Inherited Abnormalities of Fibrinogen 

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.^[1] Dysfibrinogenemia is marked by functional abnormalities of fibrinogen that may result in either bleeding or thrombosis.^[2]

Fibrinogen is a 340-kD glycoprotein that is synthesized in the liver and 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-α, B-β, and γ; 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 α and β 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 the image below).

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.

Although the primary function of fibrinogen is in fibrin clot formation, it has a multitude of other functions, including nonsubstrate thrombin binding, platelet aggregation, and fibrinolysis. Exposure of its nonsubstrate thrombin-binding sites after fibrin clot formation promotes the antithrombotic properties of fibrinogen.^[3] Therefore, disorders of fibrinogen may be associated with either a bleeding or a thrombotic predisposition.

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.

Type I fibrinogen deficiencies are generally inherited as autosomal recessive traits, whereas dysfibrinogenemias are inherited as autosomal dominant disorders in most cases.

Mutations associated with 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.

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%.^[4]

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.^[5] 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.