Low fibrinogen levels and quality impacts negatively on blood clot formation and can lead to excessive bleeding and death if left untreated. Fibrinogen deficiencies can either be inherited (congenital fibrinogen deficiency) or acquired (acquired fibrinogen deficiency). Congenital fibrinogen deficiency manifests from no detectable fibrinogen (such as for congenital afibrinogenaemia) to some detectable fibrinogen (such as for congenital hypofibrinogenaemia) (Figure 5). It is usually the result of a heterozygous or homozygous mutation in one of the three fibrinogen genes (FGA, FGB and FGG) that are located on the long arm of chromosome 4 (4q31.3). Key symptoms include uncontrollable bleeding and thrombolytic complications. The onset of bleeding can be spontaneous, or as a result of both minor and major traumas. Bleeding phenotypes can range from being asymptomatic to severe and is partially dependent on both the level and quality of fibrinogen available (Peyvandi et al., 2012). There are two types of congenital deficiency:
Congenital afibrinogenaemia is a rare inherited bleeding disorder that affects approximately 1:1,000,000 people (Tziomalos et al., 2009). It is the result of one or more recessive mutations in any of the genes that encode the three peptides (Aα, Bβ and γ) that constitute the fibrinogen hexamer. Over 245 mutations have been identified to date, each affecting either the synthesis, stability or secretion of fibrinogen (Asselta et al., 2006). Consequently, people who suffer from congenital afibrinogenaemia have almost no detectable plasma fibrinogen (less than 0.1 g/L). They are therefore unable to form blood clots normally and are at greater risk of thrombolytic complications.
Afibrinogenaemia manifests clinically as minimal bleeding to serious haemorrhage and is usually diagnosed at birth, when bleeding from the umbilical cord is difficult to stop. Other symptoms throughout life include reduced wound healing, nose bleeds and bleeding of joints, mucous membranes, the central nervous system and the gastrointestinal tract. Additionally, women sufferers experience prolonged and heavy menstruation (menorrhagia) and can experience spontaneous abortions, usually at 5 to 8 weeks of gestation, as well as postpartum haemorrhage.
Despite having a lower capacity to produce blood clots, afibrinogenaemia patients can also experience spontaneous thrombosis in peripheral arteries and in cerebral and hepatic veins (Lak et al., 1999; Oruc et al., 2006; Fuchs et al., 2007). This could be due to reduced fibrinolysis of present clots or reduced thrombin sequestration by fibrinogen. For the latter, patients that lack fibrinogen tend to display increased thrombin levels, with a subsequent increase in prothrombin activation (de Bosch et al., 2002; Mosesson et al., 2003). Further, free thrombin may stimulate platelets to release several growth factors that impact on vascular smooth muscle proliferation and blood vessel thickness (Korte et al., 1994), altogether leading to increased thrombolytic complications.
Hypofibrinogenaemia describes a partial fibrinogen deficiency with plasma levels below 1.5 g/L (de Moerloose et al., 2013; Neerman et al., 2018). The partial deficiency is mostly the result of a heterozygous mutation in the genes that encode the fibrinogen peptides. Patients of hypofibrinogenaemia tend to be asymptomatic and are usually diagnosed during some form of intervention, for instance through pre-operative testing or through major trauma when excessive bleeding is evident (Casini et al., 2016). Female sufferers are also more likely to suffer pregnancy loss and postpartum haemorrhage (Hill et al., 2006). In rare cases, liver disease may arise as a result of aggregate accumulation in the endoplasmic reticulum of hepatocytes (Brennan et al., 2000; Brennan et al., 2002; Dib et al., 2007; Brennan et al., 2010).
Dysfibrinogenaemia is a rare (15 per 100,000) autosomal dominant disorder caused mostly by heterozygous missense mutations in any one of the three genes that encode the fibrinogen peptides. Whilst there are over 100 nucleotide variations, two key mutations account for 75% of dysfibrinogenaemia cases (FGA: Arg35 and FGG: Arg301) (GEHT database). These mutations impact on the quality of fibrinogen produced rather than the quantity. There are two known mechanisms of quality defects; either fibrinogen is unable to bind thrombin, or the resulting fibrin clot cannot undergo plasmin degradation (de Moerloose et al., 2013).
Like congenital hypofibrinogenaemia, dysfibrinogenaemia patients tend to be asymptomatic, however display bleeding and thrombolytic complications upon trauma. In the absence of genetic family history, diagnosis is therefore usually made accidentally because of unusual coagulation test results, characterised by a ratio of functional activity to antigen level of approximately 0.7 or less (Casini et al., 2015).
Hypodysfibrinogenaemia is the rarest of the congenital fibrinogen disorders. Patients who suffer hypodysfibrinogenaemia present low-quality fibrinogen at reduced levels. As such, these patients share features with both hypofibrinogenaemia and dysfibrinogenaemia patients. There are at least 32 known contributor mutations in the three genes that encode the fibrinogen peptides (Casini et al., 2017). Symptoms range from being mostly asymptomatic to experiences of severe bleeds in cases of trauma, such as postpartum haemorrhage, and recurrent thrombosis.
Whilst there aren’t many reported cases of hypodysfibrinogenaemia, functional fibrinogen levels were found to be in the range of 0.1–1.1 g/L whereas antigenic fibrinogen levels were higher, at 0.31–1.8 g/L. The mean ratio of fibrinogen functional activity/antigenic levels was 0.46 (range of 0.07–1.25) (Casini et al., 2017). Indeed, hypodysfibrinogenaemia patients are often misdiagnosed as having hypofibrinogenaemia based on the fibrinogen level results.
Acquired fibrinogen deficiency is far more common in the general population and can arise as a result of consumptive and dilutional coagulopathy and due to blood loss experienced during major trauma, postpartum haemorrhage and cardiac surgery.
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