Whole Blood Thromboelastometry by ROTEM and Thrombin Generation by Genesia According to the Genotype and Clinical Phenotype in Congenital Fibrinogen Disorders

The outcome of congenital fibrinogen defects (CFD) is often unpredictable. Standard coagulation assays fail to predict the clinical phenotype. We aimed to assess the pheno- and genotypic associations of thrombin generation (TG) and ROTEM in CFD. We measured fibrinogen (Fg) activity and antigen, prothrombin fragments F1+2, and TG by ST Genesia® with both Bleed- and ThromboScreen in 22 patients. ROTEM was available for 11 patients. All patients were genotyped for fibrinogen mutations. Ten patients were diagnosed with hypofibrinogenemia, nine with dysfibrinogenemia, and three with hypodysfibrinogenemia. Among the 17 mutations, eight were affecting the Fg γ chain, four the Fg Bβ chain, and five the Fg Aα chain. No statistical difference according to the clinical phenotypes was observed among FGG and FGA mutations. Median F1+2 and TG levels were normal among the different groups. Fg levels correlated negatively with F1+2 and peak height, and positively with lag time and time to peak. The pheno- and genotypes of the patients did not associate with TG. FIBTEM by ROTEM detected hypofibrinogenemia. Our study suggests an inverse link between low fibrinogen activity levels and enhanced TG, which could modify the structure–function relationship of fibrin to support hemostasis

Whole Blood Thromboelastometry by ROTEM and Thrombin Generation by Genesia According to the Genotype and Clinical Phenotype in Congenital Fibrinogen Disorders

The outcome of congenital fibrinogen defects (CFD) is often unpredictable. Standard coagulation assays fail to predict the clinical phenotype. We aimed to assess the pheno- and genotypic associations of thrombin generation (TG) and ROTEM in CFD. We measured fibrinogen (Fg) activity and antigen, prothrombin fragments F1+2, and TG by ST Genesia® with both Bleed- and ThromboScreen in 22 patients. ROTEM was available for 11 patients. All patients were genotyped for fibrinogen mutations. Ten patients were diagnosed with hypofibrinogenemia, nine with dysfibrinogenemia, and three with hypodysfibrinogenemia. Among the 17 mutations, eight were affecting the Fg γ chain, four the Fg Bβ chain, and five the Fg Aα chain. No statistical difference according to the clinical phenotypes was observed among FGG and FGA mutations. Median F1+2 and TG levels were normal among the different groups. Fg levels correlated negatively with F1+2 and peak height, and positively with lag time and time to peak. The pheno- and genotypes of the patients did not associate with TG. FIBTEM by ROTEM detected hypofibrinogenemia. Our study suggests an inverse link between low fibrinogen activity levels and enhanced TG, which could modify the structure–function relationship of fibrin to support hemostasis

Quality control of fibrinogen secretion in the molecular pathogenesis of congenital afibrinogenemia

Congenital afibrinogenemia is a rare bleeding disorder characterized by the absence in circulation of fibrinogen, a hexamer composed of two sets of three polypeptides (Aα, Bβ and γ). Each polypeptide is encoded by a distinct gene, FGA, FGB and FGG, all three clustered in a region of 50 kb on 4q31. A subset of afibrinogenemia mutations has been shown to specifically impair fibrinogen secretion, but the underlying molecular mechanisms remained to be elucidated. Here, we show that truncation of the seven most C-terminal residues (R455-Q461) of the Bβ chain specifically inhibits fibrinogen secretion. Expression of additional mutants and structural modelling suggests that neither the last six residues nor R455 is crucial per se for secretion, but prevent protein misfolding by protecting hydrophobic residues in the βC core. Immunofluorescence and immuno-electron microscopy studies indicate that secretion-impaired mutants are retained in a pre-Golgi compartment. In addition, expression of Bβ, γ and angiopoietin-2 chimeric molecules demonstrated that the βC domain prevents the secretion of single chains and complexes, whereas the γC domain allows their secretion. Our data provide new insight into the mechanisms accounting for the quality control of fibrinogen secretion and confirm that mutant fibrinogen retention is one of the pathological mechanisms responsible for congenital afibrinogenemi

Dysfibrinogenaemia associated with a novel heterozygous mutation in FGB (c.680delG) and a mild clinical history of bleeding.

After peaking over $120 billion in 2013, U.S. net farm income fell to$56 billion in 2015 with projections of $54 billion for 2016, the lowest level since 2002 (USDA Economic Research Service). The large drop from 2013 to 2016 after nearly a decade of strong growth in agricultural income presents a substantial challenge to agricultural producers and an increased need to carefully manage risk on the farm or ranch

Balanced X autosome translocation suggests association of AMMECR1 disruption with hearing loss short stature bone and heart alterations

Univ Fed Sao Paulo, Dept Morphol & Genet, Sao Paulo, BrazilUniv Geneva, Dept Genet Med & Dev, Geneva, SwitzerlandUniv Lausanne, Ctr Integrat Genom, Lausanne, SwitzerlandBaylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USAHop Jeanne De Flandre, Clin Genet, Lille, FranceUniv Fed Sao Paulo, Dept Psychobiol, Sao Paulo, BrazilUniv Sao Paulo, Dept Pathol, Sao Paulo, BrazilFriedrich Schiller Univ, Inst Human Genet, Jena, GermanyHop Jeanne De Flandre, Inst Genet Med, Lille, FranceUniv Fed Sao Paulo, Dept Morphol & Genet, Sao Paulo, BrazilUniv Fed Sao Paulo, Dept Psychobiol, Sao Paulo, BrazilWeb of Scienc

Identifying novel genetic determinants of hemostatic balance

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/73734/1/j.1538-7836.2005.01461.x.pd