REVIEW ARTICLE Congenital structural and functional fibrinogen disorders: a primer for internists Anetta Undas1, Alessandro Casini2 1 Institute of Cardiology, Jagiellonian University Medical College, Kraków, Poland 2 Division of Angiology and Haemostasis, Faculty of Medicine, University Hospitals of Geneva, Geneva, Switzerland KEY WORDS ABSTRACT afibrinogenemia, Congenital qualitative and quantitative fibrinogen disorders represent heterogeneous rare abnormalities dysfibrinogenemia, caused by mutations in one of the 3 genes encoding individual fibrinogen polypeptide chains, located on fibrinogen, genetic chromosome 4q28. It is estimated that congenital fibrinogen disorder accounts for 8% of rare coagulation mutation 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 labora- tory findings in patients with inherited fibrinogen disorders including the risk of thromboembolism and management prior to invasive procedures. Fibrinogen structure Fibrinogen is a 340 kDa pro­ their lateral aggregation, thick fibrin fibers are tein synthesized in the liver.1 Its normal con­ crosslinked in a reaction catalyzed by thrombin­ centration in blood plasma is in the range of ­activated factor XIII.1 Fibrin, together with plate­ 1.5 to 4.0 g/l. The half­‑life of circulating fibrin­ lets and red blood cells, provide structural in­ ogen is about 3 to 4 days. The fibrinogen mole­ tegrity to the hemostatic plug under physiolog­ cule is a hexamer, made up of 3 pairs of homolo­ ical conditions and to the growing thrombus in Correspondence to: Anetta Undas, MD, PhD, gous Aα, Bβ, and γ polypeptide chains connect­ thrombotic disorders. Institute of Cardiology, Jagiellonian ed by disulfide bridges that form a central E re­ The final fibrin clot has a highly heterogeneous University Medical College, gion composed by the N­‑terminal portions of structure, determined by genetic and, to a much ul. Prądnicka 80, 31-202 Kraków, all 6 chains and 2 terminal D regions containing larger extent, environmental factors, which re­ Poland, phone: +48 12 614 30 04, email: mmundas@cyf­‑kr.edu.pl the C­‑terminal fragments of the Bβ and γ chains.1 sults in a large interindividual variability of clot Received: December 3, 2019. The C­‑terminal fragments of the Aα chains form architecture, thickness of fibers, and their branch­ Accepted: December 4, 2019. 2 Published online: globular structures located near the central E re­ ing. Lower fibrinogen concentrations are known 1 December 23, 2019. gion. After cleavage of fibrinopeptides A and to result in the formation of thicker fibrin fibers Pol Arch Intern Med. 2019; B mediated by thrombin, fibrin monomers are creating looser meshwork which is more suscep­ 129 (12): 913-920 formed, which polymerize through the interac­ tible to fibrinolysis and mechanical fragmenta­ doi:10.20452/pamw.15082 Copyright by Medycyna Praktyczna, tion of the D region with the E regions of subse­ tion, eventually leading to an increased risk of Kraków 2019 quent monomers to form protofibrils and through bleeding. On the other hand, irregular abnormal REVIEW ARTICLE Fibrinogen disorders 913 structure of fibrin, even at lower fibrinogen con­ FGA and other affecting Arg301 in exon 8 of FGG. centrations, could paradoxically increase throm­ The mechanisms underlying clinical manifesta­ botic risk by impairing fibrin degradation by plas­ tions observed in qualitative congenital fibrin­ min or facilitating clot fragmentation.2,3 ogen disorders involve abnormal formation of a fibrin clot associated with disturbed release Congenital fibrinogen disorders Genetic background of fibrinopeptides, delayed fibrin polymeriza­ Congenital disorders of fibrinogen is a hetero­ tion or defective cross­‑linking.4,8,9 A single muta­ geneous group of rare abnormalities most of­ tion altering a fibrinogen chain may result in sig­ ten caused by mutations in one of the 3 separate nificant changes in the tertiary and quaternary genes encoding individual polypeptide chains, structure of the protein causing all of the above located on chromosome 4q28 in a cluster of disorders.4,8,9 To date, about 30 different muta­ about 50 kbp (FGA, FGB, and FGG, respectively, tions causing hypodysfibrinogenemia have been for chains Aα, Bβ, and γ, but the order of genes identified (10 in the FGA gene, 5 in the FGB gene, from centromere to telomer is as follows: FGB, and 15 in the FGG gene). Most of these fibrinogen FGA, and FGG).4 So far, over 450 mutations in mutations were inherited in an autosomal dom­ FGA, FGB, and FGG genes have been registered, of inant manner.10 Combined heterozygosity was which over 250 are symptomatic (www.geht.org). found in additional 7 patients with hypodysfi­ The most common mutations (50%–80%) are brinogenemia.10 In patients with hypodysfibrin­ single­‑amino acid missense mutations. Other ogenemia, the hypofibrinogenemic phenotype re­ defects responsible for fibrinogen abnormalities sults from mutation affecting synthesis, assembly, include nonsense mutations, read frame changes and secretion or leading to an increased fibrino­ through small deletions or insertions in the cod­ gen clearance, while the dysfibrinogenemic phe­ ing part of the gene (frameshift), splicing­‑site notype results from impaired fibrin polymeriza­ mutations, and large deletions.4 Less than 5% of tion and abnormal binding of calcium ions or tis­ cases are genetic variants located in the 3’ and sue plasminogen activator.10 5’ untranslated regions of the genes.5 Still, a few The first Polish case of dysfibrinogenemia,­ Fi patients with severe fibrinogen deficiency have brinogen Kraków associated with the Asn325Ile no identified genetic cause, and the use of next­ mutation in the fibrinogen γ chain and causing ­generation sequencing can help clarify genetic hypodysfibrinogenemia with thrombotic man­ background of these disorders. ifestation, was described in 2009.11 Genetically The causative mutations described so far re­ characterized fibrinogens described for the first sult in either qualitative or quantitative fibrino­ time in Polish patients are shown in TABLE 1 (for gen disorders.4 Quantitative disorders are tradi­ the whole report, see Wypasek et al12). tionally divided into afibrinogenemia (complete absence of fibrinogen) and hypofibrinogenemia Clinical manifestations In patients with afibrino­ (proportionally reduced functional fibrinogen genemia, umbilical stump bleeding in newborns and its antigen levels).4,6 Afibrinogenemia is in­ is the typical first manifestation of the disease, herited in an autosomal recessive manner, while observed in 85% of cases.13 Bleeding in afibrino­ hypofibrinogenemia, dysfibrinogemia, and hy­ genemia may also commonly occur as nosebleeds podysfibrinogenemia are autosomal dominant.4 and less frequently cutaneous bleeding, gastro­ Afibrinogenemia is due to homozygosity or com­ intestinal hemorrhage, and genitourinary bleed­ pound heterozygosity of a null mutation.4 It is es­ ing. Intracranial bleeding, often spontaneous, is timated that quantitative congenital fibrinogen the most common cause of death in patients with disorder accounts for 8% of rare coagulation fac­ afibrinogenemia.13 Intramuscular and hemarthro­ tor deficiencies.5 The prevalence of afibrinogen­ sis also occur in afibrinogenemia, usually less re­ emia is estimated to be 1/1 000 000 or more in currently and less damaging than in severe he­ some countries where marriage of close relatives mophilia, even though severe arthropathies have is common, for example, in Iran.4 As hypofibri­ also been reported in afibrinogenemia.5 Three ad­ nogenemias are mainly caused by heterozygosi­ ditional manifestations are considered specific ty for fibrinogen gene mutation, they are much for afibrinogenemia, namely spontaneous spleen more frequent than afibrinogenemia. rupture, impaired wound healing, and the forma­ Qualitative fibrinogen disorders include dys­ tion of painful bone cysts.14 Afibrinogenemia in fibrinogenemia (normal amount of dysfunction­ women is typically associated with spontaneous al fibrinogen) and hypodysfibrinogenemia (de­ miscarriages in the first trimester of pregnancy.13 creased amount of dysfunctional fibrinogen). Other pregnancy­‑related