Recurrent Venous Thrombosis in a Hypofibrinogenemic Patient Despite a Heterozygous Deletion of the Fibrinogen Gene Cluster and Hemizygous FGB p.Pro265Leu Variant Mimicking a Homozygous Genotype

Abstract

Hypofibrinogenemia is a congenital fibrinogen disorder characterized by a proportional decrease of functional and antigenic fibrinogen levels. Herein, we present a unique case illustrating the complex genotype–phenotype relationship in hypofibrinogenemia and the inability of low fibrinogen levels to counteract hypercoagulability.

A 77-year-old male with factor V Leiden heterozygosity experienced surgery-related deep vein thrombosis at ages 65 and 71, along with poor wound healing and postoperative hematomas. Proportionally reduced functional and antigenic fibrinogen levels revealed hypofibrinogenemia. Whole exome sequencing identified a heterozygous fibrinogen gene cluster deletion and a hemizygous variant (p.Pro265Leu, rs6054) in the fibrinogen β (FGB) gene, both of which are associated with hypofibrinogenemia. The youngest son, who has noticeably higher fibrinogen levels, shares the deletion but does not carry the hemizygous FGB variant. This suggests that the FGB variant (p.Pro265Leu) contributes to a greater reduction in fibrinogen levels.

This case suggests that the coexistence of thrombotic risk factors and potentially reduced thrombin clearance—resulting from low fibrinogen levels due to a fibrinogen gene cluster deletion and a hemizygous FGB variant—may shift the hemostatic balance toward thrombosis in a patient with moderate hypofibrinogenemia.

Keywords

fibrinogen - hypofibrinogenemia - variant - deletion - thrombosis

Ethics Statement

Ethical approval was not required for this study, in accordance with local and Danish national guidelines. The patient is aware that his clinical details are included in this paper, and written informed consent was obtained from the patient for the publication of this case report.

Authors' Contributions

S.P. performed the literature review, interpreted the data, and wrote the first draft of the manuscript, and approved the final manuscript. E.B.L. supervised the recruitment of the patient, provided clinical information of the patient, and approved the final manuscript. E.A.J. also supervised the recruitment of the patient and approved the final manuscript. E.D.B. supervised the whole exome sequencing of the patient's son, interpreted the data, and approved the final manuscript. I.S.P. supervised the whole exome sequencing of the patient, interpreted the data, and approved the final manuscript. M.V.B. planned and designed the study, supervised the coagulation analyses, oversaw the literature review, interpreted the data, supervised the writing of the manuscript, and approved the final manuscript.

Publication History

Received: 22 October 2024

Accepted: 03 June 2025

Article published online:
07 August 2025

• References

• 1 Wolberg AS. Fibrinogen and fibrin: synthesis, structure, and function in health and disease. J Thromb Haemost 2023; 21 (11) 3005-3015
• 2 May JE, Wolberg AS, Lim MY. Disorders of fibrinogen and fibrinolysis. Hematol Oncol Clin North Am 2021; 35 (06) 1197-1217
• 3 Simurda T, Asselta R, Zolkova J. et al. Congenital afibrinogenemia and hypofibrinogenemia: laboratory and genetic testing in rare bleeding disorders with life-threatening clinical manifestations and challenging management. Diagnostics (Basel) 2021; 11 (11) 2140
• 4 Casini A, Moerloose P, Neerman-Arbez M. One hundred years of congenital fibrinogen disorders. Semin Thromb Hemost 2022; 48 (08) 880-888
• 5 Casini A. From routine to research laboratory: strategies for the diagnosis of congenital fibrinogen disorders. Hamostaseologie 2020; 40 (04) 460-466
• 6 Casini A. Diagnosis and classification of hereditary fibrinogen disorders. Acta Med Martiniana 2022; 22 (03) 115-121
• 7 Bor MV, Feddersen S, Pedersen IS, Sidelmann JJ, Kristensen SR. Dysfibrinogenemia—potential impact of genotype on thrombosis or bleeding. Semin Thromb Hemost 2022; 48 (02) 161-173
• 8 Sjøland JA, Sidelmann JJ, Brabrand M. et al. Fibrin clot structure in patients with end-stage renal disease. Thromb Haemost 2007; 98 (02) 339-345
• 9 Morris TA, Marsh JJ, Chiles PG. et al. High prevalence of dysfibrinogenemia among patients with chronic thromboembolic pulmonary hypertension. Blood 2009; 114 (09) 1929-1936
• 10 Brennan SO, Fellowes AP, Faed JM, George PM. Hypofibrinogenemia in an individual with 2 coding (gamma82 A-->G and Bbeta235 P-->L) and 2 noncoding mutations. Blood 2000; 95 (05) 1709-1713
• 11 Wassel CL, Lange LA, Keating BJ. et al. Association of genomic loci from a cardiovascular gene SNP array with fibrinogen levels in European Americans and African-Americans from six cohort studies: the Candidate Gene Association Resource (CARe). Blood 2011; 117 (01) 268-275
• 12 Huffman JE, de Vries PS, Morrison AC. et al. Rare and low-frequency variants and their association with plasma levels of fibrinogen, FVII, FVIII, and vWF. Blood 2015; 126 (11) e19-e29
• 13 Fabretto A, Santa Rocca M, Perrone MD, Skabar A, Pecile V, Gasparini P. De novo 6.9 Mb interstitial deletion on chromosome 4q31.1-q32.1 in a girl with severe speech delay and dysmorphic features. Am J Med Genet A 2012; 158A [phone]
• 14 Couzens A, Lebreton A, Masclaux F. et al. Hemizygous FGG p.Ala108Gly in a hypofibrinogenemic patient with a heterozygous 14.8 Mb deletion encompassing the entire fibrinogen gene cluster. Haemophilia 2022; 28 (05) e132-e135
• 15 Choi H, Kang M, Lee KH, Kim YS. Elevated level of PLRG1 is critical for the proliferation and maintenance of genome stability of tumor cells. BMB Rep 2023; 56 (11) 612-617
• 16 Kleinridders A, Pogoda HM, Irlenbusch S. et al. PLRG1 is an essential regulator of cell proliferation and apoptosis during vertebrate development and tissue homeostasis. Mol Cell Biol 2009; 29 (11) 3173-3185
• 17 Casini A, de Moerloose P. Can the phenotype of inherited fibrinogen disorders be predicted?. Haemophilia 2016; 22 (05) 667-675
• 18 Brunclikova M, Simurda T, Zolkova J. et al. Heterogeneity of genotype-phenotype in congenital hypofibrinogenemia—a review of case reports associated with bleeding and thrombosis. J Clin Med 2022; 11 (04) 1083
• 19 Miljić P, Nedeljkov-Jančić R, Zuvela M, Subota V, Dorđević V. Coexistence of hypofibrinogenemia and factor V Leiden mutation: is the balance shifted to thrombosis?. Blood Coagul Fibrinolysis 2014; 25 (06) 628-630
• 20 Bor MV. Variants leading to dysfibrinogenaemia in the fibrinogen α-chain at residue Arg19 are not solely associated with bleeding, but also with thrombotic events. Br J Haematol 2024; 204 (06) 2501-2503
• 21 Nanthan KR, Pedersen IS, Andersen DT, Bor MV. Congenital hypodysfibrinogenemia due to γ326Cys→Tyr mutation: third ever-described case associated with recurrent venous thrombosis and COVID vaccine. Acta Haematol 2024; 147 (05) 564-570
• 22 Marchi R, Walton BL, McGary CS. et al. Dysregulated coagulation associated with hypofibrinogenaemia and plasma hypercoagulability: implications for identifying coagulopathic mechanisms in humans. Thromb Haemost 2012; 108 (03) 516-526
• 23 Wolberg AS. Thrombin generation and fibrin clot structure. Blood Rev 2007; 21 (03) 131-142
• 24 Casini A, Duval C, Pan X, Tintillier V, Biron-Andreani C, Ariëns RAS. Fibrin clot structure in patients with congenital dysfibrinogenaemia. Thromb Res 2016; 137: 189-195
• 25 de Moerloose P, Casini A, Neerman-Arbez M. Congenital fibrinogen disorders: an update. Semin Thromb Hemost 2013; 39 (06) 585-595
• 26 Simurda T, Casini A, Stasko J. et al. Perioperative management of a severe congenital hypofibrinogenemia with thrombotic phenotype. Thromb Res 2020; 188: 1-4