Management of Young and Ageing Women with Afibrinogenemia and Hypofibrinogenemia

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.

Keywords

afibrinogenemia - hypofibrinogenemia - miscarriage - heavy menstrual bleeding - pregnancy - postpartum hemorrhage - thrombosis - ovarian cysts

Publikationsverlauf

Eingereicht: 06. Januar 2025

Angenommen: 27. März 2025

Artikel online veröffentlicht:
27. Mai 2025

• 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