Dusart Syndrome in a Scandinavian family characterized by arterial and venous thrombosis at young age

Ramanathan, Ramshanker; Gram, Jørgen Brodersen; Feddersen, Søren; Nybo, Mads; Larsen, Anette Enemark; Sidelmann, Johannes Jakobsen

doi:10.3109/00365513.2013.826818

Cited by 11 publications

(11 citation statements)

References 15 publications

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“…However, as previously discussed, thrombophilia‐associated mutations increase the risk of venous and arterial thrombosis, often at a young age. Among the five distinct families affected by Dusart syndrome published to date, all had an impressive history of thrombosis, which was sometimes fatal . The incomplete penetrance of the thrombotic phenotype in some families affected with congenital dysfibrinogenemia, even among families sharing the same genotype, is highly suggestive of other genetic or environmental confounders being present .…”

Section: Clinical Features Of Dysfibrinogenemiamentioning

confidence: 99%

Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management

Casini

Neerman-Arbez

Ariëns

et al. 2015

Journal of Thrombosis and Haemostasis

119

135

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Summary Congenital dysfibrinogenemia is a qualitative congenital fibrinogen disorder characterized by normal antigen levels of a dysfunctional fibrinogen. The diagnosis is usually based on discrepancies between fibrinogen activity and antigen levels, but could require more specialized techniques for the assessment of fibrinogen function, owing to some limitations in routine assays. Molecular abnormalities, which are frequently heterozygous missense mutations localized in exon 2 of FGA and exon 8 of FGG, lead to defects in one or more phases of fibrinogen to fibrin conversion, fibrin network formation, and other important functions of fibrinogen. The clinical phenotype is highly heterogeneous, from no manifestations to bleeding and/or thrombotic events. Asymptomatic propositi and relatives with the predisposing genotype are at risk of developing adverse outcomes during the natural course of the disease. Correlations between genotype and phenotype have not yet been clearly established, with the exception of some abnormal fibrinogens that severely increase the risk of thrombosis. Functional analysis of polymerization and fibrinolysis, structural studies of the fibrin network and the viscoelastic properties of fibrin clot could help to predict the phenotype of congenital dysfibrinogenemia, but have not yet been evaluated in detail. The management is essentially based on personal and family history; however, even individuals who are still asymptomatic and without a family history should be carefully assessed and monitored. Particular situations, such as pregnancy, delivery, and surgery, require a multidisciplinary approach.

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Section: Clinical Features Of Dysfibrinogenemiamentioning

confidence: 99%

Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management

Casini

Neerman-Arbez

Ariëns

et al. 2015

Journal of Thrombosis and Haemostasis

119

135

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“…Whether it is the presence of cysteine at Aα 554 or the albumin molecules bound to the fibrinogen at this position that causes the defective function, cannot be deduced. Since the initial discovery, five further cases of distinct families affected by Dusart syndrome have been reported; all had an impressive history of thrombosis, which was sometimes fatal [64][65][66][67][68]. These six cases lend support to the concept of thromboembolic diseases due to defective fibrin lysis arising from anomalies in the αC domain of fibrinogen.…”

mentioning

confidence: 93%

“…Among these cases, four presented thrombotic disorders, another presented mild bleeding (fibrinogen Sumperk II), four of them were asymptomatic (Caracas II, Grand Lyon III, Sumida, and Christchurch IV), and for the six others the clinical syndrome was unknown. Mutation of an αC domain amino acid to cysteine is associated with thrombotic disorders in the six fibrinogens Dusart (Aα R554C) of several origins, as well as in Caracas V (Aα K532C) and Bordeaux (Aα R439C); the unpaired cysteine, not being able to form a disulfide bridge, binds covalently to free ‐SH groups of albumin, resulting in formation of abnormally thin fibrin fibers that are resistant to plasmin degradation . Fibrinogen Sumperk II (double heterozygous mutation Aα G13E and S314C) presented only mild bleeding .…”

Section: Introductionmentioning

confidence: 99%

Fibrinogen αC domain: Its importance in physiopathology

Mirshahi

Varin

et al. 2019

Research and Practice in Thrombosis and Haemostasis

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Essentials The C‐terminal domain of the fibrinogen α chain (αC domain) is implicated in different severe diseases via clotting abnormalities or amyloid deposits. Certain anomalies of the fibrinogen molecule lead to amyloid deposits in the kidney, inducing renal insufficiency. In contrast, in Alzheimer's disease, fibrinogen is normal, but due to an inflammatory process, fibrinogen crosses into the brain and interacts with Aβ, leading to formation of pathological deposits. Abstract Fibrinogen, involved in coagulation, is a soluble protein composed of two sets of disulfide‐bridged Aα, Bβ, and γ‐chains. In this review, we present the clinical implications of the αC domain of the molecule in Alzheimer's disease, hereditary renal amyloidosis and a number of thrombotic and hemorrhagic disorders. In Alzheimer's disease, amyloid beta peptide (Aβ) is increased and binds to the αC domain of normal fibrinogen, triggering increased fibrin(ogen) deposition in patients’ brain parenchyma. In hereditary renal amyloidosis, fibrinogen is abnormal, with mutations located in the fibrinogen αC domain. The mutant αC domain derived from fibrinogen degradation folds incorrectly so that, in time, aggregates form, leading to amyloid deposits in the kidneys. In these patients, no thrombotic tendency has been observed. Abnormal fibrinogens with either a point mutation in the αC domain or a frameshift mutation resulting in absence of a part of the αC domain are often associated with either thrombotic events or bleeding. Mutation of an amino acid into cysteine (as in fibrinogens Dusart and Caracas V) or a frameshift mutation yielding an unpaired cysteine in the αC domain is often responsible for thrombotic events. Covalent binding of albumin to the unpaired cysteine via a disulphide bridge leads to decreased accessibility to the fibrinolytic enzymes, hence formation of poorly degradable fibrin clots, which explains the high incidence of thrombosis. In contrast, anomalies due to a frameshift mutation in the αC connector of the molecule, provoking deletion of a great part of the αC domain, are associated with bleeding.

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“…Here, a number of factors are involved. The velocity of fibrin formation, polymorphisms in the genes coding for fibrinogen and coagulation factor XIII (3,4), flow conditions, binding and function of fibrinolytic proteins and many other factors determine the structure and turnover of the fibrin clot (5)(6)(7). Alterations in fibrin structure can be related to thrombosis or bleeding (4,7).…”

Section: Introductionmentioning

confidence: 99%

“…The velocity of fibrin formation, polymorphisms in the genes coding for fibrinogen and coagulation factor XIII (3,4), flow conditions, binding and function of fibrinolytic proteins and many other factors determine the structure and turnover of the fibrin clot (5)(6)(7). Alterations in fibrin structure can be related to thrombosis or bleeding (4,7). Clinical studies have demonstrated that plasma clots from patients suffering from VTE are dense and composed of thin fibres with reduced fibrinolytic susceptibility (8,9) and fibrin structure measures are suggested as important biomarkers for thrombosis, providing assessment of the clotting capability of plasma and subsequently the fibrinolytic susceptibility of the fibrin formed (7).…”

Section: Introductionmentioning

confidence: 99%

Fibrin clot structure - pro-fibrinolytic effect of oral contraceptives in apparently healthy women

et al. 2017

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Fibrin metabolism is influenced by many factors. The velocity of fibrin formation, genetic polymorphisms, fibrinolytic features and the structure of the fibrin clot are determinants of fibrin turnover. Oral contraceptives (OCs) have significant impact on the haemostatic system, by increasing the concentration of coagulation factors, plasminogen and tissue plasminogen activator activity, and decreasing the concentration of haemostatic inhibitors. The present study addresses the influence of OCs on fibrin structure and fibrin metabolism. The study included 70 women treated with seven different OC-formulations. Blood was collected at baseline and after six months of OCs. The plasma concentration of fibrinogen, thrombin-antithrombin complex (TAT), plasminogen, plasmin-antiplasmin complex (PAP), D-Dimer and thrombin generation measures were determined. Fibrin structure measures and fibrin clot lysis not affected by the plasma concentration of plasminogen activators and inhibitors were determined. OCs increased the concentration of fibrinogen, TAT, plasminogen, PAP and D-dimer significantly and affected measures of thrombin generation (p<0.001). The maximal optical density of fibrin (p<0.001), the fibrin fibre density (p=0.03), fibrin fibre diameter (p=0.003), fibrin mass-length ratio (p<0.001) and lysis per hour (p<0.001) increased significantly upon OC-treatment. Lysis per hour was not correlated to the concentration of plasminogen. We conclude that the effect of OCs on the coagulation system is balanced by alterations in fibrin structure, facilitating clot lysis and contributing to the fibrinolytic susceptibility already present in women treated with OC. These alterations may counterbalance the OC-induced increased thrombin generation and reduced coagulation inhibitory potential, contributing to maintenance of the haemostatic balance in women receiving OCs.

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Dusart Syndrome in a Scandinavian family characterized by arterial and venous thrombosis at young age

Abstract: Excellent concordance was observed between the screening and confirmatory tests, fibrin structure analysis and fibrinogen gene analysis. Fibrin structure analysis should be considered in the laboratory algorithm for diagnosis of dysfibrinogenemia.

Cited by 11 publications

References 15 publications

Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management

Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management

Fibrinogen αC domain: Its importance in physiopathology

Fibrin clot structure - pro-fibrinolytic effect of oral contraceptives in apparently healthy women

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