LABORATORIO DE URGENCIAS

 

 

Disorders of fibrinogen 

                                                                                         

                                                                                  Carolin Bérube, Lawrence L. K. Leung

                                                                                          Up Date to Diciembre  - 2014 

 

 

 INTRODUCTION 

Normal fibrinogen circulates in the plasma at a concentration of approximately 200 to 400 mg/dL, with a half-life of four days and a catabolic rate of approximately 25 percent per day [1].
Fibrinogen has numerous functional interactions and plays a pivotal role in the hemostatic balance:

•  It is the substrate for fibrin clot formation
•  It binds to platelets to support platelet aggregation
•  It has a role in wound healing
•  The fibrin clot is a template for both thrombin binding and the fibrinolytic system.

Accordingly, any abnormality of fibrinogen (ie, hypofibrinogenemia, dysfibrinogenemia) may result in defects in one or more of these key functions. The final result of the balance between fibrin clot formation and fibrinolysis determines whether the clinical manifestations include bleeding, thrombosis, both, or neither.
While the finding of a low level of circulating fibrinogen is commonly seen as a result of acquired disorders of coagulation (eg, acute disseminated intravascular coagulation), the presence of an abnormal fibrinogen (ie, dysfibrinogenemia) is a rare condition. It is usually suspected following the finding of a prolonged thrombin time or a low fibrinogen level. In a hospital-based practice, it is most commonly observed as an acquired disorder in patients with liver disease; congenital dysfibrinogenemia is rare. The true incidence is unknown since many abnormal fibrinogens are clinically silent.
This topic review will discuss the structure and function of fibrinogen, as well as the clinical manifestations, diagnosis, and management of congenital and acquired disorders of fibrinogen.
Discussions concerning fibrinogen as an acute phase reactant, the relationship between elevated fibrinogen levels and cardiovascular disease, and abnormal fibrinolysis are presented separately.

CLASSIFICATION 

Fibrinogen disorders can be classified as quantitative or qualitative, congenital or acquired. The following terms will be used here:

•  Dysfibrinogenemia refers to the presence of a dysfunctional fibrinogen molecule.
•  Hypodysfibrinogenemia refers to those inherited fibrinogens which are both functionally abnormal as well as associated with low plasma levels (<150 mg/dL) as measured by immunologic techniques.
•  Hypofibrinogenemia is any condition associated with a reduction in the circulating level of normal fibrinogen to <150 mg/dL.
•  Afibrinogenemia is a rare autosomal recessive condition in which there is a complete lack of circulating fibrinogen.
•  Cryofibrinogenemia is a phenomenon in which there is the presence in plasma, but not serum, of a fibrinogen that precipitates on exposure to low temperatures (eg, 4ºC).

FIBRINOGEN STRUCTURE AND FUNCTION 

Human fibrinogen is a complex 340kD dimeric glycoprotein composed of two identical symmetrical halves centrally connected by three disulfide bonds. Each half consists of three polypeptide chains (ie, Aalpha, Bbeta, and gamma) coded by three different genes on chromosome 4 (FGA, FGB, FGG) and synthesized by hepatocytes. The assembly of fibrinogen takes place in the liver [2]; carbohydrate side chains are added to the beta and gamma chains before the molecule is secreted into the plasma. A small pool of fibrinogen is stored in platelet alpha-granules. Plasma fibrinogen is internalized by a process mediated by GPIIb/IIIa, and can support platelet aggregation. (Specific platelet granules).
The trinodular structure of fibrinogen can be described as a central E-region (containing the aminoterminal portions of the three polypeptide chains) and two D-regions (caboxyterminal portions) [3]. The complete amino acid sequence of fibrinogen has been determined as well as the location of residues that define the sites of some of the important functions, including fibrinopeptide cleavage, fibrin polymerization, factor XIIIa-mediated fibrin crosslinking, as well as its interaction with platelet glycoprotein IIb/IIIa [4-7].

Fibrinogen synthesis 
Fibrinogen synthesis is controlled at the level of transcription. The inducible component is mainly influenced by acute phase reactions. Fibrinogen biosynthesis increases with inflammation and stress, a process mediated by Interleukin-6. Interleukin-6 enhances transcription of fibrinogen mRNA while interleukin-1 and tumor necrosis factor-alpha suppress fibrinogen synthesis[8,9].
The acute phase response can elevate plasma fibrinogen by 2- to 20-fold. The peak elevation in fibrinogen during the acute phase occurs by three to five days, with a gradual return to baseline following resolution of the inflammation [8-10]. Polymorphisms of the B-beta fibrinogen gene have been identified; some variants are associated with elevated plasma fibrinogen concentrations, especially in smokers [11,12]. Epidemiologic studies indicate that high fibrinogen levels are associated with increased risk of cardiovascular disease, stroke, and nonvascular mortality.
The conversion of fibrinogen into insoluble fibrin can be divided in three distinct steps, as discussed in the following sections.

Fibrinopeptide cleavage 
When thrombin binds to fibrinogen it cleaves fibrinopeptides A (FPA) and B (FPB) from the aminoterminal portions of the Aalpha and Bbeta chains at the Arg16-Gly17 and the Arg14-Gly15 bonds, respectively, facilitating optimal fibrin polymerization. FPA release takes place earlier and faster than FPB release and is sufficient to induce clot formation, whereas isolated cleavage of FPB is not sufficient for this purpose.
The resultant molecule, composed of a dimer of three polypeptide chains: alpha, beta, and gamma, is referred to as a fibrin monomer, the basic unit of fibrin formation. Any structural defect of the aminoterminal region can markedly impair thrombin binding, FPA or FPB release, as well as the rate of fibrin formation [13]. It is not surprising therefore that a high proportion of the abnormal fibrinogens have mutations involving this region. Even so, the majority of the affected subjects remain asymptomatic, although some have excessive bleeding manifestations, especially after surgery or childbirth.

Fibrin polymerization 
In normal fibrinogen, release of negatively charged FPA and FPB results in spontaneous fibrin monomer polymerization to form the fibrin clot. This process is initiated by complementary non-covalent binding of the polymerization sites at the D region of one molecule to the central E domain of an adjacent fibrin monomer, forming a two molecule-thick strand or protofibril. Polymerization sites are located on the aminoterminal portion of the A alpha and B beta chains (E-domain), and the carboxyterminal portion of the gamma chains (D-domain). This is followed by longitudinal growth (D-D contact between adjacent fibrin monomers) and branching to form the final fibrin network [14]. Mutations affecting these binding sites may delay fibrin polymerization and produce heterogenous clinical manifestations.

Fibrin crosslinking 
Factor XIIIa-mediated crosslinking is the final step in fibrin clot formation. FXIII is activated by thrombin, and binds to fibrin to produce covalent bonds between D domains of the fibrin fibers. These bonds involve gamma-gamma chain as well as alpha-alpha and alpha-gamma chain interactions [15].
Crosslinking stabilizes the clot and makes the clot 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 patients with FXIII deficiency. Alternatively, increased cross-linking might predispose to thromboembolic phenomena and cardiovascular disease [16,17]. This is supported by observations concerning a normally-occurring fibrinogen variant, gamma-prime fibrinogen. Approximately 8 to 15 percent of plasma fibrinogen contains a variant gamma chain (gamma-prime) resulting from alternative splicing, yielding gamma- prime fibrinogen [18-20]. This variant is associated with clots that are structurally different, with more extensive cross-linking and greater resistance to lysis.
A study of patients undergoing coronary angiography has shown that levels of this variant fibrinogen were higher on average in coronary artery disease patients than in patients without coronary artery disease, and that this association was independent of total fibrinogen levels [21]. A case-control study performed in patients with myocardial infarction has confirmed this association [22].

Fibrinolysis 
Fibrin is a template for the assembly and activation of the fibrinolytic system. Plasminogen, tissue-type plasminogen activator (t-PA), and alpha-2-plasmin inhibitor have binding sites on the fibrin clot. Mutations affecting those regions may result in defective plasmin generation and reduced fibrinolysis [6]. The rate of fibrinolysis is also influenced by the thickness of the fibers [23]. In addition, resistance to the action of plasmin can result from mutations in the C-terminus of the Aalpha chain associated with abnormal albumin binding [24,25]. These mechanisms explain the thrombophilic, rather than the hemorrhagic, phenotype in some of these individuals.

CONGENITAL DISORDERS 

Congenital disorders of fibrinogen take the form of either the production of an abnormal fibrinogen (dysfibrinogenemia) or the complete lack of production of fibrinogen (afibrinogenemia). Each will be described below.
Inherited dysfibrinogenemia is the result of mutations in the coding region of the fibrinogen FGA, FGB, or FGG genes. Over 400 affected families have been reported in the literature. Over 90 percent are point missense mutations, leading to the production of a dysfunctional protein product [26,27]. An updated online database of fibrinogen mutations is available, which also provides data on their associated clinical manifestations [28].
Structure/function correlations can be made in several of these mutations [5,6,29]. A significant number of these mutations are located at positions Aalpha 16 Arg (the FPA cleavage site) and gamma 275 Arg (the fibrin polymerization site) [27]. Overall, dysfibrinogenemias can be silent (55 percent), or lead to a hemorrhagic (25 percent) or thrombotic diathesis (10 to 20 percent) [26,30,31]. About two percent of the mutations may be associated with both thrombotic and bleeding complications. Asymptomatic dysfibrinogenemia is often diagnosed incidentally following abnormal coagulation tests or as part of family screening studies.
Congenital 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). With rare exceptions, the mode of inheritance of the congenital dysfibrinogenemias is autosomal dominant.

Thrombotic variants 
Dysfibrinogenemia is a rare cause of thrombophilia; the other more common causes of thrombophilia should be excluded before the patient is evaluated for the presence of an abnormal fibrinogen. The prevalence of congenital dysfibrinogenemia in patients with a history of venous thrombosis has been estimated at 0.8 percent [31].
The true prevalence of thrombosis among patients with dysfibrinogenemia is unknown, but is estimated to be around 10 to 20 percent [26,31]. Venous thrombosis of the lower extremity dominates the clinical picture; arterial thrombosis or both venous/arterial thrombosis have also been reported [32]. The findings of a registry of dysfibrinogenemia and thrombophilia established by the Scientific and Standardization Subcommittee on Fibrinogen of the International Society on Thrombosis and Haemostasis were published in 1995 [31]. The registry reported 26 cases with thrombosis at young age and gathered information on family members. The mean age of first thrombosis was 27 years. A highly convincing association between dysfibrinogenemia and thrombophilia could be established for five families (Caracas V, Melun, Naples, Paris V, Vlissinger/Franckfurt IV). There was a high rate of pregnancy-related complications such as postpartum thrombosis and spontaneous abortions; 3 of the 26 families experienced severe postpartum bleeding. Fibrinogen concentrations were normal or low.

Hemorrhagic variants 
Patients with fibrinogen levels less than 50 to 100 mg/dL have a higher frequency of bleeding complications. Bleeding is also associated with fibrinogen mutations impairing fibrinopeptide release or fibrin monomer polymerization. Most bleeding manifestations are moderate, but some can be severe.
The clinical presentation is heterogenous, and may include epistaxis, menorrhagia, easy bruisability, soft tissue hemorrhage, postoperative bleeding, antepartum and postpartum bleeding, as well as hematomas and hemarthrosis. Bleeding often manifests after trauma, surgery, or during the postpartum period.

Silent mutations
Half of the reported cases of dysfibrinogenemia remain asymptomatic as observed in family members who share the defect with the propositus.

Other disease manifestations 
Hereditary renal amyloidosis secondary to deposition in the kidney of a mutant fibrinogen alpha chain has been reported. Inheritance is autosomal dominant and most affected individuals develop renal failure [33-40].
In two hypofibrinogenemia mutations, the abnormal fibrinogen may remain within the endoplasmic reticulum of the hepatocyte, leading to a form of hepatic storage disease [41,42].
Dysfibrinogenemia can rarely cause delayed wound healing and/or wound dehiscence.

Congenital afibrinogenemia 
Afibrinogenemia, or a complete or virtually complete lack of circulating fibrinogen, is a rare condition, most often with autosomal recessive inheritance in association with consanguinity [43-45]. The estimated incidence is one per million in the general population. Hemorrhagic manifestations vary from minimal to catastrophic, and may include fatal umbilical cord hemorrhage as the first disease manifestation. In later life, the disorder may be associated with bleeding from mucosal surfaces (eg, epistaxis, menorrhagia, gastrointestinal bleeding), hemorrhage into muscles and joints, intracranial bleeding, spontaneous abortions, and/or spontaneous splenic rupture.
Heterogeneity of the disease was confirmed by the observations of a survey of 100 patients with congenital hypo- or a-fibrinogenemia. The annual incidence of bleeding episodes was 0.7, with a range from zero to 16.5 episodes per year [46].
The diagnosis is established by demonstrating trace or absent immunoreactive fibrinogen in the plasma [44]. Patients with hypofibrinogenemia are usually asymptomatic, unless exposed to trauma.
The vast majority of patients with afibrinogenemia are homozygous or compound heterozygous for truncating mutations in the fibrinogen alpha chain gene [47], while patients with hypofibrinogenemia are usually asymptomatic carriers of afibrinogenemia mutations. Comprehensive reviews of the molecular mechanisms of congenital hypo- and a-fibrinogenemia have been published [48-50].

Pregnancy complications 
Normal fibrinogen concentration and function is critical for successful pregnancy outcome. Women with quantitative or qualitative fibrinogen abnormalities have an increased incidence of bleeding and thrombotic complications, recurrent spontaneous abortions, and abruptio placentae [31,51].
# Bleeding 
Fibrinogen does not appear to be necessary for fertilization and initial implantation. However, fibrinogen plays a fundamental role in maintaining the integrity of placental insertion. As an example, homozygous, Aalpha chain-deficient mutant mice have fatal uterine bleeding around the tenth day of gestation [52]. In humans, congenital hypo- or afibrinogenemia is associated with excessive bleeding and early recurrent miscarriages at 5 to 6 weeks of gestation [53].
# Thrombosis
Congenital dysfibrinogenemias are also associated with spontaneous abortion and postpartum venous thrombosis. In a registry of familial dysfibrinogenemia and thrombophilia, 15 female propositi had a total of 34 normal deliveries. However, 24 spontaneous abortions, six stillbirths, and postpartum thromboses were also observed in 7 of these 15 women. One woman developed thrombosis both during pregnancy and in the postpartum period. In contrast, two women with hypodysfibrinogenemia had excessive postpartum bleeding [31].

ACQUIRED DISORDERS

A number of clinical conditions can lead to the production of an abnormal fibrinogen and Acquired dysfibrinogenemia:
* Liver disease 
The most common cause of acquired dysfibrinogenemia is liver disease. It is observed in the majority of patients with cirrhosis, acute or chronic hepatitis, and also in metastatic hepatoma [54-59]. Fibrinogen dysfunction in this setting is manifested by prolongation of thrombin and reptilase times; fibrinogen levels are normal when measured by immunologic methods.
The abnormal fibrinogen in this setting is characterized by an increased content of sialic acid residues and delayed fibrin polymerization [60,61]. Both cleavage of the A and B fibrinopeptides and the crosslinking of fibrin by factor XIII are normal. Removal of the sialic acid from the abnormal fibrinogen normalizes the thrombin time and corrects the polymerization defect [60]. Normal fetal fibrinogen also exhibits an increased content of sialic acid residues and similar laboratory abnormalities are found [61].
Whether the abnormal fibrinogen seen in liver disease is associated with an increased bleeding risk is difficult to evaluate, since most of these individuals have other associated abnormalities of hemostasis (eg, thrombocytopenia, diminished synthesis of other coagulation factors) and/or other causes for bleeding (eg, varices, peptic ulceration). No increase in thrombotic risk has been observed.
* Other causes 
Acquired dysfibrinogenemia has also been reported in association with renal carcinoma [62], isotretinoin therapy [63], biliary obstruction [56], and digital gangrene [64]. The abnormal fibrinogen may disappear with treatment of the underlying condition [62], or may disappear spontaneously [64].

Fibrinogen antibodies 
Autoantibodies inhibiting specific functions of fibrinogen have been described. These antibodies can block fibrinopeptide release, fibrin monomer polymerization, or fibrin crosslinking.
They have been reported in systemic lupus erythematosus, ulcerative colitis, multiple myeloma, therapy with isoniazid, or without any underlying condition [30,65]. Presence of such antibodies is more commonly associated with bleeding manifestations. Clinical thrombosis associated with fibrinogen autoantibodies has been reported, many of those patients had other risk factors for thrombosis.
Antibodies can also be clinically silent, such as one patient in whom the antibody interfered with FPB release [66]. Blockage of FPA release seems to be associated with the most severe clinical manifestations. Spontaneous remissions have been reported.
Fibrin sealant or fibrin glue has been used during various surgical procedures over the last four decades. Patients exposed to fibrin glue prepared from bovine sources can develop antibodies against bovine fibrinogen, which may cross-react with human fibrinogen [67-69]. Current FDA-approved commercial fibrin sealants made of human coagulant factors (Hemaseel APR or Tisseel kit VH) should eliminate this complication.

Hypofibrinogenemia
Low levels of fibrinogen may occur when there is reduced synthesis or increased turnover of fibrinogen. As an example, patients with hepatic failure or decompensated cirrhosis may have low levels of fibrinogen for a number of reasons:

•  Production of an abnormal fibrinogen
•  Increased turnover due to the concomitant presence of disseminated intravascular coagulation

Fibrinogen is an acute phase reactant, with levels increasing as part of the acute inflammatory response. Thus, a plasma fibrinogen of 200 mg/dL, although within the normal range, may represent a significant decrease in a patient whose baseline level, because of underlying malignancy, sepsis, or inflammation, should be 800 mg/dL.
The most common clinical condition associated with hypofibrinogenemia is acute disseminated intravascular coagulation (DIC), a disorder in which there is an excessive turnover of fibrinogen, due to increased consumption. Plasma levels of fibrinogen are usually normal or increased in chronic DIC.
Other, less common causes of hypofibrinogenemia include administration of drugs which may impair hepatic synthetic function, such as l-asparaginase [70,71] and valproic acid[72].

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, and may be accompanied by disseminated intravascular coagulation. Symptoms, when present, include sensitivity to cold, Raynaud's phenomenon, purpura, urticaria, skin ulcerations or gangrene, and arterial or venous thromboses.

DIAGNOSIS 

Disorders involving fibrinogen are rare but should be considered in any patient with a history of hemorrhage or thrombosis in whom most of the common causes have been ruled out. Global screening tests, such whole blood clotting time, prothrombin time (PT) and activated partial thromboplastin time (aPTT) all require the production of a fibrin clot as an end point, and will be abnormally prolonged in patients with hypo- or afibrinogenemia. Abnormal tests results in patients with afibrinogenemia will correct completely on addition of normal plasma or purified fibrinogen. Accordingly, these tests are sensitive for the presence of a fibrinogen disorder, but lack specificity.Initial screening tests for dysfibrinogenemia should include fibrinogen concentration, as determined by both immunologic (antigenic) and clotting methods ("clottable" fibrinogen), thrombin time (TT), and reptilase time (RT). The TT is the more sensitive screening test, but its specificity is poor, since other more common causes for a prolonged thrombin time must first be excluded.
Most of the reported congenital dysfibrinogenemias have prolonged thrombin or reptilase clotting times; a normal or shortened thrombin time has been reported only with fibrinogens Oslo I and Valhalla [30]. Therefore, most patients with an abnormal fibrinogen should be detected by one of these two screening assays.
The functional assay for fibrinogen is based on the rate of fibrin formation in a clotting assay. The Clauss method, which uses a high concentration of thrombin added to citrated plasma, is the most commonly used, but other tests are available [73,74]. Such assays measure only the fibrinogen that is incorporated into the in vitro clot, and may give misleading information, since the abnormal fibrinogen may not be incorporated into the clot and/or may inhibit clotting of normal uninvolved fibrinogen molecules.
Accordingly, in the congenital dysfibrinogenemias, levels of functional fibrinogen (ie, clottable fibrinogen) are usually low or normal. In contrast, the fibrinogen concentration is usually normal or elevated when measured immunologically (eg, radial immunodiffusion, enzyme-linked immunosorbent assay, or nephelometry). Typically, most individuals with dysfibrinogenemia have a discrepancy between the level of clottable fibrinogen and that detected by immunologic assay, resulting in a low ratio of functional to immunologic fibrinogen.
Inherited dysfibrinogenemia are often suggested by the presence of similar laboratory abnormalities among family members. The specific diagnosis requires the demonstration of an abnormal protein or DNA sequence or characterization of the functional defect.
Such testing, as well as assays for fibrinogen electrophoretic migration, fibrinopeptide release, and fibrin monomer aggregation are generally available only through research laboratories.

TREATMENT 

Most patients with dysfibrinogenemia are asymptomatic and do not require treatment. For the remainder, there is considerable variability in their clinical manifestations; accordingly, management must be individualized.
Patients with a known history of previous bleeding should receive fibrinogen replacement prior to surgery. Replacement therapy is very effective when active bleeding is present. Prophylactic therapy is recommended for pregnant women.
Most of the recommendations for replacement therapy in fibrinogen disorders are derived from observations in patients with afibrinogenemia. The goal is to increase fibrinogen concentration to approximately 50 to 100 mg/dL in order to achieve normal hemostasis [45].

Cryoprecipitate 
Cryoprecipitate (cryo) is the main source of fibrinogen in the United States. Fresh frozen plasma also contains fibrinogen and may sometimes be used as an alternative, although larger volumes must be infused.
One unit of cryo contains all of the fibrinogen present in one unit of whole blood (approximately 200 to 400 mg) in a volume of 10 to 15 mL. In the average patient, each unit raises plasma fibrinogen by approximately 7 to 10 mg/dL, with a half-life of two to four days.
For minor episodes of bleeding, 1 unit of cryo per 10 kg of body weight is usually sufficient. For major surgical procedures or serious injuries, requirements may increase to 1 unit per 5 kg. As noted above, the goal is to increase fibrinogen concentration to approximately 50 to 100 mg/dL in order to achieve normal hemostasis, although higher levels may be required in some patients. Accordingly, the fibrinogen level should be determined daily; subsequent doses are based on the fibrinogen level obtained immediately before infusion, as well as prior effectiveness in achieving hemostasis.
A maintenance dose of approximately one third of the initial dose is infused daily, based on a catabolic rate of 25 percent per day and an extravascular distribution of 30 percent. The duration of therapy can vary from a few doses to up to two to three weeks following major surgery. Complications of replacement therapy include allergic reactions, the risk of transmission of infectious disease, and thrombosis [75,76]. Occasional patients with afibrinogenemia may develop antifibrinogen antibodies following replacement therapy [77,78].

Fibrinogen concentrate
A number of virally-inactivated human fibrinogen concentrates are available in Europe and other countries [45]. A recombinant fibrinogen preparation is under development.
In 2009, the United States approved the use of a virally-inactivated human fibrinogen concentrate (RiaSTAP, CSL Behring) prepared from human pooled plasma, for use in the treatment of acute bleeding episodes in patients with congenital afibrinogenemia and hypofibrinogenemia. The recommended dose of fibrinogen concentrate (mg/kg) is determined as follows:

  Dose (mg/kg) = [Target level (mg/dL) - measured level] ÷ 1.7

If the patient's fibrinogen level is not known, a dose of 70 mg/kg has been recommended [79].

Anticoagulation 
Unless there is a contraindication to their use, patients with thrombotic complications should receive anticoagulation therapy. However, the optimal duration of anticoagulation therapy in these patients is unknown. As with all anticoagulants, the benefit of anticoagulation should be weighed against a potentially higher risk of bleeding.
Management decisions should be based on the presence of risk factors for bleeding, the severity and the number of prior thrombotic events, and the phenotype of the family history. Due to the small number of affected patients, there is no data to support the use of long term anticoagulation as primary prevention in asymptomatic patients with a known thrombophilic dysfibrinogen. In any event, patient education concerning thrombotic risk factors (eg, surgery, pregnancy, oral contraceptives, immobilization) and their control is warranted..

Other agents 
Given the potential thrombogenic effect of systemic antifibrinolytic therapy, agents such as aminocaproic acid (Amicar) and tranexamic acid (Cyklokapron) may be used with caution in patients with dysfibrinogenemia and bleeding, but should not be used in patients who have thrombosis. Local treatment with these agents (eg, Amicar or Cyklokapron 5 percent mouthwash solution 10 mL four times daily for 7 to 10 days) may be useful in oral or dental surgery [80].

Pregnancy
Fibrinogen replacement therapy has changed the natural history of pregnancy in patients with undetectable functional fibrinogen levels (ie, afibrinogenemia). The first case of a successful pregnancy in a woman with afibrinogenemia was reported in 1985, using fibrinogen infusion during pregnancy [81].
Guidelines for replacement therapy were proposed based upon the correlation between measured fibrinogen levels and observed adverse outcomes in a small number of women with afibrinogenemia [82-84]. Post-partum bleeding can also be prevented by fibrinogen infusion. Weekly fibrinogen infusions are warranted to maintain trough fibrinogen levels greater than 60 to 100 mg/dL, starting as early as week four or five of gestation, in order to prevent bleeding and abortion. Fibrinogen requirements increase significantly with the number of weeks of gestation. During labor, higher fibrinogen target levels of at least 150 to 200 mg/dL with continuous infusion have been proposed to prevent placental abruption.
The severity of pregnancy complications in congenital hypofibrinogenemia is variable. Decisions about the extent and duration of fibrinogen replacement therapy should be individualized. However, fibrinogen infusion before delivery is warranted in order to prevent bleeding [85].
Based upon data from congenital afibrinogenemia, it is possible that recurrent abortion in women with dysfibrinogenemia may also be prevented by the use of prophylactic fibrinogen replacement. Whether such replacement therapy is beneficial is largely unknown, and may be associated with an increased risk of thrombosis. The abnormal fibrinogen may act in a dominant manner, preventing normal fibrin generation. There are no data in the literature to make any definitive recommendation in such circumstances.
In a registry of patients with a thrombophilic dysfibrinogen, 7 of 15 women developed postpartum thrombosis during a total of 34 normal deliveries [31]. Thus, prophylactic postpartum anticoagulation should be considered in these high risk women. In the same registry, two patients developed postpartum hemorrhage in the setting of hypodysfibrinogenemia. The patient's previous clinical history provides key elements in guiding the treatment of these women.

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INTRODUCCIÓN 

El fibrinógeno normal circula en el plasma a una concentración de aproximadamente 200 a 400 mg/dL, con una vida media de cuatro días y una tasa catabólica de aproximadamente el 25 por ciento al día [1].
El fibrinógeno tiene numerosas interacciones funcionales y desempeña un papel fundamental en el equilibrio hemostático:

  * Es el sustrato para la formación de coágulos de fibrina
  * Se une a las plaquetas para favorecer la agregación plaquetaria
  * Tiene un papel en la cicatrización de heridas
  * El coágulo de fibrina es una plantilla tanto para la unión de la trombina como para el sistema
     fibrinolítico.

Cualquier anomalía del fibrinógeno (es decir, hipofibrinogenemia, disfibrinogenemia) puede dar lugar a defectos en una o más de estas funciones clave. El resultado final del equilibrio entre la formación de coágulos de fibrina y la fibrinólisis determina si las manifestaciones clínicas incluyen hemorragias, trombosis, ambas o ninguna.
Mientras que el hallazgo de un nivel bajo de fibrinógeno circulante se ve comúnmente como resultado de trastornos adquiridos de la coagulación (por ejemplo, coagulación intravascular diseminada aguda), la presencia de un fibrinógeno anormal (es decir, disfibrinogenemia) es una condición rara. Suele sospecharse tras el hallazgo de un tiempo de trombina prolongado o un nivel de fibrinógeno bajo. En la práctica hospitalaria, se observa con mayor frecuencia como un trastorno adquirido en pacientes con enfermedades hepáticas; la disfibrinogenemia congénita es rara. La verdadera incidencia es desconocida, ya que muchos fibrinógenos anormales son clínicamente silenciosos.
En esta revisión temática se discutirá la estructura y función del fibrinógeno, así como las manifestaciones clínicas, el diagnóstico y el manejo de los trastornos congénitos y adquiridos del fibrinógeno.
Las discusiones sobre el fibrinógeno como reactante de fase aguda, la relación entre los niveles elevados de fibrinógeno y las enfermedades cardiovasculares, y la fibrinólisis anormal se presentan por separado.

CLASIFICACIÓN 

Los trastornos del fibrinógeno pueden clasificarse como cuantitativos o cualitativos, congénitos o adquiridos. Aquí se utilizarán los siguientes términos:

 * La disfibrinogenemia se refiere a la presencia de una molécula de fibrinógeno disfuncional.
 * La hipodisfibrinogenemia se refiere a aquellos fibrinógenos heredados que son funcionalmente
    anormales y que están asociados a niveles plasmáticos bajos (<150 mg/dL) medidos por técnicas
    inmunológicas.
 * La hipofibrinogenemia es cualquier condición asociada con una reducción del nivel circulante de
    fibrinógeno normal a <150 mg/dL.
 * La afibrinogenemia es una rara condición autosómica recesiva en la que hay una falta total de
    fibrinógeno circulante.
 * La criofibrinogenemia es un fenómeno en el que existe la presencia en el plasma, pero no en el suero,
    de un fibrinógeno que precipita al exponerse a bajas temperaturas (por ejemplo, 4ºC).

ESTRUCTURA Y FUNCIÓN DEL FIBRINÓGENO 

El fibrinógeno humano es una glicoproteína dimérica compleja de 340kD compuesta por dos mitades simétricas idénticas conectadas centralmente por tres enlaces disulfuro. Cada mitad consta de tres cadenas polipeptídicas (es decir, Aalpha, Bbeta y gamma) codificadas por tres genes diferentes del cromosoma 4 (FGA, FGB, FGG) y sintetizadas por los hepatocitos. El ensamblaje del fibrinógeno tiene lugar en el hígado [2]; las cadenas laterales de carbohidratos se añaden a las cadenas beta y gamma antes de que la molécula sea secretada en el plasma. Una pequeña reserva de fibrinógeno se almacena en los gránulos alfa de las plaquetas. El fibrinógeno plasmático se internaliza mediante un proceso mediado por la GPIIb/IIIa, y puede favorecer la agregación plaquetaria. (Gránulos plaquetarios específicos).
La estructura trinodular del fibrinógeno puede describirse como una región E central (que contiene las porciones aminoterminales de las tres cadenas polipeptídicas) y dos regiones D (porciones caboxiterminales) [3]. Se ha determinado la secuencia completa de aminoácidos del fibrinógeno, así como la localización de los residuos que definen los sitios de algunas de las funciones importantes, incluyendo la escisión del fibrinopéptido, la polimerización de la fibrina, el entrecruzamiento de la fibrina mediado por el factor XIIIa, así como su interacción con la glicoproteína plaquetaria IIb/IIIa [4-7].

Síntesis del fibrinógeno
La síntesis de fibrinógeno se controla a nivel de la transcripción. El componente inducible está influenciado principalmente por las reacciones de fase aguda. La biosíntesis de fibrinógeno aumenta con la inflamación y el estrés, un proceso mediado por la interleucina 6. La interleucina 6 aumenta la transcripción del ARNm del fibrinógeno, mientras que la interleucina 1 y el factor de necrosis tumoral alfa suprimen la síntesis de fibrinógeno[8,9].
La respuesta de fase aguda puede elevar el fibrinógeno plasmático entre 2 y 20 veces. El pico de elevación del fibrinógeno durante la fase aguda se produce a los tres o cinco días, con un retorno gradual a la línea de base tras la resolución de la inflamación [8-10]. Se han identificado polimorfismos del gen del fibrinógeno B-beta; algunas variantes se asocian a concentraciones elevadas de fibrinógeno en plasma, especialmente en los fumadores [11,12]. Los estudios epidemiológicos indican que los niveles elevados de fibrinógeno se asocian a un mayor riesgo de enfermedades cardiovasculares, accidentes cerebrovasculares y mortalidad no vascular.
La conversión del fibrinógeno en fibrina insoluble puede dividirse en tres pasos distintos, como se analiza en las siguientes secciones.

Escisión del fibrinopéptido 
Cuando la trombina se une al fibrinógeno, escinde los fibrinopéptidos A (FPA) y B (FPB) de las porciones aminoterminales de las cadenas Aalpha y Bbeta en los enlaces Arg16-Gly17 y Arg14-Gly15, respectivamente, facilitando la polimerización óptima de la fibrina. La liberación del FPA se produce antes y más rápidamente que la del FPB y es suficiente para inducir la formación del coágulo, mientras que la escisión aislada del FPB no es suficiente para este fin.
La molécula resultante, compuesta por un dímero de tres cadenas polipeptídicas: alfa, beta y gamma, se denomina monómero de fibrina, la unidad básica de la formación de fibrina. Cualquier defecto estructural de la región aminoterminal puede perjudicar notablemente la unión de la trombina, la liberación de FPA o FPB, así como la velocidad de formación de fibrina [13]. Por lo tanto, no es sorprendente que una alta proporción de los fibrinógenos anormales tengan mutaciones que afectan a esta región. Aun así, la mayoría de los sujetos afectados permanecen asintomáticos, aunque algunos presentan manifestaciones hemorrágicas excesivas, especialmente después de la cirugía o el parto.

Polimerización de la fibrina 
En el fibrinógeno normal, la liberación de FPA y FPB cargados negativamente da lugar a la polimerización espontánea de monómeros de fibrina para formar el coágulo de fibrina. Este proceso se inicia por la unión complementaria no covalente de los sitios de polimerización en la región D de una molécula con el dominio central E de un monómero de fibrina adyacente, formando una hebra de dos moléculas de espesor o protofibrilla. Los sitios de polimerización se encuentran en la porción aminoterminal de las cadenas A alfa y B beta (dominio E), y en la porción carboxiterminal de las cadenas gamma (dominio D). A esto le sigue el crecimiento longitudinal (contacto D-D entre monómeros de fibrina adyacentes) y la ramificación para formar la red de fibrina final [14]. Las mutaciones que afectan a estos sitios de unión pueden retrasar la polimerización de la fibrina y producir manifestaciones clínicas heterogéneas.

Reticulación de la fibrina 
La reticulación mediada por el factor XIIIa es el último paso en la formación del coágulo de fibrina. El FXIII es activado por la trombina y se une a la fibrina para producir enlaces covalentes entre los dominios D de las fibras de fibrina. Estos enlaces implican interacciones de la cadena gamma-gamma, así como de las cadenas alfa-alfa y alfa-gamma [15].
El entrecruzamiento estabiliza el coágulo y lo hace resistente a la ruptura.
Un entrecruzamiento defectuoso debido a una molécula de fibrinógeno anormal puede afectar a la resistencia mecánica del coágulo y ser responsable del retraso en la cicatrización de la herida y/o de la dehiscencia de la misma, de forma similar a los pacientes con deficiencia de FXIII. Por otra parte, el aumento de la reticulación podría predisponer a fenómenos tromboembólicos y enfermedades cardiovasculares [16,17]. Esto está respaldado por las observaciones relativas a una variante del fibrinógeno que se produce normalmente, el fibrinógeno gamma-prima. Aproximadamente entre el 8 y el 15 por ciento del fibrinógeno plasmático contiene una variante de la cadena gamma (gamma-prime) resultante de un empalme alternativo, que da lugar al fibrinógeno gamma-prime [18-20]. Esta variante se asocia a coágulos estructuralmente diferentes, con un entrecruzamiento más extenso y una mayor resistencia a la lisis.
Un estudio de pacientes sometidos a una angiografía coronaria ha demostrado que los niveles de esta variante de fibrinógeno eran más altos de media en los pacientes con enfermedad arterial coronaria que en los pacientes sin enfermedad arterial coronaria, y que esta asociación era independiente de los niveles totales de fibrinógeno [21]. Un estudio de casos y controles realizado en pacientes con infarto de miocardio ha confirmado esta asociación [22].

Fibrinólisis 
La fibrina es una plantilla para el montaje y la activación del sistema fibrinolítico. El plasminógeno, el activador tisular del plasminógeno (t-PA) y el inhibidor de la alfa-2-plasmina tienen sitios de unión en el coágulo de fibrina. Las mutaciones que afectan a estas regiones pueden dar lugar a una generación defectuosa de plasmina y a una reducción de la fibrinólisis [6]. La tasa de fibrinólisis también se ve influida por el grosor de las fibras [23]. Además, la resistencia a la acción de la plasmina puede ser el resultado de mutaciones en el C-terminal de la cadena Aalpha asociadas a una unión anormal de la albúmina [24,25]. Estos mecanismos explican el fenotipo trombofílico, más que el hemorrágico, en algunos de estos individuos.

TRASTORNOS CONGÉNITOS 

Los trastornos congénitos del fibrinógeno consisten en la producción de un fibrinógeno anormal (disfibrinogenemia) o en la ausencia total de producción de fibrinógeno (afibrinogenemia). Cada una de ellas se describe a continuación.
La disfibrinogenemia heredada es el resultado de mutaciones en la región codificante de los genes del fibrinógeno FGA, FGB o FGG. En la literatura se han descrito más de 400 familias afectadas. Más del 90 por ciento son mutaciones puntuales, que conducen a la producción de un producto proteico disfuncional [26,27]. Existe una base de datos en línea actualizada de las mutaciones del fibrinógeno, que también proporciona datos sobre sus manifestaciones clínicas asociadas [28].
Se pueden establecer correlaciones estructura/función en varias de estas mutaciones [5,6,29]. Un número importante de estas mutaciones se localizan en las posiciones Aalpha 16 Arg (el sitio de escisión del FPA) y gamma 275 Arg (el sitio de polimerización de la fibrina) [27]. En general, las disfibrinogenemias pueden ser silenciosas (55%), o dar lugar a una diátesis hemorrágica (25%) o trombótica (10-20%) [26,30,31]. Alrededor del dos por ciento de las mutaciones pueden estar asociadas a complicaciones tanto trombóticas como hemorrágicas. La disfibrinogenemia asintomática suele diagnosticarse de forma incidental tras pruebas de coagulación anormales o como parte de estudios de cribado familiar.
Las disfibrinogenemias congénitas reciben el nombre de la ciudad en la que se identificó o evaluó al paciente por primera vez. Se añaden números romanos después del nombre de la ciudad cuando hay varias disfibrinogenias de la misma ciudad (por ejemplo, Caracas V). Salvo raras excepciones, el modo de herencia de las disfibrinogenemias congénitas es autosómico dominante.

Variantes trombóticas 
La disfibrinogenemia es una causa rara de trombofilia; las otras causas más comunes de trombofilia deben excluirse antes de evaluar al paciente por la presencia de un fibrinógeno anormal. La prevalencia de la disfibrinogenemia congénita en pacientes con antecedentes de trombosis venosa se ha estimado en un 0,8% [31].
Se desconoce la verdadera prevalencia de la trombosis entre los pacientes con disfibrinogenemia, pero se estima que está en torno al 10-20% [26,31]. La trombosis venosa de las extremidades inferiores domina el cuadro clínico; también se han descrito trombosis arteriales o ambas [32]. Los resultados de un registro de disfibrinogenemia y trombofilia establecido por el Subcomité Científico y de Normalización del Fibrinógeno de la Sociedad Internacional de Trombosis y Hemostasia se publicaron en 1995 [31]. El registro informó de 26 casos con trombosis a una edad temprana y recogió información sobre los miembros de la familia. La edad media de la primera trombosis fue de 27 años. Se pudo establecer una asociación muy convincente entre la disfibrinogenemia y la trombofilia en cinco familias (Caracas V, Melun, Nápoles, París V, Vlissinger/Franckfurt IV). Hubo una alta tasa de complicaciones relacionadas con el embarazo, como trombosis posparto y abortos espontáneos; 3 de las 26 familias experimentaron hemorragias posparto graves. Las concentraciones de fibrinógeno eran normales o bajas.

Variantes hemorrágicas 
Las pacientes con niveles de fibrinógeno inferiores a 50-100 mg/dL presentan una mayor frecuencia de complicaciones hemorrágicas. Las hemorragias también se asocian a mutaciones del fibrinógeno que dificultan la liberación de fibrinopéptidos o la polimerización de monómeros de fibrina. La mayoría de las manifestaciones hemorrágicas son moderadas, pero algunas pueden ser graves.
La presentación clínica es heterogénea, y puede incluir epistaxis, menorragia, facilidad para los hematomas, hemorragia de tejidos blandos, hemorragia postoperatoria, hemorragia anteparto y posparto, así como hematomas y hemartrosis. Las hemorragias se manifiestan a menudo después de un traumatismo, una intervención quirúrgica o durante el puerperio.

Mutaciones silenciosas
La mitad de los casos notificados de disfibrinogenemia permanecen asintomáticos, tal y como se observa en los miembros de la familia que comparten el defecto con el proponente.

Otras manifestaciones de la enfermedad 
Se ha descrito una amiloidosis renal hereditaria secundaria al depósito en el riñón de una cadena alfa de fibrinógeno mutante. La herencia es autosómica dominante y la mayoría de los individuos afectados desarrollan insuficiencia renal [33-40].
En dos mutaciones de la hipofibrinogenemia, el fibrinógeno anormal puede permanecer dentro del retículo endoplásmico del hepatocito, dando lugar a una forma de enfermedad de almacenamiento hepático [41,42].
La disfibrinogenemia puede causar, en raras ocasiones, un retraso en la cicatrización de las heridas y/o una dehiscencia de las mismas.

Afibrinogenemia congénita 
La afibrinogenemia, o la falta completa o prácticamente completa de fibrinógeno circulante, es una afección rara, que suele tener una herencia autosómica recesiva asociada a la consanguinidad [43-45]. La incidencia estimada es de uno por millón en la población general. Las manifestaciones hemorrágicas varían de mínimas a catastróficas, y pueden incluir una hemorragia mortal del cordón umbilical como primera manifestación de la enfermedad. En etapas posteriores de la vida, el trastorno puede asociarse a hemorragias de las superficies mucosas (p. ej., epistaxis, menorragia, hemorragia gastrointestinal), hemorragia en músculos y articulaciones, hemorragia intracraneal, abortos espontáneos y/o rotura esplénica espontánea.
La heterogeneidad de la enfermedad fue confirmada por las observaciones de un estudio de 100 pacientes con hipo o a-fibrinogenemia congénita. La incidencia anual de episodios de hemorragia fue de 0,7, con un rango de cero a 16,5 episodios por año [46].
El diagnóstico se establece al demostrar la presencia de fibrinógeno inmunorreactivo en el plasma [44]. Los pacientes con hipofibrinogenemia suelen ser asintomáticos, a menos que estén expuestos a un traumatismo.
La gran mayoría de los pacientes con afibrinogenemia son homocigotos o heterocigotos compuestos para mutaciones de truncamiento en el gen de la cadena alfa del fibrinógeno [47], mientras que los pacientes con hipofibrinogenemia suelen ser portadores asintomáticos de mutaciones de afibrinogenemia. Se han publicado revisiones exhaustivas de los mecanismos moleculares de la hipo y a-fibrinogenemia congénitas [48-50].

Complicaciones del embarazo
La concentración y la función normales del fibrinógeno son fundamentales para el éxito del embarazo. Las mujeres con anomalías cuantitativas o cualitativas del fibrinógeno tienen mayor incidencia de complicaciones hemorrágicas y trombóticas, abortos espontáneos recurrentes y abruptio placentae [31,51].
# Sangrado 
El fibrinógeno no parece ser necesario para la fecundación y la implantación inicial. Sin embargo, el fibrinógeno desempeña un papel fundamental en el mantenimiento de la integridad de la inserción placentaria. Por ejemplo, los ratones mutantes homocigotos deficientes en la cadena Aalpha presentan una hemorragia uterina fatal alrededor del décimo día de gestación [52]. En humanos, la hipo o afibrinogenemia congénita se asocia a una hemorragia excesiva y a abortos recurrentes tempranos a las 5 o 6 semanas de gestación [53].
# Trombosis
Las disfibrinogenemias congénitas también se asocian con el aborto espontáneo y la trombosis venosa posparto. En un registro de disfibrinogenemia familiar y trombofilia, 15 mujeres propuestas tuvieron un total de 34 partos normales. Sin embargo, en 7 de estas 15 mujeres se observaron 24 abortos espontáneos, seis nacimientos de bebés muertos y trombosis posparto. Una mujer desarrolló una trombosis tanto durante el embarazo como en el posparto. En cambio, dos mujeres con hipodisfibrinogenemia tuvieron una hemorragia posparto excesiva [31].

TRASTORNOS ADQUIRIDOS

Una serie de condiciones clínicas pueden conducir a la producción de un fibrinógeno anormal y  disfibrinogenemia adquirida:
* Enfermedad hepática 
La causa más común de la disfibrinogenemia adquirida es la enfermedad hepática. Se observa en la mayoría de los pacientes con cirrosis, hepatitis aguda o crónica, y también en el hepatoma metastásico [54-59]. La disfunción del fibrinógeno en este contexto se manifiesta por la prolongación de los tiempos de trombina y reptilasa; los niveles de fibrinógeno son normales cuando se miden por métodos inmunológicos.
El fibrinógeno anormal en este contexto se caracteriza por un mayor contenido de residuos de ácido siálico y un retraso en la polimerización de la fibrina [60,61]. Tanto el clivaje de los fibrinopéptidos A y B como la reticulación de la fibrina por el factor XIII son normales. La eliminación del ácido siálico del fibrinógeno anormal normaliza el tiempo de trombina y corrige el defecto de polimerización [60]. El fibrinógeno fetal normal también presenta un contenido aumentado de residuos de ácido siálico y se encuentran anomalías de laboratorio similares [61].
Es difícil evaluar si el fibrinógeno anormal que se observa en la enfermedad hepática se asocia a un mayor riesgo de hemorragia, ya que la mayoría de estos individuos tienen otras anomalías asociadas de la hemostasia (p. ej., trombocitopenia, síntesis disminuida de otros factores de coagulación) y/o otras causas de hemorragia (p. ej., varices, úlcera péptica). No se ha observado un aumento del riesgo trombótico.
* Otras causas 
La disfibrinogenemia adquirida también se ha notificado en asociación con el carcinoma renal [62], el tratamiento con isotretinoína [63], la obstrucción biliar [56] y la gangrena digital [64]. El fibrinógeno anormal puede desaparecer con el tratamiento de la enfermedad subyacente [62], o puede desaparecer espontáneamente [64].

Anticuerpos contra el fibrinógeno 
Se han descrito autoanticuerpos que inhiben funciones específicas del fibrinógeno. Estos anticuerpos pueden bloquear la liberación de fibrinopéptidos, la polimerización de monómeros de fibrina o la reticulación de la fibrina.
Se han descrito en el lupus eritematoso sistémico, la colitis ulcerosa, el mieloma múltiple, la terapia con isoniazida o sin ninguna afección subyacente [30,65]. La presencia de estos anticuerpos se asocia con mayor frecuencia a las manifestaciones hemorrágicas. Se han notificado casos de trombosis clínica asociada a los autoanticuerpos contra el fibrinógeno; muchos de esos pacientes tenían otros factores de riesgo de trombosis.
Los anticuerpos también pueden ser clínicamente silenciosos, como en el caso de un paciente en el que el anticuerpo interfería con la liberación de FPA [66]. El bloqueo de la liberación de FPA parece estar asociado a las manifestaciones clínicas más graves. Se han comunicado remisiones espontáneas.
El sellador de fibrina o cola de fibrina se ha utilizado durante varios procedimientos quirúrgicos en las últimas cuatro décadas. Los pacientes expuesto