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DOI: 10.1055/a-2568-1255
Management of Young and Ageing Women with Afibrinogenemia and Hypofibrinogenemia
- Abstract
- Introduction
- Heavy Menstrual Bleeding
- Hemorrhagic Ovarian Cysts
- Pregnancy
- Ageing Women
- Conclusion
- References
Abstract
Congenital afibrinogenemia and hypofibrinogenemia are rare hereditary coagulation disorders characterized by the absence or deficiency of fibrinogen. These conditions pose unique challenges for women across their lifespan, including heavy menstrual bleeding (HMB), hemorrhagic ovarian cysts, complications during pregnancy and the postpartum period, as well as bleeding occurring later in life. HMB is frequent and adversely impacts quality of life, often necessitating hormonal therapy, antifibrinolytics, or fibrinogen replacement. Hemorrhagic ovarian cysts can result in life-threatening hemoperitoneum, requiring prompt intervention to manage bleeding and preserve ovarian function. Pregnancy in women with severe fibrinogen deficiencies carries a high risk of miscarriage, placental abruption, and postpartum hemorrhage. Multidisciplinary care, fibrinogen replacement, and vigilant monitoring are crucial to optimize maternal and fetal outcomes. Although understudied in this population, bleeding can occur later in their life, especially due to the increased incidence of gynecological pathologies. Tailored management strategies, including hormonal and surgical interventions, are essential. Despite recent advances in our understanding of these conditions, significant knowledge gaps persist regarding the prevalence, risk factors, and optimal management of specific complications. This review synthesizes current findings and provides practical recommendations to guide the care of young and ageing women with afibrinogenemia and hypofibrinogenemia. Further research is needed to refine treatment protocols and improve outcomes for this vulnerable population.
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Keywords
afibrinogenemia - hypofibrinogenemia - miscarriage - heavy menstrual bleeding - pregnancy - postpartum hemorrhage - thrombosis - ovarian cystsIntroduction
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]
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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]
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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.
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]
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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.
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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]
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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]
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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]
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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.
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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.
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Conflict of Interest
AC reports grants and fees paid to his institution from Sobi, Takeda, LFB, and Novo Nordisk; and has participated in advisory boards for Sobi.
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References
- 1 Weisel JW, Litvinov RI. Mechanisms of fibrin polymerization and clinical implications. Blood 2013; 121 (10) 1712-1719
- 2 Casini A. How I treat quantitative fibrinogen disorders?. Blood 2025; 145 (08) 801-810
- 3 Menegatti M, Peyvandi F. Treatment of rare factor deficiencies other than hemophilia. Blood 2019; 133 (05) 415-424
- 4 Casini A, Undas A, Palla R, Thachil J, de Moerloose P. Subcommittee on Factor XIII and Fibrinogen. Diagnosis and classification of congenital fibrinogen disorders: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (09) 1887-1890
- 5 Peyvandi F, Palla R, Menegatti M. et al.; European Network of Rare Bleeding Disorders Group. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost 2012; 10 (04) 615-621
- 6 Mohsenian S, Palla R, Menegatti M. et al. Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the Prospective Rare Bleeding Disorders Database. Blood Adv 2024; 8 (06) 1392-1404
- 7 Abdelwahab M, de Moerloose P, Casini A. High incidence of intracranial haemorrhage in Egyptian children with congenital afibrinogenaemia. Haemophilia 2023; 29 (02) 572-577
- 8 Casini A, Neerman-Arbez M, de Moerloose P. Heterogeneity of congenital afibrinogenemia, from epidemiology to clinical consequences and management. Blood Rev 2021; 48: 100793
- 9 Richard M, Celeny D, Neerman-Arbez M. Mutations accounting for congenital fibrinogen disorders: An update. Semin Thromb Hemost 2022; 48 (08) 889-903
- 10 Ramanan R, McFadyen JD, Perkins AC, Tran HA. Congenital fibrinogen disorders: Strengthening genotype-phenotype correlations through novel genetic diagnostic tools. Br J Haematol 2023; 203 (03) 355-368
- 11 Malinowski AK, Abdul-Kadir R. Planning pregnancy and birth in women with inherited bleeding disorders. Semin Thromb Hemost 2023; 49 (04) 371-381
- 12 Zhang Y, Zuo X, Teng Y. Women with congenital hypofibrinogenemia/afibrinogenemia: From birth to death. Clin Appl Thromb Hemost 2020; 26: 1076029620912819
- 13 Presky KO, Kadir RA. Women with inherited bleeding disorders - Challenges and strategies for improved care. Thromb Res 2020; 196: 569-578
- 14 Castaman G, Ruggeri M, Rodeghiero F. Congenital afibrinogenemia: successful prevention of recurrent hemoperitoneum during ovulation by oral contraceptive. Am J Hematol 1995; 49 (04) 363-364
- 15 Hugon-Rodin J, Carrière C, Claeyssens S. et al. Obstetrical complications in hereditary fibrinogen disorders: the Fibrinogest study. J Thromb Haemost 2023; 21 (08) 2126-2136
- 16 Curry N, Bowles L, Clark TJ. et al. Gynaecological management of women with inherited bleeding disorders. A UK Haemophilia Centres Doctors' Organisation Guideline. Haemophilia 2022; 28 (06) 917-937
- 17 Management of inherited bleeding disorders in pregnancy: Green-top Guideline No. 71 (joint with UKHCDO). BJOG 2017; 124 (08) e193-e263
- 18 Casini A, Abdul Kadir R, Abdelwahab M. et al. Management of pregnancy and delivery in congenital fibrinogen disorders: communication from the ISTH SSC Subcommittee on Factor XIII and Fibrinogen. J Thromb Haemost 2024; 22 (05) 1516-1521
- 19 Casini A, de Moerloose P. How I treat dysfibrinogenemia?. Blood 2021; 138 (21) 2021-2030
- 20 Hadjali-Saichi S, de Mazancourt P, Tapon-Bretaudière J. et al. Clinical, biological, and genetic features in an afibrinogenemia patient series in Algeria. Haemophilia 2022; 28 (05) 822-831
- 21 Casini A, von Mackensen S, Santoro C. et al.; QualyAfib Study Group. Clinical phenotype, fibrinogen supplementation, and health-related quality of life in patients with afibrinogenemia. Blood 2021; 137 (22) 3127-3136
- 22 Lak M, Keihani M, Elahi F, Peyvandi F, Mannucci PM. Bleeding and thrombosis in 55 patients with inherited afibrinogenaemia. Br J Haematol 1999; 107 (01) 204-206
- 23 Maas DPMSM, Saes JL, Blijlevens NMA. et al.; RBiN Study Group. High prevalence of heavy menstrual bleeding in women with rare bleeding disorders in the Netherlands: retrospective data from the RBiN study. J Thromb Haemost 2023; 21 (10) 2726-2734
- 24 van Galen K, Lavin M, Skouw-Rasmussen N. et al.; European Haemophilia Consortium (EHC) and the European Association for Haemophilia and Allied Disorders (EAHAD). European principles of care for women and girls with inherited bleeding disorders. Haemophilia 2021; 27 (05) 837-847
- 25 Kadir RA, Tarawah A, Shridhar N, Kulkarni R. Driving improvement of diagnosis and awareness of heavy menstrual bleeding in women among physicians. Haemophilia 2024; 30 (05) 1185-1192
- 26 Zia A, Stanek J, Christian-Rancy M, Savelli S, O'Brien SH. Iron deficiency and fatigue among adolescents with bleeding disorders. Am J Hematol 2022; 97 (01) 60-67
- 27 Oliveira JA, Eskandar K, Chagas J. et al. Heavy menstrual bleeding in women with inherited bleeding disorders in use of LNG-IUS: A systematic review and single-arm meta-analysis. Contraception 2024; 135: 110450
- 28 Matteson KA, Rahn DD, Wheeler II TL. et al.; Society of Gynecologic Surgeons Systematic Review Group. Nonsurgical management of heavy menstrual bleeding: a systematic review. Obstet Gynecol 2013; 121 (03) 632-643
- 29 Rizk DE, Kumar RM. Congenital afibrinogenemia: treatment of excessive menstrual bleeding with continuous oral contraceptive. Am J Hematol 1996; 52 (03) 237-238
- 30 MacKinnon HH, Fekete JF. Congenital afibrinogenemia. Vascular changes and multiple thromboses induced by fibrinogen infusions and contraceptive medication. Can Med Assoc J 1971; 104 (07) 597-599
- 31 Djambas Khayat C, Gouider E, von Mackensen S, Abdul Kadir R. Heavy menstrual bleeding in women with inherited bleeding disorders. Haemophilia 2020; 26 (Suppl. 03) 16-19
- 32 Trossaert M, Chamouard V, Biron-Andreani C. et al. Management of rare inherited bleeding disorders: Proposals of the French Reference Centre on Haemophilia and Rare Coagulation Disorders. Eur J Haematol 2023; 110 (06) 584-601
- 33 Bottini E, Pareti FI, Mari D, Mannucci PM, Muggiasca ML, Conti M. Prevention of hemoperitoneum during ovulation by oral contraceptives in women with type III von Willebrand disease and afibrinogenemia. Case reports. Haematologica 1991; 76 (05) 431-433
- 34 Özdemir Ö, Sarı ME, Kurt A, Şen E, Atalay CR. Recurrent massive haemoperitoneum associated with ruptured corpus luteum in women with congenital afibrinogenemia; case report. Turk J Obstet Gynecol 2014; 11 (04) 242-245
- 35 Cetinkaya SE, Pabuccu EG, Ozmen B, Dokmeci F. Recurrent massive hemoperitoneum due to ovulation as a clinical sign in congenital afibrinogenemia. Acta Obstet Gynecol Scand 2011; 90 (02) 192-194
- 36 Kim JH, Jeong SY, Cho DH. Massive hemoperitoneum due to a ruptured corpus luteum cyst in a patient with congenital hypofibrinogenemia. Obstet Gynecol Sci 2015; 58 (05) 427-430
- 37 Wang Y, Zhao L, Feng X. et al. Two-pronged treatment of hemoperitoneum and abnormal uterine bleeding in an adolescent girl with congenital fibrinogen deficiency. Front Med (Lausanne) 2020; 7: 181
- 38 Schneider D, Bukovsky I, Kaufman S, Sadovsky G, Caspi E. Severe ovarian hemorrhage in congenital afibrinogenemia. Acta Obstet Gynecol Scand 1981; 60 (04) 431
- 39 Koussi A, Economou M, Athanasiou-Metaxa M. Intra-abdominal hemorrhage due to a ruptured corpus luteum cyst in a girl with congenital afibrinogenemia. Eur J Pediatr 2001; 160 (03) 196
- 40 Seidizadeh O, Aliabad GM, Mirzaei I. et al. Prevalence of hemorrhagic ovarian cysts in patients with rare inherited bleeding disorders. Transfus Apher Sci 2023; 62 (03) 103636
- 41 Breen CM, Riazat MI, McCallion N, Boyle MA. Congenital hypofibrinogenaemia: a presymptomatic detection of an extremely rare bleeding disorder in preterm twins. BMJ Case Rep 2017; 2017: bcr2017219332
- 42 Saes JL, Laros-van Gorkom BAP, Coppens M, Schols SEM. Pregnancy outcome in afibrinogenemia: Are we giving enough fibrinogen concentrate? A case series. Res Pract Thromb Haemost 2020; 4 (02) 343-346
- 43 Neerman-Arbez M, Casini A. Clinical consequences and molecular bases of low fibrinogen levels. Int J Mol Sci 2018; 19 (01) 192
- 44 Neerman-Arbez M, Vu D, Abu-Libdeh B, Bouchardy I, Morris MA. Prenatal diagnosis for congenital afibrinogenemia caused by a novel nonsense mutation in the FGB gene in a Palestinian family. Blood 2003; 101 (09) 3492-3494
- 45 Asahina T, Kobayashi T, Okada Y. et al. Studies on the role of adhesive proteins in maintaining pregnancy. Horm Res 1998; 50 (Suppl. 02) 37-45
- 46 Karimi M, Bordbar M, Aali M, Bazrafshan A, Tavoosi H, Gerdabi J. Successful delivery in an patient with afibrinogenemia after three abortions: A case report and review of the literature. Haemophilia 2018; 24 (02) e63-e66
- 47 Oda T, Itoh H, Kawai K. et al. Three successful deliveries involving a woman with congenital afibrinogenaemia - conventional fibrinogen concentrate infusion vs. ‘as required’ fibrinogen concentrate infusion based on changes in fibrinogen clearance. Haemophilia 2016; 22 (05) e478-e481
- 48 Kaparou M, Danilatou V, Lydaki E. et al. Prophylactic administration of fibrinogen concentrate in a pregnant woman with congenital hypofibrinogenemia and a positive obstetric history of severe bleeding in previous cesarean section. Blood Coagul Fibrinolysis 2012; 23 (06) 566-568
- 49 Matsushita I, Uchida S, Yamaguchi A. et al. Interstitial pregnancy in a woman with congenital afibrinogenemia. J Obstet Gynaecol Res 2008; 34 (05) 914-918
- 50 Roqué H, Stephenson C, Lee MJ. et al. Pregnancy-related thrombosis in a woman with congenital afibrinogenemia: a report of two successful pregnancies. Am J Hematol 2004; 76 (03) 267-270
- 51 Kobayashi T, Asahina T, Maehara K, Itoh M, Kanayama N, Terao T. Congenital afibrinogenemia with successful delivery. Gynecol Obstet Invest 1996; 42 (01) 66-69
- 52 Grech H, Majumdar G, Lawrie AS, Savidge GF. Pregnancy in congenital afibrinogenaemia: report of a successful case and review of the literature. Br J Haematol 1991; 78 (04) 571-572
- 53 Evron S, Anteby SO, Brzezinsky A, Samueloff A, Eldor A. Congenital afibrinogenemia and recurrent early abortion: a case report. Eur J Obstet Gynecol Reprod Biol 1985; 19 (05) 307-311
- 54 Bornikova L, Peyvandi F, Allen G, Bernstein J, Manco-Johnson MJ. Fibrinogen replacement therapy for congenital fibrinogen deficiency. J Thromb Haemost 2011; 9 (09) 1687-1704
- 55 Cai H, Liang M, Yang J, Zhang X. Congenital hypofibrinogenemia in pregnancy: a report of 11 cases. Blood Coagul Fibrinolysis 2018; 29 (02) 155-159
- 56 Marchi R, Durual S, Pecheux O, Neerman-Arbez M, Casini A. Physiological correction of hereditary mild hypofibrinogenemia during pregnancy. Haemophilia 2023; 29 (03) 836-843
- 57 Valiton V, Hugon-Rodin J, Fontana P, Neerman-Arbez M, Casini A. Obstetrical and postpartum complications in women with hereditary fibrinogen disorders: A systematic literature review. Haemophilia 2019; 25 (05) 747-754
- 58 Sucker C, Geisen C, Litmathe J, Schmitt U. Concomitant hypofibrinogenemia and factor XI deficiency as rare cause of bleeding during urgent dentistry: case report and short review of the literature. Arch Clin Cases 2023; 10 (02) 110-113
- 59 Hanke AA, Elsner O, Görlinger K. Spinal anaesthesia and caesarean section in a patient with hypofibrinogenaemia and factor XIII deficiency. Anaesthesia 2010; 65 (06) 641-645
- 60 Maas DPMSM, Saes JL, Blijlevens NMA. et al.; RBiN study group. High prevalence of postpartum hemorrhage in women with rare bleeding disorders in the Netherlands: retrospective data from the RBiN study. J Thromb Haemost 2023; 21 (03) 499-512
- 61 Santoro C, Massaro F, Venosi S. et al. Severe thrombotic complications in congenital afibrinogenemia: A pathophysiological and management dilemma. Semin Thromb Hemost 2016; 42 (05) 577-582
- 62 Eising HP, Punt MC, Leemans JC, Bongers MY. Prophylactic and therapeutic strategies for intraoperative bleeding in women with von Willebrand disease and heavy menstrual bleeding: A systematic review. Blood Rev 2023; 62: 101131
- 63 James AH, Myers ER, Cook C, Pietrobon R. Complications of hysterectomy in women with von Willebrand disease. Haemophilia 2009; 15 (04) 926-931
- 64 Kadir RA, Sharief LA, Lee CA. Inherited bleeding disorders in older women. Maturitas 2012; 72 (01) 35-41
- 65 Radhakrishnan S, d'Oiron R. Ageing and women with bleeding disorders. J Haemoph Pract 2022; 9 (01) 126-131
- 66 Ramadan M, Kharroubi M, Khaza'al J. Successful conservative treatment of ovulation-related hemoperitoneum in a patient with congenital hypofibrinogenemia: A case report and review of literature. J Clin Gynecol Obstet 2020; 9 (04) 112-118
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Publication History
Received: 06 January 2025
Accepted: 27 March 2025
Article published online:
27 May 2025
© 2025. Thieme. All rights reserved.
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References
- 1 Weisel JW, Litvinov RI. Mechanisms of fibrin polymerization and clinical implications. Blood 2013; 121 (10) 1712-1719
- 2 Casini A. How I treat quantitative fibrinogen disorders?. Blood 2025; 145 (08) 801-810
- 3 Menegatti M, Peyvandi F. Treatment of rare factor deficiencies other than hemophilia. Blood 2019; 133 (05) 415-424
- 4 Casini A, Undas A, Palla R, Thachil J, de Moerloose P. Subcommittee on Factor XIII and Fibrinogen. Diagnosis and classification of congenital fibrinogen disorders: communication from the SSC of the ISTH. J Thromb Haemost 2018; 16 (09) 1887-1890
- 5 Peyvandi F, Palla R, Menegatti M. et al.; European Network of Rare Bleeding Disorders Group. Coagulation factor activity and clinical bleeding severity in rare bleeding disorders: results from the European Network of Rare Bleeding Disorders. J Thromb Haemost 2012; 10 (04) 615-621
- 6 Mohsenian S, Palla R, Menegatti M. et al. Congenital fibrinogen disorders: a retrospective clinical and genetic analysis of the Prospective Rare Bleeding Disorders Database. Blood Adv 2024; 8 (06) 1392-1404
- 7 Abdelwahab M, de Moerloose P, Casini A. High incidence of intracranial haemorrhage in Egyptian children with congenital afibrinogenaemia. Haemophilia 2023; 29 (02) 572-577
- 8 Casini A, Neerman-Arbez M, de Moerloose P. Heterogeneity of congenital afibrinogenemia, from epidemiology to clinical consequences and management. Blood Rev 2021; 48: 100793
- 9 Richard M, Celeny D, Neerman-Arbez M. Mutations accounting for congenital fibrinogen disorders: An update. Semin Thromb Hemost 2022; 48 (08) 889-903
- 10 Ramanan R, McFadyen JD, Perkins AC, Tran HA. Congenital fibrinogen disorders: Strengthening genotype-phenotype correlations through novel genetic diagnostic tools. Br J Haematol 2023; 203 (03) 355-368
- 11 Malinowski AK, Abdul-Kadir R. Planning pregnancy and birth in women with inherited bleeding disorders. Semin Thromb Hemost 2023; 49 (04) 371-381
- 12 Zhang Y, Zuo X, Teng Y. Women with congenital hypofibrinogenemia/afibrinogenemia: From birth to death. Clin Appl Thromb Hemost 2020; 26: 1076029620912819
- 13 Presky KO, Kadir RA. Women with inherited bleeding disorders - Challenges and strategies for improved care. Thromb Res 2020; 196: 569-578
- 14 Castaman G, Ruggeri M, Rodeghiero F. Congenital afibrinogenemia: successful prevention of recurrent hemoperitoneum during ovulation by oral contraceptive. Am J Hematol 1995; 49 (04) 363-364
- 15 Hugon-Rodin J, Carrière C, Claeyssens S. et al. Obstetrical complications in hereditary fibrinogen disorders: the Fibrinogest study. J Thromb Haemost 2023; 21 (08) 2126-2136
- 16 Curry N, Bowles L, Clark TJ. et al. Gynaecological management of women with inherited bleeding disorders. A UK Haemophilia Centres Doctors' Organisation Guideline. Haemophilia 2022; 28 (06) 917-937
- 17 Management of inherited bleeding disorders in pregnancy: Green-top Guideline No. 71 (joint with UKHCDO). BJOG 2017; 124 (08) e193-e263
- 18 Casini A, Abdul Kadir R, Abdelwahab M. et al. Management of pregnancy and delivery in congenital fibrinogen disorders: communication from the ISTH SSC Subcommittee on Factor XIII and Fibrinogen. J Thromb Haemost 2024; 22 (05) 1516-1521
- 19 Casini A, de Moerloose P. How I treat dysfibrinogenemia?. Blood 2021; 138 (21) 2021-2030
- 20 Hadjali-Saichi S, de Mazancourt P, Tapon-Bretaudière J. et al. Clinical, biological, and genetic features in an afibrinogenemia patient series in Algeria. Haemophilia 2022; 28 (05) 822-831
- 21 Casini A, von Mackensen S, Santoro C. et al.; QualyAfib Study Group. Clinical phenotype, fibrinogen supplementation, and health-related quality of life in patients with afibrinogenemia. Blood 2021; 137 (22) 3127-3136
- 22 Lak M, Keihani M, Elahi F, Peyvandi F, Mannucci PM. Bleeding and thrombosis in 55 patients with inherited afibrinogenaemia. Br J Haematol 1999; 107 (01) 204-206
- 23 Maas DPMSM, Saes JL, Blijlevens NMA. et al.; RBiN Study Group. High prevalence of heavy menstrual bleeding in women with rare bleeding disorders in the Netherlands: retrospective data from the RBiN study. J Thromb Haemost 2023; 21 (10) 2726-2734
- 24 van Galen K, Lavin M, Skouw-Rasmussen N. et al.; European Haemophilia Consortium (EHC) and the European Association for Haemophilia and Allied Disorders (EAHAD). European principles of care for women and girls with inherited bleeding disorders. Haemophilia 2021; 27 (05) 837-847
- 25 Kadir RA, Tarawah A, Shridhar N, Kulkarni R. Driving improvement of diagnosis and awareness of heavy menstrual bleeding in women among physicians. Haemophilia 2024; 30 (05) 1185-1192
- 26 Zia A, Stanek J, Christian-Rancy M, Savelli S, O'Brien SH. Iron deficiency and fatigue among adolescents with bleeding disorders. Am J Hematol 2022; 97 (01) 60-67
- 27 Oliveira JA, Eskandar K, Chagas J. et al. Heavy menstrual bleeding in women with inherited bleeding disorders in use of LNG-IUS: A systematic review and single-arm meta-analysis. Contraception 2024; 135: 110450
- 28 Matteson KA, Rahn DD, Wheeler II TL. et al.; Society of Gynecologic Surgeons Systematic Review Group. Nonsurgical management of heavy menstrual bleeding: a systematic review. Obstet Gynecol 2013; 121 (03) 632-643
- 29 Rizk DE, Kumar RM. Congenital afibrinogenemia: treatment of excessive menstrual bleeding with continuous oral contraceptive. Am J Hematol 1996; 52 (03) 237-238
- 30 MacKinnon HH, Fekete JF. Congenital afibrinogenemia. Vascular changes and multiple thromboses induced by fibrinogen infusions and contraceptive medication. Can Med Assoc J 1971; 104 (07) 597-599
- 31 Djambas Khayat C, Gouider E, von Mackensen S, Abdul Kadir R. Heavy menstrual bleeding in women with inherited bleeding disorders. Haemophilia 2020; 26 (Suppl. 03) 16-19
- 32 Trossaert M, Chamouard V, Biron-Andreani C. et al. Management of rare inherited bleeding disorders: Proposals of the French Reference Centre on Haemophilia and Rare Coagulation Disorders. Eur J Haematol 2023; 110 (06) 584-601
- 33 Bottini E, Pareti FI, Mari D, Mannucci PM, Muggiasca ML, Conti M. Prevention of hemoperitoneum during ovulation by oral contraceptives in women with type III von Willebrand disease and afibrinogenemia. Case reports. Haematologica 1991; 76 (05) 431-433
- 34 Özdemir Ö, Sarı ME, Kurt A, Şen E, Atalay CR. Recurrent massive haemoperitoneum associated with ruptured corpus luteum in women with congenital afibrinogenemia; case report. Turk J Obstet Gynecol 2014; 11 (04) 242-245
- 35 Cetinkaya SE, Pabuccu EG, Ozmen B, Dokmeci F. Recurrent massive hemoperitoneum due to ovulation as a clinical sign in congenital afibrinogenemia. Acta Obstet Gynecol Scand 2011; 90 (02) 192-194
- 36 Kim JH, Jeong SY, Cho DH. Massive hemoperitoneum due to a ruptured corpus luteum cyst in a patient with congenital hypofibrinogenemia. Obstet Gynecol Sci 2015; 58 (05) 427-430
- 37 Wang Y, Zhao L, Feng X. et al. Two-pronged treatment of hemoperitoneum and abnormal uterine bleeding in an adolescent girl with congenital fibrinogen deficiency. Front Med (Lausanne) 2020; 7: 181
- 38 Schneider D, Bukovsky I, Kaufman S, Sadovsky G, Caspi E. Severe ovarian hemorrhage in congenital afibrinogenemia. Acta Obstet Gynecol Scand 1981; 60 (04) 431
- 39 Koussi A, Economou M, Athanasiou-Metaxa M. Intra-abdominal hemorrhage due to a ruptured corpus luteum cyst in a girl with congenital afibrinogenemia. Eur J Pediatr 2001; 160 (03) 196
- 40 Seidizadeh O, Aliabad GM, Mirzaei I. et al. Prevalence of hemorrhagic ovarian cysts in patients with rare inherited bleeding disorders. Transfus Apher Sci 2023; 62 (03) 103636
- 41 Breen CM, Riazat MI, McCallion N, Boyle MA. Congenital hypofibrinogenaemia: a presymptomatic detection of an extremely rare bleeding disorder in preterm twins. BMJ Case Rep 2017; 2017: bcr2017219332
- 42 Saes JL, Laros-van Gorkom BAP, Coppens M, Schols SEM. Pregnancy outcome in afibrinogenemia: Are we giving enough fibrinogen concentrate? A case series. Res Pract Thromb Haemost 2020; 4 (02) 343-346
- 43 Neerman-Arbez M, Casini A. Clinical consequences and molecular bases of low fibrinogen levels. Int J Mol Sci 2018; 19 (01) 192
- 44 Neerman-Arbez M, Vu D, Abu-Libdeh B, Bouchardy I, Morris MA. Prenatal diagnosis for congenital afibrinogenemia caused by a novel nonsense mutation in the FGB gene in a Palestinian family. Blood 2003; 101 (09) 3492-3494
- 45 Asahina T, Kobayashi T, Okada Y. et al. Studies on the role of adhesive proteins in maintaining pregnancy. Horm Res 1998; 50 (Suppl. 02) 37-45
- 46 Karimi M, Bordbar M, Aali M, Bazrafshan A, Tavoosi H, Gerdabi J. Successful delivery in an patient with afibrinogenemia after three abortions: A case report and review of the literature. Haemophilia 2018; 24 (02) e63-e66
- 47 Oda T, Itoh H, Kawai K. et al. Three successful deliveries involving a woman with congenital afibrinogenaemia - conventional fibrinogen concentrate infusion vs. ‘as required’ fibrinogen concentrate infusion based on changes in fibrinogen clearance. Haemophilia 2016; 22 (05) e478-e481
- 48 Kaparou M, Danilatou V, Lydaki E. et al. Prophylactic administration of fibrinogen concentrate in a pregnant woman with congenital hypofibrinogenemia and a positive obstetric history of severe bleeding in previous cesarean section. Blood Coagul Fibrinolysis 2012; 23 (06) 566-568
- 49 Matsushita I, Uchida S, Yamaguchi A. et al. Interstitial pregnancy in a woman with congenital afibrinogenemia. J Obstet Gynaecol Res 2008; 34 (05) 914-918
- 50 Roqué H, Stephenson C, Lee MJ. et al. Pregnancy-related thrombosis in a woman with congenital afibrinogenemia: a report of two successful pregnancies. Am J Hematol 2004; 76 (03) 267-270
- 51 Kobayashi T, Asahina T, Maehara K, Itoh M, Kanayama N, Terao T. Congenital afibrinogenemia with successful delivery. Gynecol Obstet Invest 1996; 42 (01) 66-69
- 52 Grech H, Majumdar G, Lawrie AS, Savidge GF. Pregnancy in congenital afibrinogenaemia: report of a successful case and review of the literature. Br J Haematol 1991; 78 (04) 571-572
- 53 Evron S, Anteby SO, Brzezinsky A, Samueloff A, Eldor A. Congenital afibrinogenemia and recurrent early abortion: a case report. Eur J Obstet Gynecol Reprod Biol 1985; 19 (05) 307-311
- 54 Bornikova L, Peyvandi F, Allen G, Bernstein J, Manco-Johnson MJ. Fibrinogen replacement therapy for congenital fibrinogen deficiency. J Thromb Haemost 2011; 9 (09) 1687-1704
- 55 Cai H, Liang M, Yang J, Zhang X. Congenital hypofibrinogenemia in pregnancy: a report of 11 cases. Blood Coagul Fibrinolysis 2018; 29 (02) 155-159
- 56 Marchi R, Durual S, Pecheux O, Neerman-Arbez M, Casini A. Physiological correction of hereditary mild hypofibrinogenemia during pregnancy. Haemophilia 2023; 29 (03) 836-843
- 57 Valiton V, Hugon-Rodin J, Fontana P, Neerman-Arbez M, Casini A. Obstetrical and postpartum complications in women with hereditary fibrinogen disorders: A systematic literature review. Haemophilia 2019; 25 (05) 747-754
- 58 Sucker C, Geisen C, Litmathe J, Schmitt U. Concomitant hypofibrinogenemia and factor XI deficiency as rare cause of bleeding during urgent dentistry: case report and short review of the literature. Arch Clin Cases 2023; 10 (02) 110-113
- 59 Hanke AA, Elsner O, Görlinger K. Spinal anaesthesia and caesarean section in a patient with hypofibrinogenaemia and factor XIII deficiency. Anaesthesia 2010; 65 (06) 641-645
- 60 Maas DPMSM, Saes JL, Blijlevens NMA. et al.; RBiN study group. High prevalence of postpartum hemorrhage in women with rare bleeding disorders in the Netherlands: retrospective data from the RBiN study. J Thromb Haemost 2023; 21 (03) 499-512
- 61 Santoro C, Massaro F, Venosi S. et al. Severe thrombotic complications in congenital afibrinogenemia: A pathophysiological and management dilemma. Semin Thromb Hemost 2016; 42 (05) 577-582
- 62 Eising HP, Punt MC, Leemans JC, Bongers MY. Prophylactic and therapeutic strategies for intraoperative bleeding in women with von Willebrand disease and heavy menstrual bleeding: A systematic review. Blood Rev 2023; 62: 101131
- 63 James AH, Myers ER, Cook C, Pietrobon R. Complications of hysterectomy in women with von Willebrand disease. Haemophilia 2009; 15 (04) 926-931
- 64 Kadir RA, Sharief LA, Lee CA. Inherited bleeding disorders in older women. Maturitas 2012; 72 (01) 35-41
- 65 Radhakrishnan S, d'Oiron R. Ageing and women with bleeding disorders. J Haemoph Pract 2022; 9 (01) 126-131
- 66 Ramadan M, Kharroubi M, Khaza'al J. Successful conservative treatment of ovulation-related hemoperitoneum in a patient with congenital hypofibrinogenemia: A case report and review of literature. J Clin Gynecol Obstet 2020; 9 (04) 112-118