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CHAPTER 125 causing inherited fibrinogen disorders have been published and the
Several detailed and thoroughly annotated reviews of mutations
1–3
HEREDITARY FIBRINOGEN previous version of this chapter published in the eighth edition con-
4
tained tables compiling causative mutations identified before 2009.
5
ABNORMALITIES In addition, a registry for hereditary fibrinogen abnormalities can
be accessed at http://www.geht.org/databaseang/fibrinogen/ that lists
variants reported in publications, conference abstracts, and submitted
online, with original references. This chapter discusses the major molec-
Marguerite Neerman-Arbez and Philippe de Moerloose* ular mechanisms leading to disease, as well as the laboratory and clin-
ical aspects of fibrinogen disorders and their treatment, without listing
all fibrinogen gene anomalies.

SUMMARY INTRODUCTION

Hereditary fibrinogen abnormalities make up two classes of plasma fibrinogen Fibrinogen plays a major role in hemostasis as the precursor molecule
defects: (1) type I, afibrinogenemia or hypofibrinogenemia, in which there for the insoluble fibrin clot (Fig. 125–1). In addition fibrinogen par-
ticipates in numerous other biologic processes, such as inflammation,
are low or absent plasma fibrinogen antigen levels (quantitative fibrinogen wound healing, and angiogenesis. Fibrinogen binds plasminogen,
deficiencies), and (2) type II, dysfibrinogenemia or hypodysfibrinogenemia, α-antiplasmin, fibronectin, and factor XIII, among other proteins. It
in which there are normal or reduced antigen levels associated with dispro- also binds to platelets and supports platelet aggregation. After fibrino-
portionately low functional activity (qualitative fibrinogen deficiencies). In gen is converted to fibrin by thrombin, it provides nonsubstrate bind-
afibrinogenemia, most mutations of the three encoding genes of fibrinogen ing sites for thrombin; consequently, fibrinogen is sometimes termed
chains are null. In some cases, missense or late-truncating nonsense muta- antithrombin I. Fibrinogen also binds to vascular endothelial and other
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tions allow synthesis of the corresponding fibrinogen chain, but intracellular cells, plasma or tissue matrix components such as fibronectin and gly-
fibrinogen assembly and/or secretion is impaired. In certain hypofibrinogen- cosaminoglycans, and peptide growth factors. Fibrin provides a tem-
emic cases, the mutant fibrinogen molecules are produced and retained in plate for assembly and activation of the fibrinolytic system components
the rough endoplasmic reticulum of hepatocytes in the form of inclusion and is the major substrate for the enzyme plasmin (Chap. 135). Both
bodies, causing endoplasmic reticulum storage disease. Afibrinogenemia fibrinogen and fibrin serve as substrates for plasma factor XIIIa that
catalyzes covalent crosslinking/ligation.
is associated with mild to severe bleeding, whereas hypofibrinogenemia is
often asymptomatic. Thromboembolism may also occur and affected women
may suffer from recurrent pregnancy loss. Hereditary dysfibrinogenemias are STRUCTURE AND SYNTHESIS
characterized by biosynthesis of a structurally abnormal fibrinogen molecule Fibrinogen is a 340-kDa glycoprotein synthesized in hepatocytes that
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that exhibits reduced functional properties. Dysfibrinogenemia is commonly circulates in plasma at a concentration of 1.5 to 3.5 mg/mL (~4 to 10 μM).
associated with bleeding, thrombosis, or both thrombosis and bleeding, but Each fibrinogen molecule is approximately 45 nm in length. The core
in many patients it is asymptomatic. Hypodysfibrinogenemia is a subcategory structure consists of two outer D regions (or D domains) and a cen-
of this disorder. Certain mutations involving the C-terminus of the fibrinogen tral E region (or E domain) connected through coiled-coil connectors
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α chain are associated with amyloidosis, in which an abnormal fragment from (Fig. 125–2). The molecule exhibits a twofold axis of symmetry per-
the fibrinogen α C domain is deposited in the kidneys. The cause for throm- pendicular to the long axis, consisting of two sets of three polypeptide
bophilia in type II fibrinogen abnormalities often is uncertain but may involve chains (Aα, Bβ, γ) that are joined in their aminoterminal regions by
defective calcium binding, impaired tissue-type plasminogen activator-medi- disulfide bridges to form the E region. The outer D regions contain the
ated fibrinolysis, resistance to fibrinolysis, or reduced thrombin binding to globular C terminal domains of the Bβ chain (βC) and γ chain (γC).
The βC and γC domains, which are highly conserved in vertebrates, are
fibrin. Replacement therapy with fibrinogen concentrates has proven to be members of the FreD (fibrinogen-related domain) family of proteins.
useful for management of fibrinogen disorders but should be adapted to each Unlike the βC and γC domains, the C-terminal domains of the Aα chain
patient, based on the personal and family history. (αC) are intrinsically unfolded and flexible and tend to be noncovalently
tethered in the vicinity of the central E region (Fig. 125–2). The three
genes encoding fibrinogen Bβ (FGB), Aα (FGA), and γ (FGG), ordered
from centromere to telomere, are clustered in a region of approximately
9
50 kb on human chromosome 4. FGA and FGG are transcribed from
the reverse strand, in the opposite direction to FGB. Alternative splic-
10
ing results in two isoforms for the fibrinogen α chain: the common Aα
Acronyms and Abbreviations: FFP, fresh-frozen plasma; FGA, fibrinogen Aα-chain chain, encoded by exons 1 to 5, and an extended Aα-E isoform, encoded
gene; FGB, fibrinogen Bβ-chain gene; FGG, fibrinogen γ-chain gene; FpA, fibrino- by exons 1 to 6 which represents only 1 to 2 percent of transcripts. Alter-
peptide A; FpB, fibrinopeptide B; LMWH, low-molecular-weight heparin; PCR: native splicing for FGG also produces two transcripts: the major mRNA
polymerase chain reaction; TAFI, thrombin-activatable fibrinolysis inhibitor; t-PA, species contains all 10 exons and encodes the common γ chain (or γA),
tissue-type plasminogen activator. while the minor product (γ′) does not splice out intron 9 and the corre-
sponding open reading frame replaces the four codons of exon 10 with
20 alternative codons. FGB encodes a single 1.9-kb transcript with a
1.5-kb coding sequence. Each gene is separately transcribed and trans-
lated to produce nascent polypeptides of 644 amino acids (Aα), 491
* The authors thank Dr. Alessandro Casini for helpful comments and suggestions. amino acids (Bβ), and 437 amino acids (γ).

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