative capability degree of inducers could exist.