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.

 

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Keywords

fibrinogen - hypofibrinogenemia - variant - deletion - thrombosis

Introduction

Fibrinogen is a large (340 kDa) hexameric glycoprotein synthesized in the liver. The molecule comprises pairs of polypeptide chains (Aα, Bβ, and γ). Each chain is encoded by three separate genes clustered on chromosome 4q: fibrinogen Aα (FGA), fibrinogen Bβ (FGB), and fibrinogen γ (FGG).[1] [2] [3] Fibrinogen is a multifunctional protein involved in key physiological processes, including platelet aggregation at injury sites and maintaining the structural integrity of fibrin clots.[2]

Congenital fibrinogen disorders (CFDs) are rare coagulation deficiencies, accounting for 8% of bleeding disorders.[2] [4] [5] [6] They arise from mutations in fibrinogen genes, causing either type 1 (quantitative) or type 2 (qualitative) deficiencies. Type 1 includes afibrinogenemia (absence of fibrinogen) and hypofibrinogenemia (proportionally reduced antigenic and functional fibrinogen). Type 2 includes dysfibrinogenemia (normal levels of antigenic fibrinogen with reduced functional fibrinogen) and hypodysfibrinogenemia (disproportionately reduced antigenic and functional fibrinogen).[3] [4] [6]

The clinical presentation of CFDs is highly variable, ranging from asymptomatic cases to severe bleeding. Paradoxically, thrombotic events, both venous and arterial, can also occur. Typically, suspicion of fibrinogen deficiency arises from bleeding symptoms and low fibrinogen levels.[2] [6] Due to their complexity, the International Society on Thrombosis and Haemostasis (ISTH) and the Scientific and Standardization Committee (SSC) on Factor XIII and Fibrinogen have reclassified CFDs into subgroups based on fibrinogen levels and clinical presentation.[6]

We hereby present the first symptomatic case of hypofibrinogenemia associated with recurrent thrombosis and thrombophilia, characterized by a heterozygous deletion of the fibrinogen gene cluster and a hemizygous fibrinogen variant, both associated with low fibrinogen levels. We aim to highlight the complex genotype–phenotype relationship in hypofibrinogenemia while emphasizing the rarity of this case and its management.

 

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Materials and Methods

Routine Coagulation Tests

Thrombin time (TT) and fibrinogen clotting activity (Clauss method) were measured using a CS-5100 coagulation analyzer (Sysmex Corporation, distributed by Siemens Healthcare, Diagnostics, Marburg, Germany). The fibrinogen concentration was quantified using a nephelometric method with antibodies against human fibrinogen on a BN-II nephelometer (Siemens Healthcare Diagnostics, Marburg, Germany).

 

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Whole Exome Sequencing (WES)

WES for the patient and his son was performed in different laboratories. The patient's WES was conducted as previously described,[7] using the SureSelect XT HS and Clinical Research Exome v2 capture kit (Agilent, Technologies, Palo Alto, CA, USA) according to the manufacturer's protocol. Libraries were sequenced on a NovaSeq 6000 (Illumina, San Diego, CA, USA) with 2 × 150 bp reads. Mapping and variant calling were performed using an in-house pipeline with BWA and GATK4.0. The analysis focused on the fibrinogen genes, achieving a mean coverage of approximately 150X, with 100% coding regions covered >20x. Copy number variation (CNV) analysis was performed using Golden Helix, based on sequencing depth, with hg19 as the reference genome.

For the son, DNA was extracted from EDTA and WES was conducted using Human Comprehensive Exome (Twist Bioscience, San Francisco, CA, USA) according to the manufacturer's instructions. Sequencing was conducted on a NovaSeq 6000 (Illumina, San Diego, CA, USA) with a minimum coverage >30X for all regions. Mapping and variant calling were performed using an in-house bioinformatics pipeline based on best practices from GATK v.4.1.0.0. The genome build used was GRCh37/hg19. CNV analysis was performed using the gCNV tool from GATK.

 

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Fibrin Structure Analysis

Fibrin structure analysis was performed as previously described using a turbidimetric assay adjusted for fibrinogen antigen levels.[7] [8] Polymerization and intraclot lysis were analyzed at 25°C in a buffer containing citrated plasma, calcium chloride (CaCl₂), and thrombin, with or without tissue plasminogen activator (tPA, 300 ng/mL). Turbidity at 340 nm was measured every 15 seconds over 30 minutes to assess lag time, maximal velocity (V_max), and clot lysis. The fibrin mass-to-length ratio, fiber diameter, and density were determined by optical density (OD) measurements at 340 to 690 nm after overnight incubation. External lysis was evaluated using high tPA concentrations (50,000 ng/mL), with OD recorded at 340 nm every 5 minutes over 4 hours to calculate lysability. Reference intervals were established from 30 healthy individuals of both genders.

 

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Case Presentation

A 77-year-old man with a high body mass index (BMI) of 35 kg/m² experienced his first episode of deep venous thrombosis (DVT) at the age of 65. This thrombus, localized to the right crus, developed following a complicated shoulder reconstruction surgery, further exacerbated by a gastrointestinal infection and acute nephritis. At the age of 71, he had a second DVT, with thrombus extension from the right crus to the groin, involving the vena saphena, vena femoralis profunda, and vena iliaca communis externa. This episode followed knee replacement surgery complicated by poor wound healing, infection, and wound rupture. Notably, both DVTs occurred approximately 1 month after surgery and subsequent wound revisions.

Postoperative complications following both surgical interventions included hematoma formation at the surgical sites, though no hemostatic treatment was administered in either case. Fibrinogen levels were not assessed during the first DVT. However, during the second event, the patient exhibited significantly reduced fibrinogen levels, measuring 0.7 g/L. Prior to these incidents, there was no history of bleeding.

Thrombophilia testing, which was unwarranted by national guidelines due to the patient's age and provoking factors for DVT, revealed heterozygosity for the factor V Leiden (FVL) mutation following the first thrombotic event. Additional analyses, including protein S, protein C, antithrombin, prothrombin levels, and antiphospholipid antibodies, were within normal limits. The international normalized ratio (INR) and activated partial thromboplastin time (aPTT) were also normal. Further diagnostic evaluation revealed proportionally decreased functional fibrinogen (0.85 g/L) and antigenic fibrinogen levels (0.92 g/L), alongside a prolonged TT of 25 seconds ([Table 1]). These findings were consistent with a diagnosis of moderate hypofibrinogenemia (subtype 2B), defined by functional fibrinogen levels ranging from 0.5 to 0.9 g/L.

Table 1 Fibrinogen, thrombin time, fibrin structure characteristics, and genotyping of the patient and his son

Fibrinogen analysis and thrombin time	Patient	Youngest son	Reference interval
Fibrinogen (immunological) (g/L)	0.92	1.4	1.70–4.28
Fibrinogen (clot based) (g/L)	0.85	1.5	1.77–4.28
Fibrinogen ratio	0.92	0.98	0.92–1.19
Thrombin time (seconds)	25	22	<20
Fibrin structure assay
Lag time (seconds)	25	17	10–19
Vmax (OD/min)	0.14	0.32	0.62–1.34
Mass–length ratio (x1012 Da/cm)	11	20	3.9–7.1
Fibrin fiber diameter (µm)	0.19	0.25	0.12–0.16
Fibrin fiber density (x1022 Da/cm3)	4.0	4.3	3.0–4.6
Fibrin clot lysability (%)	76	67	17–97
Genotyping, fibrinogen gene
Fibrinogen alpha gene	Heterozygous deletion	Heterozygous deletion
Fibrinogen beta gene	Heterozygous deletion	Heterozygous deletion
Fibrinogen beta gene - alternative allele NM_005141.5:c.794C>T NP_005132.2:p.Pro265Leu, rs6054	Hemizygous variant	–
Fibrinogen gamma gene	Heterozygous deletion	Heterozygous deletion
Genotyping, other variants
Pleiotropic regulator 1	Heterozygous deletion	Heterozygous deletion
Factor V Leiden variant	Heterozygous variant	Heterozygous variant

To investigate genotype–phenotype associations, fibrin structure analysis and WES were performed. WES identified a heterozygous deletion affecting FGA, FGB, FGG, and pleiotropic regulator 1 gene (PLRG1), spanning 78 to 253 kb within 4q31.3 region (chr4:155.456.014–155.533805 and chr.4:155.412.458–155.665.365). The exact size is uncertain due to intronic breakpoints. Additionally, a hemizygous FGB missense variant c.794C > T (p.Pro265Leu, rs6054; MAF 0.004) was detected ([Table 1], [Fig. 1]). These findings confirmed the diagnosis of congenital hypofibrinogenemia.

Fig. 1 Results of whole exome sequencing (WES). (A) Deletion of PLRG1, FGA, FGB, and FGG is depicted, with the blue spots located on the lower yellow line. The blue squares at the bottom represent the sequential order of genes on the chromosome. (B) The position of NM_005141.5:c.794C > T (rs6054) is shown in the read depth and pile-up plots of sequencing reads (indicated by blue bar). Its location in exon 5 of different FGB transcripts is displayed in the lower panel.

Fibrin structure analysis in our patient revealed an abnormal polymerization profile, with a prolonged lag time and decreased V_max, along with increased fibrin fiber thickness and fiber mass–length ratio. The clot lysis time and fibrin density were normal ([Table 1]).

Following the second DVT and hypofibrinogenemia diagnosis, the patient sustained trauma 2 months after revision of the operated knee. This incident required the removal of a nonspontaneous hematoma. Treatment included 2 g of intravenous Riastap (human fibrinogen) and 1 g of tranexamic acid, followed by a regimen of oral tranexamic acid (1.5 g, three times daily) for 3 days. Based on the patient's history of surgery-related bleeding and subsequent replacement therapy, an ISTH bleeding assessment tool (BAT) score of 4 was assigned while the patient was on rivaroxaban. A BAT score of 4 is phenotypically consistent with a mild bleeding tendency in males.

Following the first DVT, the patient was treated with warfarin. Due to recurrent thrombosis and thrombotic risk factors, including the FVL mutation, high BMI, and advanced age, long-term anticoagulant therapy with rivaroxaban (20 mg daily) was prescribed after the second DVT. No further episodes of thrombosis or bleeding have occurred in the past 6 years.

Family History

Family history ([Fig. 2]) revealed that the patient's father had one arterial thrombosis, while his 52-year-old son suffered three venous thrombotic events. Neither were investigated for thrombophilia or CFDs. One brother died from gangrene complications, with a post-mortem autopsy revealing multiple thromboses. In contrast, his mother, two sisters, and youngest 50-year-old son have had no history of thrombosis or bleeding. The youngest son has experienced difficulties with wound healing, with fibrinogen levels showing proportionally decreased functional (1.5 g/L) and antigenic (1.4 g/L) levels, and prolonged TT of 22 seconds. WES identified a heterozygous large deletion of FGA, FGB, FGG, and PLGR1, similar to the father. He was heterozygous for the FVL mutation, like his father. In contrast to our patient, no variants were detected in the alternate allele ([Table 1]). Apart from a normal lag time, the fibrin structure profile of the son resembles that of our patient, showing decreased V_max, increased fibrin fiber thickness, and elevated fiber mass–length ratio. In conclusion, the son has mild hypofibrinogenemia, defined by functional fibrinogen levels ranging from 1 g/L to lower limit of normal.

Fig. 2 Family pedigree. Black shading indicates family members with a heterozygous fibrinogen gene cluster deletion and a heterozygous FVL mutation. A gray left segment denotes individuals carrying the hemizygous FGB variant (p.Pro265Leu, rs6054). Asterisks (*) indicate family members who have been genetically investigated. In this family, the patient and the youngest son have undergone investigation for congenital fibrinogen disorders (CFDs). Hashtag (#) indicates family members whose medical history is unknown. Lines on the figure indicate that the patient is deceased.

 

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Discussion

A 77-year-old male with recurrent provoked DVT and a heterozygous FVL mutation was diagnosed with moderate congenital hypofibrinogenemia. This diagnosis was based on decreased functional and antigenic fibrinogen levels, consistent with SSC, ISTH guideline.[6]

WES identified a large heterozygous deletion on chromosome 4 affecting the FGA, FGB, FGG, and PLRG1 genes, along with a rare hemizygous FGB variant (p.Pro265Leu, rs6054). This variant is primarily associated with uncertain or benign significance, with conflicting data regarding its effect on fibrinogen levels.[9] [10] [11] [12] Notably, some studies associated this variant with lower fibrinogen levels, as it is located within a disulfide loop, potentially affecting fibrinogen secretion and assembly.[11] [12] However, one study suggested that this variant is unlikely to cause hypofibrinogenemia and should instead be considered a naturally occurring genetic polymorphism in healthy individuals.[10] The hemizygous presence of this variant, due to large deletion of the fibrinogen gene cluster on the alternate allele, likely mimics a homozygous genotype, leading to hypofibrinogenemia. The combined effect of the fibrinogen gene deletion and the FGB variant is likely responsible for the hypofibrinogenemia observed in the patient. This statement is further supported by data from the patient's youngest son, who has mild hypofibrinogenemia with noticeably higher fibrinogen levels. He shares a similar genetic profile with his father, excluding the hemizygous FGB variant (p.Pro265Leu, rs6054). These findings indicate that the hemizygosity for FGB variant likely contributes to a significant additional reduction in fibrinogen levels.

Large deletions encompassing the entire fibrinogen gene cluster are rare in CFDs. Beyond this novel case, only two other cases of hypofibrinogenemia have been reported, involving a 14.8 and 6.9 Mb deletion of the entire fibrinogen gene cluster.[13] [14] These cases involve children with developmental delays and dysmorphic features, but no bleeding or thrombosis history. An interesting observation in one case[14] is the suspicion of a second fibrinogen gene variant, as the heterozygous deletion alone cannot explain the low plasma fibrinogen levels. This study revealed a hemizygous missense variant in the alternate allele, similar to our patient's case. The second case[13] lacks detailed information on fibrinogen levels, variants, and family history.

PLRG1 gene plays a crucial role in pre-mRNA splicing and DNA repair processes, contributing to cell cycle arrest when its expression is decreased.[15] [16] However, its clinical significance in our patient and in CFDs remains unexplored in the existing literature. Notably, two previously published cases of hypofibrinogenemia with large deletions encompassing the entire fibrinogen gene cluster also involved deletion of PLRG1,[13] [14] suggesting the close proximity of the PLRG1 gene to the fibrinogen genes.

Patients with hypofibrinogenemia are mostly asymptomatic and typically diagnosed incidentally during laboratory testing or through family history.[3] [17] [18] Mild bleeding is more commonly associated with surgery and trauma than spontaneous bleeding, as observed in our case. A fibrinogen concentration of 1.0 g/L is suggested to be sufficient to protect against spontaneous bleeding.[18] [19] Furthermore, thrombotic events can occur when exposed to thrombotic risk factors.[3] [18] In fact, more than one-third of patients with hypofibrinogenemia experience thrombosis following surgery, trauma, delivery, or after childbirth.[18]

This case highlights the complexity of the genotype–phenotype relationship in CFDs, as previously described.[7] [20] [21] First, the patient remained asymptomatic until the age of 65. Second, three clinical risk factors—surgery, infection, and high BMI—were present during both DVT events, in addition to his age. Third, the patient is heterozygous for the FVL mutation. Given these multiple coexisting risk factors, it is difficult to attribute his clinical phenotype solely to his hypofibrinogenemia genotype, as the interactions among these factors complicate the overall assessment.

The thrombotic risk in quantitative CFDs remains unclear. Thrombosis is less frequent in hypofibrinogenemia than in afibrinogenemia, as low fibrinogen typically reduces thrombotic risk.[18] However, low fibrinogen does not fully counteract hypercoagulability, and thrombosis can occur if other prothrombotic factors are present, as observed in our case.[18] One theory suggests that elevated thrombin can activate platelets, leading to unstable thrombi.[5] [18] [22] In afibrinogenemia, impaired thrombin clearance due to the absence of fibrin, which normally binds and regulates thrombin (antithrombin I), may contribute to thrombosis.[17] [22] This mechanism does not fully explain the thrombotic risk in our patient, who has 50% fibrinogen levels. It is proposed that the coexisting FVL mutation, which is associated with increased thrombin generation, may act synergistically with reduced thrombin clearance in hypofibrinogenemia, promoting a prothrombotic state.[19]

The mechanism behind paradoxical thrombosis in hypofibrinogenemia may be related to fibrin clot properties, although fibrin clot analyses are especially relevant in cases of qualitative fibrinogen disorders.[5] Thrombin levels significantly influence fibrin clot structure.[23] High concentrations can lead to dense clots that resist fibrinolysis, potentially contributing to thrombosis.[23] In our case, defective fibrin polymerization, an increased fibrin mass–length ratio, and thicker fibers were observed, contrasting with the typical thrombotic profile. Except for a normal lag time, the son's fibrin structure profile closely resembles that of the patient. These findings challenge the established link between fibrin structure and thrombosis, suggesting that thrombotic risk may not always correlate with fibrin structure measures, except in cases of dysfibrinogenemia associated with specific fibrinogen variants, such as fibrinogen Dusart.[24]

Phenotypical variability in CFDs complicates clinical management.[25] [26] In this case, as well as in data from the literature, it appears that in patients with hypofibrinogenemia, the prothrombotic effect of FVL mutation is not compensated by low fibrinogen and may even be amplified by other thrombotic risk factors.[19] Therefore, long-term antithrombotic treatment may be crucial. However, managing thrombosis in CFD patients is challenging due to the bleeding risks associated with anticoagulants. Although low-molecular-weight heparin is often recommended,[2] we chose long-term rivaroxaban for our patient due to its lower bleeding risk and greater ease of use, making it more patient-friendly.

This case illustrates the complexity of genetic interactions in hypofibrinogenemia, particularly the combined effects of a heterozygous fibrinogen gene cluster deletion and a hemizygous missense variant in FGB. The recurrence of DVT alongside an FVL mutation highlights the insufficiency of low fibrinogen levels to fully counteract hypercoagulability. Additionally, comorbidities, advanced age, and family history—encompassing both genetic and environmental factors—further shape the thrombotic phenotype.[17] [24] [25] These findings highlight the importance of personalized treatment strategies and further research on genotype–phenotype correlations in CFDs, while also emphasizing the need for regular follow-up due to the dynamic nature of hemostasis, which changes with age and comorbidities.[17]

 

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Conflicts of Interest

The authors declare that they have no conflict of interest.

Acknowledgments

We would like to thank research laboratory technicians Anette Larsen and Kathrine Overgaard at the Department of Clinical Biochemistry, University Hospital of Southern Denmark, for their excellent technical assistance in the analyses of blood samples.

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.

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Publication History

Received: 22 October 2024

Accepted: 03 June 2025

Article published online:
07 August 2025