Can Mutations Identified in Congenital Fibrinogen Disorders Explain the Clinical Manifestations?

Neerman-Arbez M, Tirefort Y, Moerloose P.  Can Mutations Identified in Congenital Fibrinogen Disorders Explain the Clinical Manifestations?  Journal of Coagulation Disorders, July 2010; 2(2):  71-79

REVIEW ARTICLE

Marguerite Neerman-Arbez^1, Yordanka Tirefort^2,3 and Philippe de Moerloose^2,3

Affiliations: ¹Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland, ²Haemostasis Unit, University Hospital of Geneva, Geneva, Switzerland and ³Faculty of Medicine, University of Geneva, Geneva, Switzerland


ABSTRACT

Hereditary fibrinogen abnormalities can be classified in 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). Various types of mutations have been described in each type of congenital fibrinogen disorder. The primary aim of this review is to deal with the relationship between the genotype and the clinical phenotype. In afibrinogenemia, 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. The majority of afibrinogenemia patients have a bleeding diathesis, and no clear relationship exists between the various mutations and the clinical manifestations, especially for the cases with thrombotic complications. In certain hypofibrinogenemic cases, the mutant fibrinogen molecules are produced and retained in the rough endoplasmic reticulum of hepatocytes, causing hepatic disease. Hereditary dysfibrinogemia patients may be asymptomatic, or they may develop bleeding or thrombotic manifestations. In contrast to afibrinogenemia, in many cases the relationship between the genotype and the bleeding or thrombotic phenotype can be explained by the type of mutation. Moreover, some cases of dysfibrinogenemia are caused by mutations involving the C-terminus of the fibrinogen α-chain and are associated with kidney amyloidosis.

Keywords: coagulation, afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, bleeding, thrombosis

Correspondence: Marguerite Neerman-Arbez, Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, 1211 Geneva, Switzerland. Tel: +41 22 379 5655; Fax: +41 22 379 5706; e-mail: Marguerite.Neerman-Arbez@unige.ch