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IntroductionInherited or acquired molecular abnormalities form a clinically heterogeneous group of fibrinogen disorders called dysfibrinogenaemia. Apart from a pediatric case report and in contrast to other clinical conditions, acquired dysfibrinogenaemia has not been previously reported in septic patients.MethodsIn an observational cohort study, 79 adult septic patients were investigated for the presence of acquired dysfibrinogenaemia at the time of their admission to the intensive care unit (ICU) of the University Hospital Frankfurt. Following established recommendations, fibrinogen clotting activity vs. antigen ratios were analyzed using Clauss fibrinogen, prothrombin-derived fibrinogen, and radial immunodiffusion (RID) fibrinogen concentration.ResultsProthrombin-derived fibrinogen levels were highest (527 ± 182 mg/dL) followed by Clauss fibrinogen (492 ± 209 mg/dL) and radial immunodiffusion fibrinogen (426 ± 159 mg/dL). Very few cases demonstrated hypofibrinogenaemia making overt disseminated intravascular coagulation (DIC) unlikely in the cohort investigated. Clauss/RID fibrinogen ratios were lower (1.17 ± 0.19) compared to prothrombin time-derived/RID ratios (1.35 ± 0.33). Using the Clauss/RID dataset, 21% of patients (16/76 patients) demonstrated values below a threshold ratio for suspected acquired dysfibrinogenaemia arbitrarily set at 1.0. In contrast, prothrombin-derived ratios were below the threshold in only 7% (4/58 patients).DiscussionThe results point to the presence of acquired dysfibrinogenaemia in part of adult septic patients. If confirmed in further studies, this may form part of a specific laboratory signature of a sepsis-associated coagulation phenotype.

Introduction: Hereditary fibrinogen disorders (HFD) are rare quantitative or qualitative fibrinogen anomalies, including afibrinogenaemia (A), hypofibrinogenaemia (H), dysfibrinogenaemia (D) and hypodysfibrinogenaemia (HD). As fibrinogen plays an essential role in pregnancy, we addressed the issue of obstetrical and postpartum complications in women with HFD. Methods: A systematic literature review, restricted to English manuscripts, was conducted according to the PRISMA guidelines. We searched through the MEDLINE database for English articles, published from January 1985 until November 2018, focusing on pregnancy in A, H, D and HD. A total of 198 articles were identified, 15 articles were added from other sources. Overall, 213 articles were screened and 54 were included in the final analysis. Results: A total of 188 pregnancies from 70 women were analysed. About half of pregnancies resulted in miscarriage; more specifically in 15 (42.9%), 36 (46.8%), 27 (42.9%) and 4 (30.8%) of A, H, D and HD patients, respectively. Preterm complications were also frequent (33.5%). Metrorrhagia, mainly in the first trimester, was observed in 21.7% of the pregnancies. Placenta abruption was reported in 5 (14.3%), 4 (5.2%), 5 (7.9%) and 1 (7.7%) of A, H, D and HD, respectively. A total of 24 (12.7%) deliveries were complicated by postpartum thrombotic events (3.2%) or postpartum haemorrhage (9.6%). A fibrinogen replacement therapy was introduced in 30% of pregnancies, as prophylaxis (81.1%) or on demand (18.9%). Conclusion: These results suggest that women with HFD are at high risk of obstetrical and postpartum complications. Prospective international registries may allow to identify more precisely the incidence of obstetrical and postpartum adverse outcomes and their management. [ABSTRACT FROM AUTHOR]

Martin W Besser,1 Stephen G MacDonald2 1Department of Haematology, 2Department of Specialist Haemostasis, The Pathology Partnership, Addenbrooke’s Hospital, Cambridge, UK Abstract: Acquired hypofibrinogenemia is most frequently caused by hemodilution and consumption of clotting factors. The aggressive replacement of fibrinogen has become one of the core principles of modern management of massive hemorrhage. The best method for determining the patient’s fibrinogen level remains controversial, and particularly in acquired dysfibrinogenemia, could have major therapeutic implications depending on which quantification method is chosen. This review introduces the available laboratory and point-of-care methods and discusses the relative advantages and limitations. It also discusses current strategies for the correction of hypofibrinogenemia. Keywords: Clauss fibrinogen assay, fibrinogen antigen, viscoelastic testing, ­gravimetric fibrinogen assay, PT-derived fibrinogen, functional fibrinogen, direct oral anticoagulant, dysfibrinogenemia, afibrinogenemia

Introduction Mutations in fibrinogen (Fgn) genes, causing dysfibrinogenaemia, can result in either a bleeding or thrombophilic diathesis. Dysfibrinogenaemia is infrequently encountered in hospital laboratories, and the utility of different assays in the diagnosis of dysfibrinogenaemia has not previously been explored in a multicentre study. We describe here an exercise in which PRO- RBDD project (prospective data collection on patients with fibrinogen and Factor XIII deficiencies) centres, and UK NEQAS centres, performed investigations for dysfibrinogenaemia. Methods Samples from donors with dysfibrinogenaemia (sample 1: gamma p.Arg301Cys, sample 2: Bbeta166Arg3Cys-Fgn Longmont, sample 3: Aalpha p.Arg35His) and a normal donor were sent to laboratories for investigation for possible dysfibrinogenaemia. Median, coefficient of variation and range were determined for each assay method. Results Results were returned from 62 UK NEQAS and 24 PRO- RBDD centres. PT, APTT, Clauss fibrinogen and thrombin times were performed by >90% of centres, with 51% performing reptilase times, and 31% fibrinogen antigen. All centres identified samples 1 and 3 as abnormal. However, 39% of centres reported a normal or raised fibrinogen for the Fgn Longmont sample, and marked differences in Clauss fibrinogen results with different reagents were noted for this sample (median 1.01 g/L vs 5.10 g/L for the two mostly widely used reagents). Conclusion In-house studies suggest that the method of detection of fibrin clot formation may result in different Clauss fibrinogen measurements with FgnLongmont plasma. It is possible that some widely used methodologies, both using optical and mechanical end-point detection systems, will fail to detect this rare fibrinogen variant. [ABSTRACT FROM AUTHOR]

Fibrinogen is a key glycoprotein of blood coagulation. During haemocoagulation fibrinogen is converted to fibrin. Congenital dysfibrinogenemia is a disease wherein an inherited abnormality in the fibrinogen molecule results in defective fibrin clot formation. Hereditary hypofibrinogenemia is a disease wherein an inherited abnormality in the fibrinogen molecule results in low fibrinogen level in plasma. 36 unrelated families in the Czech Republic suspected with either dysfibrinogenemia or afibrinogenemia were examined. Four patients presented with thrombosis, eight patients presented with bleeding tendencies and others were asymptomatic. Heterozygous point mutations Aα Arg16Cys (Fibrinogen Nový Jičín, Ostrava I), Aα Arg16His (Fibrinogen Praha II, Ostrava II), Aα Asn106Asp (Fibrinogen Plzeň), γ Tyr363Asn (Fibrinogen Praha III), γ Tyr262Cys (Fibrinogen Liberec) and γ Arg275His (Fibrinogen Brno) were found to be the direct causes of dysfibrinogenemias in the carriers. Molecular genetics experiments revealed inherited mutations in 13 unrelated families causing hereditary dysfibrinogenemia. In one case acquired dysfibrinogenemia secondary to multiple myeloma was found. [ABSTRACT FROM AUTHOR]

Dysfibrinogenaemias may present in either congenital or acquired form and are disorders of fibrinogen structure which may or may not be associated with abnormal function. More than 100 point mutations with single amino acid substitutions have been identified in over 400 families. These lead to defective DNA in the translated fibrinogen molecule. Such cases have improved our understanding of the fibrinogen-fibrin structure. Six members of a consanguineous family including a female proband, a female sibling, three male siblings and a daughter, with ages between 29 years and 53 years presented with early onset venous and premature arterial thromboembolic disease were investigated for a pro-thrombotic tendency associated with dysfibrinogenaemia. The family was investigated using standard coagulation assays and DNA sequencing of the genes encoding the FGA, FGB and FGG. All cases have dysfibrinogenaemia with a fibrinogen level 1.4 to 1.5 (1.9-4.3 g/L). Thrombophilia testing (including AT, PS & PC, F5 G1691A (FV Leiden)/ F2 (prothombin G20210A) genotypes, homocysteine, antiphosphlipid antibody, paroxysmal nocturnal haemoglobinuria by flow cytometry and Janus Kinase-2 (exon 14)) were normal. PCR amplification and sequencing of exon 2 of FBG revealed a heterozygous mutation for a c.221G> Tsubstitution, predicting the replacement of the native Arginine at position 74 with a Leucine (p.Arg74Leu). In silico analysis of p.Arg74Leu strongly support pathogenicity. A novel mutation was identified in exon 2 of FGB caused by c.221G> T substitution, predicting the replacement of Arginine at position 74 with a Leucine (p.Arg74Leu) in a proband from a Kurdish family with dysfibrinogenaemia and familial venous and arterial thrombosis. [ABSTRACT FROM AUTHOR]

Congenital fibrinogen disorders are rare diseases affecting either the quantity (afibrinogenaemia and hypofibrinogenaemia) or the quality (dysfibrinogenaemia) or both (hypodysfibrinogenaemia) of fibrinogen. In addition to bleeding, unexpected thrombosis, spontaneous spleen ruptures, painful bone cysts and intrahepatic inclusions can complicate the clinical course of patients with quantitative fibrinogen disorders. Clinical manifestations of dysfibrinogenaemia include absence of symptoms, major bleeding or thrombosis as well as systemic amyloidosis. Although the diagnosis of any type of congenital fibrinogen disorders is usually not too difficult with the help of conventional laboratory tests completed by genetic studies, the correlation between all available tests and the clinical manifestations is more problematic in many cases. Improving accuracy of diagnosis, performing genotype, analysing function of fibrinogen variants and carefully investigating the personal and familial histories may lead to a better assessment of patients' phenotype and therefore help in identifying patients at increased risk of adverse clinical outcomes. This review provides an update of various tests (conventional and global assays, molecular testing, fibrin clot analysis) and clinical features, which may help to better predict the phenotype of the different types of congenital fibrinogen disorders. [ABSTRACT FROM AUTHOR]

Heritable dysfibrinogenaemia ( HD) is a rare qualitative disorder of fibrinogen ( FGN). To better describe the clinical, laboratory and genotypic spectrum of HD, we evaluated 35 subjects identified at two UK centres using laboratory criteria. 12/35(34%) subjects with HD experienced bleeding (bleeding score >1 at any site), 3/35(9%) thrombosis and 20/35(57%) were asymptomatic. Amongst subjects with bleeding, symptoms were typically mild, at one anatomical site and seldom occurred after invasive procedures. All subject showed dry clot weight within or above laboratory reference interval (median 3·2 g/l; range 1·9-5·1), reduced Clauss fibrinogen (median 0·52 g/l; range 0·21-1·3), and prolonged thrombin (median 30·7 s; range 21·3-45·7) and reptilase (median 42·0 s; range 20·0-68·0) times. In all subjects, the prothrombin time ratio ( PTR), determined by Sysmex CA-1500 coagulometer and Innovin activator, was abnormal (median 1·42; range 1·22-1·61). The activated partial thromboplastin time ratio and PTR with other coagulometers and activators were comparatively insensitive to HD. All subjects with HD harboured heterozygous candidate nucleotide variations within known hotspots in the FGN genes. The HD variants identified in this cross-sectional study seldom have significant clinical manifestations and show similar laboratory features irrespective of genotype. Selection of coagulometer and PT activator may markedly affect the detection of new HD cases using coagulation screening tests. [ABSTRACT FROM AUTHOR]

Hereditary dysfibrinogenaemia is characterized by the presence of functionally abnormal plasma fibrinogen. Dysfibrinogenaemia is a heterogeneous disorder associated with different mutations throughout the three genes that code for the fibrinogen sub-units, affecting many different aspects of fibrinogen/fibrin activity. Dysfibrinogenaemia may be discovered during the investigation of individuals who present with bleeding or thombosis, or may be found in individuals during routine coagulation screening. More specialized coagulation tests may confirm the diagnosis of dysfibrinogenaemia but do not reliably distinguish between the different fibrinogen variants and are not usually useful in predicting bleeding or thrombotic risk. Advances in molecular diagnostics have facilitated the investigation of the molecular causes of fibrinogen disorders. Several ‘hot spot’ areas have been identified where mutations causing a high proportion of cases of dysfibrinogenaemia are found (AαArg16 and γArg275). Molecular diagnostics have also shown that many fibrinogen variants share the same causative mutation. There is a discrepancy between the quality of the molecular and functional data available for each mutation and the clinical information on individuals and their family members. However, there are accumulating data that the ‘hot spot’ mutations accounting for 60–80% of cases of dysfibringenaemia are not associated with a significant bleeding or thrombosis in the absence of other risk factors. Rapid screening for these mutations may provide reassurance for patients in the presurgical setting. [ABSTRACT FROM AUTHOR]

Objective: A 22-yr-old woman had abnormal preoperative coagulation test results and congenital dysfibrinogenaemia was suspected. Patients and methods: The patient from Liberec (Czech Republic) had a low fibrinogen plasma level as determined by Clauss method, normal fibrinogen level as determined by immunoturbidimetrical method, and prolonged thrombin time. To identify the genetic mutation responsible for this dysfibrinogen, genomic DNA extracted from the blood was analysed. Fibrin polymerisation measurement, kinetics of fibrinopeptide release, fibrinogen clottability measurement and scanning electron microscopy were performed. Results: DNA sequencing showed the heterozygous fibrinogen γ Y262C mutation. Kinetics of fibrinopeptide release was normal, however fibrin polymerisation was impaired. Fibrinogen clottability measurement showed that only about 45% molecules of fibrinogen are involved in the clot formation. Scanning electron microscopy revealed thicker fibres, which were significantly different from the normal control. Conclusion: A case of dysfibrinogenaemia, found by routine coagulation testing, was genetically identified as a novel fibrinogen variant (γ Y262C) that has been named Liberec. [ABSTRACT FROM AUTHOR]

Presents information on a study which discussed dysfibrinogenemias. Molecular biology and biochemistry of fibrinogen; Molecular defects that result in dysfibrinogenemia; Association of dysfibrinogenemia with bleeding and thrombosis.

Fibrinogen Banks Peninsula was identified in the mother of a patient referred for investigation following recurrent epistaxis. Coagulation tests revealed prolonged thrombin and reptilase times and a decreased functional fibrinogen level. Thrombin-catalysed release of fibrinopeptides A and B was normal, and no abnormalities were detected by DNA sequencing of the regions encoding the thrombin cleavage sites in the Aα and Bβ genes. Reducing SDS-PAGE and reverse-phase HPLC analysis of purified fibrinogen chains were normal, as was electrospray ionization mass spectrometry (ESI-MS) analysis of isolated Aα and Bβ chains. However ESI-MS revealed a mass of 48 345 D for the isolated γ chains, 31 D less than the measured mass of control chains (48 376 D). Since normal and abnormal γ chains were not resolved, this implies a 60–62 D mass decrease in 50% of the molecules. A 60 D decrease was confirmed when DNA sequencing indicated heterozygosity for a mutation of Tyr→Cys at codon 280 of the γ chain gene. Fibrin monomer polymerization revealed a delayed lag phase and reduced final turbidity and although factor XIIIa crosslinking of fibrinogen was normal, it is likely that this delay is due to impaired D:D self association. Recent crystallographic studies show residues γ280 and γ275 make contact across the D:D interface, suggesting a similar mechanism for the polymerization defects in fibrinogens Banks Peninsula and Tokyo II (γ275Arg→Cys). [ABSTRACT FROM AUTHOR]