AUTHOR AND EDITOR INFORMATION

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INTRODUCTION

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Background

Congenital abnormalities of fibrinogen are divided into 2 types: type I, or quantitative abnormalities (afibrinogenemia and hypofibrinogenemia), and type II, or qualitative abnormalities (dysfibrinogenemia and hypodysfibrinogenemia). Afibrinogenemia and hypofibrinogenemia result from mutations that affect plasma fibrinogen concentration and are frequently associated with a bleeding diathesis. Dysfibrinogenemia is marked by functional abnormalities of fibrinogen that may result in either bleeding or thrombosis.

Fibrinogen is a 340-kD glycoprotein that circulates in plasma at a concentration of 2-4 g/L, with a half-life of 4 days. The fibrinogen molecule is a hexamer, consisting of 3 paired polypeptide chains: A-a, B-b, and g; A and B refer to specific polypeptides on 2 of the chains. Synthesis of the protein in hepatocytes is under the control of 3 genes (one for each chain) located within 50 kilobases (kb) on chromosome 4.

The primary physiological role of fibrinogen is in hemostasis. In the final step of the coagulation cascade, fibrinogen is converted to fibrin, with formation of a fibrin clot. The first step in this conversion is thrombin cleavage of fibrinopeptides A and B from the fibrinogen a and b chains; the residual molecule is referred to as fibrin monomer. A loose fibrin clot develops as fibrin monomers spontaneously polymerize. The formation of a firm insoluble fibrin gel depends on cross-linking of the polymer by the transglutaminase activity of factor XIIIa (see Media file 1). The fibrin clot has an essential role in limiting bleeding at sites of blood vessel injury; it also provides the structure for assembly and activation of the fibrinolytic proteins.

Pathophysiology

Congenital afibrinogenemia is the result of defective fibrinogen synthesis. Although mutations have been found in all 3 of the fibrinogen genes, the most common defects are aberrant splicing and deletion mutations in the fibrinogen a gene. The molecular defects, identified through studies of specific mutations, include truncated a or g chains or aberrantly folded b chains. These mutations can interfere with peptide synthesis or assembly of the fibrinogen hexameric complex and its secretion from the hepatocyte.

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.

• Mutations associated with bleeding include the following:
• • 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.
• Mutations associated with thrombosis include the following:
• • 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

International

The frequency of afibrinogenemia is 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 one large registry of cases, at least half of the patients were asymptomatic.¹ Less than 1% of patients with venous thrombosis who were evaluated for dysfibrinogenemia were found to have this abnormality.

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.

Sex

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

CLINICAL

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History

• In afibrinogenemia, with fibrinogen levels less than 0.1 g/L, bleeding manifestations range from mild to severe. 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
  • Gastrointestinal bleeding
  • Menorrhagia and postpartum hemorrhage
  • Traumatic and surgical bleeding
  • Spontaneous splenic rupture and intracranial hemorrhage (rare)
• 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.
• Afibrinogenemia and hypofibrinogenemia can be associated with thrombosis.
• Afibrinogenemia and hypofibrinogenemia can be associated with recurrent spontaneous abortion.
• Patients with dysfibrinogenemia may experience hemorrhage (28%) or thrombosis (20%), but most are asymptomatic (60%). Dysfibrinogenemia has also been associated with poor wound healing and spontaneous abortion.

DIFFERENTIALS

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Other Problems to be Considered

Congenital afibrinogenemia and dysfibrinogenemia with bleeding must be differentiated from other congenital clotting factor deficiencies. In addition, clinical conditions that result in acquired hypofibrinogenemia, such as consumptive coagulopathy, hepatic failure, and L-asparaginase therapy, or in acquired dysfibrinogenemia, such as liver disease and some neoplasms, should be excluded.

Dysfibrinogenemia with thrombosis must be differentiated from other causes of congenital or acquired thrombophilia.

WORKUP

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Lab Studies

• Screening tests: Prothrombin time (PT) and activated partial thromboplastin time (aPTT) are prolonged in afibrinogenemia and may be prolonged in dysfibrinogenemia. Thrombin time and reptilase time are more sensitive to abnormalities of fibrinogen than the PT or aPTT. Unlike the other tests listed, reptilase time is unaffected by heparin. A prolonged reptilase time, in the presence of a normal fibrinogen concentration, provides strong evidence of a dysfibrinogenemia.
• Fibrinogen concentration: Fibrinogen levels are measured by either immunological assays or functionally as clottable protein. In afibrinogenemia, fibrinogen concentrations are low by either 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.
• 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.
• 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.

Imaging Studies

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

TREATMENT

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Medical Care

• Hemorrhage: 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. The usual starting dose for adults is 1-2 g intravenously administered. The pediatric dose is 30-100 mg/kg intravenously administered, depending on the severity and site of bleeding. Cryoprecipitate has been used as a source of fibrinogen; each bag of cryoprecipitate contains 100-250 mg of fibrinogen.
• Thrombosis: Patients presenting 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.

Surgical Care

To prevent excessive bleeding during surgical procedures, prophylactic treatment to raise fibrinogen levels to 1.0-1.5 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.

Consultations

• 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.

MEDICATION

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Drug Category: Plasma sources of fibrinogen

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.

Drug Name	Cryoprecipitate
Description	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.
Adult Dose	1 bag per 5 kg/d IV initially, then 1 bag per 15 kg/d IV; monitor fibrinogen levels to maintain >0.5-0.8 g/L
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	None reported
Pregnancy	B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals
Precautions	May cause allergic reactions or fibrinogen antibody development; may increase thrombosis risk; increases risk of transfusion-transmitted viral infection

Drug Category: Antifibrinolytics

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.

Drug Name	Tranexamic acid (Cyklokapron)
Description	Alternative to aminocaproic acid. Inhibits fibrinolysis by displacing plasminogen from fibrin.
Adult Dose	25 mg/kg PO tid/qid 10 mg/kg IV tid/qid in patients unable to take PO
Pediatric Dose	Administer as in adults
Contraindications	Documented hypersensitivity
Interactions	Limited data available; none reported
Pregnancy	C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus
Precautions	Caution in renal impairment; caution in patients with a personal or family history of thrombosis

FOLLOW-UP

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Further Outpatient Care

• Ideally, individuals with afibrinogenemia and symptomatic dysfibrinogenemias should be monitored by a comprehensive bleeding disorder care team experienced in diagnosing and managing inherited bleeding disorders.

Deterrence/Prevention

• 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 and other drugs that affect platelet function.
• Consider prophylactic therapy for patients with recurrent bleeding episodes, CNS hemorrhage, or during pregnancy for women with recurrent miscarriage.

Patient Education

• 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.

MISCELLANEOUS

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Medical/Legal Pitfalls

• Failure to make a specific diagnosis of either congenital afibrinogenemia or dysfibrinogenemia
• Failure to investigate other family members for the abnormality identified in the propositus
• Failure to appropriately treat bleeding episodes with fibrinogen replacement in patients with afibrinogenemia
• Failure to provide fibrinogen replacement prior to surgical procedures in patients with afibrinogenemia

Special Concerns

• In pregnant patients, recurrent spontaneous abortion may be prevented by routine prophylaxis with fibrinogen concentrate.
• Patients may be at risk of thrombosis, even if their primary clinical presentation is bleeding. Administration of fibrinogen replacement may increase thrombotic risk, particularly in settings that are prothrombotic such as surgery.

MULTIMEDIA

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Media file 1:  The conversion of soluble fibrinogen to insoluble fibrin.
	View Full Size Image
Media type:  Image

REFERENCES

Section 11 of 11

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1. Haverkate F, Samama M. Familial dysfibrinogenemia and thrombophilia. Report on a study of the SSC Subcommittee on Fibrinogen. Thromb Haemost. Jan 1995;73(1):151-61. [Medline].
2. Asselta R, Duga S, Tenchini ML. The molecular basis of quantitative fibrinogen disorders. J Thromb Haemost. Oct 2006;4(10):2115-29. [Medline].
3. Bolton-Maggs PH, Perry DJ, Chalmers EA, et al. The rare coagulation disorders--review with guidelines for management from the United Kingdom Haemophilia Centre Doctors' Organisation. Haemophilia. Sep 2004;10(5):593-628. [Medline].
4. Cunningham MT, Brandt JT, Laposata M, Olson JD. Laboratory diagnosis of dysfibrinogenemia. Arch Pathol Lab Med. 2002;126:499-505. [Medline].
5. Martinez J. Congenital dysfibrinogenemia. Curr Opin Hematol. Sep 1997;4(5):357-65. [Medline].
6. Parameswaran R, Dickinson JP, de Lord S, et al. Spontaneous intracranial bleeding in two patients with congenital afibrinogenaemia and the role of replacement therapy. Haemophilia. Nov 2000;6(6):705-8. [Medline].
7. Peyvandi F, Haertel S, Knaub S, Mannucci PM. Incidence of bleeding symptoms in 100 patients with inherited afibrinogenemia or hypofibrinogenemia. J Thromb Haemost. Jul 2006;4(7):1634-7. [Medline].
8. Roberts HR, Stinchcombe TE, Gabriel DA. The dysfibrinogenaemias. Br J Haematol. Aug 2001;114(2):249-57. [Medline].

Article Last Updated: Nov 8, 2007