Disorders of fibrinogen

INTRODUCTION — Fibrinogen plays a pivotal role in hemostasis and host defense and facilitates wound healing.

Fibrinogen disorders can have both hemorrhagic and thrombotic manifestations, as well as effects on pregnancy.

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

Separate topic reviews discuss other bleeding disorders:

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

●Less-common hereditary coagulation factor deficiencies – (See "Rare inherited coagulation disorders" and "Factor XI (eleven) deficiency".)

●Acquired factor inhibitors – (See "Acquired hemophilia A (and other acquired coagulation factor inhibitors)".)

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

●Disseminated intravascular coagulation (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

●Structure – 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 nomenclature Aα and Bβ come from the designation of the small fibrinopeptides A (FpA) and B (FpB), which are cleaved by thrombin leading to the α and β chains without fibrinopeptides [1]. (See 'Formation of fibrin' below.)

The trinodular 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 (AαB_βγ)₂ [2].

Polymorphisms have been described in FGA and FGB, the Aα and Bβ gene, respectively. They are associated with abnormal fibrin clot structure, leading to hypofibrinolysis, defective factor XIII-dependent fibrin cross-linking, and increased plasma fibrinogen concentration, especially in smokers [3,4]. (See 'Acquired hyperfibrinogenemia' below.)

Alternative splicing produces a normally occurring variant of the γ chain, which is referred to as "gamma-prime" (γ'). This yields γ' fibrinogen when assembled into the fibrinogen molecule [5-8]. This variant, which constitutes approximately 8 to 15 percent of plasma fibrinogen, is associated with structural changes in fibrin clots that include more extensive crosslinking and greater resistance to lysis. Another alternative splicing gives rise to a longer Aα chain (αE) in one to two percent of fibrinogen molecules [9].

●Synthesis – Fibrinogen is produced primarily in the liver. All three polypeptides (Aα, Bβ, and γ) are synthesized by hepatocytes and assembled in a stepwise manner in the liver [10,11]. Carbohydrate side chains are added to the β and γ chains before the molecule is secreted into the circulation. Synthesis is controlled at the level of transcription. Extra-hepatic synthesis occurs in the trophoblast and in epithelial cells of the lung [12,13].

There is an inflammation-induced increase in fibrinogen, mainly due to the acute phase response. As an acute phase reactant, fibrinogen is increased by interleukin-6 (IL-6)-mediated increases in transcription. The acute phase response can elevate fibrinogen 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 [14-16]. IL-1 and tumor necrosis factor-alpha suppress fibrinogen synthesis [14,15]. (See "Acute phase reactants".)

●Concentration

•Plasma – As with all clotting factors, fibrinogen is present in plasma but not serum. It circulates at a concentration of approximately 200 to 400 mg/dL, by far the highest concentration of any coagulation factor [17]. This is because fibrinogen contributes a major structural component of the clot rather than an enzymatic function.

The half-life of fibrinogen is approximately three to four days, with a catabolic rate of approximately 25 percent per day [18]. The fibrinogen catabolic pathway is mostly undetermined.

Circulating plasma fibrinogen levels increase with age, obesity, smoking, and inflammatory states; levels decrease with alcohol consumption [19].

•Platelets – The origin of platelet fibrinogen is controversial, as fibrinogen from platelets is structurally distinct from plasma fibrinogen [20,21]. A small pool of fibrinogen is principally taken up by platelets in a process mediated by platelet receptor GPIIb/IIIa and stored in platelet alpha-granules; this fibrinogen can support platelet aggregation. (See "Megakaryocyte biology and platelet production", section on 'Granules'.)

Functions in hemostasis and other processes — Fibrinogen has numerous functional interactions and plays a pivotal role in hemostatic balance.

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 prothrombin. (See "Overview of hemostasis", section on 'Thrombin generation'.)

When thrombin binds to fibrinogen, it cleaves 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. However, some homozygous fibrinogen variants with a defect in FpA release are still able to polymerize via B-b interactions [22].

Structural defects of the N-terminal regions of the Aα and Bβ chains can markedly impair thrombin binding, FpA or FpB release, and/or the rate of fibrin formation [23]. It is not surprising that many abnormal fibrinogens have mutations involving this region. However, the majority of the affected individuals are asymptomatic, although some have excessive bleeding, especially after surgery or childbirth. (See 'Clinical manifestations' below.)

●Fibrin polymerization – In hemostasis, release of negatively charged FpA and FpB causes spontaneous fibrin monomer polymerization to form the clot. The figure shows a scanning electron micrograph image of polymerized fibrin (figure 2).

Polymerization sites are located at the N-terminus of the Aα and Bβ chains (E domain) and the C-terminus of the γ chains (D domain). The process is initiated by complementary noncovalent binding of the polymerization sites through knob-hole interactions 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), lateral aggregation of protofibrils, and branching to form the fibrin network (figure 3) [24].

Pathogenic gene variants affecting these binding sites may delay fibrin polymerization and produce heterogeneous clinical manifestations. (See 'Clinical manifestations' below.)

●Fibrin crosslinking – Once polymerized, fibrin is crosslinked. This final step strengthens the clot against mechanical and enzymatic disruption. Crosslinking is mediated by activated factor XIII (FXIIIa), which binds fibrin and generates covalent bonds between D domains of the fibrin fibers (figure 3). These bonds involve γ-γ as well as α-α (alpha C region domain) and α-γ chain interactions [11,25,26].

Crosslinking stabilizes the clot and renders it resistant to disruption. Defective crosslinking 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 factor XIII deficiency. (See "Rare inherited coagulation disorders", section on 'Factor XIII deficiency (F13D)'.)

It has been proposed that increased crosslinking might predispose to cardiovascular disease [27,28]. Clots containing γ' fibrinogen may have greater crosslinking (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 [29,30]. However, there is no evidence of a clinically significant causative role. On the contrary, in a murine model, elimination of fibrin γ-chain crosslinking increased pulmonary emboli, suggesting that fibrin γ-chain crosslinking may be essential for clot stability and could reduce the risk of clot embolization [31].

Platelet aggregation — Fibrinogen binds platelets and 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 impair plasmin generation and reduce fibrinolysis [32]. The rate of fibrinolysis is also influenced by the thickness of the fibers [33]. Resistance to plasmin can result from mutations in the C-terminus of the Aα chain associated with abnormal albumin binding [34-36]. These mechanisms explain the thrombophilic phenotype in some 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 crosslinking as well as its interaction with platelet GPIIb/IIIa [32,37-39]. (See "Platelet biology and mechanism of anti-platelet drugs", section on 'Overview of platelet function'.)

Fibrin has thrombin-neutralizing activity, and it has been proposed that severe fibrinogen deficiency or dysfibrinogenemia might increase thrombosis risk because thrombin activity is generated at a normal rate, but neutralization is decreased (although further study is needed) [40]. Reduced antithrombin activity and increased thrombin generation with platelet activation and VWF-mediated platelet aggregation may occur in some individuals [2,41,42].

Resistance to fibrinolysis may contribute to some thrombotic phenotypes such as chronic thromboembolic pulmonary hypertension (CTEPH) following pulmonary embolism. In a small study involving 33 patients with CTEPH, five were found to have dysfibrinogenemia [43]. However, among dysfibrinogenemia variants described in this cohort, two appear not to be pathogenic variants, and one is usually identified in hypofibrinogenemia with fibrinogen storage disease; as a result, a clear link between CTEPH and dysfibrinogenemia is debated. (See "Epidemiology, pathogenesis, clinical manifestations and diagnosis of chronic thromboembolic pulmonary hypertension", section on 'Pathogenesis'.)

Wound healing — Fibrinogen is involved in other physiologic processes including wound healing and inflammatory and immune responses [44]. (See "Basic principles of wound healing", section on 'Epithelialization' and "An overview of the innate immune system", section on 'Integration into other systems'.)

Placental insertion — 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 [45].

Some patients with congenital fibrinogen disorders have an increased risk of pregnancy loss, obstetric 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 disorders

•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 to below the lower end of the normal range. 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 disorders

•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 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 circulating fibrinogen, fibrin, fibronectin, and other plasma proteins precipitate at low temperatures (figure 4). Cryofibrinogenemia can be asymptomatic (incidental finding in a healthy person) or associated with cutaneous or rheumatologic manifestations such as cold sensitivity, purpura, skin necrosis, or Raynaud phenomenon. (See 'Cryofibrinogenemia' below.)

HERITABLE (GENETIC) DISORDERS — Heritable fibrinogen disorders include quantitative disorders (afibrinogenemia and hypofibrinogenemia), qualitative disorders (dysfibrinogenemia), and combined disorders (hypodysfibrinogenemia) [46,47]. (See 'Types of fibrinogen abnormalities' above.)

●Databases – International databases that include all the identified variants in fibrinogen genes are available online. These include the Human fibrinogen database and the Human Gene Mutation database (HGMD) [48]. Variants have been summarized and updated in various review articles and are illustrated in the figure (figure 5) [2,47,49-52].

●Prevalence – These disorders are rare, although some individuals remain undiagnosed.

•According to a 2014 global survey of rare bleeding disorders, severe inherited fibrinogen deficiencies accounted for 1712 of 283,397 inherited bleeding disorders (0.6 percent of the total; 8 percent of rare coagulation disorders), which is approximately as common as factor V or factor X deficiency and approximately 100 times less common than hemophilia A [53].

•Support for a higher prevalence comes from reports that have found more than 50 percent of individuals with fibrinogen variants are asymptomatic and identified incidentally or through familial screening [54-56].

●Genotype-phenotype correlation – Bleeding can correlate with the fibrinogen level, but it is not always possible to predict the genotype-phenotype relationship in the congenital dysfibrinogenemias, making it difficult to anticipate whether a specific variant is more likely to cause bleeding, thrombosis, both, or neither [54,57]. Structural analysis has been used to correlate specific variants with specific alterations of protein function [32,38,58].

Congenital afibrinogenemia or hypofibrinogenemia

●Afibrinogenemia – Congenital afibrinogenemia is an extremely rare (estimated incidence one per million), autosomal recessive condition due to homozygosity or compound heterozygosity for null mutations in one of the fibrinogen genes (mainly FGA) [2,52,59-62]. Consanguinity may play a role in some kindreds.

A number of variants in FGA and other fibrinogen genes have been identified (figure 5); these may affect mRNA splicing or stability; protein production or stability; or hexamer assembly, storage, or secretion [60]. In a large 2021 case series, 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 [63].

●Hypofibrinogenemia – Congenital hypofibrinogenemia (fibrinogen or below the lower limit of normal range, typically <150 mg/dL [<1.5 g/L]) is often seen in heterozygous carriers of afibrinogenemia mutations [2,60,64-66]. A classification of congenital fibrinogen disorders published in 2018 defines hypofibrinogenemia as any value below the reference range [67]. Congenital hypofibrinogenemia is more prevalent than afibrinogenemia, but the true incidence is unknown since many cases are asymptomatic and never come to medical attention [47].

Plasma fibrinogen levels of ≥100 mg/dL are often sufficient to prevent spontaneous bleeding, and affected individuals often do not come to medical attention. However, bleeding, pregnancy loss, or liver disease may occur with surgery, trauma, or pregnancy. Bleeding risk is likely to increase as the fibrinogen level decreases to <100 mg/dL. (See 'Bleeding and abnormal clotting times' below.)

Congenital dysfibrinogenemia or hypodysfibrinogenemia — Congenital fibrinogen variants that affect fibrinogen function can be categorized as dysfibrinogenemia (normal levels of dysfunctional fibrinogen) or hypodysfibrinogenemia (dysfunctional fibrinogen at low plasma concentration). 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 dysfibrinogenemias (and hypodysfibrinogenemias) is autosomal dominant, mainly 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 [47]. Abnormalities may involve alteration of fibrinopeptide release, fibrin polymerization, fibrin crosslinking, 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 [47].

Examples of common sites of pathogenic variants ("hotspots" (figure 5)) 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 [54]. The cumulative incidences of major bleeding and thrombosis at age 50 years were 19 and 30 percent, respectively [54]. 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 [54].

As for afibrinogenemia and hypofibrinogenemia variants, 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 disorders because liver disease and disseminated intravascular coagulation (DIC) are common (table 1). 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 prevalence as high as 80 percent if a highly sensitive assay is used [68]. Dysfibrinogenemia has been seen in biliary obstruction, acute liver failure, chronic liver disease, cirrhosis, and hepatoma [68-73]. The abnormal fibrinogen has an increased content of sialic acid residues that results in delayed fibrin aggregation [74]. Cleavage of the A and B fibrinopeptides and the crosslinking of fibrin by factor XIIIa are normal. Cleavage of sialic acid from the abnormal fibrinogen restored fibrinogen function to normal in vitro [75]. The impact of this abnormal fibrinogen has not been well studied, but it is unlikely to be associated with significant alteration of bleeding risk.

●Hypofibrinogenemia – Liver disease can also reduce fibrinogen levels. Typically, this occurs with advanced liver disease severe enough to compromise liver synthetic function.

The impact of dysfibrinogenemia and hypofibrinogenemia on bleeding risk in individuals with liver disease is difficult to assess since liver disease produces numerous procoagulant and anticoagulant changes. Patient evaluation is presented separately. (See "Hemostatic abnormalities in patients with liver disease".)

DIC — Disseminated intravascular coagulation (DIC) is a consumptive coagulopathy that can cause hypofibrinogenemia and/or dysfibrinogenemia (figure 6). Increased fibrin degradation products in DIC also impair normal fibrinogen function.

Acute DIC is the most common cause of acquired hypofibrinogenemia. In chronic DIC, the fibrinogen may be normal or even increased. Patients with DIC and hypofibrinogenemia may have bleeding or thrombotic manifestations. Evaluation and management are discussed in detail separately. (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults" and "Etiology and diagnosis of coagulopathy in trauma patients".)

Hemophagocytic lymphohistiocytosis — Hemophagocytic lymphohistiocytosis (HLH) is an aggressive systemic disorder of excessive immune activation and multiorgan dysfunction. Hypofibrinogenemia is frequently seen (and is one of the syndromic criteria), often with liver enzyme abnormalities and prolonged coagulation times. The mechanism of hypofibrinogenemia is 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 fibrinogen function have been described in various conditions. Examples include [76-81]:

●Systemic lupus erythematosus (SLE)

●Rheumatoid arthritis (RA)

●Ulcerative colitis

●Multiple myeloma

●Mitochondrial myopathy

●Medications (eg, isoniazid)

These antibodies may interfere with fibrinopeptide release, fibrin monomer polymerization, or fibrin crosslinking. 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.

Some individuals have no identifiable underlying disorder.

Patients exposed to fibrin glue during surgical procedures using a product prepared from bovine sources can develop alloantibodies against bovine fibrinogen that may cross-react with human fibrinogen [82]. Commercial fibrin sealants made from human sources (eg, Tisseel kit VH, Vistaseal, Evicel, Artiss) should eliminate this 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):

●Renal carcinoma (possible paraneoplastic syndrome) [83]

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

●Isotretinoin therapy (in acute pancreatitis, mechanism unclear) [84]

●Tigecycline (mechanism unclear) [85]

●Medications that impair hepatic synthetic function (L-asparaginase, valproic acid) [86-88]

●Trauma-induced coagulopathy [89]

●Acute obstetric coagulopathy during postpartum hemorrhage [90]

●Plasma exchange using albumin as a replacement fluid

Following plasma exchange, the fibrinogen level may decrease by approximately 50 percent. In contrast, if plasma is used as a replacement fluid, 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".)

Increased fibrin split products (FSPs) or fibrin degradation products, which come from non-crosslinked fibrin, could impair optimal fibrin polymerization and the functional fibrinogen level. D-dimer, which comes from crosslinked fibrin, does not affect the fibrinogen assay.

Acquired hyperfibrinogenemia — Increased fibrinogen (hyperfibrinogenemia) can be seen in inflammation or tissue injury as an acute phase reactant. Inherited hyperfibrinogenemia has not been reported, although certain genetic variants may increase fibrinogen levels in some settings, such as pregnancy or insulin resistance [91,92]. The clinical significance is uncertain.

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

CRYOFIBRINOGENEMIA

●Definition – Cryofibrinogenemia refers to an abnormal cold insoluble protein in plasma (but not serum) (figure 4); the cryofibrinogen is composed of fibrinogen, fibrin, fibronectin, and other proteins [93-95].

●Prevalence – Cryofibrinogenemia is uncommon. Cryoglobulins (cold insoluble proteins present in both serum and plasma) are more common; a study of 335 patient samples with measurable Cryoprecipitates found that 334 were cryoglobulins and only one was a cryofibrinogen [96]. (See "Overview of cryoglobulins and cryoglobulinemia", section on 'Classification'.)

●Causes – Rare heritable forms have been reported [97-100]. Most cryofibrinogenemia is secondary to an underlying disorder (table 2):

•Autoimmune or connective tissue disorders or vasculitis [101]

•Malignancy

•Infection (hepatitis C virus, coronavirus disease 2019 [COVID-19]) [102]

Low cryofibrinogen (<50 mg/L) can also be present in individuals without an underlying condition [103-106].

●Clinical – Some people with cryofibrinogenemia are asymptomatic. Others have clinical features of hyperviscosity, vascular reactivity, and/or thrombosis. Symptomatic individuals often have cryofibrinogen levels >1 g/L. Signs and symptoms may include (table 3) [101,104-113]:

•Cold sensitivity

•Raynaud phenomenon

•Painful ulcers or skin necrosis

•Purpura

•Livedo reticularis

•Painful or pruritic erythema (perniosis) of the extremities

•Arthralgias

•Arterial thrombosis (stroke, myocardial infarction, limb or bowel ischemia, retinal artery occlusion, gangrene)

•Venous thromboembolism (VTE; pulmonary embolism, thrombophlebitis, retinal vein occlusion)

A causal relationship with thromboembolism has not been established [106,114,115].

●Laboratory – The accuracy and sensitivity of the cryofibrinogen detection is critically dependent on the method of collection and sample handling. All samples should be drawn in a prewarmed (37ºC) tube, anticoagulated (with EDTA or citrate), and maintained at 37ºC until centrifuged, ideally with a temperature-controlled centrifuge.

After separation, the plasma is refrigerated at 4ºC for 72 hours to screen for a precipitate, as illustrated in the figure (figure 4). If positive, the "cryocrit" is then quantified after additional centrifugation in a graduated tube. A cryocrit of ≥1 percent is considered abnormal. The precipitation is reversible when warmed at 37ºC. Heparin should not be used as the anticoagulant because it can bind to fibrinogen [116-119].

If a causative disorder is not obvious, a thorough evaluation including age-appropriate cancer screening should be performed.

Diagnosis of cryofibrinogenemia is based on identification of cryofibrinogen in plasma, without cryoglobulins in serum, and one or more clinically compatible features. The differential diagnosis includes cutaneous, vascular, and thrombotic conditions:

•Frostbite

•Atherosclerotic peripheral vascular disease

•Atheroemboli or septic emboli

•Hypercoagulable states

•DIC, thrombotic thrombocytopenic purpura (TTP), or hemolytic uremic syndrome (HUS)

•Antiphospholipid syndrome

•Calciphylaxis (calcium deposition, as in end-stage kidney disease [ESKD]) (see "Calciphylaxis (calcific uremic arteriolopathy)")

•Purple toes syndrome associated with warfarin therapy

•Cutaneous disorders (urticaria, livedo or livedoid vasculitis, neutrophilic dermatoses, lipodermatosclerosis, panniculitis, or perniosis [chilblains])

●Treatment – The most reliable treatment for cold-induced events is avoidance of cold and other environmental triggers. Avoidance of sympathomimetic agents (diet pills, decongestants, caffeine, tobacco smoke) seems prudent, but supporting evidence is lacking. The roles of biofeedback or other behavioral therapies are undefined.

In lymphoproliferative or connective tissue disorders, cryofibrinogens may decrease with treatment of the underlying disorder; evidence for efficacy is limited to small series or case reports [103,120-129].

Low-dose aspirin plus a glucocorticoid has been advocated for nonsevere symptoms [101]. The role of anticoagulation in the absence of thrombosis is controversial [103,112,122,130]. Anticoagulation is appropriate for treatment of thrombosis or standard prophylaxis indications. For critical acute ischemia due to cryofibrinogenemia, thrombolytic therapy (alteplase) can be used [112,131-136]. (See 'Treatment and prevention of thrombosis' below.)

CLINICAL MANIFESTATIONS

Bleeding and abnormal clotting times — Hypofibrinogenemia or dysfibrinogenemia can cause 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 as low as 50 mg/dL. (See "Approach to the child with bleeding symptoms" and "Approach to the adult with a suspected bleeding disorder".)

Mild hypofibrinogenemia (100 to 150 mg/dL) may not affect clotting times. Rare cases of dysfibrinogenemia have been reported in which the TT is normal [47,137]. (See "Clinical use of coagulation tests", section on 'Clotting times'.)

Bleeding can be mild or severe, with greater bleeding risk with afibrinogenemia or functional fibrinogen <100 mg/dL (table 4). Earlier age of onset is likely with more severe deficiency or functional impairment.

●Congenital afibrinogenemia – In congenital afibrinogenemia (absent fibrinogen), bleeding often occurs in the neonatal period, typically at the umbilical stump or after circumcision [138]. 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 [63]. 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.)

Another series of 58 children and adolescents with hereditary afibrinogenemia reported intracerebral bleeding in 31 percent; two-thirds were traumatic (eg, fall down stairs), and one teenager died [139]. After recovering, seven children (12 percent) started fibrinogen prophylaxis.

Other reports have reported that umbilical cord bleeding, which can be fatal, is the initial presentation in approximately 60 to 85 percent of cases [2,47].

Some individuals with afibrinogenemia may have a later age of onset with bleeding in the skin, gastrointestinal tract, urinary tract, or central nervous system. Many females have heavy menstrual bleeding. Pregnancy-associated hemorrhage (antepartum or postpartum) may occur. Splenic rupture has been reported [42,140]. Thrombosis may occur, sometimes after fibrinogen replacement therapy (essentially by cryoprecipitates). (See 'Treatment/prevention of bleeding' below.)

●Congenital hypofibrinogenemia – In congenital hypofibrinogenemia (fibrinogen below the lower level of the reference range, typically <150 mg/dL), 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) [141]. The annualized bleeding rate was approximately 5 to 7 per 1000 patients.

●Congenital dysfibrinogenemia – Congenital dysfibrinogenemia (or hypodysfibrinogenemia) presentations are heterogeneous. Dysfibrinogenemia with functional fibrinogen <50 to 100 mg/dL has a higher frequency of bleeding complications. However, case series have reported that the majority of individuals do not present with bleeding. In fact, over one-half of individuals in various series have been asymptomatic and identified as an incidental finding or through familial screening [54-56].

In a cohort of 101 patients with congenital dysfibrinogenemia, thrombosis was more common than bleeding [54]. At age 50, cumulative incidence of major bleeding was 19 percent and thrombosis was 30 percent. Spontaneous abortion occurred in 20 percent and postpartum hemorrhage in 21 percent.

In a systematic review of hypodysfibrinogenemia associated with bleeding, 476 bleeding events were reported in 317 individuals [142].

Most bleeding is mild (heavy menstrual bleeding, cutaneous bleeding, epistaxis), but it can be severe (operative and gastrointestinal bleeding). Other concerning sites of bleeding include intracerebral, retroperitoneal, joint/muscle, and obstetric. Notably, antepartum and postpartum hemorrhage were reported in individuals without bleeding manifestations outside pregnancy [142]. 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. (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 cause thrombotic phenotypes, despite the prominent role of fibrinogen in normal clotting and the expectation that fibrinogen disorders would cause increased bleeding (table 4) [2]. Both afibrinogenemia and dysfibrinogenemia have been associated with thrombotic manifestations.

•Afibrinogenemia – A 2016 systematic review identified 48 reports of thromboembolic complications in individuals with congenital afibrinogenemia, which included arterial and venous thromboembolism (VTE) in a variety of vascular sites [41]. 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 VTE, 30 percent arterial, and 27 percent combined arterial and VTE [63]. Recurrent thrombotic events occurred in 41 percent.

Thrombosis in unusual sites is not uncommon. In a series of 20 young patients (mean age 14.1 years), six had experienced a thrombotic event in unusual sites, including one aortic thrombosis and five in the splanchnic venous territory [143]. These events did not occur after a fibrinogen infusion.

•Dysfibrinogenemia – In a series of 101 individuals with congenital dysfibrinogenemias, there were 20 episodes of VTE and eight arterial thromboses (eg, stroke, myocardial infarction, mesenteric thrombosis) [54]. One of the 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 20-44 percent).

In a 1995 report from the International Society on Thrombosis and Haemostasis (ISTH) on 27 individuals with thrombotic dysfibrinogenemia variants, the mean age of first thrombosis was 27 years (range, 12 to 50 years) [55].

The classification of congenital fibrinogen disorders published in 2018 includes a subcategory of thrombotic dysfibrinogenemia associated with a thrombotic fibrinogen variant [67]. These mutations interfere with fibrinolysis due to defective binding to tissue-plasminogen activator and/or plasminogen at critical sites on the (dys)fibrinogen. An abnormal clot structure may also delay or impair fibrinolysis.

VTE is more common than arterial, but both can occur, sometimes in the same individual [54,55,144]. In some cases, treatments given for bleeding may contribute to thrombotic risk.

•Acquired fibrinogen disorders – Thrombosis may be due to dysfibrinogenemia or to other hemostatic abnormalities. (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)'.)

Fibrinogen abnormalities constitute an extremely rare cause of thrombophilia overall (<1 percent), and testing for dysfibrinogenemia is not a routine component of the thrombophilia evaluation unless there is a known family history of an inherited fibrinogen disorder [2,55]. (See "Overview of the causes of venous thrombosis", section on 'Inherited thrombophilia'.)

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

Obstetric complications — Compared with controls, individuals with fibrinogen abnormalities have bleeding and thrombotic complications during pregnancy and postpartum and an increased risk of recurrent pregnancy loss and abruptio placentae (table 4) [55,145].

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). Fibrinogen levels typically increase as the pregnancy progresses, along with other changes. (See "Maternal adaptations to pregnancy: Hematologic changes", section on 'Coagulation and fibrinolysis'.)

●Afibrinogenemia – The likelihood of successful pregnancy appears to correlate with the fibrinogen level [47]. In a series of 204 individuals with congenital afibrinogenemia, 85 percent of females had experienced at least one pregnancy loss [63]. When it occurs, the timing of pregnancy loss is typically at approximately five to eight weeks gestation if fibrinogen replacement therapy is not administered [47]. (See 'Conception and pregnancy' below.)

●Hypofibrinogenemia – Hypofibrinogenemia does not appear to increase the risk of miscarriage. In a series that included 149 pregnancies in individuals with hypofibrinogenemia, 106 (71 percent) resulted in live births, while early miscarriage was reported in 18 (12 percent) and intrauterine fetal death was reported in 2 (1 percent) [146]. Vaginal bleeding throughout the pregnancy was described in 7 pregnancies (5 percent). Retroplacental hematoma and postpartum hemorrhage were frequent (8 and 18 percent, respectively).

●Dysfibrinogenemia – Similar results were observed in 232 pregnancies in women with dysfibrinogenemia [146]. The rate of live birth was 71 percent, similar to that of the French general population. Postpartum hemorrhages were reported in 36 pregnancies (21 percent).

Other rare manifestations — Case reports have described other clinical manifestations (table 4).

●Renal amyloidosis – Hereditary renal amyloidosis caused by deposition of a mutant fibrinogen α chain has been reported. Inheritance is autosomal dominant, and most of the affected individuals developed kidney failure [147-154]. 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'.)

●Liver disease – Hepatic storage disease caused by accumulation of an abnormal fibrinogen in the hepatocyte endoplasmic reticulum has been reported in individuals with variants affecting exons 8 and 9 of the fibrinogen γ gene (FGG) [155]. Severity of liver disease is variable.

●Splenic rupture – Splenic rupture was reported in 5 percent of individuals with congenital afibrinogenemia in one series [63].

●Bone cysts – Painful bone cysts have been reported in congenital afibrinogenemia [156]. These appear to be rare and to predominantly affect the long bones of young individuals, possibly as a complication of bleeding. In a series of 204 individuals with congenital afibrinogenemia, painful bone cysts were reported in 18 percent [63].

●Abnormal wound healing – Delayed wound healing and/or surgical wound dehiscence has been reported in individuals with inherited afibrinogenemia or inherited dysfibrinogenemia [42,157,158]. (See "Basic principles of wound healing" and "Risk factors for impaired wound healing and wound complications".)

●Cardiovascular disease – Elevated fibrinogen levels (hyperfibrinogenemia) can be seen in 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 (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

●When to suspect – 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 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).

●History and laboratory – 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:

•PT, aPTT, TT – The PT, aPTT, and TT all depend on production of a fibrin clot as the endpoint of the assay and are abnormal in hypo and dysfibrinogenemias if severe (algorithm 2). 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'.)

•Fibrinogen – The functional fibrinogen level will be low in afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia. 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 uses the Clauss method, which measures time to clot formation after adding a high concentration of thrombin to citrated, platelet-poor patient plasma [159-162]. Functional assays measure only the fibrinogen that is incorporated into the clot; 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. In dysfibrinogenemia, the sensitivity and specificity of the Clauss method depend on the reagents, the methods, the treatment received, and the specific fibrinogen variant(s) [163,164]. The PT-derived fibrinogen overestimates fibrinogen activity in dysfibrinogenemia but is correlated to the antigen level [67].

●Evaluation for the cause – 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, DIC, or HLH, 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 relative 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 identify the causative mutation (pathogenic variant); some fibrinogen variants are associated with a more specific clinical phenotype. (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 following is confirmatory [47,137]:

●Afibrinogenemia – Absent plasma fibrinogen using both a functional assay and an immunoassay.

●Hypofibrinogenemia – Decreased plasma fibrinogen (below the lower limit of the normal range; typically, <150 mg/dL) using both a functional assay and an immunoassay.

●Dysfibrinogenemia – Discordance between functional and immunoreactive fibrinogen (low functional activity level with normal or elevated immunological level).

Genetic testing and other specialized testing — As with many genetic disorders, genetic testing has become increasingly available for confirming the diagnosis of congenital fibrinogen disorders.

Sequencing of the fibrinogen genes is offered through certain clinical laboratories. The advancement of next generation sequencing technologies makes it easier and cheaper to perform large-scale genetic analyses [52]. The usefulness of a prioritization scheme (and of skipping the analysis of most candidate exons in the fibrinogen cluster) is still reasonable in developing countries where the prevalence of fibrinogen disorders is higher. An efficient, step-wise genetic screening approach for congenital fibrinogen disorders targeting specific exons has been developed [50].

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 reproductive planning and prenatal diagnosis. It is also important to verify that the variant is indeed the cause of the clinical phenotype.

DIFFERENTIAL DIAGNOSIS

●Other causes of bleeding and/or prolonged thrombin time – Other causes of bleeding include inherited factor deficiencies (eg, hemophilia) and acquired factor inhibitors. (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)'.)

•Like fibrinogen disorders, these may cause bleeding and abnormal clotting times.

•Unlike fibrinogen disorders, most of these other conditions do not prolong the prothrombin time (PT), activated partial thromboplastin time (aPTT), or thrombin time (TT).

Other causes of a prolonged PT, aPTT, and TT include heparin, 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 inflammatory states, antiphospholipid syndrome, and inherited thrombophilias. (See "Overview of the causes of venous thrombosis" and "Clinical manifestations of antiphospholipid syndrome" and "Cryptogenic stroke and embolic stroke of undetermined source (ESUS)".)

•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.

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

Evidence to guide management is scarce because the inherited disorders are extremely rare and heterogeneous. Our practice is mostly 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 relatives). 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 [137,165,166].

Treatment/prevention of bleeding

Acute bleeding

●Fibrinogen target – For a fibrinogen disorder and clinically important bleeding or emergency surgery that would cause clinically important bleeding without other coagulation factor deficiencies, we suggest administration of fibrinogen replacement to raise the functional fibrinogen >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 [165].

These targets are based on observational data from case reports and small series that suggest hemostasis is likely to be intact with functional fibrinogen >100 mg/dL and demonstrate a low risk of adverse effects with administration of fibrinogen concentrate in individuals with inherited fibrinogen disorders [167-172]. Randomized trials comparing other fibrinogen thresholds or other therapies have not been conducted.

●Choice of product – Products for replacing fibrinogen include fibrinogen concentrates, Cryoprecipitate, and plasma products such as fresh frozen plasma (FFP).

•Congenital fibrinogen disorders – For congenital fibrinogen disorders, we suggest a fibrinogen concentrate rather than Cryoprecipitate or a plasma product. This is a US Food and Drug Administration (FDA)-approved indication for fibrinogen concentrates [173,174]. Cryoprecipitate may be used if a fibrinogen concentrate is not available, and plasma may be used if Cryoprecipitate is not available. The rationale for preferring a fibrinogen concentrate includes the small volume, ease of administration, lower risk of transfusion reactions and volume overload, and likely lower risk of thromboembolic complications.

•Acquired hypofibrinogenemias – Recommendations regarding choice of product and supporting evidence are presented in topic reviews on the specific conditions. (See "Cryoprecipitate and fibrinogen concentrate", section on 'Use in specific settings'.)

There is no role for prothrombin complex concentrates (PCCs) in treating fibrinogen disorders; PCCs do not contain fibrinogen.

●Dosing and duration of therapy

•Dosing – (See "Cryoprecipitate and fibrinogen concentrate", section on 'Cryoprecipitate (dosing and administration)'.)

•Duration – Once hemostasis is 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 to 100 mg/dL. (See 'Routine prophylaxis' below.)

●Adverse effects – (See "Cryoprecipitate and fibrinogen concentrate", section on 'Cryoprecipitate adverse effects' and "Cryoprecipitate and fibrinogen concentrate", section on 'Fibrinogen concentrate adverse effects'.)

●Additional treatments – For heavy menstrual bleeding, hormonal therapies and/or antifibrinolytic agents may be appropriate depending on the needs of the patient. (See "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Terminology, evaluation, and approach to diagnosis" and "Abnormal uterine bleeding in nonpregnant reproductive-age patients: Management".)

Management of bleeding in acquired fibrinogen disorders is more complex because other procoagulant and anticoagulant factors may also be abnormal. If fibrinogen deficiency is the predominant abnormality, fibrinogen concentrates may be appropriate, whereas individuals with multiple factor deficiencies may benefit from plasma products. An analysis of patients from the Fibrinogen Early in Severe Trauma studY (FEISTY) showed that transfusion of Cryoprecipitate was able to restore key fibrinolytic regulators, and in an in vitro study, Cryoprecipitate limited plasmin generation, allowing stronger clots to form relative to treatment with fibrinogen concentrate [175].

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 [176]. Arguments in favor of and against routine use have also been published [177,178]. Management of bleeding in these conditions is discussed in detail separately.

•Trauma – (See "Etiology and diagnosis of coagulopathy in trauma patients" and "Approach to shock in the adult trauma patient".)

•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 (DIC) – (See "Evaluation and management of disseminated intravascular coagulation (DIC) in adults", section on 'Treatment'.)

Elective surgery

●Planning – 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 [167-171]. 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 history of bleeding and those with congenital afibrinogenemia (regardless of personal or family bleeding history) should receive fibrinogen replacement prior to elective procedures that carry a risk of bleeding [165].

•Individuals 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.

●Timing – If fibrinogen replacement is used, 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 to 150 mg/dL for major surgery (often >150 mg/dL) and >50 mg/dL for minor surgery is reasonable [42,172]. Global hemostasis testing such as thromboelastography (TEG) is evolving and may be used to guide fibrinogen dosing at some institutions. (See "Etiology and diagnosis of coagulopathy in trauma patients", section on 'Viscoelastic hemostatic assays'.)

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 [179]. 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 therapies

•Fibrin glue – Fibrin glue may be used for 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 – Antifibrinolytic agents are controversial; they 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 dysfibrinogenemia with a thrombotic fibrinogen variant or a personal or family history of thrombosis [137,172]. (See 'Antifibrinolytic agents' below.)

•Thromboprophylaxis – Mechanical or pharmacologic thromboprophylaxis is important and appropriate, with the specific therapy tailored to the procedure and thromboembolic risk. (See "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients" and "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement".)

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

However, some individuals with afibrinogenemia or severe hypofibrinogenemia (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) [47,141]. Due to the high rate of cerebral bleeding in patients with afibrinogenemia, many experts use primary prophylaxis in this population [63,139].

In a series of 204 individuals with congenital afibrinogenemia, 35 percent were treated with prophylactic fibrinogen concentrate due to severe bleeding phenotype [63]. (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 practice must be individualized according to the patient's bleeding and thrombotic history, response to previous therapies, and access to fibrinogen product [141]. A target trough fibrinogen level of 50 mg/dL is considered reasonable for prophylaxis against bleeding [165]. (See 'Fibrinogen concentrate: Dosing and monitoring' below.)

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

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

●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. Other available products include Clottafact (France) and FibClot (Europe).

●Indications – 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 routinely used for the management of dysfibrinogenemia. 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.

●Initial dose – 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 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:

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

●Example calculation – A 50 kg individual with fibrinogen 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).

●Subsequent doses – Additional doses are based on the patient's trough plasma fibrinogen levels rather than a fixed dose or schedule, as pharmacokinetics vary widely among individuals according to age and weight [141,180,181]. 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.

The half-life of fibrinogen is 3 to 3.5 days (77 to 88 hours) [168]. 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.

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 (give more frequent infusions) rather than increasing the amount of fibrinogen given in each dose [165].

In a 2006 survey of clinicians who provided prophylaxis to individuals with afibrinogenemia or severe hypofibrinogenemia, a median fibrinogen dose of 53 mg/kg was given approximately once per week (range, 18 to 120 mg/kg; schedule, once per week to once per month) [141].

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 [182].

Cryoprecipitate and Fresh Frozen Plasma (FFP): Dosing and monitoring

●Indications – Cryoprecipitate (cryo) can be used as a source of fibrinogen when fibrinogen concentrate is unavailable.

●Dosing – 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 5). 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.

●Monitoring and repeat dosing – 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.

●Adverse effects – Complications with Cryoprecipitate include transfusion reactions (allergic, infectious) and thrombosis [183,184]. Extremely rarely, a patient with afibrinogenemia may have developed antibodies to fibrinogen following replacement therapy [185,186]. Additional information is presented separately. (See "Cryoprecipitate and fibrinogen concentrate".)

●Plasma Cryoprecipitate is unavailable – A plasma product such as FFP or Plasma Frozen Within 24 Hours of Collection (PF24) may be used. Dosing is approximately 10 to 15 mL/kg (table 5). (See "Clinical use of plasma components".)

Antifibrinolytic agents — Tranexamic acid or epsilon-aminocaproic acid may be used, especially to treat or prevent mucosal bleeding. However, systemic administration 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 [137].

Local treatment (eg, 5 percent mouthwash solution 10 mL four times daily for 7 to 10 days) may be useful in oral or dental surgery [187].

Conception and pregnancy — Individuals 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 [165].

The first case of a successful pregnancy in an individual with afibrinogenemia supported by fibrinogen infusion was reported in 1985 [188]. Before the availability of routine fibrinogen replacement, individuals with afibrinogenemia were unable to have a successful pregnancy. Fibrinogen appears to be required for normal placenta maintenance during the first trimester of pregnancy. (See 'Functions in hemostasis and other processes' above.)

●Complication rate – A systematic review of 188 pregnancies (70 individuals with hereditary fibrinogen disorders) from 1985 to 2018 confirmed a high rate of adverse obstetric outcomes [189]. Fibrinogen was administered in one-half of the pregnancies with afibrinogenemia and 14 to 25 percent of pregnancies with other congenital fibrinogen disorders. The following complications were observed:

•Pregnancy loss (miscarriage) in 15 of 35 pregnancies (43 percent) with afibrinogenemia and 27 of 63 pregnancies (43 percent) with dysfibrinogenemia.

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

•Placental abruption in 8 percent (quantitative and qualitative disorders).

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

•Postpartum thrombosis in six pregnancies.

The Fibrinogest study reported on the natural course of 425 pregnancies in 159 individuals with low fibrinogen between 2019 and 2021, excluding those with afibrinogenemia [146]. There were 49 individuals with hypofibrinogenemia, 95 with dysfibrinogenemia, and 15 with hypodysfibrinogenemia. Only 28 patients (8.9 percent) received fibrinogen infusions. Comparing with epidemiological data in Europe, there were increased rates of retroplacental hematoma (4.1 percent), postpartum hemorrhage (19.9 percent), and postpartum venous thromboembolism (VTE; 1.6 percent). In contrast, the rate of miscarriage (12.9 percent) was not higher than found in the French general population. Other smaller studies reported a higher prevalence of miscarriage (up to 49.7 percent) [54,55,189].

●Prevention – The following approaches may be helpful to reduce pregnancy loss, bleeding, and/or thrombosis during the pregnancy and postpartum:

•Afibrinogenemia or severe hypofibrinogenemia (fibrinogen <50 mg/dL) – Individuals with congenital afibrinogenemia or severe hypofibrinogenemia should have preconception and genetic counseling, and they should be considered for preconception fibrinogen replacement or fibrinogen administration as soon as pregnancy is confirmed. This practice is based on evidence from case reports and small series [137,167,190-194]. A 2017 joint United Kingdom Haemophilia Centre Doctors' Organisation (UKHCDO) and Royal College of Obstetricians and Gynaecologists (RCOG) guideline provides guidance for the management of pregnancy and delivery [195].

-We use a target trough level of 100 mg/dL throughout pregnancy, with monitoring every one to two weeks. Some experts use a lower trough level (>50 to 60 mg/dL) during the first trimester [165]. If a previous pregnancy has been unsuccessful, a higher trough level may be appropriate [167].

-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 [167]. If needed, it is preferable to increase the frequency of administration rather than the dose.

-During labor and for a minimum of 24 hours postpartum, target a fibrinogen of 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 [195]. Continuous infusion may prevent placental abruption. We use a target of 200 mg/dL for cesarean delivery. Early administration of tranexamic acid should be considered for postpartum bleeding. Thromboprophylaxis is considered until discharge per standard of care in the general obstetric population.

-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 if there is a bleeding phenotype or history of postpartum hemorrhage.

-To minimize thromboembolic risk, we avoid overcorrecting fibrinogen levels. If prophylactic dose low molecular weight heparin (LMWH) is indicated, it can be given while providing fibrinogen replacement.

•Mild to moderate hypofibrinogenemia (fibrinogen between 50 and the lower limit of the reference range, typically 150 mg/dL) – Individuals with mild hypofibrinogenemia (50 to 90 mg/dL) and moderate hypofibrinogenemia (100 mg/dL up to the lower limit of the reference range) are usually asymptomatic [67]. However, pregnancy could be associated with increased risk of miscarriage, bleeding, and postpartum hemorrhage. In individuals with moderate hypofibrinogenemia (fibrinogen activity 50 to 100 mg/dL), fibrinogen replacement targeting a trough fibrinogen level 100 mg/dL throughout the pregnancy to avoid the risk of placental abruption can be considered.

Fibrinogen administration is recommended for labor and delivery. Fibrinogen administration during pregnancy has not been well established; it should be considered if there is a history of recurrent miscarriages or bleeding during pregnancy.

In a series of 11 individuals with hypofibrinogenemia (mean fibrinogen 72 mg/dL; range 48 to 111 mg/dL), pregnancies were uneventful [196]. Fibrinogen replacement was provided for labor and delivery in all (mean fibrinogen at delivery, 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 – Management is challenging because clinical phenotypes and levels of functional fibrinogen are more variable; evidence to guide therapy is extremely limited [167]. The patient's previous thrombosis or bleeding history should guide treatment.

-Individuals with no 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. Individuals with fibrinogen activity <50 mg/dL are at greater risk of spontaneous abortion and postpartum bleeding.

-During pregnancy, fibrinogen replacement to raise the fibrinogen level to >150 mg/dL is recommended in case of vaginal bleeding. Others can be treated expectantly with vaginal delivery and fibrinogen given only if bleeding occurs or if Cesarean delivery is required [167]. Thromboprophylaxis is indicated when pregnancy is associated with a known dysfibrinogenemia with a thrombotic variant.

-At delivery, a fibrinogen level >150 mg/dL is required for neuraxial anesthesia; target fibrinogen >150 mg/dL for vaginal delivery in individuals with bleeding phenotype, or >200 mg/dL for cesarean delivery.

-Monitor closely for bleeding for 72 hours postpartum, with prompt use of fibrinogen replacement and tranexamic acid if there's postpartum bleeding.

-Management of recurrent miscarriages in individuals with dysfibrinogenemia is controversial; evidence is limited to case reports. Therapy may include fibrinogen replacement, anticoagulation, or both [167]. One report described successful pregnancy in three of four related individuals with recurrent pregnancy loss who were treated with continuous fibrinogen replacement as soon as pregnancy was diagnosed [197].

-Strong consideration should be given to postpartum thromboprophylaxis (LMWH) if there is a personal or family history of thrombosis and those without previous bleeding [165]. In a registry of patients with a thrombophilic dysfibrinogenemia, 7 of 15 developed postpartum thrombosis [55]. Others may be managed with mechanical thromboprophylaxis. (See "Use of anticoagulants during pregnancy and postpartum".)

Treatment and prevention of thrombosis

●Treatment – Evidence to guide treatment is limited. In general, individuals with thrombotic complications with an abnormal fibrinogen should be treated with anticoagulation unless there is a contraindication (table 6). Low molecular weight (LMW) heparins are preferred for venous thrombosis. Warfarin remains an option if the baseline prothrombin time (PT) is not prolonged. There are limited data on the efficacy and safety of the direct oral anticoagulants in these conditions [198]. The duration of anticoagulation should be similar to the general population, except for carriers of thrombophilic dysfibrinogenemia [172].

Individuals with fibrinogen >50 mg/dL can generally be safely anticoagulated.

•For congenital afibrinogenemia, anticoagulation should be accompanied by fibrinogen replacement therapy to reduce the risk of bleeding complications [165]. (See 'Fibrinogen concentrate: Dosing and monitoring' above.)

•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)'.)

●Prevention – Routine VTE prophylaxis is generally not used outside of high-risk settings such as perioperatively, during an acute medical illness, or postpartum.

Individuals with a known thrombophilic fibrinogen variant are managed similarly to other individuals with 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 [165]. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults" and "Prevention of venous thromboembolism in adults undergoing hip fracture repair or hip or knee replacement" 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 (such as 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 200 to 400 mg/dL and increases as an acute phase reactant. During clotting, fibrinogen is converted to fibrin (figure 1), which polymerizes and becomes crosslinked (figure 3); this provides a major structural component of the clot. The fibrin meshwork (figure 2) also supports platelet aggregation and serves as a template for thrombin, fibrinolytic proteins, wound healing, and placental implantation. (See 'Biology' above.)

●Genetic disorders – Congenital fibrinogen disorders can be caused by variants in FGA, FGB, or FGG (figure 5). 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 conditions (table 1). Cryofibrinogenemia (cold insoluble fibrinogen in plasma but not serum (figure 4)) is generally caused by autoimmune disorders, infections, or malignancies. (See 'Acquired abnormalities' above.)

●Clinical features – Fibrinogen disorders can present with bleeding or incidentally; thrombosis, obstetric complications, and other findings may occur (table 4). Individuals with congenital afibrinogenemia 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 – Assess the personal and family history of bleeding, thrombotic, and obstetric complications and obtain standard laboratory testing (algorithm 1). Specialized testing may be indicated in some individuals, after consultation with a bleeding disorders expert. Diagnosis is confirmed by low plasma fibrinogen level and/or reduced function. (See 'Diagnostic testing' above.)

●Differential diagnosis – The differential includes inherited and acquired bleeding and thrombotic disorders and other causes of pregnancy morbidity. Prolongation of the PT, aPTT, and TT may be caused by some anticoagulants, paraproteins in multiple myeloma, and antibodies in patients exposed to bovine thrombin. (See 'Differential diagnosis' above.)

●Management

•Bleeding

-Target fibrinogen level – 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.

-Product – When fibrinogen replacement is required for a congenital fibrinogen disorder, we suggest fibrinogen concentrate rather than Cryoprecipitate or plasma (Grade 2C). This is an approved indication based on lower risk of transfusion reactions and volume overload. Management of bleeding in acquired fibrinogen disorders is more complex because other coagulation factors are also likely to be abnormal; Cryoprecipitate and/or other blood products and clotting factor concentrates may be used. (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 may be appropriate in individuals with thrombotic variants. (See 'Elective surgery' above.)

•Prophylaxis – For most patients with congenital fibrinogen disorders who have not had a severe bleed, we suggest not using routine prophylaxis (Grade 2C). Due to the high risk of cerebral bleeding in afibrinogenemia, many experts use primary prophylaxis in these individuals.

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. (See 'Routine prophylaxis' above and 'Conception and pregnancy' above.)

•Thrombosis – Thrombosis is treated with anticoagulation; standard prophylactic indications should be followed. (See 'Treatment and prevention of thrombosis' above.)