Deletion of alanine 2201 in the FVIII C2 domain results in mild hemophilia A by impairing FVIII binding to VWF and phospholipids and destroys a major FVIII antigenic determinant involved in inhibitor development

The C2 domain of factor VIII (FVIII) mediates FVIII binding to von Willebrand factor (VWF) and phospholipids (PLs), thereby determining the stability and the activity of FVIII. A deletion of Ala2201 (Del2201) was identified in the FVIII C2 domain of 2 unrelated patients with mild hemophilia A (FVIII:C 11%-33%). This mutation prevents FVIII binding to a human monoclonal antibody recognizing the C2 domain and inhibiting FVIII binding to VWF and phospholipids. By comparison to healthy FVIII, Del2201 FVIII had a significantly reduced binding to VWF, which likely contributes to reduced FVIII levels in plasma. Del2201 FVIII interaction with phospholipids was evaluated in an FXa generation assay, using various concentrations of synthetic phospholipid vesicles mimicking an activated platelet surface. At the lowest phospholipid concentration allowing FXa generation, Del2201 FVIII activity was reduced 3-fold. This is the first report of a mutation altering FVIII binding to phospholipids and occurring in patients with hemophilia A.     

Activation of Notch3 in Glomeruli Promotes the Development of Rapidly Progressive Renal Disease

Notch3 expression is found in the glomerular podocytes of patients with lupus nephritis or focal segmental GN but not in normal kidneys. Here, we show that activation of the Notch3 receptor in the glomeruli is a turning point inducing phenotypic changes in podocytes promoting renal inflammation and fibrosis and leading to disease progression. In a model of rapidly progressive GN, Notch3 expression was induced by several-fold in podocytes concurrently with disease progression. By contrast, mice lacking Notch3 expression were protected because they exhibited less proteinuria, uremia, and inflammatory infiltration. Podocyte outgrowth from glomeruli isolated from wild-type mice during the early phase of the disease was higher than outgrowth from glomeruli of mice lacking Notch3. In vitro studies confirmed that podocytes expressing active Notch3 reorganize their cytoskeleton toward a proliferative/migratory and inflammatory phenotype. We then administered antisense oligodeoxynucleotides targeting Notch3 or scramble control oligodeoxynucleotides in wild-type mice concomitant to disease induction. Both groups developed chronic renal disease, but mice injected with Notch3 antisense had lower values of plasma urea and proteinuria and inflammatory infiltration. The improvement of renal function was accompanied by fewer deposits of fibrin within the glomeruli and by decreased peritubular inflammation. Finally, abnormal Notch3 staining was observed in biopsy samples of patients with crescentic GN. These results demonstrate that abnormal activation of Notch3 may be involved in the progression of renal disease by promoting migratory and proinflammatory pathways. Inhibiting Notch3 activation could be a novel, promising approach to treat GN.     

Blood Transfusion in Elderly Patients with Acute Myocardial Infarction: Data from the RICO Survey

Background

Red blood cell transfusion benefit during acute myocardial infarction remains unclear in the elderly. We aimed to assess the transfusion impact on 1-year mortality in acute myocardial infarction patients aged ≥65 years, according to their age and hemoglobin nadir.

Predictive value of myocardial tomoscintigraphy in asymptomatic diabetic patients after percutaneous coronary intervention

Objective: This study was designed to assess the prognostic value of myocardial tomoscintigraphy perfusion imaging after percutaneous coronary intervention (PCI) in asymptomatic diabetic patients. Methods: One hundred and fourteen diabetic patients were followed up during 27±16 (mean±SD) months after the myocardial tomoscintigraphy. PCI-related events were studied after myocardial tomoscintigraphy stress testing and included major cardiac events (MACE) (cardiovascular death, myocardial infarction) and revascularization (bypass surgery or new PCI). Stress myocardial tomoscintigraphy imaging was performed 5±5 months after PCI and ischemia was considered as present if at least 2 contiguous segments were showing reversible defects. Results: Persistent silent ischemia was found in 49/114 (43%) patients. No difference was observed between the two groups for MACE: four among the 65 (6%) non ischemic patients versus 2 among the 49 (4%) ischemic patients (NS). In contrast, 15 (31%) among the ischemic patients and 4 (6%) among the non ischemic patients underwent iterative revascularization (p<0.01). The relative risk of revascularization for patients with significant ischemia was 5.5 versus non ischemic patients (p<0.001). Conclusion: After PCI, in asymptomatic diabetic patients followed by myocardial tomoscintigraphy a high frequency of persistent silent ischemia was found and associated with a high risk for repeat interventional procedure, although no increase in major cardiac events was observed.     

Risk factors of fibrosis in alcohol-induced liver disease

In patients with nonalcoholic steatohepatitis (NASH), age, obesity, and diabetes mellitus are independent predictors of the degree of fibrosis. The relative risk for fibrosis adjusted for sex was also associated with increasing grade of Perls stain. The aim of this study was to determine whether the risk factors for fibrosis described in NASH are also risk factors in alcohol-induced liver disease. A total of 268 alcoholic patients with negative hepatitis B virus and hepatitis C virus serology underwent liver biopsy. Fibrosis was assessed semiquantitatively by a score fluctuating between 0 to 8. Liver iron overload was assessed by Perls staining and graded in 4 classes. We have used multivariate regression with partial correlation analysis to assess the variability of fibrosis score according to the value of 7 variables: sex, age, body mass index (BMI) in the past year before the hospitalization when the patient was asymptomatic, daily alcohol intake over the past 5 years, total duration of alcohol abuse, Perls grade, and blood glucose level. In the multivariate regression, fibrosis score was positively correlated with age (P =.001), BMI (P =.002), female sex (P <.05), Perls grade (P <.05), and blood glucose level (P <.05). Twenty percent of the variability of fibrosis score was explained by the 7 variables. In conclusion, after adjustment for daily alcohol intake and total duration of alcohol abuse, BMI, Perls grade, and blood glucose are also independent risk factors for fibrosis in alcohol-induced liver disease, raising therapeutic implications for the management of these patients.     

Heart rate reduction through lifestyle modification: reply

We thank Drs Michalsen and Dobos for their comments. Restingheart rate is indeed a strong predictor of mortality in patientswith coronary artery disease.¹