Identification of a novel F11 missense mutation (Ile463Ser) in a family with congenital factor XI deficiency

We investigated an asymptomatic 19-year-old patient with factor XI deficiency diagnosed in the context of presurgical laboratory screening. The F11 gene was analyzed and a novel missense mutation I463S in exon 12 was identified in heterozygosity in the proband. His mother, also diagnosed with asymptomatic factor XI deficiency, was found to be heterozygous for the same mutation. This novel amino acid substitution in the serine protease catalytic domain appears to be responsible for the low factor XI levels in both individuals

Mutation of the translation initiation codon in FGA causes congenital afibrinogenemia

Congenital afibrinogenemia is characterized by the complete absence of fibrinogen, the precursor of the major protein constituent of the blood clot, fibrin. Extensive allelic heterogeneity has been found for this disorder and more than 40 mutations, the majority in FGA, have been identified in homozygosity or in compound heterozygosity. However, the continuous genetic analysis of additional patients still allows the identification of novel mutations and thus the greater understanding of fibrinogen structure and function. Here we report the identification of a novel missense mutation in FGA exon 1 affecting the translation initiation codon: c.1 A>T (ATG>TTG) M1L, identified in a young boy from Madagascar in compound heterozygosity with a second mutation in FGA exon 4: c.385 C>T (CGA>TGA) R129X. The patient suffered from occasional severe arthralgias (shoulder, knee) most likely caused by intra-articular bleeding with subsequent inflammation

Syndrome des anticorps antiphospholipides: beaucoup de nouveautés

Recently some key papers and consensus have shed some new light on antiphospholipid syndrome (APS). Concerning the tests the search for lupus anticoagulant is now better defined. A modified antibeta2-glycoprotein I assay has been shown to be more specific for clinical complications. It seems necessary to still perform anticardiolipin antibodies in case of pregnancy morbidity but not in case of thrombosis which raises the question of two separate clinical entities with different pathologic mechanisms. Concerning the pathophysiology, new data emphasize the role of complement and underscore the role of genetic predisposition. The data of some large cohort followed prospectively such as the European cohort (1000 APS patients) as well the data of some registries (APS in children and patients with a catastrophic APS) bring some new important information on the clinical aspects of the syndrome. Finally this review will propose some algorithms to treat patients with APS

Fluvastatin increases the expression of adhesion molecules, monocyte chemoattractant protein-1 and tissue factor in HUVEC stimulated by patient IgG fractions containing antiphospholipid antibodies

The presence of antiphospholipid antibodies (APLA) is associated with an increased risk of recurrent thrombosis and pregnancy loss. APLA are able to activate endothelial cells (EC) and induce an increase in the expression of inflammatory marker proteins, such as leukocyte adhesion molecules, tissue factor or the monocyte chemoattractant protein-1 (MCP-1). Our objective was to investigate the effect of statins on EC activation induced by APLA in vitro. IgG was purified from the plasma of six patients with APLA and from healthy controls. EC were incubated with patient IgG or with control IgG, in the presence or absence of 5microM of fluvastatin, and expression of the leukocyte adhesion molecules, VCAM-1 and E-selectin, analyzed by flow cytometry and by quantitative reverse transcriptase-PCR (QRT-PCR). The expression of tissue factor and the chemokine MCP-1 was analyzed by QRT-PCR alone. Incubation of EC with patient IgG increased the expression of VCAM-1, E-selectin, tissue factor and MCP-1. Prior treatment of the cells with fluvastatin further increased the expression of these proteins. The fluvastatin effect was reversed by co-incubation with mevalonate or geranylgeranylpyrophosphate and mimicked by the geranylgeranyl transferase inhibitor GGTI-286. Our results show that in cultured human EC, statins increase the extent of inflammatory activation induced by APLA. This effect appears to be mediated by an inhibitory effect of statins on one or more geranylgeranylated protein(s)

Dynamics of Expression of Programmed Cell Death Protein-1 (PD-1) on T Cells After Allogeneic Hematopoietic Stem Cell Transplantation

Immune exhaustion contributes to treatment failure after allogeneic hematopoietic stem cell transplantation (HSCT) for hematological malignancies. Immune checkpoint blockade, including programmed cell death protein-1 (PD-1) blockade, is a promising strategy to improve the antitumor effect of allogeneic HSCT with high rates of response reported in patients treated for disease relapse. However, severe and sometimes fatal Graft- vs.-Host-Disease (GvHD) has been reported as a complication. Little is known about the dynamics of PD-1 expression on immune effector cells after allogeneic HSCT. In the present study, we analyzed PD-1 expression on T cell subpopulations isolated from 105 allogeneic HSCT recipients. Our analysis revealed a significant increase in proportions of PD-1-expressing CD4 and CD8 T cells early after allogeneic HSCT followed by a progressive normalization of PD-1 expression at CD8 but not CD4 T cell surface. Analysis of co-expression of two other exhaustion markers, 2B4 and CD160, revealed a preferential expansion of PD-1-single positive cells. Moreover, the analysis of granzyme B and perforin expression in PD-1+ and PD-1- CD8 T cells from HSCT recipients did not reveal any impairment in cytotoxic molecules production by PD-1-expressing CD8 T cells. Analyzing the association between clinical factors and the expression of PD-1 on T cells, we identified the use of in vivo and/or ex vivo T-cell depletion as the factor most strongly associated with elevated PD-1 levels on T cells. Our results extend our knowledge of the regulation of PD-1 expression at T cell surface after allogeneic HSCT, a crucial information for the optimization of post-transplantation PD-1 blocking therapies

A rare case of primary cutaneous follicle centre lymphoma presenting as a giant tumour of the scalp and combined with JAK2V617F positive essential thrombocythaemia

Primary cutaneous follicle centre lymphoma (PCFCL) is a rare cutaneous B cell lymphoma in middle-age adults with excellent prognosis. Here we present a case of a patient with a PCFCL in the form of a giant tumour of the scalp in combination with a myeloproliferative neoplasm, JAK2V617F positive essential thrombocythaemia. This case may be of interest because of the favourable outcome in spite of the large size of the PCFCL, the rare combination with essential thrombocythaemia and because it contributes to discussion on the role of JAK2 mutation in such patients

Validation of the disease risk index for outcome of patients undergoing allogeneic hematopoietic stem cell transplantation after T cell depletion

Identification of pretransplantation risk factors is important in evaluating patient outcomes after hematopoietic stem cell transplantation. Current scoring schemes, such as the European Group for Blood and Marrow Transplantation risk score or the Hematopoietic Cell Transplantation-Specific Comorbidity Index, may under-rate disease and disease status at the time of transplantation. The recently published Disease Risk Index (DRI) specifically investigates these aspects by defining 4 risk groups (low, intermediate, high, very high) with significant differences in overall survival (OS). We retrospectively investigated whether the DRI could be applied at the transplantation center of Geneva's University Hospitals (Geneva, Switzerland), where 64% of patients are underwent transplantation with T cell-depleted grafts (TDEP). We analyzed 409 patients with various hematological malignancies who underwent transplantation between January 1998 and October 2012. Using the DRI, the 4-year OS for the low, intermediate, high, and very high groups was 82%, 53%, 27%, and 31%, respectively (P < .0001). For TDEP patients, the 4-year OS for low, intermediate, and high overall risk groups was 86%, 53%, and 33%, respectively (P < .0001). As patients in the very high overall risk group are usually not eligible for TDEP, our group comprised too few patients (n = 3) for meaningful analysis. For non-TDEP patients, the 4-year OS for low, intermediate, high, and very high overall risk groups was 63%, 54%, 22%, and 18%, respectively (P < .0001). Our results confirm the prognostic value of the DRI in a cohort with a majority of TDEP patients