Congenital fibrinogen deficiency (CFD) is a rare, hereditary bleeding disorder. CFD may correspond to a quantitative deficiency of fibrinogen, which is referred to as afibrinogenemia or hypofibrinogenemia, or the production of dysfunctional fibrinogen, warranting the diagnosis of dysfibrinogenemia. Patients suffering from afibrinogenemia, hypofibrinogenemia, or certain types of dysfibrinogenemia present a hemorrhagic diathesis. On the other hand, dysfibrinogenemia may also be associated with thrombophilia.
In 85% of all cases, congenital afibrinogenemia manifests in umbilical cord bleeding. Otherwise, the child's propensity to bleed is observed in the neonatal period. While mucosal hemorrhages resulting in epistaxis or bleeding gums are frequently reported, blood loss from the gastrointestinal tract or urogenital system is rare . Muscle hematomas and hemarthrosis are regularly observed  , but subcutaneous bleedings and bruises, which are clinical hallmarks of other types of hemophilia, are less common in CFD and affect <50% of all patients . Although unusual, patients with afibrinogenemia are permanently at risk of life-threatening hemorrhages of the central nervous system . Females in fertile age may suffer from menorrhagia or menometrorrhagia, and they may have major difficulties to carry to term. Abortion within the first trimester of pregnancy is commonly described, regardless of the genotype of the unborn child  .
In general, the severity of CFD depends on the concentration of functional fibrinogen, so that afibrinogenemia is associated with more severe bleeding events than hypofibrinogenemia . Indeed, patients with hypofibrinogenemia tend to remain asymptomatic until trauma occurs  . Nevertheless, the presentation of quantitative CFD may vary, even among those individuals with the same genotype. Hypofibrinogenemia may interfere with fertility, prevent women from carrying to term, and has even been related to liver disease .
The clinical presentation of dysfibrinogenemia is heterogeneous and ranges from moderate or mild hemophilia to asymptomatic to a tendency to thrombosis . With regard to the latter, deep vein thrombosis, thrombophlebitis, and pulmonary embolism are most frequently reported . Paradoxically, both arterial and venous thrombotic complications have also occasionally been described in patients with afibrinogenemia   .
headache, hemiparesis, dysarthria Recurrent PE F 22 years Cryo: Resume Cryo LMWH day 21 twice daily for 3 months for PE Resume LMWH FC 20 g per weekfor 2.5 weeks, off 2 weeks 18 g per weekfor 2 weeks 10 g per week for 3 months 5 g per week for 2 weeks [onlinelibrary.wiley.com]
seizure, hydrocephalus Developmental delay but improving None Toledano, 2008  Afib Injection site hematomas M 2 days FC 300 mg kg 1 160 mg kg 1 42 mg dL 1 at 33.5 h 100 mg dL 1 at 48 h trough Resolved Hypocalcemia (3.58 mg dL 1) possibly related [onlinelibrary.wiley.com]
The patient's propensity to bleed, which is reflected in anamnestic data and clinical observations, warrants the diagnosis of hemophilia. Occurrence at birth or very early in life raises suspicion as to a hereditary disorder, but neither allows for a reliable diagnosis nor for the differentiation of bleeding disorders. Coagulation studies generally serve as the first step towards a clarification of that issue. In this context, platelet count, fibrinogen levels, activated partial thromboplastin time (APTT), prothrombin time (PT), and thrombin time (TT) should be assessed. In case of quantitative CFD, these studies reveal reduced concentrations of fibrinogen and the prolongation of all bleeding times, which rely on the formation of fibrin as their endpoint . Antigen levels may be within reference ranges in patients with dysfibrinogenemia, but bleeding times are also prolonged. Functional assays have to be carried out to demonstrate a qualitative deficiency of fibrinogen, and they should yield a low activity-to-antigen ratio .
Despite demographic data indicating a hereditary disease, mixing studies should be carried out to rule out the presence of an inhibitor. In case of CDF, mixing of the patient's plasma with normal plasma will correct abnormal bleeding times. Finally, the diagnosis of CFD may be confirmed by the identification of the underlying mutation. Molecular genetic studies are highly recommended to associate dysfibrinogenemia with a particular phenotype .
On-demand treatment is indicated in most cases of CFD. However, patients suffering from severe hemophilia and those who experienced life-threatening hemorrhages may benefit from regular administrations of fibrinogen. Weekly or biweekly applications are generally recommended to this end and aim at fibrinogen levels of 0.5-1.0 g/l. In any case, the advantages of prophylactic applications of fibrinogen should be carefully weighed against the threat of thrombosis and thromboembolism . This applies to surgical patients receiving fibrinogen replacement therapy until complete healing and women requiring prolonged treatment during pregnancy. In pregnant women, target plasma levels of fibrinogen are as described above, but higher concentrations should be aimed for during delivery. Ideally, plasma levels are raised to 1.5 g/l then   .
Symptomatic therapy typically consists in the administration of fibrinogen concentrates, cryoprecipitates, or fresh frozen plasma . It may be complemented by the application of antifibrinolytics or, for local hemostasis, fibrin glue. Estrogen-progestogen preparations are helpful to reduce menstrual blood loss in women suffering from menorrhagia  .
Thrombotic episodes often require the concurrent use of fibrinogen and anticoagulants like low-molecular-weight heparin, regardless of the underlying type of CFD . No recommendations have been published regarding possible prophylaxis of thrombosis and thromboembolism in patients with prothrombotic dysfibrinogenemia .
Umbilical cord bleeding due to afibrinogenemia may be lethal, and significant morbidity and mortality are associated with the thrombotic complications of afibrinogenemia and dysfibrinogenemia . With regards to quantitative CFD and dysfibrinogenemia with a hemorrhagic diathesis, relative protection from major bleeding events is to be expected if plasma fibrinogen concentrations are raised >0.7 g/l, and the risk of life-threatening hemorrhages reduces to negligible values if plasma levels of >1.0 g/l are achieved . Data regarding the long-term outcome of prothrombotic dysfibrinogenemia are not available .
Fibrinogen circulates as a heterohexamer consisting of each two Aα chains, Bβ chains, and γ chains. They are encoded by genes FGA, FGB, and FGG, which are all located on the long arm of chromosome 4. Pathogenic mutations resulting in CFD have been described in all three genes and amount to a total of about 200 molecular defects  . Afibrinogenemia and hypofibrinogenemia are generally related to null mutations, while missense mutations account for the majority of cases of dysfibrinogenemia . While afibrinogenemia and hypofibrinogenemia are assumed to be inherited in an autosomal recessive manner, most variants of dysfibrinogenemia follow an autosomal dominant mode of inheritance .
Doubts remain with regard to the presence of modifier genes that may explain phenotypic differences between individuals with the same genotype. Although no such modifiers could be identified to date, research interests in the molecular background of afibrinogenemia and dysfibrinogenemia haven't declined: Knowledge regarding genotype-phenotype correlations for these conditions may allow for the prediction of bleeding and thrombosis risks, it is hoped. For some types of fibrinogen, such correlations could be recognized: Fibrinogens Caracas V (FGA, c.1595C>G), Chapel Hill III/Dusart/Paris V (FGA, c.1717C>G), Christchurch II/Ijmuiden/London VIII/St-Germain III/Vicenza III (FGB, c.130C>T), New York I (FGB, deletion of exon 2), Nijmegen (FGB, c.220C>T), Naples (FGB, c.292G>A), and Melun (FGG, c.1169A>T) have been related to an increased risk of thrombosis .
The overall prevalence of afibrinogenemia has been estimated at 1 in 1,000,000 people, but it is assumed to be higher where consanguineous marriage is practiced. Hypofibrinogenemia and dysfibrinogenemia are more common but tend to remain undetected, so precise data regarding their epidemiology cannot be provided. About 500 cases of dysfibrinogenemia have been reported since the first description of the disease in 1958 . Males and females are affected equally by CFD .
The conversion of fibrinogen to cross-linked fibrin is the concluding step in the final common pathway of coagulation. It's a prerequisite for the formation of a stable thrombus and the culmination of what is referred to as secondary hemostasis. This is by far the most widely known function of fibrinogen, but it is not the only one. Fibrinogen is also involved in primary hemostasis, due to its ability to form bridges between activated thrombocytes. This way, fibrinogen facilitates the formation of a primary platelet plug . The complete absence of fibrinogen thus causes severe hemophilia by impeding the aggregation of platelets and by interrupting the coagulation cascade, regardless of its intrinsic or extrinsic activation.
Different mechanisms may underly the prothrombotic activity of abnormal fibrinogen. Under physiological conditions, fibrin limits by binding thrombin, its major activator, in a sort of negative-feedback loop. If this regulatory mechanism doesn't work, patients may become prone to thrombosis. This is commonly observed in certain types of dysfibrinogenemia, but, surprisingly, has also been postulated as a possible cause of thrombotic complications in quantitative CFD . Besides dysfunctional feedback mechanisms, the risk of thrombotic complications may be increased by abnormal fibrinogen impairing fibrinolysis .
Affected families may benefit from genetic counseling. The prenatal diagnosis of CFD is feasible and should be established if the family harbors a pathogenic mutation causing afibrinogenemia . Hypofibrinogenemia and dysfibrinogenemia are unlikely to interfere with prenatal development so that the corresponding studies can be postponed until after birth.
Prophylaxis of hemorrhages should be considered in all cases of afibrinogenemia and may be offered from birth . Due to the long half-life of fibrinogen, weekly or biweekly applications of fibrinogen concentrates suffice to maintain plasma levels between 0.5 and 1.0 g/l. Further increases in the concentration of fibrinogen are associated with high risks of thrombotic complications and should be avoided.
CFD is a general term referring to any quantitative or qualitative deficiency of fibrinogen, the most abundant clotting factor in the human circulation. Three major types of CFD should be distinguished :
- Afibrinogenemia, a complete lack of fibrinogen
- Hypofibrinogenemia, associated with plasma levels of fibrinogen <1.5 g/l
- Dysfibrinogenemia, where abnormal fibrinogen is circulating that may hinder or favor the formation of blood clots
In literature, afibrinogenemia and hypofibrinogenemia, both variants of quantitative CFD, may also be referred to as CFD type 1, whereas CFD type 2 stands for qualitative deficiencies of fibrinogen . Notwithstanding the utility of these classification systems, the genetic and clinical aspects of CFD are more complex. This particularly applies to dysfibrinogenemia, since the abnormal structure of fibrinogen may interfere with the formation of thrombi or promote blood clotting. Thus, affected individuals may present with a hemorrhagic diathesis or a tendency to thrombosis.
This article aims at summarizing the features of all types of CFD, but the interested reader is strongly encouraged to revise the specific contents on this platform that treat with congenital afibrinogenemia, congenital hypofibrinogenemia, and hereditary dysfibrinogenemia.
Hereditary fibrinogen Aα chain amyloidosis will not be discussed in this article, but excellent literature on this topic is available elsewhere  .
Congenital fibrinogen deficiency (CFD) is a rare, hereditary bleeding disorder. Distinct mutations of the genes encoding for fibrinogen may interrupt the synthesis of this clotting factor o may result in the production of dysfunctional fibrinogen. Accordingly, afibrinogenemia (no fibrinogen at all), hypofibrinogenemia (reduced amounts of functional fibrinogen), and dysfibrinogenemia (formation of abnormal fibrinogen) are distinguished. But how does fibrinogen affect the balance between procoagulant and anticoagulant reactions?
Under physiological conditions, fibrinogen is converted to fibrin in the final step of the coagulation cascade. Cross-linked fibrin constitutes the matrix of stable blood clots. Thus, in the absence of fibrinogen, durable thrombi cannot be formed, and the patient becomes prone to hemorrhages. This condition is present at birth, and severe cases manifest in umbilical cord bleeding, mucosal hemorrhages, hematoma formation, or bleeding into joint spaces within the neonatal period. Patients with mild to moderate CFD tend to remain asymptomatic until they sustain traumatic injuries, or, with regard to women, until they reach the fertile age. Female CFD patients often describe prolonged, heavy menstrual flows, and they may suffer recurrent losses of pregnancy.
Somewhat surprisingly, certain types of CFD manifest in an increased risk of thrombosis and thromboembolism. This may happen if abnormal fibrinogen is produced that favors the formation of blood clots.
Treatment of hemorrhagic CFD mainly consists in replacing fibrinogen. However, this type of therapy bears the risk of an overcompensation, thereby predisposing the patient to thrombotic disease. Thrombosis, in turn, is treated with anticoagulants that counteract fibrinogen. To maintain the delicate equilibrium between both extremes of the coagulation system, each therapy needs to be adjusted to the patient's individual needs. In cases of mild or moderate CFD, it is best maintained by the body itself, and treatment isn't required unless the patient becomes symptomatic, pregnant, or is about to undergo surgery. Permanent therapy is recommended in case of severe CFD to prevent life-threatening vascular accidents.
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