Inherited Abnormalities of Fibrinogen

Mutations impacting fibrinogen synthesis or processing give rise to quantitative fibrinogen deficiencies, while mutations causing abnormal polymerization, cross-linking, or assembly of the fibrinolytic system lead to qualitative defects.[9]  Genetic defects and pathogenic mechanisms that have been identified include deletions, point mutations resulting in premature termination codons, missense mutations disturbing fibrinogen assembly or secretion, and unilateral isodisomy related to a significant deletion. Although mutations have been found in all three of the fibrinogen genes, the most common defects are aberrant splicing and deletion mutations in the fibrinogen A gene. Mutation-related molecular defects, identified through studies of specific mutations, include truncated α or γ chains or aberrantly folded β chains. Mutations can interfere with peptide synthesis or assembly of the fibrinogen hexameric complex and its secretion from the hepatocyte.[11, 12] These disorders are usually diagnosed in the newborn period, when they can present with umbilical cord bleeding.

Congenital dysfibrinogenemia is the result of mutations that give rise to functional abnormalities. The presence of an associated bleeding tendency or an increased risk of thrombosis depends on the effect of the specific mutation.

Type I (quantitative) fibrinogen deficiencies are generally inherited as autosomal recessive traits, whereas type II (qualitative) dysfibrinogenemias are inherited as autosomal dominant disorders in most cases.

Mutations associated with bleeding

There is a strong correlation between fibrinogen activity level and severity of bleeding. Abnormalities at the thrombin cleavage site of the Aα chain result in impaired release of fibrinopeptide A, inhibiting the conversion of fibrinogen to fibrin. Absent or slow fibrinopeptide release with delayed polymerization of the fibrin monomers has been associated with mutations in all 3 of the fibrinogen genes. Abnormal fibrinogens that exhibit defective cross-linking by factor XIIIa have been associated with abnormal wound healing.

In a study of 102 patients with congenital dysfibrinogenemia, Zhou et al found bleeding in 27.5% of them and thrombosis in 3.9%, while 68.6% of patients were asymptomatic. Thromboelastography results differed significantly between patients with hot-spot mutations at AαArg35(16) and γArg301(275), although such differences were not found between patients with and without bleeding. Thromboelastography results were normal in patients with mutations at AαArg35(16), AαPro37(18), or AαArg38(19).[13]

Mutations associated with thrombosis

Impaired fibrinopeptide B release results in abnormalities of polymerization that are associated with thrombotic events.

Abnormalities that interfere with plasminogen binding or activation on the fibrin clot result in reduced fibrinolysis and are associated with clinical thrombosis.

Defective fibrin binding of thrombin (a process that normally limits thrombin activity) results in prolonged activity of unbound thrombin, leading to amplification of fibrin clot formation and enhanced platelet activation. Mutations may be clinically silent.

Frequency

United States

A North American Registry of Rare Bleeding Disorders has been successful in collecting valuable information on inherited fibrinogen disorders and other rare bleeding disorders, with respect to disease prevalence, genotyping frequency, diagnostic events, clinical manifestations, treatment, and prophylaxis strategies, as well as disease and treatment-related complications. Among all the reported cases of fibrinogen disorders in this registry, afibrinogenemia accounted for 24% of cases, hypofibrinogenemia accounted for 38%, and dysfibrinogenemia accounted for 38%.[14] More recently, other resources for clinicians include the Rare Coagulation Disorders Resource Room.

International

The frequency of afibrinogenemia is estimated to be 1-2 cases per million people; a high rate of consanguinity has been reported. Inherited dysfibrinogenemia in the general population is rare, but determination of the true incidence is difficult because many patients are asymptomatic. In addition to the North American Registry, several other recent registries from Italy, Iran, and the United Kingdom have greatly improved understanding of the clinical spectrum of presentation. In one large registry of cases, at least half of the patients were asymptomatic.[15] Less than 1% of patients with venous thrombosis who were evaluated for dysfibrinogenemia were found to have this abnormality. A registry in Europe is also collecting data on this rare disorder.

Mortality/Morbidity

Deaths attributable to afibrinogenemia are associated with bleeding, most commonly postoperative bleeding and intracranial hemorrhage. Recurrent spontaneous abortions can occur in women with afibrinogenemia. Patients with dysfibrinogenemia are at risk of bleeding or thrombosis.[16]

Sex

Afibrinogenemia is autosomal recessive, with a male-to-female ratio of 1:1. Dysfibrinogenemias may manifest either autosomal recessive or autosomal dominant inheritance.

Afibrinogenemia poses a major risk during pregnancy and after delivery. Indeed, dysfibrinogenemia and thrombosis may be overrepresented in women because of the increased risk of thrombosis associated with pregnancy and the postpartum period.

Age

The age at diagnosis varies. Afibrinogenemia is often first diagnosed in the newborn period because of umbilical cord bleeding.[17]

Hypofibrinogenemia (ie, less severely reduced fibrinogen levels) is associated with fewer bleeding episodes and may be first diagnosed at the time of a traumatic or surgical challenge that results in bleeding.

Dysfibrinogenemias are commonly diagnosed in adulthood.

In afibrinogenemia, with fibrinogen levels less than 0.1 g/L, bleeding manifestations range from mild to severe.[8, 9] Umbilical cord hemorrhage frequently provides an early alert to the abnormality. Factor XIII deficiency is the other congenital bleeding diathesis typically associated with umbilical cord bleeding. Other bleeding manifestations include the following:

• Epistaxis and oral mucosal bleeding

• Hemarthrosis and muscle hematoma

• GI bleeding

• Menorrhagia and postpartum hemorrhage

• Traumatic and surgical bleeding

• Spontaneous splenic rupture and intracranial hemorrhage (rare)[7]

In patients with hypofibrinogenemia, bleeding episodes are usually mild, and, in many cases, no spontaneous clinical bleeding is present; bleeding may occur following trauma or surgery.[8, 9]

Afibrinogenemia and hypofibrinogenemia can be associated with thrombosis. Afibrinogenemia and hypofibrinogenemia can be associated with recurrent spontaneous abortion.

Patients with dysfibrinogenemia may experience hemorrhage or thrombosis, but most are asymptomatic.[10] In a study of 250 cases of dysfibrinogenemia, 55% involved no symptoms, with detection occurring by chance, while 25% had bleeding tendency, and 20% tended toward thrombosis.[15]  Dysfibrinogenemia has also been associated with poor wound healing, wound dehiscence, and spontaneous abortion. Skin necrosis and, less commonly, arterial thromboses have also been described. Only 0.8% of patients with a history of venous thrombosis have dysfibrinogenemia. A high incidence of thrombosis and spontaneous abortion is seen in women with history of thrombophilic dysfibrinogenemia.[15]

The prevalence of fibrinogen disorders is uncertain, and some fibrinogen deficiencies and dysfunction are not detected by standard anticoagulation screening tests; the prothrombin time (PT) and activated partial thromboplastin time (aPTT) are normal provided some fibrinogen is available for clot formation. Even in fully specialized coagulation laboratories, the diagnosis of some fibrinogen disorders can be quite challenging. Precise detection of one or more molecular defects in some cases can provide a more accurate prenatal or postnatal diagnosis and identify patients at risk for thrombosis rather than bleeding.[18]

Screening tests

PT and aPTT are prolonged in afibrinogenemia and may be prolonged in hypofibrinogenemia and dysfibrinogenemia. However, these tests have a poor sensitivity to mild fibrinogen deficiency or dysfunction.

In testing for thrombin time, a reagent containing thrombin is added to citrated plasma and the time to clot formation is measured. The thrombin time is prolonged by fibrin degradation products (FDPs), afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, thrombin inhibitors, bovine thrombin antibodies from previous exposure to bovine thrombin, and high concentrations of serum proteins (multiple myeloma). This test is more sensitive than PT or aPTT for quantitative and qualitative defects in fibrinogen. However, the specificity is poor because a prolonged thrombin time can occur in the presence of heparin, high concentration of FDPs, and direct thrombin inhibitors. Furthermore, results can significantly vary between laboratories as the test is not standardized.

A study by Jacquemin et al indicated that qualitative fibrinogen abnormalities can be distinguished from quantitative ones by analyzing the amplitude of coagulation curves derived from thrombin time tests. The investigators found that in patients with dysfibrinogenemia caused by a p.Arg301(275)Cys substitution (resulting from a heterozygous point mutation in the fibrinogen molecule’s γ polypeptide chain), the coagulation curve amplitudes were similar to those associated with persons with no fibrinogen disorder. In patients with acquired hypofibrinogenemia, however, the amplitudes were lower than in the rest of the cohort.[19]

A snake venom that directly activates fibrinogen by cleaving fibrinopeptide A is used as a reagent in the reptilase time test. The advantage over the thrombin time is that this test is not affected by heparin. A prolonged reptilase time, in the presence of a normal fibrinogen concentration, provides strong evidence of a dysfibrinogenemia. However, this test does not detect all forms of dysfibrinogenemia. Elevated fibrinogen levels due to an acute phase reaction can be associated with prolonged reptilase times, possibly due to increased sialyation and/or phosphorylation.[20]

Clottable fibrinogen

A functional assay by the Clauss method is one of the most common tests used to measure fibrinogen activity. In this method, a reagent containing a high concentration of thrombin that triggers clot formation when added to citrated plasma is used. The time to clot formation is recorded and is read off of a reference curve for tests performed with known concentrations of fibrinogen. Most laboratories these days perform this test on instruments with a photo-optical endpoint analyzer, and lipemia and/or hyperbilirubinemia may interfere with this assay.

Fibrinogen antigen

Various immunoassays are commercially available for the quantitative measurement of fibrinogen assay. These assays do not assess fibrinogen function. In afibrinogenemia, fibrinogen concentrations are low using the clottable or quantitative antigen method, usually less than 0.1 g/L, and often undetectable in symptomatic individuals. In dysfibrinogenemia, a discrepancy may be found between fibrinogen measured in a functional assay (low) and fibrinogen measured immunologically (normal); however, in some dysfibrinogenemias, a concordant decrease in the 2 assays is observed. A fibrinogen antigen–to–clottable fibrinogen ratio may help to distinguish dysfibrinogenemia (high ratio) from hypofibrinogenemia (ratio close to 1).[21]

Genotyping

Genotyping identification of the specific molecular defect may be useful in both afibrinogenemia and dysfibrinogenemia. Mutation analysis has not identified any correlation with phenotype or ethnic background. However, it can be useful in diagnosis confirmation, screening of relatives for carrier status, family counseling, and prenatal diagnosis. A review of all available clinical and genetic data from 50 homozygous afibrinogenemic patients demonstrated no clear genotype/phenotype correlations.[6] One possible explanation for this variability is the existence of modifier genes or alleles. Some variants may increase the severity of bleeding whereas others may ameliorate the phenotype. Such modifiers have yet to be identified; however, common variants predisposing to thrombophilia may have a role in decreasing the severity of bleeding.[22]

Thrombophilia evaluation

Because dysfibrinogenemia is a rare cause of thrombosis (< 1%), patients in whom dysfibrinogenemia is diagnosed in the setting of thrombosis should have a complete investigation for other risk factors, inherited and acquired, that may have contributed to the thrombotic event.

In the investigation of suspected bleeding, appropriate imaging studies (eg, brain CT scanning or MRI) may reveal the presence of suspected central nervous system (CNS) hemorrhage.

A study by Nagler et al looking at the long-term clinical course and laboratory data associated with four patients with congenital afibrinogenemia indicated that regular fibrinogen replacement or orthotopic liver transplantation can produce long-term remission. Arterial thrombi were found to have resolved after 6-12 months in the two patients who underwent such treatment, while the two who received infrequent fibrinogen replacement had recurrent thromboembolic events.[23]

Hemorrhage

Fibrinogen administration may offer a prophylactic benefit to patients with afibrinogenemia. The level of fibrinogen activity should be maintained at over 0.5 to 1.0 g/L via adjustment of dosage and how frequently the agent is taken. Pregnant women with afibrinogenemia must receive prophylaxis as early as possible, with such treatment continuing through pregnancy and after delivery.[24]  For patients with clinical bleeding associated with afibrinogenemia or dysfibrinogenemia, replacement of fibrinogen to a level of more than 0.8 g/L is usually adequate to maintain hemostasis, although levels greater than 1 g/L have been recommended for CNS hemorrhage. Plasma-derived fibrinogen concentrates have the advantage of virus inactivation.[25, 26] Plasma recovery of fibrinogen with the use of fibrinogen concentrate is 1.8 mg/mL per mg/kg infused. Replacement with 70 mg/kg is recommended prior to surgical procedures and severe bleeding episodes, and 40 mg/kg for mild to moderate bleeding.

The half-life of fibrinogen is approximately 3.5 days, and afibrinogenemic patients can usually be managed postoperatively with infusion of replacement therapy every 2-3 days for major surgery.

Children have more rapid plasma fibrinogen clearance and may require higher and more frequent dosing for surgery and major bleeding. The therapeutic goal is to achieve a plasma fibrinogen activity level of 100-150 mg dL-1 prior to surgery that is maintained until hemostasis is achieved and wound healing is complete.[27]

Cryoprecipitate has been used as a source of fibrinogen; each bag of cryoprecipitate contains 100-250 mg of fibrinogen. The guidelines for dysfibrinogenemia are not standardized due to a lack of sufficient data in bleed management.

A study by Khayat et al indicated that in patients with inherited afibrinogenemia, a standard fibrinogen concentrate infusion dose (defined in the report as 40-100 mg/kg) does not induce hypercoagulability. While a statistically significant rise in endogenous thrombin potential and thrombin peak was found at 1 hour post infusion, the increases were nonetheless lower than those seen in healthy controls. The investigators also determined that at 1 hour the fibrin polymerization parameters “were comparable to those of patients with inherited hypofibrinogenemia matched for fibrinogen plasma levels.”[28]

Fibrinogen dosage calculation[9]

Dose (g) = desired increment in g/L x plasma volume (plasma volume is 0.07 x (1-hematocrit) x weight (kg)

The patient's personal and family history of bleeding and thrombosis should be taken into consideration for appropriate dosing of replacement therapy. In addition, the pharmacokinetics of fibrinogen after replacement therapy widely varies, and individual dose adjustment is recommended.

Thrombosis

Patients who present with thrombosis associated with dysfibrinogenemia should receive anticoagulation therapy. The duration of therapy has not been established for this particular group of patients; the decision depends on the clinical situation and the presence of other contributing factors. If the patient has had multiple thromboembolic events, a single life-threatening event, or has additional inherited risk factors, protracted anticoagulation therapy is recommended.

Spontaneous abortion

Recurrent spontaneous abortion may be prevented by routine prophylaxis with fibrinogen concentrates starting early in pregnancy.

Acquired inhibitors

Acquired inhibitors have been reported after replacement therapy and should be considered in previously treated patients who demonstrate poor hemostasis with usual therapies.

To prevent excessive bleeding during surgical procedures, prophylactic treatment to raise fibrinogen levels to 1-1.5 g/L during the procedure is recommended. Replacement should be continued for 4-14 days following surgery, depending on the nature of the surgical procedure and time to complete healing.

Consultation with a hematologist/hemostasis specialist is advisable for patients who require fibrinogen replacement therapy. Genetic counseling and family studies should be part of a complete evaluation.

Class Summary

Fibrinogen concentrates and cryoprecipitate are both derived from human plasma. The advantage of fibrinogen concentrates is that virus inactivation is incorporated into the preparation of this product. More precise dosing can be achieved with concentrates, as the fibrinogen concentration in cryoprecipitate may vary.

Fibrinogen concentrate, human (RiaSTAP)

Approved by the FDA in 2009. Indicated for the treatment of acute bleeding episodes in patients with congenital fibrinogen deficiency, including afibrinogenemia and hypofibrinogenemia. Not indicated for dysfibrinogenemia. Available as single-use vials containing 900-1300 mg lyophilized fibrinogen concentrate powder for reconstitution. Actual fibrinogen potency for each lot is printed on vial label and carton.

Fibrinogen concentrate (Haemocomplettan P, Clottagen, Fibrinogen HT)

Fibrinogen concentrates are derived from human plasma and have been virus-inactivated to improve their safety. In the United States, human fibrinogen is available as an orphan drug from Alpha Therapeutics.

Cryoprecipitate

Can be used when fibrinogen concentrates are not available. Unlike fibrinogen concentrates, it does not undergo virus inactivation. The precipitate formed when fresh frozen plasma (FFP) is slowly thawed. It contains factor VIII, factor XIII, fibrinogen, von Willebrand factor (vWF), and fibronectin. Each bag provides 100-250 mg fibrinogen.

Class Summary

These are useful in conjunction with fibrinogen replacement for the treatment of mucosal bleeding, particularly bleeding involving the oronasopharynx. Inhibition of local fibrinolysis allows maintenance of the clot and decreases the frequency of rebleeding.

Aminocaproic acid (Amicar)

Lysine analogue that inhibits fibrinolysis by blocking binding of plasmin or plasminogen activators to lysine residues on fibrin.

Tranexamic acid (Cyklokapron)

Alternative to aminocaproic acid. Inhibits fibrinolysis by displacing plasminogen from fibrin.

Ideally, individuals with afibrinogenemia and symptomatic dysfibrinogenemia should be monitored by a comprehensive bleeding disorder care team experienced in diagnosing and managing inherited bleeding disorders; team members should be associated with a hemophilia and inherited bleeding disorders treatment center. Special attention should be paid to providing prophylactic treatment to pregnant women with afibrinogenemia as early as possible, with therapy administered both during pregnancy and after delivery.[24]

In patients with afibrinogenemia and symptomatic dysfibrinogenemia, thrombosis risk is another consideration, and in many of these individuals, anticoagulants and fibrinogen need to be administered concurrently.[24]

Individuals who may require plasma-derived coagulation factor concentrates should be immunized with the hepatitis A and hepatitis B vaccine.

Patients should avoid taking aspirin, ibuprofen, and other nonsteroidal anti-inflammatory drugs (NSAIDs), as well as other medications that affect platelet function.

Prophylactic therapy is needed for patients with recurrent bleeding episodes or CNS hemorrhage or during pregnancy to prevent miscarriage. Indeed, females of childbearing age with afibrinogenemia must be educated with regard to the condition's effect on pregnancy and childbirth and the necessity of prophylaxis with fibrinogen.

Patients and families should be provided with instruction and educational materials to enhance understanding of their coagulation disorder, improve their ability to recognize the symptoms and signs of bleeding and/or thrombosis, and to identify emergency situations.

Patients should know how to contact their treatment center for immediate treatment and where to go to receive emergency care.

Patients should wear a MedicAlert bracelet or carry other identification of their hemostatic disorder and recommended therapy.