Clinical Consequences and Molecular Bases of Low Fibrinogen Levels

Neerman-Arbez, Marguerite; Casini, Alessandro

doi:10.3390/ijms19010192

Cited by 49 publications

(52 citation statements)

References 92 publications

(97 reference statements)

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confidence: 99%

Fibrinogen concentrates in hereditary fibrinogen disorders: Past, present and future

Casini

Moerloose²

2019

Haemophilia

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Hereditary fibrinogen disorders (HFD) are rare coagulation disorders resulting from mono-or bi-allelic mutations in fibrinogen genes. 1According to the levels of fibrinogen activity and antigen, HFD are classified into quantitative (afibrinogenemia and hypofibrinogenemia) or qualitative (dysfibrinogenemia and hypodysfibrinogenemia) disorders. 2 The spectrum of symptoms is broad and heterogeneous among patients with HFD, even if bleeding is the most common complication of all HFD sub-types. 3 The bleeding phenotype is mostly correlated to the fibrinogen level, 4 ranging from life-threatening haemorrhage to postsurgical bleeding. In afibrinogenemia, the majority of patients suffer from severe bleeding such as umbilical cord bleeds, muscle haematomas, haemarthroses and bleeding in the central nervous system. 5 Paradoxically, thrombotic events can occur in patients with afibrinogenemia, even in the absence of fibrinogen administration. 6 In hypofibrinogenemia, spontaneous bleeding is less frequent and complications are mainly associated with trauma or surgery. 7 In dysfibrinogenemia, the cumulative incidence of major bleeding has been estimated to be about 19% at 50 years of age. 8 However, some dysfibrinogen variants are strongly associated with an increased risk of thrombosis. 9 In all types of HFD, surgery and pregnancy are high-risk bleeding situations.As for most coagulation factor deficiencies, in HFD, the bleeding prevention and management is based on replacement of the lacking protein. Three sources of fibrinogen are currently available: fresh frozen plasma, cryoprecipitate and lyophilized fibrinogen concentrate. 10 The latter is the best option, although still not widely available. It confers several advantages compared to fresh frozen plasma and cryoprecipitate: (a) it represents a safer therapeutic option due AbstractHereditary fibrinogen disorders (HFD) are rare coagulation disorders. Even if the spectrum of symptoms is broad depending on the sub-type, bleeding is the most common complication. Of the available sources of fibrinogen replacement, fibrinogen concentrate provides a safer and more effective option to treat and prevent bleeding.Recent clinical trials on established and new fibrinogen concentrates have increased our knowledge on the clinical pharmacology of these products, pointing out possible age and weight differences for dose adjustment. The efficacy of fibrinogen infusions has been demonstrated, especially for the management of acute bleeding with an excellent response based on investigator rating. The target fibrinogen levels in the setting of both minor and major surgeries have been better specified. The safety has been confirmed with a low number of adverse events but there still remains concern over possible thrombotic risks. Pharmacological, clinical aspects and future perspectives on the utilization of fibrinogen concentrates in the treatment and prevention of bleeding in patients with HFD are reviewed.

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Fibrinogen concentrates in hereditary fibrinogen disorders: Past, present and future

Casini

Moerloose²

2019

Haemophilia

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“…In general, the bleeding phenotype in hypofibrinogenemic patients depends on the fibrinogen plasma value. Above 1 g/L, most patients are completely asymptomatic [38].…”

Section: Clinical Featuresmentioning

confidence: 99%

Genetic Variants in the FGB and FGG Genes Mapping in the Beta and Gamma Nodules of the Fibrinogen Molecule in Congenital Quantitative Fibrinogen Disorders Associated with a Thrombotic Phenotype

Šimurda

Brunclíková

Asselta

et al. 2020

IJMS

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Fibrinogen is a hexameric plasmatic glycoprotein composed of pairs of three chains (Aα, Bβ, and γ), which play an essential role in hemostasis. Conversion of fibrinogen to insoluble polymer fibrin gives structural stability, strength, and adhesive surfaces for growing blood clots. Equally important, the exposure of its non-substrate thrombin-binding sites after fibrin clot formation promotes antithrombotic properties. Fibrinogen and fibrin have a major role in multiple biological processes in addition to hemostasis and thrombosis, i.e., fibrinolysis (during which the fibrin clot is broken down), matrix physiology (by interacting with factor XIII, plasminogen, vitronectin, and fibronectin), wound healing, inflammation, infection, cell interaction, angiogenesis, tumour growth, and metastasis. Congenital fibrinogen deficiencies are rare bleeding disorders, characterized by extensive genetic heterogeneity in all the three genes: FGA, FGB, and FGG (enconding the Aα, Bβ, and γ chain, respectively). Depending on the type and site of mutations, congenital defects of fibrinogen can result in variable clinical manifestations, which range from asymptomatic conditions to the life-threatening bleeds or even thromboembolic events. In this manuscript, we will briefly review the main pathogenic mechanisms and risk factors leading to thrombosis, and we will specifically focus on molecular mechanisms associated with mutations in the C-terminal end of the beta and gamma chains, which are often responsible for cases of congenital afibrinogenemia and hypofibrinogenemia associated with thrombotic manifestations.

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“…3 Paradoxically, thrombosis in both venous and arterial sites are also a typical complication of congenital FIB disorders, in addition to bleeding symptoms. 4,5 In their study, the authors identified 2 novel FIB mutations in 2 Slovak families with quantitative FIB disorders and concluded the development of thrombotic complications was spontaneous since the patient and his son did not receive substitution therapy with the FIB concentrate in the period of their recurrent thromboses manifestation. 5 Due to their specific physiological characteristics, female patients tend to have congenital hypofibrinogenemia/afibrinogenemia, such as spontaneous recurrent abortion, menorrhagia, infertility, antepartum and postpartum hemorrhage, and so on.…”

Section: Introductionmentioning

confidence: 99%

Women With Congenital Hypofibrinogenemia/Afibrinogenemia: From Birth to Death

Zhang

Zuo

Teng

2020

Clin Appl Thromb Hemost

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Congenital fibrinogen disorders are a group of most frequent rare coagulation disorder, characterized by deficiency and/or defects in the fibrinogen molecule. Quantitative disorders include hypofibrinogenemia and afibrinogenemia. Due to their specific physiological characteristics, female patients tend to have congenital hypofibrinogenemia/afibrinogenemia, such as spontaneous recurrent abortion, menorrhagia, infertility, antepartum and postpartum hemorrhage, and so on. Current studies of congenital hypofibrinogenemia/afibrinogenemia mainly focus on different types of fibrinogen mutations, etiology/pathogenesis, and some rare case reports of the diseases. So far, there is no study available to systematically review the specific features of female patients with congenital bleeding disorders. This review aims to deal with hematological, gynecologic and obstetric issues, and relevant clinical management of congenital hypofibrinogenemia/afibrinogenemia at different life stages of female patients. We believe this review provides valuable reference for clinicians in the field of hematology, obstetrics, as well as gynecology.

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Clinical Consequences and Molecular Bases of Low Fibrinogen Levels

Cited by 49 publications

References 92 publications

Fibrinogen concentrates in hereditary fibrinogen disorders: Past, present and future

Fibrinogen concentrates in hereditary fibrinogen disorders: Past, present and future

Genetic Variants in the FGB and FGG Genes Mapping in the Beta and Gamma Nodules of the Fibrinogen Molecule in Congenital Quantitative Fibrinogen Disorders Associated with a Thrombotic Phenotype

Women With Congenital Hypofibrinogenemia/Afibrinogenemia: From Birth to Death

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