Familial thrombophilia associated with fibrinogen Paris V: Dusart syndrome

Tarumi, Takashi; Martincic, Danko; Thomas, A.; Janco, Robert L.; Hudson, Mary; Baxter, Patrícia; Gailani, David

doi:10.1182/blood.v96.3.1191.015k47_1191_1193

Cited by 11 publications

(12 citation statements)

References 15 publications

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“…In vitro assays demonstrate that this mutation results in the formation of clots with thin fibres, increased branching, decreased porosity and increased resistance to lysis compared with normal clots [8]. The association of this mutation with thrombosis in unrelated kindred (Dusart, Chapel Hill III, Paris V) [9] provides strong circumstantial evidence for the role of this mutation and its functional consequences on clot structure and stability in the observed thrombotic events.…”

Section: Contributions Of Plasma Proteins To Fibrin Formation Structmentioning

confidence: 93%

Plasma and cellular contributions to fibrin network formation, structure and stability

Wolberg

2010

Haemophilia

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Growing evidence suggests that fibrin network structure and stability are important determinants of haemostasis and thrombosis, with alterations in fibrin structure implicated as a causative mechanism in various haemostatic and thrombotic disorders. In haemophilia, for example, deficiency of factor VIII or IX reduces the rate and peak of thrombin generation and produces coarse fibrin clots that show increased susceptibility to fibrinolysis. More recently, studies have shown significant effects of cellular activity and integrin composition on fibrin network and stability. Platelets support the formation of a dense, stable fibrin network via interactions between the alphaIIbbeta3 integrin and the fibrin network, whereas tissue factor-bearing cells regulate fibrin structure and stability predominantly via procoagulant activity. Highly procoagulant extravascular cells (e.g. fibroblasts and smooth muscle cells) support the formation of dense fibrin networks that resist fibrinolysis, whereas unstimulated intravascular cells (e.g. endothelial cells) produce coarser networks that are susceptible to fibrinolysis. Moreover, cellular contributions produce heterogeneous clots in which fibrin network density and stability decrease with increasing distance from the cell surface. Together, these findings suggest that specific plasma and cellular mechanisms link thrombin generation, clot stability and haemostatic or thrombotic outcome. Understanding these mechanisms may provide new therapeutic targets in the management of bleeding and thrombotic disorders.

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Section: Contributions Of Plasma Proteins To Fibrin Formation Structmentioning

confidence: 93%

Plasma and cellular contributions to fibrin network formation, structure and stability

Wolberg

2010

Haemophilia

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“…4 In case of thrombosis, recommendations for general population are valuable, although patients with fibrinogen mutations associated with an increased susceptibility to thrombosis (mentioned earlier) should be treated with long-term anticoagulation. 90,91 Most patients receive vitamin K antagonists (despite the fact that the international normalized ratio is not an appropriate indicator in case of a prolonged baseline PT) or low-weight-molecular heparin while a few have been successfully treated with new oral anticoagulants. 92 It is important to note that patients still asymptomatic at the time of diagnosis may develop symptoms during the natural course of the disease.…”

Section: Management Of Dysfibrinogenemia and Hypodysfibrinogenemiamentioning

confidence: 99%

Clinical Features and Management of Congenital Fibrinogen Deficiencies

Casini

Moerloose

Neerman-Arbez

2016

Semin Thromb Hemost

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Congenital fibrinogen disorders are rare diseases affecting either the quantity (afibrinogenemia and hypofibrinogenemia) or the quality (dysfibrinogenemia) or both (hypodysfibrinogenemia) of plasmatic fibrinogen. Afibrinogenemia is often diagnosed at birth following prolonged umbilical cord bleeding and is characterized by spontaneous bleeding in all tissues, while hypofibrinogenemic patients are more often asymptomatic. Spontaneous spleen ruptures, painful bone cysts, cardiovascular events, and intrahepatic inclusions can complicate the clinical course of patients with quantitative fibrinogen disorders. Clinical manifestations of dysfibrinogenemia are very heterogeneous, from absence of symptoms to major bleeding or thrombosis, chronic thromboembolic pulmonary hypertension, and renal amyloidosis. Hypodysfibrinogenemic patients can suffer from both major bleeding and recurrent thrombosis. Pregnancy of women with congenital fibrinogen disorders is a high-risk situation. Owing to the absence of controlled randomized studies, clinical management is mainly based on expert consensus. For the treatment and/or the prevention of bleeding, plasma-derived fibrinogen concentrates are the optimal choice. Treatment of thrombosis may be challenging. More specifically, management strategies should be tailored to each patient, taking the personal and familial history of bleeding and thrombosis, the genotype, and the specific clinical situation into account.

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“…Variants associated with an AαArg554Cys mutation have been reported in several unrelated families, in each case in association with thrombophilia, and no evidence of a bleeding disorder [67–69]. Both the Fibrinogen Dusart [67] and Chapel Hill III variants with this mutation [68] have been shown to co‐segregate with recurrent severe thromboembolism and pulmonary embolism.…”

Section: Clinical Features Of Dysfibrinogenaemiamentioning

confidence: 99%

Diagnosis, clinical features and molecular assessment of the dysfibrinogenaemias

Hill

Dolan

2008

Haemophilia

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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 (AalphaArg16 and gammaArg275). 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.

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Familial thrombophilia associated with fibrinogen Paris V: Dusart syndrome

Cited by 11 publications

References 15 publications

Plasma and cellular contributions to fibrin network formation, structure and stability

Plasma and cellular contributions to fibrin network formation, structure and stability

Clinical Features and Management of Congenital Fibrinogen Deficiencies

Diagnosis, clinical features and molecular assessment of the dysfibrinogenaemias

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