INTRODUCTION — Fibrinogen plays a pivotal role in normal hemostasis as a substrate for conversion to fibrin, a support for thrombin generation and platelet aggregation, and a facilitator of wound healing. Fibrin also forms a template for subsequent fibrinolysis and wound healing. A number of inherited and acquired fibrinogen disorders have been described; these can have both hemorrhagic and thrombotic manifestations, as well as effects on pregnancy, depending on the specific defect.

This topic describes the pathophysiology, clinical presentation, diagnosis, and treatment of inherited and acquired fibrinogen disorders.

Separate topic reviews discuss other disorders of hemostasis and thrombosis:

●Other rare coagulation disorders – (see "Rare inherited coagulation disorders" and "Factor XI (eleven) deficiency")

●Hemophilia – (see "Clinical manifestations and diagnosis of hemophilia")

●Acquired factor inhibitors – (see "Acquired inhibitors of coagulation")

●Liver disease – (see "Hemostatic abnormalities in patients with liver disease")

●DIC – (see "Evaluation and management of disseminated intravascular coagulation (DIC) in adults")

●Unexplained bleeding – (see "Approach to the adult with a suspected bleeding disorder")

●Abnormalities of fibrinolysis – (see "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis")

BIOLOGY

Fibrinogen synthesis and circulating levels — Human fibrinogen (coagulation factor I; FG; FBG) is a 340 kD hexameric glycoprotein (GP) composed of two symmetrical halves that are centrally connected by three disulfide bonds (figure 1). Each half of the protein consists of three polypeptide chains (ie, A-alpha [Aα], B-beta [Bβ], and gamma [γ]) encoded by three different genes on chromosome 4 (FGA, FGB, and FGG). The tri-nodular structure of fibrinogen can be described as a central E region (containing the amino-terminal [N-terminal] portions of the three polypeptide chains) and two D regions (C-terminal portions) [1]. The fully assembled hexamer can be designated (AαBβγ)₂ [2].

Fibrinogen is produced exclusively in the liver. It circulates in the plasma at a concentration of approximately 200 to 400 mg/dL, by far the highest concentration of any plasma coagulation factor [3]. This is because fibrinogen contributes a major structural component of the clot rather than an enzymatic function. The half-life of circulating fibrinogen is approximately three to four days, with a catabolic rate of approximately 25 percent per day [4]. As with all clotting factors, fibrinogen is present in plasma but not serum.

A small pool of fibrinogen is taken up by platelets in a process mediated by platelet GPIIb/IIIa and stored in platelet alpha-granules; this fibrinogen can support platelet aggregation. (See "Megakaryocyte biology and the production of platelets", section on 'Specific platelet granules'.)

Fibrinogen synthesis is controlled at the level of transcription. Circulating plasma fibrinogen levels increase with age, obesity, smoking, and inflammatory states; levels decrease with alcohol consumption [5]. The inducible component is mainly influenced by the acute phase response. As an acute phase reactant, fibrinogen biosynthesis is increased by interleukin-6 (IL-6)-mediated increases in transcription of the fibrinogen mRNA. The acute phase response can elevate plasma fibrinogen by 2- to 20-fold, with a peak elevation by three to five days and a gradual return to baseline following resolution of the inflammatory stimulus [6-8]. IL-1 and tumor necrosis factor-alpha suppress fibrinogen synthesis [6,7]. (See "Acute phase reactants".)

All three polypeptides (Aα, Bβ, and γ) are synthesized by hepatocytes and are assembled into fibrinogen in the liver [9]. Carbohydrate side chains are added to the β and γ chains before the molecule is secreted into the plasma. Polymorphisms in the Bβ gene have been described that are associated with increased plasma fibrinogen concentration, especially in smokers [10,11]. (See 'Acquired hyperfibrinogenemia' below.)

Alternative splicing produces a normally occurring variant of the γ chain, referred to as "gamma-prime" (γ'), which yields γ' fibrinogen when assembled into the fibrinogen molecule [12-15]. This variant, which constitutes approximately 8 to 15 percent of plasma fibrinogen, is associated with structural changes in fibrin clots that include more extensive cross-linking and greater resistance to lysis.

Functions in hemostasis and other processes — Fibrinogen has numerous functional interactions and plays a pivotal role in hemostatic balance. Fibrinogen is the precursor to fibrin, and it binds platelets, supporting platelet aggregation, and thrombin, promoting coagulation. The fibrin clot serves as a template for the fibrinolytic system and forms a scaffold on which wound healing occurs. The final result of the balance between fibrin clot formation and fibrinolysis determines whether the clinical manifestations include bleeding, thrombosis, both, or neither.

●Formation of fibrin – Fibrinogen is the soluble precursor to fibrin, an insoluble protein that provides the major structural element of the clot. The conversion of fibrinogen into insoluble fibrin can be divided into three distinct steps:

•Fibrinopeptide cleavage – Thrombin (factor IIa) is generated from the coagulation cascade (see "Overview of hemostasis", section on 'Thrombin generation'). When thrombin binds to fibrinogen, it cleaves fibrinopeptides A and B (FPA and FPB) from the N-terminal portions of the Aα and Bβ chains at the Arg16-Gly17 and the Arg14-Gly15 bonds, respectively (figure 1). The resultant molecule is referred to as fibrin monomer, which is the basic unit of fibrin and facilitates optimal fibrin polymerization. FPA is released faster and earlier than FPB. FPA release is sufficient to induce clot formation, whereas isolated cleavage of FPB is insufficient.

Any structural defect of the N-terminal region of the Aα and Bβ chains can markedly impair thrombin binding, FPA or FPB release, and/or the rate of fibrin formation [16]. It is therefore not surprising that a high proportion of abnormal fibrinogens have mutations involving this region. Even so, the majority of the affected individuals are asymptomatic, although some have excessive bleeding manifestations, especially after surgery or childbirth. (See 'Clinical manifestations' below.)

•Fibrin polymerization – In normal hemostasis, release of negatively charged FPA and FPB results in spontaneous fibrin monomer polymerization to form the fibrin clot. Polymerization sites are located on the N-terminal portion of the Aα and Bβ chains (E domain), and the C-terminal portion of the γ chains (D domain). The process is initiated by complementary noncovalent binding of the polymerization sites at the D region of one molecule to the central E domain of an adjacent fibrin monomer (figure 1), forming a two-molecule-thick strand or protofibril. This is followed by longitudinal growth (D-D contact between adjacent fibrin monomers) and branching to form the final fibrin network (figure 2) [17]. Mutations affecting these binding sites may delay fibrin polymerization and produce heterogeneous clinical manifestations. (See 'Clinical manifestations' below.)

•Fibrin cross-linking – Once polymerized, fibrin is cross-linked. This final step strengthens the clot against mechanical and enzymatic disruption. Cross-linking is mediated by the activated form of coagulation factor XIII (FXIIIa). Activation of FXIII is mediated by thrombin, after which FXIIIa binds to fibrin and generates covalent bonds between D domains of the fibrin fibers (figure 2). These bonds involve γ-γ as well as α-α and α-γ chain interactions [18].

Cross-linking stabilizes the clot and renders it resistant to disruption. Defective cross-linking due to an abnormal fibrinogen molecule may affect the mechanical resistance of the clot and be responsible for delayed wound healing and/or wound dehiscence, similar to that seen in patients with FXIII deficiency. (See "Rare inherited coagulation disorders", section on 'Factor XIII deficiency (F13D)'.)

Based on in vitro studies, it has been proposed that increased cross-linking might predispose to thromboembolic phenomena and cardiovascular disease [19,20]. As noted above, clots containing γ' fibrinogen may have greater cross-linking (see 'Fibrinogen synthesis and circulating levels' above), and observational studies have found higher circulating levels of γ' fibrinogen (independent of circulating fibrinogen levels) in individuals with cardiac disease [21,22]. However, there is no evidence of a clinically significant causative role.

●Platelet aggregation – Fibrinogen facilitates platelet aggregation, although platelet aggregation may also occur in the absence of fibrinogen (eg, via von Willebrand factor [VWF]). The binding of fibrinogen to platelets to support platelet aggregation is discussed in detail separately. (See "Overview of hemostasis", section on 'Platelet aggregation'.)

●Fibrinolysis – The fibrin clot is a template for the assembly and activation of the fibrinolytic system; it includes binding sites for plasminogen, tissue-type plasminogen activator (t-PA), and α-2-antiplasmin. (See "Overview of hemostasis", section on 'Clot dissolution and fibrinolysis'.)

Mutations affecting these binding regions may result in defective plasmin generation and reduced fibrinolysis [23]. The rate of fibrinolysis is also influenced by the thickness of the fibers [24]. In addition, resistance to the action of plasmin can result from mutations in the C-terminus of the Aα chain associated with abnormal albumin binding [25,26]. These mechanisms explain the thrombophilic, rather than the hemorrhagic, phenotype in some of these individuals. (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis", section on 'Overview of the fibrinolytic system'.)

The locations have been mapped for certain amino acid residues that define the sites of some of the important functions of fibrinogen, including fibrinopeptide cleavage, fibrin polymerization, and factor XIIIa-mediated fibrin cross-linking as well as its interaction with platelet GPIIb/IIIa [23,27-29]. (See "Platelet biology", section on 'Overview of platelet function'.)

Fibrin also has a thrombin-neutralizing activity, and it has been proposed that hypofibrinogenemia or dysfibrinogenemia might increase the risk of thrombosis because thrombin activity is generated at a normal rate, but neutralization is decreased due to reduced functional fibrin, although further study is needed to explain observed thrombotic phenotypes [30]. Reduced antithrombin activity and increased thrombin generation with platelet activation and VWF-mediated platelet aggregation may occur in some individuals [2,31,32]. Resistance to fibrinolysis may contribute to some thrombotic phenotypes such as chronic thromboembolic pulmonary hypertension (CTEPH) following pulmonary embolism. In a cohort of 33 patients with CTEPH, five were found to have dysfibrinogenemia with abnormal fibrin structure and/or resistance to fibrinolysis [33].

In addition to hemostasis, fibrinogen is involved in other physiologic processes. As an example, the fibrin clot serves as a template for stages of wound healing, as described separately (see "Basic principles of wound healing", section on 'Epithelialization'). During pregnancy, fibrinogen plays a fundamental role in maintaining the integrity of placental insertion. In a mouse model of homozygous, Aα chain deficiency, fatal uterine bleeding occurs at approximately the tenth day of gestation [34]. As discussed below, some patients with congenital fibrinogen disorders have an increased risk of pregnancy loss, obstetrical bleeding, or thrombosis during pregnancy or postpartum. (See 'Obstetric complications' below.)

Types of fibrinogen abnormalities — Disorders of fibrinogen can be inherited or acquired and can involve abnormalities in the amount of fibrinogen (quantitative defect), abnormalities in the function of the fibrinogen molecule (qualitative defect), or both (table 1).

●Quantitative defects

•Afibrinogenemia – Absence of circulating fibrinogen due to a rare inherited autosomal recessive condition. Afibrinogenemia may be associated with bleeding, obstetric complications, and (rarely) thrombosis. (See 'Congenital afibrinogenemia or hypofibrinogenemia' below.)

•Hypofibrinogenemia – Reduced level of circulating fibrinogen (eg, <150 mg/dL). As discussed below, the threshold for clinical bleeding is <100 mg/dL (see 'Bleeding and abnormal clotting times' below). Hypofibrinogenemia can be inherited or acquired (due to decreased synthesis or increased turnover [consumption]). Some individuals have phenotypes similar to afibrinogenemia; many affected individuals are asymptomatic. (See 'Congenital afibrinogenemia or hypofibrinogenemia' below and 'Acquired hypo- or dysfibrinogenemia' below.)

•Hyperfibrinogenemia – Increased level of circulating fibrinogen (eg, >450 mg/dL). Hyperfibrinogenemia is typically a transient, acquired finding that occurs in the setting of acute inflammation or injury (as an acute phase process) and often is observed as an incidental finding; routine testing for hyperfibrinogenemia is not advised. (See 'Acquired hyperfibrinogenemia' below.)

●Qualitative defects

•Dysfibrinogenemia – Presence of a dysfunctional fibrinogen molecule. Dysfibrinogenemia can be inherited or acquired (eg, in liver disease). Dysfibrinogenemias can be associated with bleeding, thrombosis, or both. (See 'Congenital dysfibrinogenemia or hypodysfibrinogenemia' below and 'Acquired hypo- or dysfibrinogenemia' below.)

•Hypodysfibrinogenemia – Reduced level of circulating fibrinogen that is also functionally abnormal. Hypodysfibrinogenemia can be inherited or acquired and can be associated with bleeding, thrombosis, or both.

•Cryofibrinogenemia – Cryofibrinogenemia is an acquired condition in which a circulating fibrinogen precipitates (in plasma, not serum) at low temperatures (eg, 4°C). Cryofibrinogenemia can be asymptomatic (incidental finding in a healthy person) or associated with cutaneous or rheumatologic manifestations (eg, cold sensitivity, purpura, skin necrosis, Raynaud phenomenon). (See 'Acquired cryofibrinogenemia' below and "Cryofibrinogenemia".)

HERITABLE (GENETIC) DISORDERS — Congenital (heritable) fibrinogen disorders include quantitative defects (afibrinogenemia and hypofibrinogenemia), qualitative defects (dysfibrinogenemia), and combined defects (hypodysfibrinogenemia) [35,36]. (See 'Types of fibrinogen abnormalities' above.)

International databases that include all the identified variants in fibrinogen genes are available through the International Society of Thrombosis and Hemostasis and an online fibrinogen database; these have been summarized in various review articles and are illustrated in the figure (figure 3) [2,36-38].

These disorders are rare. According to a 2014 global survey of rare bleeding disorders, inherited fibrinogen deficiencies accounted for 1712 of 283,397 inherited bleeding disorders (0.6 percent of the total; 8 percent of the rare coagulation factor disorders), which is approximately as common as factor V or factor X deficiency and approximately 100 times less common than hemophilia A [39].

Importantly, bleeding can correlate with the level of circulating fibrinogen, but it is not always possible to predict the genotype-phenotype relationship in the congenital dysfibrinogenemias, making it difficult to anticipate whether a specific mutation is more likely to cause bleeding, thrombosis, both, or neither [40,41]. In some cases, structural analysis of fibrinogen has been used to correlate specific mutations with specific alterations of protein function [23,28,42]. More than half of individuals with these inherited defects are asymptomatic and identified as an incidental finding or through familial screening [40,43,44].

Congenital afibrinogenemia or hypofibrinogenemia — Congenital fibrinogen deficiency can be categorized as afibrinogenemia or hypofibrinogenemia [36].

●Afibrinogenemia – Congenital afibrinogenemia (undetectable circulating fibrinogen) is an extremely rare disorder (estimated incidence one per million), typically occurring as an autosomal recessive condition in which affected individuals are homozygous or compound heterozygous for truncating mutations in the gene encoding the fibrinogen α chain (FGA) [2,45-48]. Consanguinity may play a role in some families. A number of mutations in FGA have been identified, as well as in the other fibrinogen genes (figure 3); these mutations may affect mRNA splicing or stability; protein production or stability; or hexamer assembly, storage, or secretion [46]. In a large case series from 2021, most variants were in FGA, common variants included an 11 kilobase deletion, the frameshift mutation c.510+1T>G, and a nonsense mutation c.635T>G [49].

●Hypofibrinogenemia – Congenital hypofibrinogenemia (circulating fibrinogen <150 mg/dL [<1.5 g/L]) is often seen in heterozygous carriers of afibrinogenemia mutations [2,46,50,51]. A classification of congenital fibrinogen disorders published in 2018 defines hypofibrinogenemia as any value below the reference range [52]. Congenital hypofibrinogenemia is more prevalent than afibrinogenemia, but the true incidence is unknown since many cases are asymptomatic and never come to medical attention [36].

Plasma fibrinogen levels of approximately 100 mg/dL or above are often sufficient to prevent clinical bleeding, thrombosis, or pregnancy loss, and affected individuals often do not come to medical attention for their hypofibrinogenemia. However, bleeding or pregnancy loss (or liver disease (see 'Other rare manifestations' below)) may occur in certain high-risk settings such as surgery, trauma, or pregnancy. Bleeding risk and severity is likely to increase as the fibrinogen level decreases below 100 mg/dL. (See 'Bleeding and abnormal clotting times' below.)

Congenital dysfibrinogenemia or hypodysfibrinogenemia — Congenital fibrinogen variants can be categorized as dysfibrinogenemia (normal levels of dysfunctional fibrinogen) or hypodysfibrinogenemia (dysfunctional fibrinogen at low plasma concentration [<150 mg/dL]). In both cases, the fibrinogen antigen level does not reflect the level of functional fibrinogen, which must be measured using a functional assay. (See 'Diagnostic testing' below.)

Transmission of most dysfibrinogenemias (and hypodysfibrinogenemias) is autosomal dominant, caused by heterozygosity for a missense mutation in the coding region of one of the fibrinogen genes that leads to production of an abnormal fibrinogen protein [36]. Abnormalities may involve alteration of fibrinopeptide release, fibrin polymerization, fibrin cross-linking, or fibrinolysis. Congenital dysfibrinogenemia is quite rare but occurs more frequently than congenital afibrinogenemia; the true incidence is unknown since many cases are asymptomatic and never come to medical attention [36].

Examples of common sites of pathogenic variants ("hotspots" (figure 3)) and their functional effects include:

●FGA exon 2 mutations that affect fibrinopeptide A (FPA) cleavage

●FGG exon 8 mutations that affect the fibrin polymerization site

In a 2015 study that included 101 patients with inherited dysfibrinogenemia, mutations at the FGA hotspot accounted for 24 percent and variants at the FGG hotspot accounted for 51 percent of all mutations [40]. The cumulative incidences of major bleeding and thrombosis at age 50 years were 19 and 30 percent, respectively [40]. Certain mutations may be associated with both bleeding and thrombosis (see 'Clinical manifestations' below). In this same cohort of 101 patients, no association could be established between the common hotspot mutations and clinical phenotype of bleeding or thrombosis [40].

Inherited dysfibrinogenemias are named after the city where the patient was first identified or evaluated. Roman numerals are added after the city name when there are several dysfibrinogens from the same city (eg, Caracas V).

ACQUIRED ABNORMALITIES

Acquired hypo- or dysfibrinogenemia — Acquired fibrinogen disorders are more common than inherited defects because liver disease and disseminated intravascular coagulation (DIC) are common (table 1). It is also worth noting that, since fibrinogen is an acute phase reactant that normally increases in the setting of inflammation, it is possible that an apparently normal fibrinogen level in an individual with an inflammatory condition may actually represent a significant decline from the patient's baseline.

Liver disease — Liver disease can cause dysfibrinogenemia and/or hypofibrinogenemia; the latter most often accompanies more severe liver disease and cirrhosis.

●Dysfibrinogenemia – Liver disease is the most common cause of acquired dysfibrinogenemia, with prevalences as high as 80 percent if a highly sensitive assay is used [53]. Dysfibrinogenemia has been seen in many types of liver disease, including biliary obstruction, acute liver failure, chronic liver disease, cirrhosis, and hepatoma [53-58]. The abnormal fibrinogen is characterized by an increased content of sialic acid residues that results in delayed fibrin aggregation [59]. Both cleavage of the A and B fibrinopeptides and the cross-linking of fibrin by factor XIIIa are normal. Cleavage of sialic acid from the abnormal fibrinogen restored fibrinogen function to normal in vitro [60]. The impact of this abnormal fibrinogen on bleeding risk has not been well studied, but it is unlikely to be associated with significant alteration of bleeding risk.

●Hypofibrinogenemia – Liver disease can also cause reduced levels of fibrinogen. Typically, this occurs with advanced liver disease severe enough to compromise liver synthetic function. While the major mechanism is reduced production, in some cases abnormal fibrinogens produced in the setting of liver disease have increased turnover, leading to low fibrinogen levels.

The impact of dysfibrinogenemia and hypofibrinogenemia on bleeding risk in individuals with liver disease is difficult to assess since liver disease is associated with a complex combination of procoagulant and anticoagulant changes. Our approach to patient evaluation is presented separately. (See "Hemostatic abnormalities in patients with liver disease".)

Disseminated intravascular coagulation — Disseminated intravascular coagulation (DIC) is a consumptive coagulopathy that can lead to hypofibrinogenemia and/or dysfibrinogenemia (figure 4). Increased levels of fibrin degradation products seen in DIC also impair normal fibrinogen function. Acute DIC is the most common cause of acquired hypofibrinogenemia. By contrast, in chronic DIC, the fibrinogen may be normal or even increased. Patients with DIC and hypofibrinogenemia may have bleeding or thrombotic manifestations. The acute coagulopathy of trauma may be a form of partially compensated acute DIC. Patient evaluation and management are discussed in detail separately. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults" and "Coagulopathy in trauma patients".)

Hemophagocytic lymphohistiocytosis — Hemophagocytic lymphohistiocytosis (HLH) is an aggressive systemic disorder in which excessive immune activation leads to multiorgan dysfunction. Hypofibrinogenemia is frequently seen (and is one of the syndromic criteria), often accompanied by liver enzyme abnormalities and prolonged coagulation times. The mechanism of hypofibrinogenemia is somewhat paradoxical and not well explained, especially since inflammation typically raises the fibrinogen level. (See "Clinical features and diagnosis of hemophagocytic lymphohistiocytosis" and 'Fibrinogen synthesis and circulating levels' above.)

Treatment of bleeding in HLH and the role of monitoring fibrinogen along with other disease markers are discussed in detail separately. (See "Treatment and prognosis of hemophagocytic lymphohistiocytosis".)

Antifibrinogen antibodies — Autoantibodies that inhibit specific functions of fibrinogen have been described in various conditions. These antibodies may interfere with fibrinopeptide release, fibrin monomer polymerization, or fibrin cross-linking. Some individuals have no identifiable underlying disorder; in other cases, individuals have underlying conditions that are associated with increased prevalence of autoantibodies. Examples include the following [61-66]:

●Systemic lupus erythematosus (SLE)

●Rheumatoid arthritis (RA)

●Ulcerative colitis

●Multiple myeloma

●Mitochondrial myopathy

●Medications (eg, isoniazid)

In RA, the autoantibody is directed against citrullinated fibrinogen (in which arginine is post-translationally modified to citrulline). Additional details regarding this modification in RA are presented separately. (See "Pathogenesis of rheumatoid arthritis", section on 'Citrullinated proteins and peptides'.)

Autoantibodies are more likely to cause bleeding manifestations than thrombosis. In some cases, the autoantibody may be clinically silent.

Patients exposed to fibrin glue (eg, for hemostasis during surgical procedures) using a product prepared from bovine sources can develop alloantibodies against bovine fibrinogen that may cross-react with human fibrinogen [67]. Commercial fibrin sealants made from human sources (eg, Tisseel kit VH, Vistaseal, Evicel) should eliminate this potential complication. (See "Fibrin sealants", section on 'Formulations and use'.)

Other causes (medications, paraneoplastic, plasma exchange) — Acquired dysfibrinogenemia and hypofibrinogenemia have also been reported in association with other conditions (table 1). Examples include:

●Renal carcinoma (possible paraneoplastic syndrome) [68]

●Multiple myeloma (impaired fibrin polymerization due to the paraprotein)

●Isotretinoin therapy (in the setting of acute pancreatitis, mechanism unclear) [69]

●Tigecycline (mechanism unclear) [70]

●Medications that impair hepatic synthetic function (eg, L-asparaginase, valproic acid) [71-73]

●Plasma exchange (PEX) using albumin as a replacement fluid

Following PEX, the fibrinogen level may decrease by approximately 50 percent. In contrast, if PEX is performed using plasma as a replacement fluid (eg, as in the treatment of acquired autoimmune thrombotic thrombocytopenic purpura [TTP]), changes in fibrinogen are negligible. (See "Therapeutic apheresis (plasma exchange or cytapheresis): Indications and technology", section on 'Replacement fluids'.)

As with the acquired systemic disorders discussed above, hypofibrinogenemia may be accompanied by other coagulation abnormalities. Primary fibrinolytic states leading to hypofibrinogenemia are rare. (See "Thrombotic and hemorrhagic disorders due to abnormal fibrinolysis".)

High levels of fibrin split products (FSPs) or fibrin degradation products, which come from non-cross-linked fibrin, could impair optimal fibrin polymerization and the functional fibrinogen level. By contrast, D-dimer, which comes from cross-linked fibrin, does not affect the fibrinogen assay.

Acquired hyperfibrinogenemia — Increased fibrinogen levels (hyperfibrinogenemia) can be seen in the setting of inflammation or tissue injury as an acute phase reactant. Inherited causes of hyperfibrinogenemia have not been reported, although certain polymorphisms may lead to increased fibrinogen levels in some settings, such as pregnancy or insulin resistance [74,75]. The clinical significance of these is uncertain.

Epidemiologic studies indicate that high fibrinogen levels are associated with increased risk of cardiovascular disease, stroke, and nonvascular mortality, but causality has not been demonstrated. This subject is discussed in more detail separately. (See "Overview of possible risk factors for cardiovascular disease", section on 'Coagulation factors'.)

Acquired cryofibrinogenemia — Cryofibrinogenemia refers to the presence in plasma (but not serum) of an abnormal cold-insoluble protein, composed of a combination of fibrinogen, fibrin, and fibronectin. This condition is seen most frequently in autoimmune disorders, malignancy, thrombotic disorders, and infections (eg, hepatitis C virus infection) and may be accompanied by disseminated intravascular coagulation (DIC). Symptoms, when present, include sensitivity to cold, Raynaud phenomenon, purpura, urticaria, skin ulcerations or gangrene, and/or arterial or venous thromboses. Cryofibrinogenemia is discussed in detail separately. (See "Cryofibrinogenemia".)

CLINICAL MANIFESTATIONS

Bleeding and abnormal clotting times — An abnormality of fibrinogen may be suspected if there is prolongation of the prothrombin time (PT), activated partial thromboplastin time (aPTT), and/or thrombin time (TT). The sensitivity of the PT and aPTT assays differ depending on the laboratory, and some individuals may have a normal aPTT despite fibrinogen activity levels as low as 50 mg/dL. Abnormal clotting times may be encountered in the evaluation of unexplained bleeding or on routine laboratory testing (eg, if the individual is hospitalized for an unrelated reason). The PT and aPTT are usually tested (along with the platelet count) as initial screening tests for hemostasis, and the TT is tested in individuals with prolongation of both the PT and aPTT. (See "Approach to the child with bleeding symptoms" and "Approach to the adult with a suspected bleeding disorder".)

Hypofibrinogenemia and dysfibrinogenemia with fibrinogen activity levels <100 mg/dL will cause prolongation of the PT, aPTT, and TT, as well as the reptilase time (RT). The RT is a version of the TT that uses reptilase rather than thrombin and hence is abnormal in fibrinogen disorders; RT is usually used to distinguish underlying coagulation disorders from abnormal clotting times caused by heparin in the sample. Mild hypofibrinogenemia (fibrinogen between 100 and 150 mg/dL) may not cause abnormal clotting times. Rare cases of dysfibrinogenemia have been reported in which the TT is normal [36,76]. (See "Clinical use of coagulation tests", section on 'Clotting times'.)

Bleeding in patients with fibrinogen disorders can be mild or severe, with greater bleeding risk in those with afibrinogenemia or lower levels of functional fibrinogen (especially below 100 mg/dL) (table 2). The age of onset is also variable, with earlier onset in those with more severe deficiency or functional impairment. The following illustrate the range of bleeding phenotypes:

●Congenital afibrinogenemia – In congenital afibrinogenemia (absence of detectable fibrinogen), bleeding often occurs in the neonatal period. One of the larger case series that included 204 individuals with congenital afibrinogenemia reported that one-third had at least one bleed per month and one-fourth had a history of intracerebral bleeding [49]. Other common sites of bleeding included muscle hematomas, hemarthroses, and perioperative bleeds. The average International Society on Thrombosis and Haemostasis Bleeding Assessment Tool (ISTH-BAT) score (bleedingscore.certe.nl) was 14, consistent with a severe bleeding disorder. Many of these individuals also experienced thrombotic events. (See 'Thrombosis' below.)

Other reports have reported that umbilical cord bleeding, which can be fatal, is the initial presentation in approximately 60 to 85 percent of cases [2,36]. Some individuals with afibrinogenemia may have a later age of onset with bleeding in the skin, gastrointestinal tract, urinary tract, or central nervous system. Joint bleeding is relatively rare. Some females have heavy menstrual bleeding but others do not. Pregnancy-associated hemorrhage (antepartum or postpartum) may occur. Splenic rupture has been reported [32,77]. Thrombosis may occur, particularly after fibrinogen replacement therapy. (See 'Treatment/prevention of bleeding' below.)

●Congenital hypofibrinogenemia – In congenital hypofibrinogenemia (fibrinogen <150 mg/dL, often much lower), the frequency and characteristics of bleeding are variable. In a series of 100 individuals with congenital hypofibrinogenemia, the median fibrinogen level was 6 mg/dL (range, 0 to 116 mg/dL) [30]. The annualized bleeding rate was approximately 5 to 7 per 1000 patients.

●Congenital dysfibrinogenemia – In congenital dysfibrinogenemia (or hypodysfibrinogenemia), the clinical presentation is heterogeneous. In general, inherited dysfibrinogenemia with functional fibrinogen levels below 50 to 100 mg/dL are associated with a higher frequency of bleeding complications. However, case series have reported that the majority of individuals do not present with bleeding. In fact, over half of individuals in various series have been asymptomatic and identified as an incidental finding or through familial screening [40,43,44]. In the largest published cohort of 101 patients with congenital dysfibrinogenemia, thrombosis was more common than bleeding manifestations [40]. The cumulative incidences of major bleeding and thrombosis at age 50 were 19 and 30 percent, respectively. The risks of spontaneous abortion and postpartum hemorrhage were also significant at 20 and 21 percent, respectively. Most bleeding manifestations are mild, but some can be severe. The most common bleeding manifestation is heavy menstrual bleeding in women, followed by cutaneous bleeding, operative bleeding, and gastrointestinal bleeding. Other concerning sites of bleeding have been reported, including intracerebral, retroperitoneal, joint/muscle, and obstetric. Spontaneous life-threatening bleeds are rare.

●Acquired disorders – Acquired fibrinogen disorders may have bleeding due to low fibrinogen levels and/or other hemostatic abnormalities such as thrombocytopenia and/or other factor deficiencies. Bleeding manifestations are discussed in more detail separately. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Bleeding and thrombosis' and "Hemostatic abnormalities in patients with liver disease", section on 'Bleeding'.)

Thrombosis — Paradoxically, some fibrinogen disorders are associated with thrombotic phenotypes, despite the prominent role of fibrinogen in normal clotting and the expectation that fibrinogen disorders would cause increased bleeding (table 2). The following illustrate the range of thrombotic phenotypes:

●The majority of individuals with congenital fibrinogen disorders do not have thrombosis, but arterial and venous thrombotic complications have been reported [2].

•A 2016 systematic review identified 48 reports of thromboembolic complications in individuals with congenital afibrinogenemia, which included arterial and venous thromboses in a variety of vascular sites [31]. The median age at the time of the first event was 31 years, and in some cases there was a triggering event such as infection or trauma. Most were treated with fibrinogen replacement; some were also given an anticoagulant or an antiplatelet agent (see 'Management' below). Outcomes were mostly good, although a few required surgery (eg, to resect infarcted bowel).

•A series of 204 individuals with congenital afibrinogenemia reported that a thrombotic event had occurred in 18 percent, with 43 percent venous, 30 percent arterial, and 27 percent combined arterial and venous [49]. Recurrent thrombotic events occurred in 41 percent.

●The majority of individuals with congenital dysfibrinogenemias (or hypodysfibrinogenemias) do not have thrombosis, although approximately 20 to 30 percent may have a thrombotic event at some point [40,43]. In a series of 101 individuals with congenital dysfibrinogenemias, there were 20 episodes of venous thromboembolism and eight arterial thromboses (eg, stroke, myocardial infarction, mesenteric thrombosis) [40]. One of the thrombotic events may have been associated with fibrinogen replacement therapy. The annualized thrombotic rate was 7.6 per 1000 patients, and the estimated cumulative incidence of thrombotic events at age 50 years was 30 percent (95% CI, 20 to 44 percent). In a 1995 report from the International Society on Thrombosis and Haemostasis (ISTH) that focused on 27 individuals with thrombotic variants of dysfibrinogenemia, the mean age of first thrombosis was 27 years (range, 12 to 50 years) [43]. For those who do have a thrombosis, venous sites are more common than arterial, but both can occur, sometimes in the same individual [40,43,78]. Digital artery occlusion associated with red blood cell aggregation has also been reported [61].

●Acquired fibrinogen disorders may have thrombosis due to dysfibrinogenemia or to hemostatic abnormalities that may increase the risk of thrombosis. These risks are discussed in more detail separately. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Bleeding and thrombosis' and "Hemostatic abnormalities in patients with liver disease", section on 'Portal vein thrombosis (PVT)' and "Hemostatic abnormalities in patients with liver disease", section on 'Venous thromboembolism (VTE)'.)

While individuals with fibrinogen disorders can have thromboembolic events, fibrinogen abnormalities constitute an extremely rare cause of thrombophilia overall (<1 percent), and evaluation for dysfibrinogenemia is not a routine component of the thrombophilia evaluation unless there is a known family history of an inherited fibrinogen disorder [2,43]. Common causes of thrombophilia are discussed separately. (See "Overview of the causes of venous thrombosis", section on 'Inherited thrombophilia'.)

The mechanism by which reduced fibrinogen levels or impaired fibrinogen function contribute to an increased thrombotic risk is unclear and may involve enhanced thrombin generation, increased platelet aggregation, or reduced fibrinolysis, as discussed above (see 'Functions in hemostasis and other processes' above). The increased risk of thrombosis with fibrinogens Caracas V and Tokyo V are thought to be due to an abnormally tight fibrin network that resists fibrinolysis [78,79]. In some cases, treatments given for bleeding may contribute to an increased thrombotic risk. (See 'Treatment/prevention of bleeding' below.)

Cardiovascular disease associated with hyperfibrinogenemia is discussed below. (See 'Other rare manifestations' below.)

Obstetric complications — Compared with controls, women with quantitative or qualitative fibrinogen abnormalities have an increased incidence of bleeding and thrombotic complications during pregnancy and postpartum, as well as an increased risk of recurrent pregnancy loss and abruptio placentae (table 2) [43,80].

The likelihood of successful pregnancy appears to correlate with the fibrinogen level [36]. In a series of 204 individuals with congenital afibrinogenemia, 85 percent of females had experienced at least one pregnancy loss [49]. When it occurs, the timing of pregnancy loss is typically at approximately five to eight weeks gestation if fibrinogen replacement therapy is not administered [36]. (See 'Conception and pregnancy' below.)

The role of fibrinogen appears to be in the integrity of placental insertion rather than in earlier stages such as fertilization or initial implantation (see 'Functions in hemostasis and other processes' above). As discussed separately, fibrinogen levels typically increase as the pregnancy progresses, along with other changes. (See "Maternal adaptations to pregnancy: Hematologic changes", section on 'Coagulation and fibrinolysis'.)

Other rare manifestations — Case reports have described other clinical manifestations in certain inherited fibrinogen disorders (table 2).

●Renal amyloidosis – A hereditary form of renal amyloidosis caused by renal deposition of a mutant fibrinogen α chain has been reported. Inheritance is autosomal dominant and most of the affected individuals have developed renal failure [81-88]. Coagulation assays are not affected. A database of FGA gene mutations associated with hereditary amyloidosis is available at Mutations in Hereditary Amyloidosis. (See "Overview of amyloidosis", section on 'Pathogenesis' and "Renal amyloidosis", section on 'Hereditary renal amyloidosis'.)

●Hepatic storage disease – A form of hepatic storage disease caused by accumulation of an abnormal fibrinogen in the hepatocyte endoplasmic reticulum has been reported in individuals with mutations affecting exons 8 and 9 of the gene for fibrinogen γ (FGG) [89]. It is characterized by hypofibrinogenemia and variable severity of liver disease.

●Splenic rupture – Splenic rupture has been reported in individuals with congenital afibrinogenemia (incidence, 5 percent in a large series) [49].

●Bone cysts – Painful bone cysts have been reported in individuals with congenital afibrinogenemia [90]. These appear to be rare and to predominantly affect the long bones, possibly as a complication of bleeding. In a series of 204 individuals with congenital afibrinogenemia, painful bone cysts were reported in 18 percent [49].

●Abnormal wound healing – Delayed wound healing and/or surgical wound dehiscence has been reported in individuals with inherited afibrinogenemia or inherited dysfibrinogenemia [32,91,92]. (See "Basic principles of wound healing" and "Risk factors for impaired wound healing and wound complications".)

●Cardiovascular disease – Elevated fibrinogen levels (hyperfibrinogenemia) have been associated with inflammatory states and cardiovascular disease (see 'Fibrinogen synthesis and circulating levels' above and 'Acquired hyperfibrinogenemia' above), although a causative relationship may not exist, and there do not appear to be management implications specifically related to fibrinogen levels. Fibrinogen acts as an antithrombin; thus, low fibrinogen levels can be prothrombotic. Dysfibrinogenemia can be associated with arterial thrombosis, as noted above (see 'Thrombosis' above). The relationship between fibrinogen abnormalities and cardiovascular disease is discussed in more detail separately. (See "Overview of secondary prevention of ischemic stroke" and "Cardiovascular benefits and risks of moderate alcohol consumption".)

DIAGNOSTIC TESTING

Initial evaluation — A fibrinogen disorder may be suspected in an individual with unexplained bleeding, thrombosis, or pregnancy morbidity for whom other testing did not uncover a cause (algorithm 1). It may also come to attention in an asymptomatic individual with unexplained prolonged baseline prothrombin time (PT) or activated partial thromboplastin time (aPTT) or in an individual with a known familial fibrinogen disorder. Testing for dysfibrinogenemia is often added as a second- or third-line evaluation for an individual with thrombosis after more common thrombophilias have been eliminated. Acquired hypofibrinogenemia and dysfibrinogenemia may be seen in patients with liver disease, disseminated intravascular coagulation (DIC), or hemophagocytic lymphohistiocytosis (HLH).

The initial evaluation includes a personal and family history focusing on bleeding, thrombotic, and obstetric complications; a PT, aPTT, and thrombin time (TT; also called thrombin clotting time); and a plasma fibrinogen level. The following is supportive of a fibrinogen disorder in the appropriate clinical setting (typically a condition known to cause an acquired fibrinogen disorder or positive family history of an inherited fibrinogen disorder):

●Prolongation of PT, aPTT, and/or TT (algorithm 2). These tests all depend on production of a fibrin clot as the endpoint of the assay. The sensitivity of these tests varies depending on the assay and laboratory-specific reagents, and prolongation will typically detect a fibrinogen level <100 mg/dL, although some aPTT assays will not become prolonged unless the fibrinogen level is below 50 mg/dL. As a general rule, the TT and PT are more sensitive than the aPTT. Although the TT is a more sensitive screening test, its specificity is poor since there are other common causes for a prolonged TT. Similar to the TT, reptilase time (RT) is a useful screening test and is not affected by the presence of heparin; in some cases, prolongation of the RT may be more significant than the TT. If a mixing study has been done on one or more of these tests, it may show correction in the setting of afibrinogenemia or hypofibrinogenemia but not dysfibrinogenemia because a functionally abnormal fibrinogen may act as an inhibitor in a mixing study. (See "Clinical use of coagulation tests", section on 'Thrombin time (TT)' and "Clinical use of coagulation tests", section on 'Use of mixing studies'.)

●Abnormally low fibrinogen level (eg, <150 mg/dL). Of note, artifactually low levels of fibrinogen can be seen when blood clots in an improperly collected sample; if there is visible clotting in a plasma sample or the result is discordant with the clinical picture, the test should be repeated before embarking on an extensive laboratory evaluation.

The plasma fibrinogen assay typically reports functional fibrinogen activity (also called clottable fibrinogen) as a level in mg/dL. The most common laboratory test assays fibrinogen activity using the Clauss method, which measures time to clot formation after a high concentration of thrombin is added to citrated, platelet-poor patient plasma [93-96]. Functional assays measure only the fibrinogen that is incorporated into the clot formed in the test tube; certain abnormal fibrinogens may produce an abnormally low level if they fail to be incorporated into the clot or may inhibit clotting of normal fibrinogen.

If the fibrinogen level is low, the need for additional testing depends on the clinical setting and the likelihood of other diagnoses. Testing for fibrinogen disorders is often pursued after more common conditions are ruled out, as described in the following examples:

●In an ill individual with a known or suspected acquired cause of hypofibrinogenemia, such as liver disease, disseminated intravascular coagulation (DIC), or hemophagocytic lymphohistiocytosis (HLH), no additional testing of fibrinogen is necessary, and management is directed at resolving the underlying condition and preventing or treating bleeding and/or thrombosis. (See 'Management' below.)

●In an individual with unexplained bleeding, thrombosis, and/or pregnancy morbidity after more common causes of these findings have been eliminated and a fibrinogen disorder is suspected, TT and fibrinogen antigen level should be obtained. Additional details of the evaluation depend on the patient and family history and the prominent clinical features, as discussed separately. (See "Approach to the child with bleeding symptoms" and "Approach to the adult with a suspected bleeding disorder" and "Overview of the causes of venous thrombosis" and "Recurrent pregnancy loss: Evaluation" and "Clinical use of coagulation tests".)

●In an asymptomatic individual for whom the abnormality was an incidental finding, repeat fibrinogen level should be obtained for confirmation. Acquired conditions such as low-grade DIC, medication-induced abnormalities, and chronic liver disease should be ruled out first. If no apparent explanation is found, additional testing is indicated with TT, RT, and fibrinogen antigen level.

●In a family member of an individual with known hypofibrinogenemia or afibrinogenemia, screening with a PT, aPTT, TT, RT, fibrinogen activity, and antigen levels should be obtained. If abnormalities suggestive of a fibrinogen disorder are documented, genetic testing may be offered to determine whether the defect is inherited. (See 'Diagnostic confirmation' below.)

Consultation with a specialized coagulation laboratory and/or a clinician with expertise in coagulation testing may be appropriate.

Diagnostic confirmation — The diagnosis of a fibrinogen disorder is confirmed by the following [36,76]:

●Afibrinogenemia – Demonstration of absent plasma fibrinogen using both a functional assay and an immunoassay.

●Hypofibrinogenemia – Demonstration of low plasma fibrinogen (<150 mg/dL) using both a functional assay and an immunoassay.

●Dysfibrinogenemia – Demonstration of a discrepancy between functional and immunoreactive fibrinogen (eg, low functional activity level with normal or elevated immunological level).

As with many genetic disorders, genotyping has become increasingly available for confirming the diagnosis of congenital fibrinogen disorders. Sequencing of the fibrinogen genes is offered through certain clinical laboratories. An efficient, step-wise genetic screening approach for congenital fibrinogen disorders targeting specific exons has been developed [38]. If an inherited disorder is suspected, family history and genetic testing for disease-causing variants may be appropriate, although this testing is not required for diagnosis (algorithm 1). Other specialized assays for fibrinogen electrophoretic migration, fibrinopeptide release, and fibrin monomer aggregation are generally available only in research laboratories. Identification of a familial variant may be helpful in evaluating asymptomatic family members of an affected individual, or for preconception planning and prenatal diagnosis. It is also important to verify that the variant is indeed the cause of the clinical phenotype.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis of fibrinogen disorders includes other inherited and acquired bleeding and thrombotic disorders and other causes of pregnancy morbidity.

●Other causes of bleeding and/or prolonged thrombin time – Other causes of bleeding include a large number of inherited and acquired disorders such as inherited factor deficiencies (eg, hemophilia) and acquired factor inhibitors. Like fibrinogen disorders, these may be associated with bleeding and abnormal clotting times. Unlike fibrinogen disorders, most of these other conditions do not cause prolongation of the prothrombin time (PT), activated partial thromboplastin time (aPTT), or thrombin time (TT). Exceptions include the presence of heparin (low molecular weight or unfractionated heparin) due to heparin administration to the patient or a heparin flush used in an indwelling catheter. Like fibrinogen disorders, heparin in the sample can prolong the PT, aPTT, and TT, but, unlike fibrinogen disorders, heparin is associated with a normal reptilase time (RT). (See "Approach to the child with bleeding symptoms" and "Approach to the adult with a suspected bleeding disorder" and "Clinical use of coagulation tests", section on 'Reptilase time (RT)'.)

In addition to heparin, other causes of a prolonged PT, aPTT, and TT include direct thrombin inhibitors (dabigatran, argatroban, and bivalirudin); hypoalbuminemia; paraproteins (eg, as in multiple myeloma), which impair fibrinogen polymerization; and antibodies to thrombin (eg, in patients exposed to bovine thrombin preparations). Like fibrinogen disorders, some of these may be associated with bleeding. Unlike fibrinogen disorders, these conditions are not associated with abnormalities of fibrinogen function or immunoreactive fibrinogen levels. (See "Clinical use of coagulation tests", section on 'Thrombin time (TT)'.)

●Other causes of thrombosis and/or pregnancy loss – Other causes of thrombosis include a large number of inherited and acquired disorders, including inflammatory states, antiphospholipid syndrome, and inherited thrombophilias. Like fibrinogen disorders, these conditions may be inherited or acquired. Unlike fibrinogen disorders, these other conditions do not cause prolongation of the PT, aPTT, and TT or abnormalities of fibrinogen function or immunoreactive fibrinogen levels. (See "Overview of the causes of venous thrombosis" and "Clinical manifestations of antiphospholipid syndrome" and "Cryptogenic stroke".)

MANAGEMENT — The main goal of management is to prevent or treat serious bleeding and thrombosis and to prevent obstetrical complications. Not all patients require an intervention, since many individuals with mild dysfibrinogenemia or mild hypofibrinogenemia are clinically asymptomatic.

For those who do require hemostatic support, evidence to guide management is scarce because the inherited disorders are extremely rare and heterogeneous. For the most part, our practice is based on our clinical experience and that of other experts. Previous approaches that have worked in a specific patient are noted and used for that patient (and for affected family members with inherited disorders). Our practice is generally consistent with 2004 and 2014 guidelines from the United Kingdom Haemophilia Centres Doctors' Organisation (UKHCDO) and a 2016 consensus from a panel with expertise in bleeding disorders [76,97,98].

Treatment/prevention of bleeding

Acute bleeding — For patients with clinically important bleeding (or a need for emergency surgery that would cause clinically important bleeding) and isolated afibrinogenemia, hypofibrinogenemia (plasma fibrinogen level <100 to 150 mg/dL), or dysfibrinogenemia, without other coagulation factor deficiencies, we suggest raising the functional fibrinogen level to >100 to 150 mg/dL until hemostasis is achieved, using the higher range for more severe bleeding or more hemostatically challenging surgery. For the most severe bleeding (such as intracerebral bleeding), a target of 150 to 200 mg/dL is used [97].

These target levels are based on observational data from case reports and small series that suggest hemostasis is likely to be intact with functional fibrinogen levels above 100 mg/dL and demonstrate a low risk of adverse effects with administration of fibrinogen concentrate in individuals with inherited fibrinogen disorders [99-103]. Randomized trials comparing other fibrinogen thresholds or other therapies have not been conducted.

Products for replacing fibrinogen include fibrinogen concentrates and plasma products. These have not been directly compared with each other in randomized trials, and each has advantages and disadvantages [104]. We suggest use of a fibrinogen concentrate rather than other sources of fibrinogen, such as Cryoprecipitate or plasma, because the concentrates carry a lower risk of transfusion reactions and volume overload. Fibrinogen concentrate may also be associated with a lower risk of thrombosis compared with these other products as it does not contain other coagulation factors. For patients who do not have access to fibrinogen concentrate, we would use Cryoprecipitate because it is an excellent source of fibrinogen in a small volume. For those without access to Cryoprecipitate, we would use plasma. Involvement of a specialist with expertise in rare bleeding disorders is advised. Dosing is outlined below. (See 'Fibrinogen concentrate: Dosing and monitoring' below and 'Cryoprecipitate and Fresh Frozen Plasma (FFP): Dosing and monitoring' below.)

Once hemostasis has been established, a target fibrinogen level of >50 mg/dL is used until wound healing is complete. For individuals with afibrinogenemia or severe hypofibrinogenemia who have had a major bleed, secondary prophylaxis may be used to maintain trough activity levels >50 mg/dL. (See 'Routine prophylaxis' below.)

For women with heavy menstrual bleeding, additional treatments such as hormonal therapies and/or antifibrinolytic agents may be appropriate depending on the needs of the patient. These therapies for heavy menstrual bleeding are presented in detail separately. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Evaluation and approach to diagnosis" and "Abnormal uterine bleeding: Management in premenopausal patients".)

In contrast to isolated fibrinogen defects, which are likely to be inherited, management of bleeding in acquired fibrinogen disorders is more complex; this is because other coagulation factors (procoagulant and anticoagulant) are also likely to be abnormal. For individuals for whom fibrinogen deficiency is the predominant abnormality, fibrinogen concentrates may be appropriate, whereas those with multiple factor deficiencies may benefit from plasma products that contain other coagulation factors.

A review of the role of fibrinogen concentrates in acquired bleeding disorders has evaluated the available evidence and concluded that it is premature to advise routine use [105]. Arguments in favor of and against routine use have also been published [106,107]. Management of bleeding in these conditions is discussed in detail separately.

●Trauma – (see "Coagulopathy in trauma patients" and "Initial management of NON-hemorrhagic shock in adult trauma")

●Postpartum hemorrhage – (see "Postpartum hemorrhage: Medical and minimally invasive management")

●Liver disease – (see "Hemostatic abnormalities in patients with liver disease", section on 'Bleeding')

●Disseminated intravascular coagulation – (see "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Treatment')

There is no role for prothrombin complex concentrates in treating fibrinogen disorders, as these concentrates do not contain fibrinogen.

Elective surgery — Multidisciplinary consultation that includes a hemostasis expert is prudent prior to any elective procedure to determine the expected bleeding risk and develop a treatment plan. Evidence to guide decision making comes from case series [99-103]. Decisions should take into account the type of surgery, the severity of fibrinogen disorder, and the personal and/or family bleeding and thrombosis phenotypes. Patients with a known history of previous bleeding and those with congenital afibrinogenemia (regardless of personal or family bleeding history) should receive fibrinogen replacement prior to surgery and elective procedures that carry a risk of bleeding [97]. By contrast, an individual with moderate hypofibrinogenemia (eg, fibrinogen activity level >50 mg/dL) without a bleeding history can often be managed conservatively without prophylactic replacement therapy for low bleeding risk procedures.

For those treated with fibrinogen replacement, the first dose is given on the day of the procedure and an adequate level is confirmed before beginning the procedure. A target level of >100 mg/dL for major surgery and >50 mg/dL for minor surgery is reasonable [32]. Global hemostasis testing such as thromboelastography (TEG) is evolving and may be used to guide fibrinogen dosing at some institutions (see "Coagulopathy in trauma patients", section on 'Thromboelastography'). The level is maintained above >50 mg/dL postoperatively until hemostasis is assured. Some experts use a target fibrinogen level of >100 mg/dL until wound healing [108]. The duration of therapy can vary from a few doses to up to two to three weeks, with longer durations for the more hemostatically challenging procedures. Dosing calculations are discussed below. (See 'Fibrinogen concentrate: Dosing and monitoring' below and 'Cryoprecipitate and Fresh Frozen Plasma (FFP): Dosing and monitoring' below.)

Other possible perioperative interventions may include the following:

●Fibrin glue may be used in some cases, especially surfaces that are not amenable to suturing, cautery, or other procedures. (See "Fibrin sealants" and "Overview of topical hemostatic agents and tissue adhesives".)

●Antifibrinolytic agents are controversial. Use of an antifibrinolytic agent may be appropriate for some individuals, especially those undergoing mucosal or dental procedures. However, there may be an increased risk of thrombotic complications, and these agents should be used with caution in individuals with a personal or family history of thrombosis [76]. (See 'Role of antifibrinolytic agents' below.)

●Thromboprophylaxis (mechanical or pharmacologic) is important and appropriate for individuals with fibrinogen disorders who undergo surgery, with the specific therapy tailored to the surgical procedure and thromboembolic risk. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients" and "Prevention of venous thromboembolism in adult orthopedic surgical patients".)

Routine prophylaxis — Most patients with fibrinogen disorders do not require routine primary prophylaxis in the absence of a history of a severe bleeding event (ie, most are treated with "on-demand" fibrinogen replacement therapy at the time of bleeding, surgery, or pregnancy). (See 'Acute bleeding' above and 'Elective surgery' above and 'Conception and pregnancy' below.)

However, some individuals with afibrinogenemia or severe hypofibrinogenemia (eg, fibrinogen <10 mg/dL) may be treated prophylactically with fibrinogen concentrates or Cryoprecipitate, similar to routine factor replacement in severe hemophilia, especially if they have had a previous bleeding event (ie, as secondary prophylaxis) [30,36]. In a series that included 204 individuals with congenital afibrinogenemia, 35 percent were treated with regular prophylaxis using a fibrinogen concentrate due to their severe bleeding phenotype [49]. (See 'Bleeding and abnormal clotting times' above.)

It is difficult to assess the efficacy of primary and secondary prophylaxis due to small numbers of affected individuals, and thus practice must be individualized according to the patient's bleeding and thrombotic history and response to previous therapies [30]. A target trough fibrinogen level of 50 mg/dL is considered reasonable for prophylaxis against bleeding [97]. (See 'Fibrinogen concentrate: Dosing and monitoring' below.)

Additional settings in which prophylactic administration of fibrinogen replacement may be appropriate include the following:

●During pregnancy, especially if there has been prior pregnancy loss attributed to the fibrinogen disorder. (See 'Conception and pregnancy' below.)

●During anticoagulation for a thrombotic complication, especially if there is a history of bleeding, afibrinogenemia, or severe hypofibrinogenemia. (See 'Treatment and prevention of thrombosis' below.)

Fibrinogen concentrate: Dosing and monitoring — Fibrinogen concentrates (eg, RiaSTAP, Haemocomplettan, FIBRYGA [previously called FIBRYNA]) are prepared from pooled human plasma and are available as lyophilized powders (approximately 1 g [1000 mg]/vial) that are reconstituted in a small volume.

Administration of a fibrinogen concentrate is used to treat or prevent bleeding and to prevent pregnancy loss in patients with congenital afibrinogenemia or moderate to severe hypofibrinogenemia. Fibrinogen concentrates are not used for the management of dysfibrinogenemia. The dose and intensity of monitoring depend on the clinical situation, with more aggressive treatment for more severe bleeding or more hemostatically challenging surgery.

The initial dose calculation for the dose in mg/kg body weight is based on the following formula:

The fibrinogen level is expressed in mg/dL. The correction factor is in mg/dL or mg/kg. The correction factor is 1.7 for RiaSTAP and Haemocomplettan and 1.8 for FIBRYGA. Thus, the dose in mg is calculated as follows:

For FIBRYGA in children <12 years of age, divide by 1.4 instead of 1.8.

As an example, a 50 kg individual with a fibrinogen level of 0 mg/dL and a desired level of 150 mg/dL would be given 4100 to 4400 mg, rounded to the nearest vial size (approximately four 1000 mg vials).

If the patient's fibrinogen level is not known, the product information states that a dose of 70 mg/kg can be used for initial dosing.

Subsequent doses are based on the patient's trough plasma fibrinogen levels rather than a fixed dose or schedule as pharmacokinetics vary widely among individuals [30]. The half-life of fibrinogen is usually 3 to 3.5 days (77 to 88 hours) [100]. Thus, as a general rule, plasma fibrinogen levels can be measured once per day (more frequently if increased or unexpected bleeding occurs); the interval may be extended as healing is completed. The amount of fibrinogen concentrate in subsequent doses will be lower (approximately one-half to one-third the initial dose) since the patient's fibrinogen level will not return to zero between doses. A common dosing interval for postoperative management is every two to four days depending on the trough level and the underlying indication for replacement. If the trough level is too low, it is preferable to shorten the dosing interval (ie, give more frequent infusions) rather than increasing the amount of fibrinogen given in each dose [97].

Replacement guidelines for patients with dysfibrinogenemia are not well defined due to the heterogeneity of the phenotype and the greater risk of thrombosis. Fibrinogen replacement is usually limited to on-demand if there is abnormal bleeding.

Dosing in early pregnancy is discussed below. (See 'Conception and pregnancy' below.)

In a 2006 survey of clinicians who provided prophylaxis to individuals with afibrinogenemia or severe hypofibrinogenemia (eg, <10 mg/dL), a median fibrinogen dose of 53 mg/kg was given approximately once per week (19 patients surveyed; dose range, 18 to 120 mg/kg; schedule, once per week to once per month) [30].

Cost may be a consideration in the availability of fibrinogen concentrate. A survey of 30 transfusion medicine fellowship directors in the United States found that the majority do not use fibrinogen concentrate for bleeding, with cost and off-label indication as one of the primary reasons [109].

Cryoprecipitate and Fresh Frozen Plasma (FFP): Dosing and monitoring — Cryoprecipitate (cryo) can be used as a source of fibrinogen when fibrinogen concentrate is unavailable. One unit of Cryoprecipitate contains all of the fibrinogen present in one unit of whole blood (approximately 200 to 400 mg) in a volume of 10 to 20 mL (table 3). Each unit of Cryoprecipitate raises the plasma fibrinogen concentration by approximately 7 to 10 mg/dL, with a half-life of approximately four days.

●For severe bleeding, 1 unit per 5 kg of body weight (eg, 10 units in a 50 kg individual) can be administered.

●For minor bleeding, 1 unit per 10 kg (eg, 5 units in a 50 kg individual) may be sufficient.

As with fibrinogen concentrate, the plasma fibrinogen level is monitored at the appropriate interval (daily for major bleeding or major surgery, less often for minor bleeding or minor surgery), and repeat doses are administered to maintain the level above the appropriate threshold.

Complications with Cryoprecipitate include transfusion reactions (eg, allergic, infectious) and thrombosis [110,111]. Rarely, patients with afibrinogenemia have developed antibodies to fibrinogen following replacement therapy [112,113]. Additional information about dosing and potential adverse effects is presented separately. (See "Clinical use of Cryoprecipitate".)

If Cryoprecipitate is unavailable, a plasma product such as Fresh Frozen Plasma (FFP) or Plasma Frozen Within 24 Hours of Collection (PF24) may be used. Dosing is approximately 10 to 15 mL/kg, as presented separately (table 3). (See "Clinical use of plasma components".)

Role of antifibrinolytic agents — Antifibrinolytic agents such as tranexamic acid or epsilon-aminocaproic acid may be used, especially to treat or prevent mucosal bleeding. However, systemic administration of these agents has been associated with thrombosis, and these agents should not be used (or should be used with extreme caution) in patients with a personal or family history of thrombosis [76]. Local treatment with these agents (eg, 5 percent mouthwash solution 10 mL four times daily for 7 to 10 days) may be useful in patients undergoing oral or dental surgery [114].

Conception and pregnancy — Women with congenital fibrinogen disorders are at increased risk of pregnancy loss, subchorionic hematomas, placental abruption, and postpartum hemorrhage. Pregnancy in an individual with a congenital fibrinogen disorder is considered high risk, and consultation between experts in rare bleeding disorders and high-risk pregnancy is advised [97]. The first case of a successful pregnancy in a woman with afibrinogenemia supported by fibrinogen infusion was reported in 1985 [115]. Before the availability of routine fibrinogen replacement, women with afibrinogenemia rarely had a successful pregnancy. As noted above, fibrinogen appears to be required for normal placental implantation during the first trimester of pregnancy. (See 'Functions in hemostasis and other processes' above.)

A systematic review of obstetrical and postpartum complications in 188 pregnancies in 70 women with hereditary fibrinogen disorders reported between 1985 and 2018 confirmed a high rate of adverse obstetrical outcomes in individuals with either quantitative or qualitative fibrinogen disorders [116]. There were 14 women with afibrinogenemia, 22 with hypofibrinogenemia, 26 with dysfibrinogenemia, and 8 with hypodysfibrinogenemia. Fibrinogen was administered in half of the pregnancies in women with afibrinogenemia and 14 to 25 percent of pregnancies in women with other congenital fibrinogen disorders. The following complications were observed:

●Pregnancy loss (miscarriage) in approximately half, including 15 of 35 pregnancies (43 percent) in women with afibrinogenemia and 27 of 63 pregnancies (43 percent) in women with dysfibrinogenemia.

●Metrorrhagia in 22 percent of pregnancies during the first trimester.

●High rate of placental abruption (8 percent overall) in both quantitative and qualitative disorders.

●High incidence of postpartum hemorrhage (19percent), although none were observed in women with afibrinogenemia receiving fibrinogen replacement.

●Postpartum thrombosis in six pregnancies.

The following approaches may be helpful to prevent pregnancy loss, bleeding, and/or thrombosis during the pregnancy and postpartum:

●Afibrinogenemia or severe hypofibrinogenemia (fibrinogen <50 mg/dL) – For women with congenital afibrinogenemia or severe hypofibrinogenemia, fibrinogen is administered as soon as pregnancy is confirmed. This practice is based on evidence from case reports and small series [76,99,117-120]. A joint United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) and Royal College of Obstetricians and Gynaecologists (RCOG) guideline published in 2017 provides specific guidance for the management of pregnancy and delivery in those conditions [121].

•We start replacement therapy as early as four to five weeks of gestation and continue throughout pregnancy and delivery.

•We use a target trough level of 100 mg/dL, with monitoring every one to two weeks. Some experts use a lower trough level (eg, >50 to 60 mg/dL) during the first trimester [97]. If a previous pregnancy has been unsuccessful, it may be possible to use a higher trough level [99].

•The required dose is likely to increase significantly as the pregnancy progresses (due to increased clearance). Typical reported doses range from 2 g twice weekly during the first trimester to 5 g three to four times per week close to term [99].

•During labor and for a minimum of 24 hours postpartum, the target fibrinogen level is at least 150 to 200 mg/dL; the UKHCDO/RCOG 2017 guideline recommends target levels of 150 to 200 mg/dL for at least three days [121]. Continuous infusion may prevent placental abruption. We use a target of 200 mg/dL for cesarean delivery.

•After the first 24 hours postpartum, a fibrinogen level >50 mg/dL is appropriate until healing is complete. Consideration should be given to a higher trough level for the first 72 hours in women with a bleeding phenotype or a history of postpartum hemorrhage.

•Fibrinogen replacement is associated with increased risk of thrombosis. To minimize thromboembolic risk, we avoid overcorrecting fibrinogen levels. If prophylactic dose LMWH is indicated in women with low bleeding risk, it can be given while providing fibrinogen replacement.

●Moderate hypofibrinogenemia (fibrinogen between50 and 150 mg/dL) – Women with moderate hypofibrinogenemia are usually asymptomatic. However, pregnancy in those individuals is associated with increased risk of miscarriage, bleeding, and postpartum hemorrhage. While fibrinogen replacement for labor and delivery is recommended, the role of fibrinogen substitution during pregnancy has not been well established. It should be considered in the antenatal period in women with recurrent miscarriages or bleeding during pregnancy.

In a series of 12 full-term pregnancies in 11 women with hypofibrinogenemia (pre-pregnancy mean fibrinogen level, 72 mg/dL; range 48 to 111 mg/dL), the pregnancies were uneventful and the fibrinogen level remained stable throughout the pregnancy [122]. Fibrinogen replacement was provided for labor and delivery in all, with a mean fibrinogen level at delivery of 153 mg/dL (range 79 to 254 mg/dL); it was not clear how many received replacement during pregnancy. There was no preterm delivery, postpartum hemorrhage, or thrombosis.

●Dysfibrinogenemia – For women with congenital dysfibrinogenemia, management is more challenging because clinical phenotypes and levels of functional fibrinogen are more variable; evidence to guide therapy is extremely limited [99]. The patient's previous clinical history of thrombosis or bleeding should be used to guide the treatment of these women.

•The management of pregnant women without a prior history of bleeding or thrombosis should be discussed by a multidisciplinary team. Routine use of replacement therapy during pregnancy in these individuals is not indicated. Pregnant women with fibrinogen activity of less than 50 mg/dL are more prone to spontaneous abortion and postpartum bleeding.

•Women with a bleeding phenotype (or family history of bleeding during pregnancy) can be given fibrinogen during the pregnancy or delivery. Others can be treated expectantly with vaginal delivery and fibrinogen given only if bleeding occurs or if Cesarean delivery is required [99].

•Management of recurrent miscarriages in individuals with dysfibrinogenemia is controversial, and evidence is limited to case reports. Therapy may include fibrinogen replacement, anticoagulation, or both [99]. One report described successful pregnancy in three of four related women with a history of recurrent pregnancy loss who were treated with continuous fibrinogen replacement therapy initiated as soon as pregnancy was diagnosed [123]. Another successful pregnancy was reported in a patient with personal history of miscarriage and positive family history of thrombosis who was treated with fibrinogen concentrates and low-dose enoxaparin throughout pregnancy [124].

•Strong consideration should be given to postpartum thromboprophylaxis (eg, with low molecular weight heparin) in women with a personal or family history of thrombosis and/or those without previous bleeding [97]. In a registry of patients with a thrombophilic dysfibrinogenemia, 7 of 15 women developed postpartum thrombosis during a total of 34 normal deliveries [43]. Others may be managed with mechanical thromboprophylaxis. (See "Use of anticoagulants during pregnancy and postpartum".)

Treatment and prevention of thrombosis — Evidence to guide treatment of thrombosis in patients with fibrinogen disorders is limited. In general, individuals with thrombotic complications resulting from an abnormal fibrinogen should be treated with anticoagulation unless there is a contraindication (table 4). Low molecular weight heparins are the anticoagulant of choice for venous thrombosis. Warfarin remains an option for long-term anticoagulation. There are no data on the efficacy and safety of the direct oral anticoagulants in these conditions. The duration of anticoagulation should be similar to the management of thrombosis in the general population.

●Individuals with moderate hypofibrinogenemia (eg, fibrinogen level >50 mg/dL) can generally be safely anticoagulated.

●For those with congenital afibrinogenemia, anticoagulation should be accompanied by fibrinogen replacement therapy (see 'Fibrinogen concentrate: Dosing and monitoring' above) to reduce the risk of bleeding complications [97].

●Individuals with inherited dysfibrinogenemias do not need fibrinogen replacement; these individuals are managed with anticoagulation.

●For acquired dysfibrinogenemias, treatment of the underlying cause is pursued along with anticoagulation, as discussed separately. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Treatment' and "Hemostatic abnormalities in patients with liver disease", section on 'Venous thromboembolism (VTE)'.)

In contrast to treatment of thrombosis, routine venous thromboembolism (VTE) prophylaxis is generally not used outside of high-risk settings in which it is appropriate, such as perioperatively, during an acute medical illness, or postpartum. Individuals with a known thrombophilic fibrinogen variant are managed similarly to other individuals with a known thrombophilia. Aspirin can be used without replacement therapy in some individuals with afibrinogenemia after evaluation of the bleeding risk, as noted in a survey of specialized centers [97]. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults" and "Prevention of venous thromboembolism in adult orthopedic surgical patients" and "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

All individuals with a thrombophilic fibrinogen variant should be educated about additional risk factors for thrombosis, signs and symptoms of thromboembolism, and risk reduction strategies (eg, avoiding prolonged immobilization). (See "Overview of the causes of venous thrombosis", section on 'Acquired risk factors'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Acquired bleeding disorders" and "Society guideline links: Rare inherited bleeding disorders".)

SUMMARY AND RECOMMENDATIONS

●Role in hemostasis – Fibrinogen circulates at a concentration of 200 to 400 mg/dL and increases as an acute phase reactant. During clotting, fibrinogen is converted to fibrin, which polymerizes and provides a major structural component of the clot (figure 2). Fibrin also supports platelet aggregation and serves as a template for the binding of thrombin, fibrinolytic proteins, wound healing, and placental implantation (figure 1). (See 'Biology' above.)

●Genetic disorders – Congenital fibrinogen disorders can be caused by mutations in FGA, FGB, or FGG (figure 3). These rare disorders can be quantitative (afibrinogenemia and hypofibrinogenemia), qualitative (dysfibrinogenemia), or both (hypodysfibrinogenemia). (See 'Heritable (genetic) disorders' above.)

●Acquired disorders – Acquired hypofibrinogenemia and dysfibrinogenemia can be caused by liver disease, disseminated intravascular coagulation (DIC), hemophagocytic lymphohistiocytosis (HLH), and other disorders (table 1). (See 'Acquired abnormalities' above.)

●Clinical features – Fibrinogen disorders can present with bleeding or incidentally; thrombosis, obstetric complications, and other rare findings may occur (table 2). The clinical phenotype is most severe in individuals with congenital afibrinogenemia, who have a high rate of bleeding, thrombosis, bone cysts, and pregnancy loss. The prothrombin time (PT), activated partial thromboplastin time (aPTT), and/or thrombin time (TT) are typically prolonged; fibrinogen levels and/or function are decreased. (See 'Clinical manifestations' above.)

●Evaluation – The evaluation of a suspected fibrinogen disorder includes a personal and family history of bleeding, thrombotic, and obstetric complications and laboratory testing (algorithm 1). Additional specialized testing may be indicated in some individuals, done in consultation with an expert in rare bleeding disorders. Diagnosis is confirmed by a functional assay and immunoassay that show an abnormality in the plasma fibrinogen level and/or function. (See 'Diagnostic testing' above.)

●Differential diagnosis – The differential diagnosis includes other inherited and acquired bleeding and thrombotic disorders and other causes of pregnancy morbidity. Simultaneous prolongation of the PT, aPTT, and TT may be caused by heparins and direct thrombin inhibitors (dabigatran, argatroban, and bivalirudin), paraproteins in multiple myeloma, and antibodies in patients exposed to bovine thrombin. (See 'Differential diagnosis' above.)

●Management

•Bleeding – For patients with afibrinogenemia, hypofibrinogenemia, or dysfibrinogenemia who have clinically important bleeding or require emergency surgery, we suggest raising the functional fibrinogen level to >100 to 150 mg/dL (Grade 2C). The higher range is used for more severe bleeding or more hemostatically challenging surgery. For intracerebral bleeding, the target is 150 to 200 mg/dL. When fibrinogen replacement is required, we suggest a fibrinogen concentrate rather than Cryoprecipitate or plasma (Grade 2C). The risk of transfusion reactions and volume overload is lower with a concentrate. Management of bleeding in acquired fibrinogen disorders is more complex because other coagulation factors are also likely to be abnormal. (See 'Acute bleeding' above and 'Fibrinogen concentrate: Dosing and monitoring' above and 'Cryoprecipitate and Fresh Frozen Plasma (FFP): Dosing and monitoring' above.)

•Surgery – Elective surgery is managed in consultation with a hemostasis expert. Interventions may include fibrinogen replacement, fibrin glue, and/or an antifibrinolytic agent. More aggressive thromboprophylaxis than usual may be appropriate in individuals with thrombotic variants. (See 'Elective surgery' above.)

•Prophylaxis – For most patients who have not had a severe bleed, we suggest not using routine prophylaxis (Grade 2C). Secondary prophylaxis may be appropriate after a life-threatening bleed, and primary prophylaxis may be appropriate in selected individuals with a severe familial bleeding phenotype. A period of prophylactic fibrinogen may be reasonable during pregnancy or if anticoagulation is required, especially for severe deficiency of functional fibrinogen. (See 'Routine prophylaxis' above and 'Conception and pregnancy' above and 'Treatment and prevention of thrombosis' above.)