Rare Congenital Fibrinogen Deficiencies
Fibrinogen, a 340-kDa complex glycoprotein synthesized in the liver, has a multitude of functions in the final steps of the coagulation cascade, including fibrin clot formation, activated FXIII-mediated fibrin cross-linking, nonsubstrate thrombin binding, platelet aggregation, and fibrinolysis.1-3
The conversion of fibrinogen to insoluble fibrin is a pivotal step in the coagulation pathway. After fibrin clot formation, exposure of the nonsubstrate thrombin–binding sites in fibrinogen promotes antithrombotic properties.4 Thus, because of its multi-faceted roles in coagulation, quantitative and qualitative modifications of fibrinogen can result in bleeding and/or thrombotic phenotypes.
Fibrinogen and fibrin bind and sequester thrombin, thus down-regulating thrombin activity. This physiologic function was determined to be so important that fibrinogen was initially named antithrombin I. In the absence of fibrinogen and fibrin, thrombin lacks a critical regulatory pathway and is available for activation of platelets and other blood and vascular cells.5
Genetic mutations in the three linked genes coding for fibrinogen give rise to a number of disorders known collectively as congenital fibrinogen deficiency (CFD). The three genes –FGA, FGB, FGG – are located on chromosome 4q and code for the three polypeptide chains Aα, Bβ and γ in a pairwise manner to form the hexameric circulating molecule.
Fibrin is produced by proteolytic cleavage of the fibrinogen alpha and beta chains by thrombin, releasing fibrinopeptides (FP) A and B thereby allowing polymerization to occur. Cleavage of fibrinopeptide A (FPA, Aα 1-16) by thrombin exposes a polymerization site in the E domain that binds to the carboxyterminal region of the fibrin monomers (Figure 1).
Figure 1. Fibrinogen consists of three pairs of polypeptide chains Aα, Bβ, and γ, joined by disulfide bonds to form a symmetric dimeric structure (Top). The NH2 terminals of all 6 chains form the central domain (E domain) of the molecule containing fibrinopeptides A and B (FPA and FPB) sequences, which are cleaved by thrombin during enzymatic conversion to fibrin. Enzymatic conversion of fibrinogen to fibrin (Bottom) by thrombin cleavage results in release of FPA and FPB. Binding sites for thrombin, t-PA, and FXIII are indicated on the fibrin or fibrinogen molecule. Abnormalities at the thrombin cleavage site of the Aα chain can cause impaired release of fibrinopeptide A, inhibiting the conversion of fibrinogen to fibrin and leading to bleeding.
Adapted from Acharya A, Dimichele D. Rare inherited disorders of fibrinogen. Haemophilia. 2008;14:1151–1158.
FPB (Bb 1-14) cleavage occurs more slowly and contributes to lateral fibril and fiber association. Absent or slow fibrinopeptide B release with delayed polymerization of the fibrin monomers can cause a bleeding phenotype, while impaired fibrinopeptide B release results in abnormalities of polymerization that are associated with thrombotic events.
Finally, the soluble fibrin clot is stabilized by activated FXIII transglutamination to form gamma–gamma dimers and alpha polymers. Plasmin cleavage sites include regions between D and E domains in all 3 chains producing fragments Y, D, E. Abnormal fibrinogens that exhibit defective cross-linking by activated FXIII have been associated with bleeding and abnormal wound healing, while abnormalities that interfere with plasminogen binding or activation on the fibrin clot result in clinical thrombosis.1
Congenital fibrinogen deficiencies (CFD) are rare inherited disorders including both quantitative and qualitative defects. Quantitative defects are characterized by reduced quantities of both the clottable protein and the immunoreactive antigen (afibrinogenemia and hypofibrinogenemia). Qualitative defects (dysfibrinogenemia) are characterized by low clotting protein activity with normal or mildly reduced antigen.
The first clinical report of bleeding due to CFD dates back to a 1920 report that described a 9-year old boy suffering from recurrent bleeding episodes since birth who lacked detectable fibrinogen in his blood.6 This bleeding syndrome, afibrinogenemia, was subsequently demonstrated to follow an autosomal recessive inheritance pattern with variable phenotype.7,8
Based on fibrinogen assay methods, fibrinogen disorders are classified as follows:
Afibrinogenemia (homozygous or, more commonly in the US, compound heterozygous states), refers to the total absence of fibrinogen as measured by antigenic and functional assays.Afibrinogenemia in some reports is defined as < 50 or < 20 mg dL-1, due to the inability of some assays to discriminate fibrinogen concentrations below these levels. These less sensitive assays do not prove a total absence of fibrinogen and probably contribute to the 25% rate of asymptomatic patients identified as afibrinogenemic.
Hypofibrinogenemia (heterozygous state, which can be confirmed only by genetic studies) is defined by a decreased level of normal fibrinogen (activity and antigen between 20 mg dL–1 and the lower limit of the normal range for the performing laboratory).
Dysfibrinogenemia is characterized by a structural abnormality of the fibrinogen molecule resulting in altered functional properties. Classically, the functional assay of fibrinogen yields low levels as compared with the immunological assay. However, clottable fibrinogen levels may be normal and concordant with the antigen level in some cases, such as where the abnormal fibrinogen has defective plasminogen binding with decreased fibrinolysis. The definition and classification of CFD have changed with increasing sophistication of assay methods; hence many cases classified originally as hypofibrinogenemia are now classified as hypodysfibrinogenemia.
Hypodysfibrinogenemia is defined by both quantitative and qualitative defects in fibrinogen resulting in levels ranging from 20 mg dL–1 to the lower limit of the normal range for the performing laboratory.
The estimated prevalence of afibrinogenemia, the most severe form of the disorder, is approximately 1 in 1,000,000.9 However, knowledge on the incidence of these disorders has been confounded by publication bias. In populations where consanguinity is more common, as noted in the Iranian Registry, the prevalence may be similar to other autosomal recessive disorders.9,10 In fact, a 7–fold higher incidence of fibrinogen disorders was observed in the Iranian Registry for Rare Bleeding Disorders in comparison to similar registries in Italy and U.K.9
The most recent World Federation of Hemophilia (WFH) annual global survey conducted in 2009, and the European Network of Rare Bleeding Disorders (EN-RBD) found that 7% to 8% of rare bleeding disorders are congenital fibrinogen disorders.11,12 The prevalence of heritable dysfibrinogenemia has been estimated as 15 per 100,000 of individuals undergoing routine coagulation laboratory testing.13