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Stephen O Brennan - One of the best experts on this subject based on the ideXlab platform.
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fibrinogen columbus a novel gamma gly200val mutation causing Hypofibrinogenemia in a family with associated thrombophilia
2007Co-Authors: Ryan L Davis, Michael W Mosesson, Bryce A Kerlin, Jason A Canner, Frederick B Ruymann, Stephen O BrennanAbstract:Fibrinogen is an essential component of the coagulation cascade and the acute phase response. The native 340 kDa molecule has a symmetrical trinodular structure composed of a central E-domain connected to outer D-domains by triple helical coiled-coils.1 Several mutations known to cause Hypofibrinogenemia occur within the C-terminal gammaD-domain and have helped to elucidate the structurally and functionally important areas of this domain.2-5 Here we report the identification of a novel point mutation gammaG200V (fibrinogen Columbus) causing Hypofibrinogenemia and co-segregating with three genetic thrombophilia risk factors.
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novel fibrinogen mutation γ 313 ser asn associated with Hypofibrinogenemia in two unrelated families
2006Co-Authors: Michael Meyer, Frauke Bergmann, Stephen O BrennanAbstract:Congenital Hypofibrinogenemia is a rare disorder caused by a number of different mutations in the fibrinogen genes. The aim of the study was the elucidation of molecular defects in two unrelated families with Hypofibrinogenemia. DNA samples from the patients were screened for mutations in the fibrinogen genes by direct sequencing of polymerase chain reaction-amplified gene segments. Isolated plasma fibrinogen was studied by sodium dodecyl sulfate electrophoresis and electrospray ionization mass spectrometry in order to detect variant polypeptides. Fibrin polymerization was analyzed both in plasma and using purified fibrinogen samples. A novel mutation in the FGG gene (G7590A) was found in all patients from the two families with Hypofibrinogenemia. This mutation causes the amino acid exchange 313 Ser-->Asn in the gamma chain. When plasma fibrinogen from a heterozygous individual was analyzed for the presence of variant gamma chains by reverse-phase high-performance liquid chromatography and electrospray ionization mass spectrometry, only normal gamma chains could be detected. The molecular defect affecting an evolutionary highly conserved amino acid residue in human fibrinogen interferes with plasma expression of the variant molecules and is causative for the observed hypofibrinogenemic phenotype.
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fibrinogen saint germain ii Hypofibrinogenemia due to heterozygous γ n345s mutation
2005Co-Authors: Emmanuelle De Raucourt, Stephen O Brennan, Philippe De Mazancourt, Ghassan J Maghzal, Michael W MosessonAbstract:We have identified a novel heterozygous fibrinogen γchain mutation, γN345S (Fibrinogen Saint-Germain II), in a subject with Hypofibrinogenemia. There was no evidence by mass spectrometry of plasma fibrinogen containing the mutant chain. The Hypofibrinogenemia was discovered in a 26-year-old man who experienced extensive deep venous thrombosis of the left leg associated with pulmonary embolism. Investigation of potential thromboembolic risk factors revealed heterozygosity of the factor V R506Q mutation (factor V Leiden) and heterozygosity of the prothrombin gene G20210A mutation.The Hypofibrinogenemia may be contributory to the thrombophilic manifestations.
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fibrinogen mannheim ii a novel γ307 his tyr substitution in the γd domain causes Hypofibrinogenemia
2004Co-Authors: Amy Dear, Stephen O Brennan, Carlerik Dempfle, W Kirschstein, Peter M GeorgeAbstract:Summary. Background: In recent years it has become clear that the molecular investigation of Hypofibrinogenemia provides unique insight into regions of the fibrinogen molecule that are important in molecular assembly, secretion and stability. Objectives: To investigate a case of Hypofibrinogenemia at the molecular level. Patients and methods: The study was conducted on a 37-year-old woman from Mannheim, Germany, who had an antigenic plasma fibrinogen concentration of 0.86 g L−1. Mutation screening was performed by DNA sequencing and the effect of the identified mutation was investigated at the protein level. Results: Analysis of exon 8 of the fibrinogen γ gene identified a heterozygous CATTAT transition at codon 307. This novel HisTyr substitution was not detected when plasma fibrinogen was analyzed by electrospray ionization mass spectrometry. The mutation predicts a mass increase of 26 Da in the γ chain, but purified γ chains had a normal mass, indicating non-expression of the γTyr307 chain in plasma fibrinogen. Conclusions: This work reports a novel γ307 HisTyr mutation (fibrinogen Mannheim II) that causes Hypofibrinogenemia. Crystal structures show that His307 is located immediately adjacent to three residues that have been implicated in fibrin polymerization at the D:D interface. However, the histidine residue appears critical in maintaining structure of the fibrinogen γD domain, rather than in determining function.
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novel fibrinogen γ375 arg trp mutation fibrinogen aguadilla causes hepatic endoplasmic reticulum storage and Hypofibrinogenemia
2002Co-Authors: Stephen O Brennan, Ghassan J Maghzal, Benjamin L Shneider, Ronald E Gordon, Margret S Magid, Peter M GeorgeAbstract:The proposita and her sister had chronically elevated liver function test results, and needle biopsy specimens showed scattered eosinophilic inclusions within the hepatocytes. On immunoperoxidase staining, the inclusions reacted strongly with anti-fibrinogen antisera; on electron-microscopic (EM) examination, the material appeared confined to the endoplasmic reticulum (ER) and was densely packed into tubular structures with a swirling fingerprint appearance. Coagulation investigations showed low functional and antigenic fibrinogen concentrations that were indicative of Hypofibrinogenemia. Amplification and DNA sequencing showed a heterozygous CGG-->TGG mutation at codon 375 of the fibrinogen gamma chain gene. This novel gamma375 Arg-->Trp substitution segregated with Hypofibrinogenemia in 3 family members and was absent from 50 normal controls. When purified plasma fibrinogen chains were examined by sodium dodecyl sulfate/polyacrylamide gel electrophoresis, reverse-phase chromatography, electrospray ionization mass spectrometry, and isoelectric focusing, only normal gamma chains were detected. In conclusion, we propose that this nonconservative mutation causes a conformational change in newly synthesized molecules and that this provokes aggregation within the ER and in turn causes the observed Hypofibrinogenemia. Whereas the mutation site, gamma375, is located in the gammaD domain at the jaws of the primary E-to-D polymerization site, purified plasma fibrinogen showed normal polymerization, supporting our contention that molecules with variant chains never reach the circulation but accumulate in the ER.
Marguerite Neermanarbez - One of the best experts on this subject based on the ideXlab platform.
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a novel nonsense mutation in fgb c 1421g a p trp474ter in the beta chain of fibrinogen causing Hypofibrinogenemia with bleeding phenotype
2020Co-Authors: Tomas Simurda, Marguerite Neermanarbez, Alessandro Casini, Jana Zolkova, Dusan Loderer, Rui Vilar, Eliska Ceznerova, Zuzana Kolkova, Monika Brunclikova, Ingrid SkornovaAbstract:Congenital Hypofibrinogenemia is a rare bleeding disorder characterized by a proportional decrease of functional and antigenic fibrinogen levels. Hypofibrinogenemia can be considered the phenotypic expression of heterozygous loss of function mutations occurring within one of the three fibrinogen genes (FGA, FGB, and FGG). Clinical manifestations are highly variable; most patients are usually asymptomatic, but may appear with mild to severe bleeding or thrombotic complications. We have sequenced all exons of the FGA, FGB, and FGG genes using the DNA isolated from the peripheral blood in two unrelated probands with mild Hypofibrinogenemia. Coagulation screening, global hemostasis, and functional analysis tests were performed. Molecular modeling was used to predict the defect of synthesis and structural changes of the identified mutation. DNA sequencing revealed a novel heterozygous variant c.1421G>A in exon 8 of the FGB gene encoding a Bβ chain (p.Trp474Ter) in both patients. Clinical data from patients showed bleeding episodes. Protein modelling confirmed changes in the secondary structure of the molecule, with the loss of three β sheet arrangements. As expected by the low fibrinogen levels, turbidity analyses showed a reduced fibrin polymerisation and imaging difference in thickness fibrin fibers. We have to emphasize that our patients have a quantitative fibrinogen disorder; therefore, the reduced function is due to the reduced concentration of fibrinogen, since the Bβ chains carrying the mutation predicted to be retained inside the cell. The study of fibrinogen molecules using protein modelling may help us to understand causality and effect of novel genetic mutations.
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congenital fibrinogen disorders an update
2013Co-Authors: Philippe De Moerloose, Alessandro Casini, Marguerite NeermanarbezAbstract:Hereditary fibrinogen abnormalities comprise two classes of plasma fibrinogen defects: Type I, afibrinogenemia or Hypofibrinogenemia, which has absent or low plasma fibrinogen antigen levels (quantitative fibrinogen deficiencies), and Type II, dysfibrinogenemia or hypodysfibrinogenemia, which shows normal or reduced antigen levels associated with disproportionately low functional activity (qualitative fibrinogen deficiencies). In afibrinogenemia and Hypofibrinogenemia, most mutations of the FGA, FGB, or FGG fibrinogen encoding genes are null mutations. In some cases, missense or late truncating nonsense mutations allow synthesis of the corresponding fibrinogen chain but intracellular fibrinogen assembly and/or secretion are impaired. Afibrinogenemia is associated with mild-to-severe bleeding, whereas Hypofibrinogenemia is most often asymptomatic. Thromboembolism may occur either spontaneously or in association with fibrinogen substitution therapy. Women with afibrinogenemia suffer from recurrent pregnancy loss but this can also occur in women with Hypofibrinogenemia. Dysfibrinogenemia, caused mainly by missense mutations, is commonly associated with bleeding, thrombophilia, or both; however, most individuals are asymptomatic. Hypodysfibrinogenemia is a subcategory of this disorder. Even in specialized laboratories, the precise diagnosis of some fibrinogen disorders may be difficult. Determination of the molecular defects is important because it gives the possibility to confirm the diagnosis, to elaborate a diagnostic strategy, to distinguish in some cases that the patient is at risk of thrombosis rather than bleeding, and to enable prenatal diagnosis. However, genotype–phenotype correlations are not easy to establish. Replacement therapy is effective in treating bleeding episodes, but because the pharmacokinetics of fibrinogen after replacement therapy is highly variable among patients, it is important to adjust the treatment individually.
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characterisation of a novel nonsense mutation in fgg fibrinogen poznan causing hypofibrinogenaemia with a mild bleeding tendency
2010Co-Authors: Krystyna Zawilska, Richard J Fish, Lucyna Molendowiczportala, Philippe De Moerloose, Anetta Undas, Marguerite NeermanarbezAbstract:Characterisation of a novel nonsense mutation in FGG (Fibrinogen Poznan) causing hypofibrinogenaemia with a mild bleeding tendency -
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fibrinogen gamma375 arg trp mutation fibrinogen aguadilla causes hereditary Hypofibrinogenemia hepatic endoplasmic reticulum storage disease and cirrhosis
2006Co-Authors: Laura Rubbiabrandt, Marguerite Neermanarbez, Annelaure Rougemont, Pierrejean Male, Laurent SpahrAbstract:Hypofibrinogenemia is a rare inherited disorder characterized by low levels of circulating fibrinogen, caused by mutations within 1 of the 3 fibrinogen genes. We report here the case of a 61-year-old man with chronic liver function test alterations. Liver biopsy examination revealed chronic hepatitis complicated by cirrhosis and weakly eosinophilic globular cytoplasmic inclusions within the hepatocytes, faintly stained with PAS-diastase. On immunohistochemistry, the inclusions reacted strongly with human antifibrinogen antibodies. Coagulation investigations of the propositus and his 2 sons showed low functional and antigenic fibrinogen concentrations that were indicative of Hypofibrinogenemia. A liver biopsy performed on the 28-year-old son demonstrated the same globular cytoplasmic inclusions, albeit without associated chronic liver disease. PCR amplification followed by sequencing showed that all 3 were heterozygous for a CGG>TGG mutation at codon 375 of the fibrinogen gamma-chain gene (FGG), corresponding to an Arg>Trp substitution. This is the first in an adult male and the second published case with a discernible hepatic fibrinogen endoplasmic reticulum storage disease due to an FGG Arg375Trp (fibrinogen Aguadilla) mutation. Our results suggest that familial Hypofibrinogenemia should be considered in the differential diagnosis of a progressive liver disease associated to hepatocellular intracytoplasmic globular inclusions.
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hypofibrinogenaemia caused by a novel fgg missense mutation w253c in the gamma chain globular domain impairing fibrinogen secretion
2005Co-Authors: Dung Vu, J Lazur, L Palumbo, Angelika Batorova, Philippe De Moerloose, Marguerite NeermanarbezAbstract:BACKGROUND: Inherited disorders of fibrinogen are rare and affect either the quantity (hypofibrinogenaemia and afibrinogenaemia) or the quality of the circulating fibrinogen (dysfibrinogenaemia). Extensive allelic heterogeneity has been found for all three disorders: in congenital afibrinogenaemia >30 mutations, the majority in FGA, have been identified in homozygosity or in compound heterozygosity. Several mutations have also been identified in patients with hypofibrinogenaemia; many of these are heterozygous carriers of afibrinogenaemia null mutations. OBJECTIVE: To report the case of a patient from Slovakia diagnosed with hypofibrinogenaemia characterised by fibrinogen concentrations of around 0.7 g/l. RESULTS: The patient was found to be heterozygous for a novel missense mutation W253C (W227C in the mature protein) in the C-terminal globular domain of the fibrinogen gamma chain. Co-expression of the W253C FGG mutant cDNA (fibrinogen Bratislava) in combination with wild-type FGA and FGB cDNAs showed that fibrinogen molecules containing the mutant gamma chain can assemble intracellularly but are not secreted into the media, confirming the causative nature of the identified mutation. CONCLUSIONS: Current analysis of fibrinogen Bratislava indicates that the domains important for the processes of hexamer assembly and hexamer secretion should not be considered as strictly restricted to one or other fibrinogen chain.
Peter M George - One of the best experts on this subject based on the ideXlab platform.
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fibrinogen mannheim ii a novel γ307 his tyr substitution in the γd domain causes Hypofibrinogenemia
2004Co-Authors: Amy Dear, Stephen O Brennan, Carlerik Dempfle, W Kirschstein, Peter M GeorgeAbstract:Summary. Background: In recent years it has become clear that the molecular investigation of Hypofibrinogenemia provides unique insight into regions of the fibrinogen molecule that are important in molecular assembly, secretion and stability. Objectives: To investigate a case of Hypofibrinogenemia at the molecular level. Patients and methods: The study was conducted on a 37-year-old woman from Mannheim, Germany, who had an antigenic plasma fibrinogen concentration of 0.86 g L−1. Mutation screening was performed by DNA sequencing and the effect of the identified mutation was investigated at the protein level. Results: Analysis of exon 8 of the fibrinogen γ gene identified a heterozygous CATTAT transition at codon 307. This novel HisTyr substitution was not detected when plasma fibrinogen was analyzed by electrospray ionization mass spectrometry. The mutation predicts a mass increase of 26 Da in the γ chain, but purified γ chains had a normal mass, indicating non-expression of the γTyr307 chain in plasma fibrinogen. Conclusions: This work reports a novel γ307 HisTyr mutation (fibrinogen Mannheim II) that causes Hypofibrinogenemia. Crystal structures show that His307 is located immediately adjacent to three residues that have been implicated in fibrin polymerization at the D:D interface. However, the histidine residue appears critical in maintaining structure of the fibrinogen γD domain, rather than in determining function.
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novel fibrinogen γ375 arg trp mutation fibrinogen aguadilla causes hepatic endoplasmic reticulum storage and Hypofibrinogenemia
2002Co-Authors: Stephen O Brennan, Ghassan J Maghzal, Benjamin L Shneider, Ronald E Gordon, Margret S Magid, Peter M GeorgeAbstract:The proposita and her sister had chronically elevated liver function test results, and needle biopsy specimens showed scattered eosinophilic inclusions within the hepatocytes. On immunoperoxidase staining, the inclusions reacted strongly with anti-fibrinogen antisera; on electron-microscopic (EM) examination, the material appeared confined to the endoplasmic reticulum (ER) and was densely packed into tubular structures with a swirling fingerprint appearance. Coagulation investigations showed low functional and antigenic fibrinogen concentrations that were indicative of Hypofibrinogenemia. Amplification and DNA sequencing showed a heterozygous CGG-->TGG mutation at codon 375 of the fibrinogen gamma chain gene. This novel gamma375 Arg-->Trp substitution segregated with Hypofibrinogenemia in 3 family members and was absent from 50 normal controls. When purified plasma fibrinogen chains were examined by sodium dodecyl sulfate/polyacrylamide gel electrophoresis, reverse-phase chromatography, electrospray ionization mass spectrometry, and isoelectric focusing, only normal gamma chains were detected. In conclusion, we propose that this nonconservative mutation causes a conformational change in newly synthesized molecules and that this provokes aggregation within the ER and in turn causes the observed Hypofibrinogenemia. Whereas the mutation site, gamma375, is located in the gammaD domain at the jaws of the primary E-to-D polymerization site, purified plasma fibrinogen showed normal polymerization, supporting our contention that molecules with variant chains never reach the circulation but accumulate in the ER.
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fibrinogen brescia hepatic endoplasmic reticulum storage and Hypofibrinogenemia because of a γ284 gly arg mutation
2000Co-Authors: Stephen O Brennan, Jane Wyatt, Daniela Medicina, Francesco Callea, Peter M GeorgeAbstract:The proposita suffered from liver cirrhosis and biopsy showed type 1 membrane-bound fiberglass inclusions. The hepatic inclusion bodies were weakly periodic acid-Schiff diastase-positive, and on immunoperoxidase staining reacted specifically with anti-fibrinogen antisera. Coagulation investigations revealed low functional and antigenic fibrinogen together with a prolonged thrombin time of 37 seconds (normal, 17 to 22 seconds) suggestive of a hypodysfibrinogenemia. DNA sequencing of all three fibrinogen genes showed a single heterozygous mutation of GGG (Gly)-->CGG (Arg) at codon 284 of the gamma-chain gene. However, examination of purified fibrinogen chains by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, reverse-phase high-performance liquid chromatography, ion-exchange high-performance liquid chromatography, and isoelectric focusing, failed to show any evidence of the mutant gamma(Br) chain in plasma fibrinogen. This finding was substantiated by electrospray ionization mass spectrometry, which showed only a normal gamma (and Bbeta) chain mass, but a large increase in the portion of their disialo isoforms. We speculate that misfolding of the variant protein causes hepatic retention and the subsequent Hypofibrinogenemia, and that the functional defect (dysfibrinogenemia) results from hypersialylation of otherwise normal Bbeta and gamma chains consequent to the liver cirrhosis. These conclusions were supported by studies on six other family members with Hypofibrinogenemia, and essentially normal clotting times, who were heterozygous for the gamma284 Gly-->Arg mutation.
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Hypofibrinogenemia in an individual with 2 coding γ82 a g and bβ235 p l and 2 noncoding mutations
2000Co-Authors: Stephen O Brennan, Andrew P Fellowes, James M Faed, Peter M GeorgeAbstract:We investigated the molecular basis of Hypofibrinogenemia in a man with a normal thrombin clotting time. Protein analysis indicated equal plasma expression of 2 different Bβ alleles, and DNA sequencing confirmed heterozygosity for a new Bβ235 P→L mutation. Protein analysis also revealed a novel γD chain, present at a ratio of 1:2 relative to the γA chain. Mass spectrometry indicated a 14 d decrease in the γD-chain mass, and DNA sequencing showed this was caused by a novel γ82 A→G substitution. DNA sequencing established heterozygosity for 2 further mutations: T→C in intron 4 of the A gene and A→C in the 3′ noncoding region of the Bβ gene. Studies on the man's daughter, together with plasma expression levels, discounted both the A and Bβ mutations as the cause of the low fibrinogen, suggesting that the γ82 mutation caused the Hypofibrinogenemia. This was supported by analysis of 31 normal controls in whom the Bβ mutations were found at polymorphic levels, with an allelic frequency of 5% for the Bβ235 mutation and 42% for the Bβ 3′ untranslated mutation. The γ82 mutation was, however, unique to the propositus. Residue γ82 is located in the triple helix that separates the E and D domains, and aberrant packing of the helices may explain the decreased fibrinogen concentration.
Jeannie Callum - One of the best experts on this subject based on the ideXlab platform.
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which is the preferred blood product for fibrinogen replacement in the bleeding patient with acquired Hypofibrinogenemia cryoprecipitate or fibrinogen concentrate
2020Co-Authors: Melissa M Cushing, Jeannie Callum, Keyvan Karkouti, Thorsten HaasAbstract:The importance of the targeted treatment of acquired Hypofibrinogenemia during hemorrhage with a concentrated fibrinogen product (either cryoprecipitate or fibrinogen concentrate) cannot be underestimated. Fibrinogen concentrate is a pathogen inactivated, pooled product that offers a highly purified single factor concentrate. Cryoprecipitate is a pooled product that comes with a spectrum of other coagulation factors which may further enhance (additional procoagulant effect) or even disturb (prothrombotic risk) hemostasis. The pros and cons of each product are discussed.
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effect of fibrinogen concentrate vs cryoprecipitate on blood component transfusion after cardiac surgery the fibres randomized clinical trial
2019Co-Authors: Jeannie Callum, Michael E Farkouh, Damon C Scales, Nancy M Heddle, Mark Crowther, Vivek RaoAbstract:Importance Excessive bleeding is a common complication of cardiac surgery. An important cause of bleeding is acquired Hypofibrinogenemia (fibrinogen level Objective To determine if fibrinogen concentrate is noninferior to cryoprecipitate for treatment of bleeding related to Hypofibrinogenemia after cardiac surgery. Design, Setting, and Participants Randomized clinical trial at 11 Canadian hospitals enrolling adult patients experiencing clinically significant bleeding and Hypofibrinogenemia after cardiac surgery (from February 10, 2017, to November 1, 2018). Final 28-day follow-up visit was completed on November 28, 2018. Interventions Fibrinogen concentrate (4 g; n = 415) or cryoprecipitate (10 units; n = 412) for each ordered dose within 24 hours after cardiopulmonary bypass. Main Outcomes and Measures Primary outcome was blood components (red blood cells, platelets, plasma) administered during 24 hours post bypass. A 2-sample, 1-sided test for the ratio of the mean number of units was conducted to evaluate noninferiority (threshold for noninferiority ratio, Results Of 827 randomized patients, 735 (372 fibrinogen concentrate, 363 cryoprecipitate) were treated and included in the primary analysis (median age, 64 [interquartile range, 53-72] years; 30% women; 72% underwent complex operations; 95% moderate to severe bleeding; and pretreatment fibrinogen level, 1.6 [interquartile range, 1.3-1.9] g/L). The trial met the a priori stopping criterion for noninferiority at the interim analysis after 827 of planned 1200 patients were randomized. Mean 24-hour postbypass allogeneic transfusions were 16.3 (95% CI, 14.9 to 17.8) units in the fibrinogen concentrate group and 17.0 (95% CI, 15.6 to 18.6) units in the cryoprecipitate group (ratio, 0.96 [1-sided 97.5% CI, −∞ to 1.09;P Conclusions and Relevance In patients undergoing cardiac surgery who develop clinically significant bleeding and Hypofibrinogenemia after cardiopulmonary bypass, fibrinogen concentrate is noninferior to cryoprecipitate with regard to number of blood components transfused in a 24-hour period post bypass. Use of fibrinogen concentrate may be considered for management of bleeding in patients with acquired Hypofibrinogenemia in cardiac surgery. Trial Registration ClinicalTrials.gov Identifier:NCT03037424
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protocol for a phase iii non inferiority randomised comparison of a new fibrinogen concentrate versus cryoprecipitate for treating acquired hypofibrinogenaemia in bleeding cardiac surgical patients the fibres trial
2018Co-Authors: Jeannie Callum, Michael E Farkouh, Nancy M Heddle, Mark Crowther, Vivek Rao, Keyvan Karkouti, Damon C ScalesAbstract:Introduction Coagulopathic bleeding is a serious complication of cardiac surgery to which an important contributor is acquired hypofibrinogenaemia (plasma fibrinogen Methods and analysis FIBrinogen REplenishment in Surgery (FIBRES) is a multicentre, randomised (1:1), active-control, single-blinded, phase III trial in adult cardiac surgical patients experiencing clinically significant bleeding related to acquired hypofibrinogenaemia. The primary objective is to demonstrate that fibrinogen concentrate (Octafibrin/Fibryga; Octapharma) is non-inferior to cryoprecipitate. All patients for whom fibrinogen supplementation is ordered by the clinical team within 24 hours of cardiopulmonary bypass will receive 4 g of fibrinogen concentrate or 10 units of cryoprecipitate (dose-equivalent to 4 g), based on random allocation and deferred consent. The primary outcome is total red cell, platelet and plasma transfusions administered within 24 hours of bypass. Secondary outcomes include major bleeding, fibrinogen levels and adverse events within 28 days. Enrolment of 1200 patients will provide >90% power to demonstrate non-inferiority. One preplanned interim analysis will include 600 patients. The pragmatic design and treatment algorithm align with standard practice, aiding adherence and generalisability. Ethics and dissemination The study is approved by the local research ethics board and will be conducted in accordance with the Declaration of Helsinki, Good Clinical Practice guidelines and regulatory requirements. Patient consent prior to treatment is waived, as per criteria in the Tri-Council Policy Statement. Results will be published in the scientific/medical literature, and at international congresses. Non-inferiority of purified fibrinogen concentrate would support its use in acquired hypofibrinogenaemia. The results are likely to improve care for cardiac surgical patients experiencing significant bleeding, an understudied yet high-risk population. Trial registration number NCT03037424; Pre-results.
Michael A Mazzeffi - One of the best experts on this subject based on the ideXlab platform.
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pro con debate fibrinogen concentrate or cryoprecipitate for treatment of acquired Hypofibrinogenemia in cardiac surgical patients
2021Co-Authors: Nadia B Hensley, Michael A MazzeffiAbstract:Cryoprecipitate has been the gold standard for treating acquired Hypofibrinogenemia in cardiac surgery for nearly 50 years. More recently, fibrinogen concentrate has been used off-label in the United States and is the standard in European countries and Canada to treat the acquired Hypofibrinogenemia during cardiac surgery. Fibrinogen concentrate has multiple potential advantages including rapid reconstitution, greater dose predictability, viral inactivation during processing, and reduced transfusion-related adverse events. However, because fibrinogen concentrate lacks the other components contained in the cryoprecipitate, it may not be the "ideal" product for replacing fibrinogen in all cardiac surgical patients, particularly those with longer cardiopulmonary bypass duration. In this Pro-Con commentary article, we discuss the advantages and disadvantages of using fibrinogen concentrate and cryoprecipitate to treat acquired Hypofibrinogenemia in cardiac surgical patients.
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viscoelastic signals for optimal resuscitation in trauma kaolin thrombelastography cutoffs for diagnosing Hypofibrinogenemia visor study
2019Co-Authors: Jonathan H Chow, Justin E Richards, Jonathan J Morrison, Samuel M Galvagno, Kenichi A Tanaka, Marta J Madurska, Peter Rock, Thomas M Scalea, Michael A MazzeffiAbstract:BACKGROUND:Acute traumatic coagulopathy is common in trauma patients. Prompt diagnosis of Hypofibrinogenemia allows for early treatment with cryoprecipitate or fibrinogen concentrate. At present, optimal cutoffs for diagnosing Hypofibrinogenemia with kaolin thrombelastography (TEG) have not been est