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International audience; IntroductionCerebral venous sinus thrombosis (CVST) is a rare disease with highly variable clinical presentation and outcomes. Clinical studies suggest a role of inflammation and coagulation in CVST outcomes. The aim of this study was to investigate the association of inflammation and hypercoagulability biomarkers with CVST clinical manifestations and prognosis.MethodsThis prospective multicenter study was conducted from July 2011 to September 2016. Consecutive patients referred to 21 French stroke units and who had a diagnosis of symptomatic CVST were included. High-sensitivity C-reactive protein (hs-CRP), neutrophil-to-lymphocyte ratio (NLR), D-dimer, and thrombin generation using calibrated automated thrombogram system were measured at different time points until 1 month after anticoagulant therapy discontinuation.ResultsTwo hundred thirty-one patients were included. Eight patients died, of whom 5 during hospitalization. The day 0 hs-CRP levels, NLR, and D-dimer were higher in patients with initial consciousness disturbance than in those without (hs-CRP: 10.2 mg/L [3.6-25.5] vs 23.7 mg/L [4.8-60.0], respectively; NLR: 3.51 [2.15-5.88] vs 4.78 [3.10-9.59], respectively; D-dimer: 950 μg/L [520-2075] vs 1220 μg/L [950-2445], respectively). Patients with ischemic parenchymal lesions (n = 31) had a higher endogenous thrombin potential5pM than those with hemorrhagic parenchymal lesions (n = 31): 2025 nM min (1646-2441) vs 1629 nM min (1371-2090), respectively (P = .0082). Using unadjusted logistic regression with values >75th percentile, day 0 hs-CRP levels of >29.7 mg/L (odds ratio, 10.76 [1.55-140.4]; P = .037) and day 5 D-dimer levels of >1060 mg/L (odds ratio, 14.63 [2.28-179.9]; P = .010) were associated with death occurrence.ConclusionTwo widely available biomarkers measured upon admission, especially hs-CRP, could help predict bad prognosis in CVST in addition to patient characteristics. These results need to be validated in other cohorts.

International audience; No abstract available

Background Severe acute respiratory syndrome caused by the novel coronavirus (SARS-CoV-2) is frequently associated with gastrointestinal manifestations. Herein we evaluated the interest in measuring the intestinal fatty acid-binding protein (I-FABP), a biomarker of intestinal injury, in COVID-19 patients. Methods Serum I-FABP was analyzed in 28 consecutive patients hospitalized for a PCR-confirmed COVID-19, in 24 hospitalized patients with non-COVID-19 pulmonary diseases, and 79 patients admitted to the emergency room for abdominal pain. Results I-FABP serum concentrations were significantly lower in patients with COVID-19, as compared to patients with non-COVID-19 pulmonary diseases [70.3 pg/mL (47–167.9) vs. 161.1 pg/mL (88.98–305.2), respectively, p = 0.008]. I-FABP concentrations in these two populations were significantly lower than in patients with abdominal pain without COVID-19 [344.8 pg/mL (268.9–579.6)]. I-FABP was neither associated with severity nor the duration of symptoms. I-FABP was correlated with polymorphonuclear cell counts. Conclusions In this pilot study, we observed a low I-FABP concentration in COVID-19 patients either with or without gastrointestinal symptoms, of which the pathophysiological mechanisms and clinical impact remain to be established. Further explorations on a larger cohort of patients will be needed to unravel the molecular mechanism of such observation, including the effects of malabsorption and/or abnormal lipid metabolism.

Pregnancy in women with inherited thrombocytopenias is a major matter of concern as both the mothers and the newborns are potentially at risk of bleeding. However, medical management of this condition cannot be based on evidence because of the lack of consistent information in the literature. To advance knowledge on this matter, we performed a multicentric, retrospective study evaluating 339 pregnancies in 181 women with 13 different forms of inherited thrombocytopenia. Neither the degree of thrombocytopenia nor the severity of bleeding tendency worsened during pregnancy and the course of pregnancy did not differ from that of healthy subjects in terms of miscarriages, fetal bleeding and pre-term births. The degree of thrombocytopenia in the babies was similar to that in the mother. Only 7 of 156 affected newborns had delivery-related bleeding, but 2 of them died of cerebral hemorrhage. The frequency of delivery-related maternal bleeding ranged from 6.8% to 14.2% depending on the definition of abnormal blood loss, suggesting that the risk of abnormal blood loss was increased with respect to the general population. However, no mother died or had to undergo hysterectomy to arrest bleeding. The search for parameters predicting delivery-related bleeding in the mother suggested that hemorrhages requiring blood transfusion were more frequent in women with history of severe bleedings before pregnancy and with platelet count at delivery below 50 × 10(9)/L. Fil: Noris, Patrizia. Istituti di Ricovero e Cura a Carattere Scientifico. Policlinico San Matteo di Pavia; Italia. Università degli Studi di Pavia; Italia Fil: Schlegel, Nicole. Université Paris Diderot - Paris 7; Francia Fil: Klersy, Catherine. Istituti di Ricovero e Cura a Carattere Scientifico. Policlinico San Matteo di Pavia; Italia Fil: Heller, Paula Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Civaschi, Elisa. Università degli Studi di Pavia; Italia Fil: Pujol Moix, Nuria. Universitat Autònoma de Barcelona; España Fil: Fabris, Fabrizio. Università di Padova; Italia Fil: Favier, Remi. Inserm; Francia. Armand Trousseau Children’s Hospital; Francia. French Reference Center for Inherited Platelet disorders; Francia Fil: Gresele, Paolo. Università di Perugia; Italia Fil: Latger Cannard, Véronique. Centre Hospitalo-Universitaire. Service d’Hématologie Biologique; Francia. Reference French Centre. Centre de Compétence Nord-Est des Pathologies Plaquettaires; Francia Fil: Cuker, Adam. University of Pennsylvania; Estados Unidos Fil: Nurden, Paquita. Hôpital Xavier Arnozan; Francia Fil: Greinacher, Andreas. Institut für Immunologie und Transfusionsmedizin; Alemania Fil: Cattaneo, Marco. Università degli Studi di Milano; Italia Fil: De Candia, Erica. Università Cattolica del Sacro Cuore; Italia Fil: Pecci, Alessandro. Università degli Studi di Pavia; Italia Fil: Hurtaud Roux, Marie Françoise. Université Paris Diderot - Paris 7; Francia Fil: Glembotsky, Ana Claudia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones Médicas. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones Médicas; Argentina Fil: Muñiz Diaz, Eduardo. Banc de Sang i Teixits de Catalunya. Immunohematology Department; España Fil: Randi, Maria Luigia. Università di Padova; Italia Fil: Trillot, Nathalie. Centre Hospitalier Régional Universitaire de Lille. Pôle Biologie Pathologie Génétique. Institut d’Hématologie-Transfusion; Francia Fil: Bury, Loredana. Università di Perugia; Italia Fil: Lecompte, Thomas. Hôpitaux Universitaires de Genève; Suiza. Université de Genève. Faculté de Médecine; Suiza Fil: Marconi, Caterina. Università di Bologna; Italia Fil: Savoia, Anna. Università degli Studi di Trieste; Italia Fil: Balduini, Carlo L.. Istituti di Ricovero e Cura a Carattere Scientifico Burlo Garofolo. Institute for Maternal and Child Health; Italia. Università degli Studi di Pavia; Italia Fil: European Hematology Association Scientific Working Group on Thrombocytopenias and Platelet Function Disorders. No especifica

Cryptogenic cirrhosis (CC) is diagnosed in 5-30% of cirrhotic patients overall and 7% of patients who undergo liver transplantation for cirrhosis. In our series of patients transplanted for CC, pre-transplant clinical and histological data and the post-transplant course were reexamined in an attempt to identify the aetiology. Among the 881 patients transplanted in our centre between 1987 and 2000, 28 patients with a median age of 46 yr (range: 18-69) at transplantation were initially classified as having CC. Two patients were excluded because of intense ischaemic lesions caused by chemoembolization prevented histological analysis of the native liver (n = 1) and because of cryptic HBV infection (n = 1). Among the remaining 26 patients, four groups were individualized: (i) patients with chronic inflammatory liver disease with autoimmune features (n = 14, 54%); (ii) patients with features suggestive of non-alcoholic fatty liver disease (n = 3, 11.5%); (iii); patients with incomplete septal cirrhosis (ISC) and vascular liver disease (n = 3), and (iv) patients with unresolved CC (n = 6, 23%). In the autoimmune liver disease group, the median International Autoimmune Hepatitis score was 12.5 (range: 11-19) after reevaluation and review of the post-transplantation course was helpful to confirm the diagnosis with the occurrence of active graft hepatitis in nine patients, with autoantibodies in five patients. The vascular group was characterized by lesions of obliterative portal venopathy and ISC in all native livers. Diagnosis of NAFLD was based on the clinical background of obesity and/or type 2 diabetes and the presence of steatosis or steatohepatitis in native livers and graft biopsies. A definite aetiological diagnosis can be achieved in the majority of patients initially diagnosed with CC. Autoimmune liver disease emerged as the main aetiology (14 of 26 patients, 54%) and frequently recurred on the grafted liver (nine cases). In all cases a precise diagnosis is obviously of practical interest for better management of post-transplant survey and treatment.

UNLABELLED Treatment of auto-immune cytopenia refractory to front line therapy with intravenous immunoglobulins and steroids is a matter of concern. We assessed the efficacy and safety of mycophenolate mofetil in a prospective open preliminary study. STUDY DESIGN Adult patients with steroid refractory auto-immune cytopenias were included. Mycophenolate mofetil (MMF) was added to treatment given at the time of inclusion, and efficacy was evaluated in term of improvement of platelet/haemoglobin levels and in term of reduction of previously given drugs, if any. All auto-immune thrombocytopenic purpura (AITP) patients had serologic assessment for associated auto-antibodies at the time of inclusion. Cytopenias associated with other auto-immune diseases, lymphoproliferative diseases or HIV infection were excluded. RESULTS From November 1999 through November 2003, 13 patients were included (nine AITP, three auto-immune haemolytic anaemia (AIHA), one Evans' syndrome; four males, nine females; age: 35-72 yr). For AITP patients, an overall response of 78% was observed. Retrospective analysis showed no significant difference between patients having a short disease duration (

Objective. Spontaneous intracranial bleeding is now a widely recognized complication and cause of mortality in patients with Alagille syndrome. The pathogenesis of intracranial bleeding in these patients remains unclear. The aim of the study was to look for other sites of bleeding in these patients that could suggest a factor of multiorgan morbidity. Methods. The records of 174 patients with Alagille syndrome were reviewed, and 38 (22%) patients without liver failure who experienced hemorrhage that led to a drop in hemoglobin level of at least 3 g/dL or to blood transfusion were identified. Results. In 38 patients, 49 bleeding episodes occurred at a median age of 3.75 years (range: 1 month–27 years). Seventeen patients had 23 episodes of spontaneous bleeding; 21 patients bled during surgery or other medical procedures, and 5 among these 21 patients also had a spontaneous bleeding episode. Nine patients bled at least twice. Median platelets count and prothrombin time were normal. Severe cholestasis existed in 33 patients. One patient has a deletion of the 20p12 region, and 13 of 17 patients studied have a JAGGED1 mutation. Blood transfusion was necessary in 23 patients. Eight patients died secondary to bleeding (4 after surgery, 2 after gastrointestinal bleeding, 1 after needle liver biopsy, and 1 after intracranial bleeding). Conclusion. These results suggest that patients with Alagille syndrome are at special risk for bleeding; this should be taken into account before deciding on an invasive procedure. The mechanism of the bleeding is still unclear; the role of hypercholesterolemia cannot be excluded, but it may be speculated that JAGGED1 signaling abnormalities may impair the hemostatic function.

Summary. The structure of red blood cell (RBC) membranes in homozygous sickle cell disease (SCD) is significantly disturbed, with an increased exposure of aminophospholipids (phosphatidylserine and phosphatidylethanolamine) at the outer surface, responsible for a procoagulant activity of SS RBCs. Aminophospholipids are known not only to promote procoagulant reactions, but also to support inhibition of blood coagulation by the protein C system. The aim of the present study was to examine whether SS RBCs could serve as a catalytic surface for the inactivation of factor Va by activated protein C (APC). Venous blood was obtained from 19 consecutive SS patients and 13 controls (AA). In all SS patients, the amount of phosphatidylserine exposed at the outer surface of RBCs was increased compared with controls, as demonstrated by a prothrombinase assay. In addition, SS RBCs significantly (P

Antithrombin (AT) is a major physiological inhibitor of hemostasis. We report 22 novel antithrombin gene (SERPINC1) mutations associated with antithrombin deficiency in 17 French and five German families. They were all present at the heterozygous state. Nine missense mutations accounted for type I deficiency, defined by equally low antithrombin activity and antigen level. Most of them (7/9) affected highly conserved serpin residues and were associated with venous thrombosis occuring at a young age (before age 32). One splice site, one nonsense mutation, three small deletions and one insertion were also identified as a cause for type I antithrombin deficiency. Seven other missense mutations were identified in type II or unclassified AT deficiency; g.5270C>T (p.T147I, T115I) and g.5281A>T (p.I151F, I119F) change residues in the heparin binding region, g.13267C>G (p.P439A, P407A) and g.13271T>C (p.F440S, F408S) affect amino acids in the pleiotropic region, g.2372G>A (p.G25D, G-8D) changes a signal peptide amino acid, g.2456G>C (p.C53S, C21S) affects one of the three disulfide bonds of the protein, and g.7585A>T (p.M347K, M315K) changes a nonconserved residue on strand 2C. © 2006 Wiley-Liss, Inc.

We have identified a homozygous GA substitution in the donor splice site of intron 6 (IVS6 + 1GA) of the cytidine monophosphate (CMP)-sialic acid transporter gene of Lec2 cells as the mutation responsible for their asialo phenotype. These cells were used in complementation studies to test the activity of the 2 CMP-sialic acid transporter cDNA alleles of a patient devoid of sialyl-Le(x) expression on polymorphonuclear cells. No complementation was obtained with either of the 2 patient alleles, whereas full restoration of the sialylated phenotype was obtained in the Lec2 cells transfected with the corresponding human wild-type transcript. The inactivation of one patient allele by a double microdeletion inducing a premature stop codon at position 327 and a splice mutation of the other allele inducing a 130-base pair (bp) deletion and a premature stop codon at position 684 are proposed to be the causal defects of this disease. A 4-base insertion in intron 6 was found in the mother and is proposed to be responsible for the splice mutation. We conclude that this defect is a new type of congenital disorder of glycosylation (CDG) of type IIf affecting the transport of CMP-sialic acid into the Golgi apparatus.

Purpose Children ultimately diagnosed with nonimmune chronic thrombocytopenia are often referred to pediatric hematology clinics with a provisional diagnosis of autoimmune thrombocytopenic purpura (AITP). The authors' aim was to establish in these patients the features characterizing the mechanism of thrombocytopenia. Patients and Methods The authors performed a retrospective review of the case records of seven children (three boys and four girls, aged 5 months to 7 years) with misdiagnosed chronic AITP referred to a single pediatric hematology center between 1990 and 2000. Results In the seven children, the suspected diagnosis on referral was AITP and the final diagnosis was inherited thrombocytopenia. Abnormalities of platelets and/or leukocyte morphology were present in all of them. Other features suggestive of inherited thrombocytopenia included a history of familial thrombocytopenia (2/7), failure of steroids and/or intravenous immunoglobulins to raise the platelet count to normal levels (5/7), and moderate increase of Indium-111 platelet turnover in the two patients tested. Platelet-associated IgG (PaIgG) was above the normal threshold in the four children tested; the direct monoclonal antibody immobilization of platelet antigens (MAIPA) test was negative in the four children tested and the serum test was positive in two boys. Bone marrow examination revealed either a normal (4/7) or an elevated (3/7) number of megakaryocytes. Conclusions Family history and blood cell morphology analysis in experienced hands are the first steps in discriminating AITP from inherited thrombocytopenia in children with isolated chronic thrombocytopenia. In contrast, bone marrow examination and search for specific autoantibodies using the MAIPA test are of little help. An isotopic platelet life span study, when available, should be performed before considering splenectomy to exclude the diagnosis of inherited thrombocytopenia, especially when steroids and/or IgG IV administration failed to raise the platelet count.

Early diagnosis of acute mesenteric ischemia (AMI) remains a clinical challenge, and no biomarker has been consistently validated. We aimed to assess the accuracy of three promising circulating biomarkers for diagnosing AMI—citrulline, intestinal fatty acid-binding protein (I-FABP), and d-lactate. A cross-sectional diagnostic study enrolled AMI patients admitted to the intestinal stroke center and controls with acute abdominal pain of another origin. We included 129 patients—50 AMI and 79 controls. Plasma citrulline concentrations were significantly lower in AMI patients compared to the controls [15.3 μmol/L (12.0–26.0) vs. 23.3 μmol/L (18.3–29.8), p = 0.001]. However, the area under the receiver operating curves (AUROC) for the diagnosis of AMI by Citrulline was low: 0.68 (95% confidence interval = 0.58–0.78). No statistical difference was found in plasma I-FABP and plasma d-lactate concentrations between the AMI and control groups, with an AUROC of 0.44, and 0.40, respectively. In this large cross-sectional study, citrulline, I-FABP, and d-lactate failed to differentiate patients with AMI from patients with acute abdominal pain of another origin. Further research should focus on the discovery of new biomarkers.