Download Rare inherited disorders of fibrinogen

Haemophilia (2008), 14, 1151–1158
DOI: 10.1111/j.1365-2516.2008.01831.x
ORIGINAL ARTICLE
Rare inherited disorders of fibrinogen
S. S. ACHARYA and D. M. DIMICHELE
Department of Pediatrics, Weill Medical College of Cornell University, New York, USA
Summary. Fibrinogen, a hexameric glycoprotein
encoded by three genes – FGA, FGB, FGG – clustered
on chromosome 4q is involved in the final steps of
coagulation as a precursor of fibrin monomers
required for the formation of the haemostatic plug.
Inherited disorders of fibrinogen abnormalities are
rare and not as well clinically characterized as some
other inherited bleeding disorders. To characterize
the clinical manifestations, molecular defects and
treatment modalities of these rare disorders, a Medline search from January 1966 to September 2007 for
these disorders reported in large studies and registries
was undertaken. Inherited fibrinogen disorders can
manifest as quantitative defects (afibrinogenemia and
hypofibrinogenemia) or qualitative defects (dysfibrinogenemia). Quantitative fibrinogen deficiencies may
result from mutations affecting fibrinogen synthesis,
or processing while qualitative defects are caused by
mutations causing abnormal polymerization, defec-
Introduction
Fibrinogen is a 340-kDa glycoprotein synthesized in
the liver, with a multitude of functions including
fibrin clot formation, non-substrate thrombin binding, platelet aggregation and fibrinolysis [1]. The first
clinical report of congenital afibrinogenemia dates
back to 1920 when a 9-year-old boy suffering from
recurrent bleeding episodes since birth and lacking
fibrinogen in blood was described and shown subsequently to be autosomal recessive in inheritance
with variable penetrance [2,3]. The estimated prevalence of afibrinogenemia which is the most severe
form of the disorder is around 1 in 1 000 000 [4] and
Correspondence: Suchitra S. Acharya, MD, Weill Medical College
of Cornell University, Pediatric Hematology/Oncology, 525 East
68th Street, P-695, New York, NY 10021, USA.
Tel.: 212-746-3418; fax: 212-746-8986;
e-mail: [email protected]
Accepted after revision 5 July 2008
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd
tive cross-linking or defective assembly of the fibrinolytic system. Clinical manifestations vary from
being asymptomatic to developing catastrophic
life-threatening bleeds or thromboembolic events.
Management of bleeds includes use of purified
plasma-derived concentrates, cryoprecipitate or fresh
frozen plasma. Use of some of these products carries
risks of viral transmission, antibody development and
thromboembolic events. Establishment of registries in
Iran, Italy and North America has fostered a better
understanding of these disorders with an attempt to
explore molecular defects. Rare Bleeding Disorder
Registries developed through the United States and
international efforts hopefully will encourage development and licensure of safer, effective products.
Keywords: bleeding, congenital afibrinogenemia,
dysfibrinogenemia, fibrinogen genes, hypofibrinogenemia, thrombosis
recent registries from Italy, Iran and North America
have greatly improved understanding of the clinical
spectrum of presentation [5–7]. However, knowledge on the incidence of these disorders has been
confounded by publication bias. In populations
where consanguinity is high, as noted in the Iranian
Registry, the prevalence may be similar to other
autosomal recessive disorders [5,8]. In fact, a sevenfold higher incidence of fibrinogen disorders was
observed in the Iranian Registry for Rare Bleeding
Disorders in comparison with similar registries in
Italy and United Kingdom [8].
Conversion of fibrinogen to insoluble fibrin plays a
pivotal role in haemostatic balance and exposure of
its non-substrate thrombin-binding sites after fibrin
clot formation promotes anti-thrombotic properties
[9]. Thus, because of its multi-faceted roles in
coagulation, quantitative and qualitative modifications of this molecule can result in bleeding or
thrombotic phenotypes. Consequently, these fibrinogen disorders can present as afibrinogenemia or
1151
1152
S. S. ACHARYA and D. M. DIMICHELE
hypofibrinogenemia (quantitative defects) or dysfibrinogenemia (qualitative defects) and hence, clinical
manifestations include the potential for either mucocutaneous and/or deep tissue bleeding tendencies or
thrombotic tendencies. This review will focus on
characterizing these rare inherited fibrinogen disorders with respect to clinical presentations, diagnostic
criteria including molecular defects and the possibility of genotype–phenotype correlations and current
products used in their management.
Material and methods
This report consists of available data on these
inherited fibrinogen disorders including the estimated
incidence, identified gene defects, clinical manifestations, diagnostic considerations and current treatment strategies. This was achieved through a Medline
search conducted for the English language literature
published from January 1966 to September 2007.
The key terms fibrinogen, bleeding, clotting, thrombosis, fibrinogen genes were used, supplemented with
additional cross-references through bibliographies. In
order to avoid selection bias we included data from
larger studies and published registries.
Structure–function relationship
Fibrinogen is secreted into the bloodstream as a
disulphide-linked hexamer composed of two identical heterotrimers, each consisting of one Aa, one Bb
and one c chain with molecular masses of 67 (610
residues), 57 (461 residues) and 47 kDa (411 resi-
dues), respectively [9]. The hexamer is characterized
by a symmetrical structure with a central E domain,
connected to two peripheral D domains (Fig. 1). The
three chains are encoded by paralogous genes (FGA,
FGB and FGG coding for Aa, Bb and c chains,
respectively), clustered in a 50-kb region on chromosome 4 (4q31.3–4q32.1) [10].
Conversion of fibrinogen to fibrin occurs after
removal of fibrinopeptides A (FPA) and B (FPB) by
thrombin from the N-termini of the Aa and Bb
chains at the Arg16–Gly17 and the Arg14–Gly15
bonds, respectively. FPA release takes place faster
and earlier than FPB release and is sufficient to
induce clot formation. Abnormalities at the thrombin cleavage site can cause impaired release of FPA,
inhibiting conversion of fibrinogen to fibrin leading
to bleeding. FPB (Bb 1–14) cleavage occurs more
slowly and contributes to lateral fibril and fibre
association. Absent or slow FPB release with delayed
polymerization of the fibrin monomers can cause a
bleeding phenotype while impaired FPB release
results in abnormalities of polymerization that are
associated with thrombotic events. Finally, the soluble fibrin clot is stabilized by the amidolytic action
of activated factor XIII (FXIII) to form gamma–
gamma dimers and alpha polymers. Plasmin cleavage
sites include regions between D and E domains in all
the three chains producing fragments Y, D and E
(Fig. 1). Abnormal fibrinogens that exhibit defective
cross-linking by activated FXIII have been associated
with abnormal wound healing while abnormalities
that interfere with plasminogen binding or activation
on the fibrin clot result in clinical thrombosis (9).
(a)
D domain
D domain
(b)
D domain
Haemophilia (2008), 14, 1151–1158
D domain
Fig. 1. Schematic representation of the
fibrinogen molecule. Fibrinogen consists of
three pairs of polypeptide chains, Aa, Bb
and c, joined by disulphide bonds to form a
symmetric dimeric structure (a). The NH2
terminals of all six 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 (b) by thrombin cleavage results in
release of FPA and FPB. Binding sites for
IIa, tissue plasminogen activator and factor
XIII are indicated on the fibrinogen or fibrin
molecule.
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd
INHERITED FIBRINOGEN DISORDERS
Types of fibrinogen disorders
The normal plasma fibrinogen concentration is
approximately 1.5–3.5 g L)1 with a half-life of
about 4 days. Inherited fibrinogen disorders are
traditionally categorized on the basis of plasma
concentration as follows: quantitative or type 1
deficiencies (including afibrinogenemia and hypofibrinogenemia) with reduced levels of antigen and
functional activity and qualitative or type II deficiencies (including dysfibrinogenemias and hypodysfibrinogenemias) with normal or reduced
antigen levels associated with abnormal functional
activity. Functional activity assay measures clottable
protein on the basis of either coagulation time or
velocity (Clauss or thrombin clotting method). The
antigen level is measured by most labs using a radioimmunodiffusion assay. Quantitative fibrinogen
deficiencies may result from mutations affecting
fibrinogen synthesis, assembly, intracellular processing (with or without endoplasmic retention), domain
stability and protein secretion. Qualitative defects
are caused by mutations in any of the three fibrinogen genes affecting any one of the functional
properties of fibrinogen, including absence or
delayed release of FPA and FPB, delayed or enhanced
polymerization, defective cross-linking, decreased
thrombin binding and defective assembly of the
fibrinolytic system.
1153
(7%), menometrorrhagia, first-trimester abortions,
ante-partum and postpartum haemorrhage, hemoperitoneum after corpus luteum rupture have been
reported [12,13]. In one series of 13 pregnancies in
six women with afibrinogenemia, seven (54%) ended
in spontaneous abortion at 6–7 weeks gestation
supporting requirement of fibrinogen for embryo
implantation [14]. Further, impaired wound healing
and wound dehiscence postsurgery has been reported
because of the non-tensile clot and inadequate
deposition of healing proteins delaying wound
healing.
Paradoxical arterial and venous thromboembolic
events can occur in afibrinogenemia in the presence
of co-inherited thrombophilia, after replacement
therapy and without any of these risk factors
[15,16]. It is hypothesized that afibrinogenemia
patients can generate thrombin in the initial and
secondary burst of thrombin generation promoting
enhanced thrombin generation [17]. Fibrin can also
act as antithrombin I by sequestering and downregulating thrombin activity. Hence, thrombin not
trapped by the clot is available for platelet activation
in the arterial wall [17]. In fibrinogen knock-out mice
the number of embolized thrombi was sixfold higher
than the wild-type leading to vessel occlusion supporting the anti-thrombotic properties of fibrinogen
[18].
Hypofibrinogenemia
Clinical manifestations
Afibrinogenemia is often diagnosed in the newborn
period because of umbilical cord bleeding. Hypofibrinogenemia is associated with fewer bleeding
episodes and may not be diagnosed until a traumatic
or surgical challenge occurs. Dysfibrinogenemias are
commonly diagnosed in adulthood [11].
Afibrinogenemia
Afibrinogenemia is associated with a bleeding tendency, which is highly variable including life-threatening and spontaneous/trauma-related bleeds.
Bleeding can start in the neonatal period with 85%
presenting with umbilical cord bleeding [5] or
bleeding into the skin, gastrointestinal (GI) tract,
genitourinary tract or central nervous system (CNS)
bleeding (5%) [7,8]. Musculoskeletal bleeding occurs
less frequently with haemarthroses reported in 54%
of the patients [6–8]. Unusual manifestations such as
spontaneous rupture of the spleen and presence of
bone cysts in afibrinogenemia [12] have also been
reported. In females, normal menses, menorrhagia
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd
Hypofibrinogenemia the patients have similar bleeding patterns but have a milder course and may follow
invasive procedures or major trauma largely exceeding spontaneous events (80% vs. 20%) [7]. In a
questionnaire report on 100 patients with inherited
fibrinogen disorders from 10 different countries from
North America and Europe the most frequent
haemorrhagic symptom was observed to be menorrhagia (46%) followed by muscle haematoma
(12%), GI bleeding (5%) with no cases of CNS,
intraperitoneal bleeding, miscarriage or thrombosis
reported in this group [19]. A familial hypofibrinogenemia with hepatic storage disease associated with
different point mutations in the fibrinogen gamma
chain have been described [20,21].
Dysfibrinogenemia
Dysfibrinogenemia the patients have an unpredictable clinical phenotype. A compilation of 250
patients revealed asymptomatic patients (53%),
bleeders (26%) and clotters (21%) some of whom
also had bleeding [22]. Postpartum thrombosis,
Haemophilia (2008), 14, 1151–1158
1154
S. S. ACHARYA and D. M. DIMICHELE
spontaneous abortions, stillbirths are described in the
ISTH database [23]. Pregnant women with dysfibrinogenemia are at particular risk for bleeding following vaginal delivery, C-section and regional
analgesia. Patients may also experience delayed
wound healing and dehiscence. Data from the United
Kingdom Health Centre DoctorsÕ Organisation
reported an association between deep vein thrombosis, thrombophlebitis and pulmonary embolus in 26
index patients with dysfibrinogenemia at a young age
(mean age: 32 years). The prevalence of dysfibrinogenemia in patients with a history of venous thrombosis is low, i.e. 0.8% as deduced from nine studies
on 2376 patients [23]. The thrombotic risk increases
with acquired risk factors and coinheritance of other
thrombophilia [24]. Skin necrosis has been described
with certain dysfibrinogenemias (fibrinogen Marburg) and less commonly arterial thromboses [23].
Laboratory diagnosis
Afibrinogenemia (homozygous/compound heterozygous state) is characterized by the complete absence
or reduced amounts of immunoreactive fibrinogen as
measured by antigenic and functional assays (less
than 0.1 g L)1). All coagulation tests which depend
on fibrin as the endpoint, i.e. prothrombin time (PT),
activated partial thromboplastin time (aPTT),
thrombin time (TT) and reptilase time are infinitely
prolonged. Fibrinogen is undetectable by both functional (Clauss) and antigenic assays. With more
sensitive enzyme-linked immunosorbent assays (ELISA), afibrinogenemia could be defined as unmeasurable level of functional fibrinogen associated with
trace amounts of immunoreactive fibrinogen.
Hypofibrinogenemia (heterozygous state) is
defined by a decreased level of normal fibrinogen
(activity and antigen between 0.5 g L)1 and lower
limit of normal range for local laboratory). As
hypofibrinogenemia is a proportional decrease of
functional and immunoreactive fibrinogen, most
fibrin-based coagulation tests are variably prolonged,
the most sensitive test being thrombin time (usually
prolonged at fibrinogen activity < 1 g L)1). The total
clot-based and immunogenic fibrinogen levels are
both reduced to a similar level as the functional
fibrinogen. Tests should be interpreted with regard to
possibility of acquired hypofibrinogenemia – consumptive coagulopathy, hepatic failure, l-asparaginase therapy and family studies may be helpful in
differentiating from the congenital variety.
Dysfibrinogenemia is characterized by a structural
abnormality of the fibrinogen molecule resulting
in altered functional properties. Classically, the
Haemophilia (2008), 14, 1151–1158
functional assay of fibrinogen yields low levels
compared with immunological assays but levels
may be concordant and functional levels may be
normal. Therefore, a discrepancy between clottable
protein and immunologically measured fibrinogen is
characteristic of dysfibrinogenemia. A prolonged
reptilase time in the presence of a normal functional
fibrinogen provides strong evidence of dysfibrinogenemia. A normal or increased antigen with a lower
functional level resulting in a low functional antigen
ratio (most commonly 1:2) is usually diagnostic [25].
The sensitivity of coagulation tests to dysfibrinogenemia depends on the specific mutation, reagents and
techniques [26]. A definitive diagnosis can be established by demonstrating the molecular defect. However, as these disorders are dominantly inherited,
family studies may be helpful to differentiate from
acquired dysfibrinogenemia. In the small percentage
that presents with thrombosis, a thrombophilia work
up to exclude co-existing prothrombotic defects may
be useful. Hypodysfibrinogenemia which is defined
by both quantitative and qualitative defects in
fibrinogen result in levels ranging from 0.5 to
1.2 g L)1.
Molecular diagnosis
Afibrinogenemia and hypofibrinogenemia mutations
Mutations causing afibrinogenemia have been
detected in all three genes; the majority found to
date are in FGA which are mainly deletions, frameshift, nonsense or splicing mutations. These can lead
to deficiency of fibrinogen by several mechanisms:
these can act at the DNA level, RNA level by
affecting mRNA splicing or stability or at the protein
level by affecting protein synthesis, assembly or
secretion [11]. In a database compiled by Hans and
Biot these mutations have been associated with
clinical bleeding and thromboses there being no
genotype–phenotype correlation which could possibly be related to modifier genes or common variant
thrombophilic genes [22]. There seems to be considerable overlap between the causative mutations
accounting for afibrinogenemia and hypofibrinogenemia. In many cases asymptomatic patients are in
fact heterozygous for null mutations which in
homozygosity or heterozygosity would cause afibrinogenemia. Mutations of the FGA gene which include
null mutations, large deletions (11 kb, 1238 bp and
15 kb in the FGA gene), frameshift (IVS4+A>G and
)1138C>T in the FGA gene), splice-site and early
truncating nonsense mutations are the most frequently identified mutations irrespective of geographic
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd
INHERITED FIBRINOGEN DISORDERS
locations in individuals of European and nonEuropean descent [27]. In contrast, the spectrum of
mutations in FGG and FGB includes an excess of
missense mutations in the C-terminal globular
domains [28]. It is important to identify these
mutations for designing efficient strategies for mutation detection in new cases. In the majority of
patients with afibrinogenemia or hypofibrinogenemia
for whom the causative mutation has been identified
there is no intracellular accumulation of the mutant
fibrinogen chain. However, missense mutations identified in the FGG can cause fibrinogen deficiency in
the heterozygous state owing to intracellular retention of the mutant gamma chain and progressive
liver disease with hepatocellular intracytoplasmic
inclusions [20,21].
Dysfibrinogenemia mutations
Consistent with dominant transmission of dysfibrinogenemia, the majority of patients with dysfibrinogenemia are heterozygous for missense mutations in
one of the three fibrinogen genes leading to delayed
or absent FPA release or defective fibrin polymerization. Mutations at these sites are estimated to
account for approximately 45% of dysfibrinogenemia mutations [22]. The majority of these mutations are in FGA. Thus, dysfibrinogenemia can cause
either a bleeding disorder or thrombophilia; some
mutations can cause both. Not all are symptomatic;
many are in fact discovered following routine laboratory tests before surgery, by prolonged TT.
Individuals (65%) with FGG mutations are asymptomatic with 5% having bleeding symptoms and
30% thrombosis [29]. A defective binding of thrombin to abnormal fibrin which leads to increased
thrombin levels has been implicated in thrombosis
(fibrinogens Malmo, Naples, New York I, Pamplona
II and Poitiers) and a defective stimulatory function
of abnormal fibrin in the tissue plasminogen activator-mediated fibrinolysis has also been implicated in
thrombotic events (fibrinogens Argenteuil, Chapel
Hill III, Date, New York I, Nijmegen, Pamplona II
and Paris V) [23]. These ÔthrombophilicÕ mutations
have been found predominantly in the C-terminal
domain of the Aa chain and the thrombin cleavage
site of the Bb chain [30]. Interestingly, dysfibrinogens
Marburg and Bern V both a chain mutation form
clots which are fragile with failure to form normal
fibrin aggregates leading to bleeding symptoms.
However, there is also impaired fibrinolysis leading
to thrombotic complications [29]. Therefore, with
dysfibrinogenemias there may be a potential for
genotype–phenotype correlations. A database is
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd
1155
available on the Study Group on Hemostasis and
Thrombosis: http://www.geht.org/databseang/fibrinogen [22], which lists all fibrinogen variants identified to date in patients with dys-, hypo- and
afibrinogenemia. Thus, mutation analysis can provide a valuable tool for diagnosis confirmation,
identification of potential carriers and prenatal diagnosis.
Prenatal diagnosis
Afibrinogenemia and hypofibrinogenemia are autosomal recessive in inheritance while dysfibrinogenemia is autosomal dominant. Hence, pregnant
females with a family history, especially those with
a history of consanguinity should be appropriately
counselled with regard to risks of producing a child
with the disease. If the mutation is known, genetic
testing should be planned early in pregnancy by
chorionic villous sampling in order to aid appropriate and safe delivery of the affected child. In babies
born to known/suspected carrier parents, cord
blood testing for genetic defects may be offered.
Indirect prenatal diagnosis by the use of linkage
studies could also be performed in these disorders
[11]. Avoidance of arterial sticks, intramuscular
injections, traumatic interventions and screening for
intracranial bleeds by head ultrasound at birth is
recommended.
Management
Afibrinogenemia and hypofibrinogenemia
Replacement therapy is generally effective in treating
bleeding episodes in congenital afibrinogenemia.
PatientÕs personal and family history of bleeding or
thrombosis can help guide therapy. Options for
replacement include plasma-derived fibrinogen concentrate (used in Europe), cryoprecipitate (used in
the United States) and fresh frozen plasma [31,32].
Clinical situations include spontaneous bleeding and
surgery as postoperative bleeding is reported in 40%
in the Iranian series [6].
Antifibrinolytic agents may be used especially for
dental procedures. Caution needs to be exerted in
those with a history of thrombosis and other risk
factors such as pregnancy, surgery and immobilization when they may be at increased risk for
thrombosis.
During pregnancy, treatment is recommended as
soon as possible to prevent foetal loss (as early as
6–7 weeks to aid in implantation) and continued
throughout pregnancy and postpartum with the
Haemophilia (2008), 14, 1151–1158
1156
S. S. ACHARYA and D. M. DIMICHELE
aim of maintaining levels above 0.5 g L)1.
Oestrogen–progesterone preparations may be helpful
in menorrhagia in the absence of a thrombotic
tendency [33].
Dosage. In general, level of fibrinogen to be
achieved is 1.0 g L)1 and should be maintained
until haemostasis is achieved and wound healing is
complete. In the United States, cryoprecipitate in a
dose of 1 bag per 5 kg body weight followed by 1
bag per 15 kg body weight is used. It could be
continued daily or every other day in the absence of
consumption with close monitoring of fibrinogen
activity depending on the clinical indication and
response [31].
Dosage calculation. Dose (g) = desired increment in
g L)1 · plasma volume (plasma volume is 0.07 · (1–
haematocrit) · weight (kg).
replacement products will depend on the clinical
response and laboratory monitoring. Topical fibrin
glue or antifibrinolytic agents may be advocated for
superficial bleeds.
In a pregnant woman with a bleeding phenotype,
recommendations for afibrinogenemia/hypofibrinogenemia can be followed. During delivery, it should
be assumed that the baby has dysfibrinogenemia and
invasive monitoring should be avoided. Caution
should be exercised when interpreting dysfibrinogenemia tests at birth because of physiological or
acquired dysfibrinogenemia in the newborn. Thromboprophylaxis in women with a personal or family
history of thrombosis should include compression
stockings with low molecular weight heparin and/or
replacement products reserved strictly for thrombotic
events. For those with a bleeding phenotype vaginal
delivery can be conducted by observation and
replacement therapy only if bleeding occurs and
maintained until wound healing is complete.
Dysfibrinogenemia
The guidelines for dysfibrinogenemia are not standardized with lack of sufficient data in bleed management. As the dysfunctional fibrinogen can
interfere with the function of the infused fibrinogen
and assays used for monitoring, functional level of
fibrinogen should be raised above 1.0 g L)1 depending on the clinical response and maintained until
wound healing is complete [31]. Repeat doses of
Complications of disease and treatment
Acquired inhibitors have been reported after replacement therapy [34]. In addition, treatment associated
thromboembolic complications could be averted by
administering small doses of heparin along with
fibrinogen concentrate [16]. Successful use of direct
thrombin inhibitors such as Lepirudin in individuals
who suffered recurrent thrombosis despite adequate
Table 1. Clinical, laboratory characterization and treatment recommendations for rare inherited disorders of fibrinogen.
Transmission
Impact
Fibrinogen level
Symptoms
Laboratory
Treatment
Afibrinogenemia
Hypofibrinogenemia
Dysfibrinogenemia
Autosomal recessive
(both parents are carriers)
One in 1 million
<0.1 g L)1 plasma
Autosomal dominant* and
recessive**
Less than afibrinogenemia
Between 0.1 g L)1 and lower
limit of normal for lab
Umbilical cord bleeding
Cutaneous bleeding
Gastrointestinal haemorrhage
Intracranial bleeding (infrequent)
Articular bleeding
aPTT is normal; increased PT-N,
TT mildly prolonged, fibrin
assay between 0.1 g L)1 and
lower limit for lab
Autosomal dominant*
and recessive**
1 in 1 million
£1.5 and 3.5 g L)1 of
plasma
No symptoms
Haemorrhage
Thrombosis
Umbilical cord bleeding
Cutaneous bleeding
Gastrointestinal haemorrhage
Intracranial bleeding (infrequent)
Articular bleeding
PTT, aPTT, TT markedly
prolonged; all fibrin assays
zero or trace
Cryoprecipitate/fibrinogen
concentrate/antifibrinolytic agents
Cryoprecipitate/fibrinogen
concentrate/antifibrinolytic agents
PT, aPTT are normal.
increased TT and
reptilase time; fibrin
assay is normal; higher
fibrinogen for immunogenic
than thrombin clotting method
Cryoprecipitate/fibrinogen
concentrate with
anticoagulants in thrombosis
aPTT, activated partial thromboplastin time; PT, prothrombin time; TT, thrombin time; PT-N, prothrombin time-normal.
*Only one parent is a carrier.
**Both parents are carriers.
Haemophilia (2008), 14, 1151–1158
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd
INHERITED FIBRINOGEN DISORDERS
heparin and aspirin [35] has also been explored.
Finally, routine surveillance for disease- and treatment-related complications and immunization
against hepatitis in a comprehensive care setting is
highly recommended.
1157
Acknowledgements
The authors thank Susan Parker for secretarial
assistance. This project was partly funded by the
ChildrenÕs Cancer and Blood Foundation.
Prophylaxis
Disclosures
Prophylactic infusions of cryoprecipitate have been
employed after life-threatening bleeds such as
intracranial bleeds. However, this strategy needs
to be judicious given the possibility of transmission
of infectious agents, allergic reactions, venous
access problems, development of inhibitors and
the risk of thrombo-embolic complications. Moreover, the prophylaxis schedule may need to be
tailored based on individual pharmacokinetics,
which is highly variable on replacement therapy
[36]. In a retrospective analyses, the mean number
of bleeding episodes on demand and prophylaxis
were not significantly different (0.7 vs. 0.5) [19].
Hence, caution needs to be exercised before
routinely recommending prophylaxis. The clinical,
laboratory and recommended treatments are summarized in Table 1.
The authors stated that they had no interests which
might be perceived as posing a conflict or bias.
Clinical trials
None of the fibrinogen concentrates are available in
the United States at the present time. A prelicensure
phase II pharmacokinetic study sponsored by CSLBehring with a plasma- derived concentrate – Haemocomplettan – which enrolled 15 subjects was
completed in April 2008. The results of this trial will
be presented to the Food and Drug Administration
for licensing approval.
Individuals doing research in pathophysiology/
molecular basis
1. M. Neerman-Arbez,
Geneva,
Switzerland;
[email protected]
2. D. Galanakis, New York, USA; dgalanak@path.
som.sunysb.edu
3. D.H. Farrell, Portland, USA; [email protected]
4. M.W. Mosesson, Milwaukee, USA; mwmosesson
@bcsew.edu
5. P.M. George, Christchurch, New Zealand; peter.
[email protected]
6. S. Duga, Milan, Italy; [email protected]
Links to organizations – professional, lay:
National Hemophilia Foundation Orientation manual for Healthcare workers: http://www.hemophilia.
org/NHFWeb/Resource/
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd
References (* indicates key references)
*1 Mosesson MW, Siebenlist KR, Meh DA. The structure
and biological features of fibrinogen and fibrin. Ann N
Y Acad Sci 2001; 936: 11–30.
2 Rabe F, Salomon E. Uber-faserstoffmangel in Blute bei
einem Falle von Haemophilie. Arch Int Med 1920;
95: 2.
3 Werder E. Congenital afibrinogenemia. Helv Paediatr
Acta 1963; 18: 208–29.
4 Martinez J, Palascak J, Peters C. Functional and
metabolic properties of human asialofibrinogen. J Lab
Clin Med 1977; 89: 367–77.
5 Mannucci PM, Duga S, Peyvandi F. Recessively
inherited coagulation disorders. Blood 2004; 104:
1243–52.
*6 Lak M, Keihani M, Elahi F, Peyvandi F, Mannucci PM.
Bleeding and thrombosis in 55 patients with inherited
afibrinogenaemia. Br J Haematol 1999; 107: 204–6.
*7 Acharya SS, Coughlin A, Dimichele DM, North
American Rare Bleeding Disorder Study Group. Rare
Bleeding Disorder Registry: deficiencies of factors II, V,
VII, X, XIII, fibrinogen and dysfibrinogenemias.
J Thromb Haemost 2004; 2: 248–56.
*8 Peyvandi F, Duga S, Akhavan S, Mannucci PM. Rare
coagulation deficiencies. Haemophilia 2002; 8: 308–
21.
*9 Asselta R, Duga S, Tenchini ML. The molecular basis
of quantitative fibrinogen disorders. J Thromb Haemost 2006; 4: 2115–29.
10 Kent WJ, Sugnet CW, Furey TS, et al. The Human
Genome Browser at UCSC. Genome Res 2002; 12:
996–1006.
*11 Neerman-Arbaz M. Molecular basis of fibrinogen
deficiency. Pathophysiol Haemost Thromb 2006; 35:
187–98.
12 al-Mondhiry H, Ehmann WC. Congenital afibrinogenemia. Am J Hematol 1994; 46: 343–7.
13 Kobayashi T, Asahina T, Maehara K, Itoh M, Kanayama
N, Terao T. Congenital afibrinogenemia with successful
delivery. Gynecol Obstet Invest 1996; 42: 66–9.
*14 Suh TT, Holmback K, Jensen NJ, et al. Resolution of
spontaneous bleeding events but failure of pregnancy in
fibrinogen-deficient mice. Genes Dev 1995; 9: 2020–33.
*15 Girolami A, Ruzzon E, Tezza F, Scandellari R, Vettore
S, Girolami B. Arterial and venous thrombosis in rare
Haemophilia (2008), 14, 1151–1158
1158
16
17
18
*19
20
21
*22
*23
24
*25
26
S. S. ACHARYA and D. M. DIMICHELE
congenital bleeding disorders: a critical review. Haemophilia 2006; 12: 345–51.
Dupuy E, Soria C, Molho P, et al. Embolized ischemic
lesions of toes in an afibrinogenemic patient: possible
relevance to in vivo circulating thrombin. Thromb Res
2001; 102: 211–9.
Mosesson MW. Antithrombin I. Inhibition of thrombin
generation in plasma by fibrin formation. Thromb
Haemost 2003; 89: 9–12.
Ni H, Denis CV, Subbarao S, et al. Persistence of
platelet thrombus formation in arterioles of mice
lacking both von Willebrand factor and fibrinogen.
J Clin Invest 2000; 106: 385–92.
Peyvandi F, Haertel S, Knaub S, Mannucci PM. Incidence of bleeding symptoms in 100 patients with
inherited afibrinogenemia or hypofibrinogenemia.
J Thromb Haemost 2006; 4: 1634–7.
Rubbia-Brandt L, Neerman-Arbez M, Rougemont AL,
Malé PJ, Spahr L. Fibrinogen gamma375 arg–>trp
mutation (fibrinogen Aguadilla) causes hereditary
hypofibrinogenemia, hepatic endoplasmic reticulum
storage disease and cirrhosis. Am J Surg Pathol 2006;
30: 906–11.
Medicina D, Fabbretti G, Brennan SO, George PM,
Kudryk B, Callea F. Genetic and immunological characterization of fibrinogen inclusion bodies in patients
with hepatic fibrinogen storage and liver disease. Ann
NY Acad Sci 2001; 936: 522–5.
Hans M, Biot F. A database for human fibrinogen
variants. Ann N Y Acad Sci 2001; 936: 89–90.
Haverkate F, Samama M. Familial dysfibrinogenemia
and thrombophilia. Report on a study of the SSC
Subcommittee on Fibrinogen. Thromb Haemost 1995;
73: 151–61.
Siebenlist KR, Mosesson MW, Meh DA, DiOrio JP,
Albrecht RM, Olson JD. Coexisting dysfibrinogenemia
(gammaR275C) and factor V Leiden deficiency
associated with thromboembolic disease (fibrinogen
Cedar rapids). Blood Coagul Fibrinolysis 2000; 11:
293–304.
Hayes T. Dysfibrinogenemia and thrombosis. Arch
Pathol Lab Med 2002; 126: 1387–90.
Lefkowitz JB, DeBoom T, Weller A, Clarke S, Lavrinets D. Fibrinogen Longmont: a dysfibrinogenemia
Haemophilia (2008), 14, 1151–1158
*27
28
*29
*30
*31
*32
33
*34
35
*36
that causes prolonged clot-based test results only when
using an optical detection method. Am J Hematol
2000; 63: 149–55.
Neerman-Arbez M, de Moerloose P, Bridel C, et al.
Mutations in the fibrinogen A alpha gene account for
the majority of cases of congenital afibrinogenemia.
Blood 2000; 96: 149–52.
Vu D, de Moerloose P, Batorova A, Lazur J, Palumbo L,
Neerman-Arbez M. Hypofibrinogenaemia caused by a
novel FGG missense mutation (W253C) in the gamma
chain globular domain impairing fibrinogen secretion.
J Med Genet 2005; 42: e57.
Roberts HR, Stinchcombe TE, Gabriel DA. The
dysfibrinogenaemias. Br J Haematol 2001; 114: 249–
57.
McDonagh J. Dysfibrinogenemia and other disorders
of fibrinogen structure or function. In: Colman R,
Hirsh J, Marder V, Clowes A, George J, eds. Hemostasis and Thrombosis, 4th edn. Philadelphia, PA:
Lippincott Williams & Wilkins, 2001: 855–92.
Kreuz W, Meili E, Peter-Salonen K, et al. Efficacy and
tolerability of a pasteurised human fibrinogen concentrate in patients with congenital fibrinogen deficiency.
Transfus Apher Sci 2005; 32: 247–53.
Santagostino E, Mancuso ME, Morfini M, et al. Solvent/detergent plasma for prevention of bleeding in
recessively inherited coagulation disorders: dosing,
pharmacokinetics and clinical efficacy. Haematologica
2006; 91: 634–9.
Rizk DE, Kumar RM. Congenital afibrinogenemia:
treatment of excessive menstrual bleeding with continuous oral contraceptive. Am J Hematol 1996; 52:
237–8.
RaÕanani P, Levi Y, Varon D, Gitel S, Martinowitz U.
Congenital afibrinogenemia with bleeding, bone cysts
and antibodies to fibrinogen. Harefuah 1991; 121:
291–3.
Schuepbach RA, Meili EO, Schneider E, Peter U, Bachli
EB. Lepirudin therapy for thrombotic complications in
congenital afibrinogenaemia. Thromb Haemost 2004;
91: 1044–6.
Kreuz W, Meili E, Peter-Salonen K, et al. Pharmacokinetic properties of a pasteurised fibrinogen concentrate. Transfus Apher Sci 2005; 32: 239–46.
2008 The Authors
Journal compilation 2008 Blackwell Publishing Ltd