eMedicine Specialties > Pediatrics: General Medicine > Hematology

Inherited Abnormalities of Fibrinogen

Author: Sara J Israels, MD, FRCPC, Professor of Pediatric Hematology/Oncology, Section Head of Pediatric Hematology/Oncology/BMT, Department of Pediatrics and Child Health, University of Manitoba
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Updated: Feb 12, 2009

Introduction

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 A α 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

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.

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