Abstract
Congenital qualitative and quantitative fibrinogen disorders represent heterogeneous rare abnormalities caused by mutations in one of the 3 genes encoding individual fibrinogen polypeptide chains, located on chromosome 4q28. It is estimated that congenital fibrinogen disorder accounts for 8% of rare coagulation factor deficiencies. Most of congenital fibrinogen disorders are suspected in individuals with bleeding tendency or coincidentally discovered, for instance prior to surgery. Fibrinogen disorders could be also found in patients with thrombotic events, impaired wound healing, and recurrent spontaneous abortions. Afibrinogenemia manifests as mild to severe bleeding, while hypofibrinogenemia is often asymptomatic. Dysfibrinogenemia, a qualitative fibrinogen disorder, is associated with bleeding, thrombosis, or with no symptoms. Recent recommendations issued by the International Society on Thrombosis and Haemostasis in 2018 do not encourage routine evaluation of thrombin time or other coagulation tests in patients with suspected congenital fibrinogen disorders, highlighting the value of fibrinogen antigen measurement and genetic analysis, added to the key finding, that is, reduced fibrinogen concentration determined with a coagulometric assay. The current review summarizes practical issues in diagnostic workup and clinical management of patients with afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia from a perspective of internists who may encounter patients with reduced fibrinogen concentration in everyday practice. Despite the fact that hematologists are in front line for the management of patients with bleeding tendency, internists should be aware of the clinical and laboratory findings in patients with inherited fibrinogen disorders including the risk of thromboembolism and management prior to invasive procedures.
Highlights
Congenital fibrinogen disorders Genetic backgroundCongenital disorders of fibrinogen is a hetero geneous group of rare abnormalities most of ten caused by mutations in one of the 3 separate genes encoding individual polypeptide chains, located on chromosome 4q28 in a cluster of about 50 kbp (FGA, FGB, and FGG, respectively, for chains Aα, Bβ, and γ, but the order of genes from centromere to telomer is as follows: FGB, FGA, and FGG).[4]
Congenital qualitative and quantitative fibrinogen disorders represent heterogeneous rare abnormalities caused by mutations in one of the 3 genes encoding individual fibrinogen polypeptide chains, located on chromosome 4q28
The fibrinogen mole cule is a hexamer, made up of 3 pairs of homolo gous Aα, Bβ, and γ polypeptide chains connect ed by disulfide bridges that form a central E re gion composed by the N‐terminal portions of all 6 chains and 2 terminal D regions containing the C‐terminal fragments of the Bβ and γ chains.[1]
Summary
Congenital disorders of fibrinogen is a hetero geneous group of rare abnormalities most of ten caused by mutations in one of the 3 separate genes encoding individual polypeptide chains, located on chromosome 4q28 in a cluster of about 50 kbp (FGA, FGB, and FGG, respectively, for chains Aα, Bβ, and γ, but the order of genes from centromere to telomer is as follows: FGB, FGA, and FGG).[4]. The mechanisms underlying clinical manifesta tions observed in qualitative congenital fibrin ogen disorders involve abnormal formation of a fibrin clot associated with disturbed release of fibrinopeptides, delayed fibrin polymeriza tion or defective cross‐linking.[4,8,9] A single muta tion altering a fibrinogen chain may result in sig nificant changes in the tertiary and quaternary structure of the protein causing all of the above disorders.[4,8,9] To date, about 30 different muta tions causing hypodysfibrinogenemia have been identified (10 in the FGA gene, 5 in the FGB gene, and 15 in the FGG gene) Most of these fibrinogen mutations were inherited in an autosomal dom inant manner.[10] Combined heterozygosity was found in additional 7 patients with hypodysfi brinogenemia.[10] In patients with hypodysfibrin ogenemia, the hypofibrinogenemic phenotype re sults from mutation affecting synthesis, assembly, and secretion or leading to an increased fibrino gen clearance, while the dysfibrinogenemic phe notype results from impaired fibrin polymeriza tion and abnormal binding of calcium ions or tis sue plasminogen activator.[10]. Patients with afibrin ogenemia may have thromboembolic events as sociated with or without fibrinogen substitution
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