Keywords
afibrinogenemia - hypofibrinogenemia - miscarriage - heavy menstrual bleeding - pregnancy
- postpartum hemorrhage - thrombosis - ovarian cysts
Introduction
Fibrinogen, a hexameric glycoprotein, is composed of three polypeptide chains (α,
β, and γ) that are encoded by the FGA, FGB, and FGG genes located on chromosome 4. Hepatocytes secrete it into the circulation, where
it reaches concentrations of 1.5 to 4 g/L in healthy individuals. At the end of the
coagulation cascade, thrombin cleaves fibrinopeptides A and B from the α and β fibrinogen
chains, triggering the spontaneous polymerization process that ultimately forms a
fibrin network.[1]
Congenital afibrinogenemia and hypofibrinogenemia are rare hereditary coagulation
disorders, characterized by a deficiency in fibrinogen.[2] Afibrinogenemia is defined as the complete absence of fibrinogen, whereas hypofibrinogenemia
is defined by a partial decrease.[3] More specifically, hypofibrinogenemia is classified as severe when the fibrinogen
level is less than 0.5 g/L, moderate when the fibrinogen level is between 0.5 and
0.9 g/L, and mild when the fibrinogen level is greater than 0.9 g/L.[4] The bleeding phenotype of patients is mostly dependent on fibrinogen levels. Major
bleeding occurs in afibrinogenemia and severe hypofibrinogenemia, and essentially
traumatic bleeding in moderate and mild hypofibrinogenemia.[5] In an international study of 204 patients with afibrinogenemia, the median International
Society of Thrombosis and Hemostasis Bleeding Assessment Tool was 14, with no differences
between adult and child patients. However, umbilical and cerebral bleeding are common
complications in children, reported in 48% and 31% of patients, respectively.[6]
[7] Furthermore, the tendency to thrombosis is a paradoxical complication of afibrinogenemia
and severe hypofibrinogenemia, which highlights the complex role of fibrinogen in
the coagulation cascade and the hemostasis balance.[8] A number of fibrinogen mutations have been identified in quantitative fibrinogen
disorders, mainly null mutations in FGA and FGB.[9] The most prevalent mutations are the 11-kb deletion of FGA and the donor splice site mutation c.510 + 1G > T in FGA.[10]
These conditions lead to distinctive challenges for women across all life stages.[11]
[12] Heavy menstrual bleeding (HMB), often from menarche, is frequent and may lead to
chronic anemia. Hemorrhagic ovarian cysts can cause life-threatening bleeding.[13]
[14] Pregnancy is a high-risk situation, with an increased incidence of miscarriage,
placental abruption, and postpartum hemorrhage (PPH) in the absence of adequate fibrinogen
replacement.[15] Perimenopausal and postmenopausal bleeding and bleeding due to underlying gynecological
pathologies may be exacerbated by the fibrinogen deficiency.[16] Despite advances in our understanding of the epidemiology of fibrinogen disorders,
the management of these clinical situations remains challenging and requires a multidisciplinary
approach.
General recommendations on management of gynecological issues and pregnancy in bleeding
disorders have recently been proposed by the United Kingdom Haemophilia Centre Doctors
Organisation[16]
[17] and more detailed on fibrinogen disorders by the factor XIII and fibrinogen Subcommittee
of the International Society of Thrombosis and Hemostasis.[18] Given the rarity of these conditions and the limited data available—particularly
in specific subpopulations such as ageing women—more detailed, evidence-based recommendations
may not yet be feasible. The current suggestions likely reflect the best available
expert consensus in the absence of robust clinical studies. The objective of this
review is to synthesize the findings of recent studies and recommendations and offer
practical recommendations to optimize the care of women across their lifespan, from
childhood to elderly years. Dysfibrinogenemia is a distinct condition that differs
significantly from afibrinogenemia and hypofibrinogenemia in terms of diagnosis, genetics,
clinical presentation, and management. For reasons of clarity, we have chosen to focus
on afibrinogenemia and hypofibrinogenemia. For a more comprehensive overview of dysfibrinogenemia
management, readers are referred to two recent expert consensus papers.[18]
[19]
Heavy Menstrual Bleeding
HMB represents a significant concern for women with quantitative fibrinogen disorders.[2] The prevalence of HMB is high in individuals with afibrinogenemia and severe hypofibrinogenemia,
although it varies across the series.[20] In an international cross-sectional study comprising 204 patients with afibrinogenemia,
42 (73.7%) of adult women reported HMB.[21] In this study, HMB had an adverse effect on women's health-related quality of life,
manifesting as limitations in daily activities, changes in social functioning, and
impaired relationships.[21] Similar prevalence were reported in an Iranian cohort of 55 patients with afibrinogenemia,
where 70% of women had HMB.[22] In a retrospective international study comprising 16 women with afibrinogenemia
and 18 with hypofibrinogenemia of varying severity, HMB was observed in 33% of cases.[6] A retrospective analysis of data from the Rare Bleeding Disorder in the Netherlands
(RBiN) study revealed that 13 out of 19 women with fibrinogen disorders experienced
HMB.[23]
The management of HMB necessitates a multidisciplinary approach, integrating the expertise
of hematologists, gynecologists, pediatrics, and other specialists, ideally prior
to menarche.[13]
[24] Regular monitoring of hemoglobin, iron status, and fibrinogen levels is essential
for guiding treatment adjustments and preventing complications such as anemia or uncontrolled
bleeding.[25]
[26] The prevention of HMB begins with the administration of hormonal therapy which addresses
menstrual flow.[16] Hormonal therapy, including combined oral contraceptives, progestin-only methods,
or the levonorgestrel-releasing intrauterine system, provides control by suppressing
or regulating menstruation.[12]
[27]
[28] In case of severe HMB, continuous or extended-cycle hormonal regimens may be employed
to eliminate menstruation altogether.[29] As previously mentioned, women with afibrinogenemia and severe hypofibrinogenemia
are also at risk of thrombosis. This complex dual risk must be carefully managed,
when evaluating the choice of hormonal therapy in reproductive-aged women.[30] The adjunctive use of antifibrinolytic agents such as tranexamic acid may further
reduce menstrual bleeding.[16]
[31] When hormonal and antifibrinolytics are not efficacious, fibrinogen infusion may
be necessary with the aim of achieving a fibrinogen level of 1.5 g/L.[32]
Hemorrhagic Ovarian Cysts
Hemorrhagic Ovarian Cysts
In addition to HMB, women are at risk of hemorrhagic ovarian cysts.[2] These can be follicular or corpus luteum cysts and may present as an emergency in
case of hemoperitoneum.[12]
[14]
[33]
[34]
[35]
[36]
[37]
[38]
[39] Hemorrhagic ovarian cysts can be a life-threatening complication, and the diagnosis
may be missed due to their rarity. Moreover, as highlighted in [Table 1], these events can occur at a young age, emphasizing the need for increased awareness
among clinicians.
Table 1
Cases reporting ovarian cysts and hemoperitoneum and related treatments in women with
afibrinogenemia and hypofibrinogenemia
|
Study
|
Type of fibrinogen disorder
|
Age of first report (years)
|
Treatment
|
Comment
|
|
Schneider et al., 1981[38]
|
Afibrinogenemia
|
22
|
Oophorectomy
|
One episode
|
|
Bottini et al., 1991[33]
|
Afibrinogenemia
|
15
|
Removal of peritoneal blood, wedge ovary resection, ovariectomy, COC
|
Three episodes, including one severe with Ht 29%
|
|
Castaman et al., 1995[14]
|
Afibrinogenemia
|
14
|
Wedge ovary resection, removal of peritoneal blood, COC
|
Two episodes, without recurrence after 5 years of COC introduction
|
|
Koussi et al., 2001[39]
|
Afibrinogenemia
|
14
|
Conservative, COC
|
Monitoring by CT scan and discharged on the ninth day
|
|
Özdemir et al., 2004[34]
|
Afibrinogenemia
|
24
|
Conservative, wedge ovarian resection, oophorectomy, COC
|
Five episodes, two requiring a laparotomy
|
|
Cetinkaya et al., 2011[35]
|
Afibrinogenemia
|
24
|
Wedge ovarian resection, COC
|
Two episodes with hemorrhagic shock, one 3 months after COC stopping
|
|
Kim et al., 2015[36]
|
Hypofibrinogenemia
|
18
|
Wedge ovarian resection, COC
|
One episode with hemorrhagic shock
|
|
Wang et al., 2020[37]
|
Hypofibrinogenemia
|
14
|
Conservative, COC
|
Monitoring and discharged on the fourth day
|
|
Ramadan et al., 2020[66]
|
Hypofibrinogenemia
|
26
|
Conservative, COC
|
Monitoring and discharged on the sixth day
|
|
Zhang et al., 2020[12]
|
Hypofibrinogenemia
|
14
|
Conservative, COC
|
No recurrence after 8 months of follow-up
|
Abbreviations: COC, combined oral contraceptives; Ht, hematocrit.
A retrospective study from Iran examined 210 patients with rare bleeding disorders
who were suspected of having hemorrhagic ovarian cysts.[40] Following clinical and ultrasound examination, two of the seven women with afibrinogenemia
or hypofibrinogenemia (with a median age of 15 years) were diagnosed with an ovarian
hemorrhagic cyst.
Hormonal therapy, by inhibiting ovulation, is the first option to decrease the risk
of developing hemorrhagic ovarian cysts.[14] The oral contraceptive should ideally be prescribed continuously in order to prevent
menstruation as well as ovulation.[29] Hemoperitoneum is a life-threatening bleeding that requires emergency management.
Several approaches have been described, including laparoscopy or laparotomy to evacuate
the hemoperitoneum, ovarian cystectomy, or even oophorectomy.[14]
[33]
[34]
[35]
[36]
[38] A conservative management approach has also been reported with success, especially
in hypofibrinogenemia.[12]
[37]
Pregnancy
The management of pregnancy in women with afibrinogenemia and hypofibrinogenemia necessitates
a multidisciplinary approach at every stage, from preconception to delivery, in order
to mitigate the increased risks of obstetric complications, bleeding, and thrombosis.
The following sections outline some key steps and offer practical recommendations
for their management.
Preconception Counseling
It is recommended that women with afibrinogenemia and hypofibrinogenemia undergo comprehensive
preconception counseling.[18] This entails an assessment of the patient's personal and family history of bleeding,
a determination of the patient's basal fibrinogen levels, and a discussion of the
potential risks associated with pregnancy, including those related to bleeding, obstetrics,
and thrombosis.[41] A frequent question pertains to the potential risks of miscarriage in cases of afibrinogenemia
and hypofibrinogenemia. Optimizing fibrinogen levels through replacement therapy prior
to conception or during the early stages of pregnancy has been demonstrated to reduce
the risk of pregnancy loss and facilitate safer maternal outcomes in women with afibrinogenemia
and severe hypofibrinogenemia.[42] In women with mild to moderate hypofibrinogenemia, the risk of miscarriage is likely
to be similar to or slightly elevated relative to the general population. The FibrinoGEST
Study, an international multicentric study involving 149 pregnancies in women with
hypofibrinogenemia, revealed that 106 (71.1%) women had a live birth, 18 (12.1%) had
an early miscarriage, and 2 (1.3%) had an intrauterine fetal death.[15] Similarly, a retrospective study involving 16 pregnancies in hypofibrinogenemia
documented 3 miscarriages (14%).[6]
Another frequent question concerns the risk of having a child affected by the same
fibrinogen disorder. Genetic counseling is a crucial element of preconception planning
for women with afibrinogenemia or hypofibrinogenemia, as the biological and clinical
phenotype of these conditions is inherited in an autosomal recessive and dominant
pattern, respectively.[43] In the event that both parents are heterozygous carriers of the mutated gene (i.e.,
hypofibrinogenemia), there is a 25% probability that their offspring will inherit
two copies of the mutated gene (i.e., afibrinogenemia); a 50% probability that their
offspring will inherit one copy (i.e., hypofibrinogenemia); and a 25% probability
that their offspring will not inherit any mutations. In the event that only one parent
is a carrier of afibrinogenemia or hypofibrinogenemia, there is a 50% and 25% probability,
respectively, that the child will manifest hypofibrinogenemia. This knowledge enables
prospective parents to make informed decisions, including the utilization of prenatal
genetic testing or preimplantation genetic diagnosis in cases of in vitro fertilization.[44] Furthermore, genetic counseling offers the chance to educate family members about
neonatal risks. Finally, the autosomal inheritance of severe forms is more prevalent
in populations where consanguineous marriage often occurs. The presence of language
barriers can further impede access to genetic counseling and health care services,
highlighting the need for culturally and linguistically appropriate counseling approaches.
Antenatal Care
Fibrinogen replacement is mandatory to support placental implantation and maintain
pregnancy to term in women with afibrinogenemia and severe hypofibrinogenemia.[45] Despite limited data, there is strong evidence supporting the efficacy of fibrinogen
replacement during pregnancy.[42]
[46]
[47]
[48]
[49]
[50]
[51]
[52]
[53] The minimal trough fibrinogen level remains undetermined; however, there is a consensus
among experts that levels higher than 1 g/L should be targeted.[17]
[18]
[54] Generally, this target can be achieved by the infusion of 50–75 mg/kg of fibrinogen
concentrate once or twice a week. The replacement regimen depends on individualized
pharmacokinetics, but also on logistics aspects such as the venous access, the adherence
to fibrinogen prophylaxis, and the accessibility to fibrinogen concentrates. As pregnancy
progresses, there is an increase in fibrinogen clearance, which consequently necessitates
an increase in the frequency of fibrinogen infusions.[47] Therefore, a monthly fibrinogen assessment is recommended.[18]
In women with mild and moderate hypofibrinogenemia, there is an increase of fibrinogen
levels throughout the pregnancy, sometimes reaching “normal” fibrinogen levels.[55]
[56] Thus, fibrinogen replacement therapy is generally not indicated, except in case
of vaginal bleeding or placenta abruption.[57]
[58] In the FibrinoGEST study, 7/149 (4.7%) pregnancies in women with hypofibrinogenemia
were complicated by vaginal bleeding and 12/149 (8%) by retroplacental and placental
abruption.[15]
Delivery
For women with afibrinogenemia and severe hypofibrinogenemia, delivery must be planned
in coordination with the blood bank, the laboratory, and the multidisciplinary clinical
team, including obstetricians, hematologists, anesthesiologists, and neonatologists.[18] Regardless of the delivery modality, fibrinogen replacement is necessary to achieve
a peak fibrinogen level higher than 1.5 g/L. It is imperative to avoid the utilization
of forceps, ventouse, fetal blood sampling, and fetal scalp electrodes when the infant
is at risk of severe fibrinogen deficiency.[17] In mild to moderate hypofibrinogenemia, fibrinogen levels often spontaneously reach
1.5 g/L at term. In that case, spontaneous delivery is allowed.
Central neuraxial anesthesia should be avoided in women with fibrinogen levels below
1.5 g/L. Despite the fact that this procedure can be safely performed when fibrinogen
levels are adequately substituted,[59] neuraxial anesthesia is not frequently offered to women with fibrinogen disorders
due to concerns of bleeding complications. In the FibrinoGEST Study, one-third of
the deliveries (n = 29, 29%) were managed without anesthesia due to the underlying hypofibrinogenemia.[15]
Postpartum
PPH is a frequent complication. The RBiN study reported detailed data on 40 deliveries
from 13 women with hypofibrinogenemia of various severities. Overall, 21 (35%) were
complicated by PPH, without differences among patients receiving a fibrinogen prophylaxis
or not.[60] A similar finding was reported in the FibrinoGEST Study, which documented 19 (18.2%)
cases of PPH following 106 deliveries.[15] Therefore, close clinical and biological monitoring is necessary after birth, and
early fibrinogen supplementation and antifibrinolytic agents should be prescribed
in case of bleeding.
The pregnancy and the delivery may confer a significant thrombotic risk factor, especially
in women receiving cryoprecipitate as prophylaxis.[50]
[61] Consequently, it is imperative to discuss the administration of adequate fibrinogen
substitution and thromboprophylaxis during the assessment of delivery and postpartum
care plans.[18] In case of fibrinogen replacement, the administration of low-molecular-weight heparin
as pharmacologic thromboprophylaxis is recommended until the patient is discharged.
The extension of thromboprophylaxis to 4 to 6 weeks on fibrinogen prophylaxis may
be considered depending on the patient's clinical phenotype and other thrombotic risk
factors.[2]
[18]
Ageing Women
There are no data evaluating the prevalence of bleeding in ageing women with afibrinogenemia
and hypofibrinogenemia. However, it is expected that the prevalence will be similar
to that in women with severe von Willebrand disease or hemophilia.[62]
[63] With fibrinogen replacement, life expectancy in women with afibrinogenemia and severe
hypofibrinogenemia can be expected to approach normal, while women with mild to moderate
hypofibrinogenemia generally have a normal life expectancy. As women with fibrinogen
disorders age, they may face an elevated risk of bleeding related to late gynecological
issues, including menopausal and postmenopausal complications. Clinicians managing
women with afibrinogenemia or hypofibrinogenemia should, therefore, remain vigilant
for symptoms of menopausal (increased HBM due to anovulatory cycles) and postmenopausal
bleeding, especially in the presence of acquired gynecological pathologies. Prompt
evaluation is essential to rule out serious underlying causes such as endometrial
hyperplasia, fibroids, or gynecological malignancies,[64] as well as to manage any potential complications related to excessive bleeding.[65] Treatment strategies typically involve a multidisciplinary approach. Therapeutic
options may include fibrinogen replacement therapy, hormonal regulation, considering
the thrombotic risk, or surgical interventions such as hysteroscopy or endometrial
ablation, depending on the severity of symptoms and underlying pathology. Given the
lack of specific studies on this subgroup, further research is warranted to better
understand the prevalence, risk factors, and optimal management of postmenopausal
bleeding in women with fibrinogen disorders.
Conclusion
Women with congenital afibrinogenemia and hypofibrinogenemia encounter substantial
health challenges related to bleeding and thrombosis, necessitating comprehensive,
multidisciplinary care across all life stages. Individualized management strategies
are imperative in addressing bleeding risks in case of HMB, hemorrhagic ovarian cysts,
pregnancy complications, and bleeding occurring later in life. While current guidelines
provide a framework for care, substantial gaps in knowledge, particularly regarding
ageing women, underscore the necessity for further research. Consequently, ongoing
studies and enhanced collaboration between hematologists and gynecologists are imperative
to optimize outcomes and enhance quality of life for affected women.
