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2154 Part XII: Hemostasis and Thrombosis Chapter 125: Hereditary Fibrinogen Abnormalities 2155

Nonsense Mutations but a later age of onset is not unusual. Bleeding may occur in the skin,
Many nonsense mutations accounting for afibrinogenemia and hypo- gastrointestinal tract, genitourinary tract, or the central nervous sys-
fibrinogenemia have been identified. Of the nine nonsense mutations tem with intracranial hemorrhage being the major cause of death. Joint
identified in FGB, four are located in FGB exon 8. In particular, two bleeding, which is common in patients with severe hemophilia, is less
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FGB nonsense mutations—W467X (W437X) and W470X (W440X)— frequent: in a series of 72 patients with severe fibrinogen deficiency,
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are localized very close to the β-chain C-terminus and are expected to hemarthrosis was observed in 25 percent of cases. There is an intrigu-
cause the synthesis of βC chains truncated of only 25 and 22 residues, ing susceptibility of spontaneous rupture of the spleen in afibrinogene-
respectively. 44,45 Expression studies in transfected COS cells performed mic patients. Bone cysts have also been described as a rare complication
for both mutations showed that the mutations allowed individual chain of afibrinogenemia and appear to benefit from prophylactic therapy
synthesis and intracellular assembly of the hexamer but impaired secre- with fibrinogen concentrate. 58
tion, suggesting that an intact FGB C-terminal domain is necessary for Menstruating women may experience menometrorrhagia but
fibrinogen secretion into the circulation. 46 some have normal menses. First trimester abortion is usual in afibrin-
ogenemic women. The importance of fibrinogen in pregnancy was
Missense Mutations demonstrated in studies with fibrinogen knockout mice that cannot
Null mutations, that is, large deletions, frameshift, early truncating carry fetuses to term. Women may also have antepartum and postpar-
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nonsense, and splice-site mutations account for the majority of afibrin- tum hemorrhage. Hemoperitoneum after rupture of the corpus luteum
ogenemia alleles, as expected. Missense mutations leading to complete has also been observed.
fibrinogen deficiency are therefore particularly interesting, revealing Paradoxically both arterial and venous thromboembolic compli-
the functional importance of individual residues or three-dimensional cations are observed in afibrinogenemic patients. These complications
structures. Missense mutations are clustered in the highly conserved can occur in the presence of concomitant risk factors such as a coin-
C-terminal globular domains of the γ and Bβ chains. Expression stud- herited thrombophilic risk factor or after replacement therapy. However,
1,43
ies in transfected cells for five FGB missense mutations, all identified in in many patients, no known risk factors are present. Many hypotheses
homozygosity or compound heterozygosity in afibrinogenemic patients, have been put forward to explain this predisposition to thrombosis. One
showed that these mutations, like the late-truncating nonsense mutations explanation is that even in the absence of fibrinogen platelet aggrega-
discussed previously, allowed individual chain synthesis and intracellu- tion is possible because of the action of von Willebrand factor and, in
lar assembly of the hexamer but again impaired secretion. 47–50 Further contrast to patients with severe hemophilia, afibrinogenemic patients
characterization of the FGB G444S (G414S) mutant using immunostain- are able to generate thrombin, both in the initial phase of limited pro-
ing for fibrinogen and visualization by confocal microscopy revealed that duction and also in the secondary burst of thrombin generation. In
the secretion-impaired mutant was retained in the ER proving the exis- some patients, an increase of prothrombin activation fragments or
tence of an efficient quality control mechanism for fibrinogen secretion. 46 thrombin–antithrombin complexes has been observed, which may
Several missense mutations have been identified in FGG in het- reflect enhanced thrombin generation. These abnormal levels can be
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erozygosity in patients with hypofibrinogenemia. For the majority of normalized by fibrinogen infusions.
these mutations, analysis of patient plasma fibrinogen by mass spec- As previously mentioned, fibrin also acts as antithrombin I by
trometry confirmed absence of the mutant γ chain in the circulation. both sequestering and downregulating thrombin activity. Thrombin
6
Others have been studied at the functional level in transfected cells: which is not trapped by the clot is available for platelet activation and
fibrinogen Matsumoto IV C179R (C153R) was found to impair intra- smooth muscle cell migration and proliferation, particularly in the
cellular hexamer assembly, whereas fibrinogen Bratislava W253C arterial vessel wall. Thrombus formation is maintained in fibrinogen-
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(W227C) was found to impair fibrinogen secretion. 52 deficient mice, and in fibrinogen-deficient zebrafish, but the throm-
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bus is unstable and has a tendency to embolize. Similarly, the absence of
Mutations Causing Hepatic Endoplasmic Reticulum fibrinogen in human plasma results in large but loosely packed thrombi
Retention and Hypofibrinogenemia under flow conditions. 63
In the majority of patients with afibrinogenemia or hypofibrinogenemia
there is no evidence of intracellular accumulation of the mutant fibrino- Hypofibrinogenemia
gen chain. This implies the existence of an efficient degradation pathway Hypofibrinogenemia patients are very often heterozygous carriers of afi-
for fibrinogen mutants that allow individual chain synthesis and assem- brinogenemia mutations. These patients are usually asymptomatic with
1
bly but not secretion. Four mutations, all in FGG, are known to cause fibrinogen levels of approximately 1.0 g L , levels which are in theory
−1
hypofibrinogenemia accompanied by hepatic storage disease. These high enough to protect against bleeding and maintain pregnancy. How-
are three missense mutations (fibrinogen Brescia, Aguadilla, and Al ever they can bleed when exposed to trauma, or if they have a second
duPont, 53–55 and a 15-bp deletion at the end of FGG exon 8 (fibrinogen associated hemostatic abnormality. Hypofibrinogenemic women may
Angers), which creates a new FGG exon 8–intron 8 junction and donor also suffer from pregnancy loss.
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splice site. All four mutations cause fibrinogen deficiency in the hete-
rozygous state because of the absence of the mutant γ chain in patient LABORATORY FEATURES
plasma, but also progressive liver disease associated with hepatocellular
cytoplasmic inclusions. The molecular mechanism by which these muta- The clinical diagnosis is established by functional and immunologic
tions, localized in the five-stranded β-sheet of γC and hole “a,” which are measurements of fibrinogen concentration backed by genetic analyses.
crucial for fibrin polymerization, leads to impaired secretion, retention
in the ER, and formation of aggregates remains to be determined. Phenotype Analysis
Absence of immunoreactive fibrinogen is essential for the diagnosis of
CLINICAL FEATURES congenital afibrinogenemia. All coagulation tests that depend on the for-
mation of fibrin as the end point—that is, prothrombin time (PT), par-
Afibrinogenemia tial thromboplastin time (PTT), or thrombin time (TT)—are infinitely
Bleeding because of afibrinogenemia usually manifests in the neona- prolonged. Plasma activity of all other clotting factors is usually normal.
tal period, with 85 percent of cases presenting umbilical cord bleeding, Some abnormalities in platelet functions tests can be observed which

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