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R. Vilar et al.
orders varies from 1 in 106 persons in East Asians to 24.5 in 106 persons in non-Finnish Europeans.36 Subjects with moderate or mild hypofibrinogenemia are usually asymp- tomatic since their fibrinogen levels are sufficient to pre- vent bleeding and pregnancy failure.37 However, in the presence of another hemostatic abnormality or trauma, they may also bleed and suffer pregnancy loss or postpar- tum hemorrhage. In some cases, due to mutations in FGG, the mutant fibrinogen forms aggregates in the endoplas- mic reticulum of hepatocytes and can cause liver disease.19
Qualitative fibrinogen disorders are commonly associat- ed with heterozygous missense mutations in one of the fibrinogen genes and are more frequent than severe quan- titative disorders. Although the exact prevalence is not established, it is estimated to be 1 in 100 to 1,000 individ- uals (0.1-1.0%).36 Two mutation “hotspots” account for over 70% of the detected dysfibrinogenemia mutations. They are at the Arg35 codon in exon 2 of FGA, encoding a critical residue in the thrombin cleavage site of the Aα chain, and the Arg301 codon in exon 8 of FGG, encoding part of the γ chain “hole A” fibrin polymerization site.20 Other causative missense mutations are mainly located in the COOH-terminus of the Aα chain which, unlike the Bβ and γ chains, does not contain a large, highly conserved globular domain. Thus, missense mutations in this region do not have a severe impact on hexamer assembly and secretion but can produce a dysfunctional fibrinogen mol- ecule present in the patient’s circulation. Of note, almost all dysfibrinogenemic variants affect fibrin polymeriza- tion, which results in a variable tendency for bleeding. An updated list of dysfibrinogenemia variants and related phenotypes is available in a recent review38 and an open- access online database (http://site.geht.org/base-fibrinogene/).
Patients with dysfibrinogenemia are frequently asymp- tomatic but can suffer from bleeding and/or thromboem- bolic complications.39 Women are particularly at risk of adverse clinical outcomes, including miscarriages or post- partum thromboses.19 Symptoms are heterogeneous with a poor segregation of the clinical phenotype even among carrier relatives of the same causative mutation. Using integrative hemostatic models, taking into account the molecular anomaly, fibrin clot properties and family histo- ry, may improve assessment of a patient’s phenotype.
Acquired fibrinogen diseases are far more common than inherited ones. Acquired hypofibrinogenemia may result from different causes including disseminated intravascular coagulation, in which activation and consumption of coagulation factors depletes their plasma availability. Fibrin degradation products seen in disseminated intravas- cular coagulation further impair normal fibrinogen func- tion.40 Low fibrinogen levels due to disseminated intravas- cular coagulation are commonly observed in patients with acute promyelocytic leukemia.41 Patients with liver disease can also have low plasma fibrinogen due to impaired pro- duction. Hemodilution, massive hemorrhage or medica- tion affecting liver protein biosynthesis can also contribute to hypofibrinogenemia.42 Acquired dysfibrinogenemia results from a health condition e.g., liver disease affecting post-translational modifications of fibrinogen, notably sia- lylation. Autoantibodies interfering with the physiological functions of fibrinogen have also been reported.42 As reviewed previously,43 several studies have investigated the use of fibrinogen replacement in acquired coagu- lopathies. Although it is an important treatment option for acquired coagulopathic bleeding, more studies in different
clinical settings are necessary to optimize the dosage. In addition, hyperfibrinolysis contributes to the bleeding manifestations in these acquired coagulopathies, high- lighting the importance of a subtle balance between fibrin formation and fibrin degradation.44 Lysine analogues (e.g. tranexamic acid) have proven their efficacy in selected clinical situations, such as major trauma (CRASH-2 trial45) and postpartum hemorrhage (WOMAN trial46).
Cardiovascular disease
Thrombosis occurs in the major cardiovascular diseases (CVD): ischemic heart disease, stroke, and venous throm- boembolism.47 Arterial thrombosis is associated with the formation and rupture of an atherosclerotic plaque leading to accumulation of platelets, whereas venous thrombosis is linked to endothelial dysfunction and blood stasis which trigger the aggregation of fibrin and red blood cells.48
The involvement of elevated fibrinogen as a risk factor for CVD remains controversial. Early prospective studies found a clear relationship between plasma fibrinogen and CVD event risk49-51 and the most comprehensive analysis to date confirmed this.52 Data from 154,211 subjects with no known history of coronary heart disease or stroke, from 31 prospective studies, revealed associations between fibrinogen level, major ischemic cardiovascular events and nonvascular mortality. The hazard ratio for coronary heart disease and stroke was 1.8 per g/L increase in plasma fibrinogen. Similar conclusions were drawn from a study on the presence and severity of new-onset coronary atherosclerosis in the Han Chinese population.53 In 2,288 subjects referred for coronary angiography, plas- ma fibrinogen was positively associated with the presence and severity of coronary atherosclerosis, after adjustment for cardiovascular risk factors.
Biases in these evaluations may exist due to unmea- sured confounding factors and causality between plasma fibrinogen and CVD events cannot be demonstrated. The elevated fibrinogen levels measured may result from an inflammatory state caused by the underlying pathology, and therefore be a consequence of the illness itself. Nevertheless, further evidence reinforces the hypothesis that the fibrinogen level may directly influence CVD events or progression. Intravenous infusion of human fib- rinogen into mice, giving a 1.7-fold increase in plasma fib- rinogen, led to resistance to thrombolysis, increased thrombus fibrin content, quicker fibrin formation, greater fibrin network density and increased clot strength and sta- bility.54
The appeal of fibrinogen as a causal factor for CVD comes from its roles in both thrombosis and inflamma- tion.52,53 Higher levels of fibrinogen can promote CVD events through different pathways (Figure 1A), which, even if they result from a pre-existing inflammatory con- dition, may further contribute to a poorer clinical state. Fibrinogen may favor atherogenesis when converted to fibrin and its atherogenic degradation products, or trigger lipid deposition and local inflammation resulting in the formation, destabilization, and rupture of atherosclerotic plaques. Promotion of thrombogenesis is another possible mechanism. Fibrin(ogen) acts as a scaffold for blood clots, enhancing platelet aggregation and fibrin formation, mak- ing thrombi more resistant to lysis.55 Furthermore,
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haematologica | 2020; 105(2)