Congenital hypofibrinogenemia is a quantitative (Type I) congenital fibrinogen disorder caused by mutations in the fibrinogen genes FGA, FGB, or FGG, leading to proportionally reduced functional and antigenic plasma fibrinogen (typically <1.5 g/L). In the simple form, the defect is a loss-of-function: heterozygosity for null or hypomorphic alleles roughly halves fibrinogen output, the liver is structurally normal, and the bleeding tendency is mild and strongly dependent on the residual fibrinogen level (patients are frequently asymptomatic). This entry covers the simple quantitative form; the mechanistically distinct hepatic fibrinogen storage disease (toxic gain-of-function FGG variants causing hepatocyte ER aggregation) is treated as a separate entity.
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name: Congenital Hypofibrinogenemia
creation_date: '2026-05-16T00:00:00Z'
updated_date: '2026-05-18T19:00:00Z'
category: Genetic
parents:
- Bleeding Disorder
- Coagulation Disorder
disease_term:
preferred_term: congenital hypofibrinogenemia
term:
id: MONDO:0015096
label: familial hypofibrinogenemia
description: >-
Congenital hypofibrinogenemia is a quantitative (Type I) congenital fibrinogen
disorder caused by mutations in the fibrinogen genes FGA, FGB, or FGG, leading
to proportionally reduced functional and antigenic plasma fibrinogen
(typically <1.5 g/L). In the simple form, the defect is a loss-of-function:
heterozygosity for null or hypomorphic alleles roughly halves fibrinogen
output, the liver is structurally normal, and the bleeding tendency is mild
and strongly dependent on the residual fibrinogen level (patients are
frequently asymptomatic). This entry covers the simple quantitative form; the
mechanistically distinct hepatic fibrinogen storage disease (toxic
gain-of-function FGG variants causing hepatocyte ER aggregation) is treated as
a separate entity.
prevalence:
- population: General population
notes: >-
Inherited fibrinogen disorders are rare; a precise population prevalence for
congenital hypofibrinogenemia is not well established, and many heterozygous
carriers are detected incidentally.
evidence:
- reference: PMID:29316703
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Inherited disorders of fibrinogen are rare."
explanation: >-
The review states that inherited fibrinogen disorders, including
quantitative defects such as hypofibrinogenemia, are rare.
pathophysiology:
- name: Reduced Fibrinogen Synthesis
description: >-
Heterozygosity for fibrinogen null or hypomorphic alleles (large deletions,
frameshift, nonsense, splice-site, or secretion-impairing missense
mutations) reduces the amount of normal fibrinogen produced and secreted by
hepatocytes, producing proportionally low circulating fibrinogen.
cell_types:
- preferred_term: hepatocyte
term:
id: CL:0000182
label: hepatocyte
downstream:
- target: Impaired Fibrin Clot Formation
description: >-
Reduced circulating fibrinogen limits the substrate available for
thrombin-mediated conversion to fibrin.
evidence:
- reference: PMID:29316703
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Hypofibrinogenemia is generally caused by heterozygosity for these mutations."
explanation: >-
The review attributes hypofibrinogenemia to heterozygosity for the
fibrinogen-deficiency mutation classes, i.e. a loss-of-function mechanism.
- reference: PMID:29316703
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "causative mutations can be divided into two main classes: null mutations with no protein production at all and mutations producing abnormal protein chains which are retained inside the cell"
explanation: >-
The review describes the two causative-mutation classes underlying
quantitative fibrinogen deficiency.
- name: Impaired Fibrin Clot Formation
description: >-
Low plasma fibrinogen limits fibrin polymerization, so clot-based
coagulation assays are prolonged in proportion to the residual fibrinogen
level.
biological_processes:
- preferred_term: blood coagulation, fibrin clot formation
modifier: DECREASED
term:
id: GO:0072378
label: blood coagulation, fibrin clot formation
downstream:
- target: Bleeding Diathesis
description: >-
Impaired fibrin clot formation predisposes to a level-dependent bleeding
tendency.
evidence:
- reference: PMID:29316703
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In hypofibrinogenemia, standard clotting assays are variably prolonged according to the circulating fibrinogen level."
explanation: >-
The review notes that clotting assays are prolonged in proportion to the
circulating fibrinogen level in hypofibrinogenemia.
- name: Bleeding Diathesis
description: >-
The bleeding tendency is mild and strongly correlated with the residual
coagulant fibrinogen level; many patients are asymptomatic, and bleeding is
typically provoked by trauma or surgery rather than spontaneous.
evidence:
- reference: PMID:29316703
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "a mean fibrinogen activity level of at least 0.7 g/L protected from spontaneous bleeding, while patients with a level above 1.0 g/L did not experience bleeds"
explanation: >-
The retrospective cohort data quantify the level-dependence of the
bleeding phenotype in fibrinogen deficiency.
phenotypes:
- name: Hypofibrinogenemia
category: Hematologic
frequency: VERY_FREQUENT
description: >-
Defining laboratory feature: proportionally reduced functional and
antigenic plasma fibrinogen, conventionally below 1.5 g/L.
phenotype_term:
preferred_term: Hypofibrinogenemia
term:
id: HP:0011900
label: Hypofibrinogenemia
evidence:
- reference: PMID:29316703
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypofibrinogenemia is characterized by fibrinogen levels lower than 1.5 g/L"
explanation: >-
The review defines hypofibrinogenemia by reduced circulating fibrinogen,
making low fibrinogen an obligate feature of the disorder.
- name: Abnormal Bleeding
category: Hematologic
description: >-
Bleeding is variable and level-dependent; hypofibrinogenemic patients are
frequently asymptomatic, with symptomatic bleeding usually provoked by
trauma or surgery.
phenotype_term:
preferred_term: Abnormal bleeding
term:
id: HP:0001892
label: Abnormal bleeding
evidence:
- reference: PMID:29316703
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "In afibrinogenemia bleeding is the main symptom, whereas in hypofibrinogenemia patients are more frequently asymptomatic."
explanation: >-
The review contrasts the frequently asymptomatic course of
hypofibrinogenemia with the bleeding-dominated phenotype of afibrinogenemia.
- name: Persistent Bleeding After Trauma
category: Hematologic
description: >-
In symptomatic patients, bleeding is typically linked to trauma or surgery
rather than occurring spontaneously.
phenotype_term:
preferred_term: Persistent bleeding after trauma
term:
id: HP:0001934
label: Persistent bleeding after trauma
evidence:
- reference: PMID:29316703
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "the bleeding phenotype is usually linked to trauma, surgery"
explanation: >-
The review notes that symptomatic bleeding in hypofibrinogenemia is
usually provoked by trauma or surgery.
- name: Menorrhagia
category: Hematologic
description: >-
Depending on the fibrinogen level, affected women may experience heavy
menstrual bleeding.
phenotype_term:
preferred_term: Menorrhagia
term:
id: HP:0000132
label: Menorrhagia
evidence:
- reference: PMID:29316703
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "hypofibrinogenemic women are also affected by menorrhagia"
explanation: >-
The review reports menorrhagia among hypofibrinogenemic women, dependent
on fibrinogen level.
- name: Obstetrical complications
category: Reproductive
description: >-
Hypofibrinogenemic women are at risk of obstetrical complications
including recurrent placental abruption and pregnancy loss, reflecting
the requirement of fibrinogen for placental integrity and fetal-maternal
vascular development throughout pregnancy.
phenotype_term:
preferred_term: Obstetrical complications including recurrent placental abruption
term:
id: HP:0001197
label: Abnormality of prenatal development or birth
evidence:
- reference: PMID:29316703
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "such as recurrent placenta abruption, suggesting insufficient fibrinogen to sustain placenta development"
explanation: >-
The review directly reports obstetrical complications including recurrent
placental abruption in hypofibrinogenemic women, attributing these to
insufficient fibrinogen for placental integrity.
inheritance:
- name: Autosomal dominant inheritance
inheritance_term:
preferred_term: Autosomal dominant inheritance
term:
id: HP:0000006
label: Autosomal dominant inheritance
description: >-
Congenital hypofibrinogenemia is caused by heterozygous loss-of-function
mutations in FGA, FGB, or FGG; a single pathogenic allele roughly halves
fibrinogen output, producing the quantitative deficiency characteristic
of this disorder.
evidence:
- reference: PMID:29316703
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Hypofibrinogenemia is generally caused by heterozygosity for these mutations."
explanation: >-
The review states that hypofibrinogenemia is caused by heterozygosity
for null or hypomorphic fibrinogen gene mutations, confirming
autosomal dominant (heterozygous) inheritance.
genetic:
- name: FGA
gene_term:
preferred_term: FGA
term:
id: hgnc:3661
label: FGA
association: Causative
evidence:
- reference: PMID:29316703
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "encoded by the fibrinogen gene cluster FGB, FGA, and FGG on human chromosome 4"
explanation: >-
The review identifies FGA as one of the three fibrinogen
chain-encoding genes whose mutations cause quantitative fibrinogen deficiency.
- name: FGB
gene_term:
preferred_term: FGB
term:
id: hgnc:3662
label: FGB
association: Causative
evidence:
- reference: PMID:29316703
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "encoded by the fibrinogen gene cluster FGB, FGA, and FGG on human chromosome 4"
explanation: >-
The review identifies FGB as one of the three fibrinogen
chain-encoding genes whose mutations cause quantitative fibrinogen deficiency.
- name: FGG
gene_term:
preferred_term: FGG
term:
id: hgnc:3694
label: FGG
association: Causative
evidence:
- reference: PMID:29316703
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "more than 200 different mutations have been identified as accounting for afibrinogenemia or hypofibrinogenemia"
explanation: >-
The review documents that mutations across the three fibrinogen genes,
including FGG, account for afibrinogenemia and hypofibrinogenemia.
treatments:
- name: Fibrinogen Replacement Therapy
description: >-
Fibrinogen supplementation (fibrinogen concentrate) for on-demand
management of bleeding episodes or perioperative/peripartum prophylaxis;
asymptomatic patients with adequate residual levels generally require no
treatment.
treatment_term:
preferred_term: Pharmacotherapy
term:
id: NCIT:C15986
label: Pharmacotherapy
therapeutic_agent:
- preferred_term: fibrinogen concentrate
term:
id: NCIT:C81126
label: Fibrinogen Human
evidence:
- reference: PMID:36055263
supports: SUPPORT
evidence_source: HUMAN_CLINICAL
snippet: "Fibrinogen supplementation is the cornerstone of bleeding management in fibrinogen disorders."
explanation: >-
The review identifies fibrinogen supplementation as the mainstay of
bleeding management in congenital fibrinogen disorders.
references:
- reference: PMID:30076675
title: 'Diagnosis and classification of congenital fibrinogen disorders: communication from the SSC of the ISTH.'
findings: []
- reference: PMID:36055263
title: One Hundred Years of Congenital Fibrinogen Disorders.
findings: []
- reference: PMID:29316703
title: Clinical Consequences and Molecular Bases of Low Fibrinogen Levels.
findings: []
notes: >-
Scope note: this entry models the simple quantitative (Type I) form
(loss-of-function, liver structurally normal). Hepatic fibrinogen storage
disease (HFSD) — toxic gain-of-function FGG missense variants near
polymerization pocket "hole a" causing hepatocyte endoplasmic-reticulum
fibrinogen aggregation and a distinct hepatopathy — is mechanistically
distinct and is curated as a separate entity (see issue #2727). Tracker: #2727.
This report is based on cached reference abstracts available in references_cache/.
Congenital hypofibrinogenemia is caused by heterozygous loss-of-function mutations in one of three fibrinogen chain genes: FGA (Aα chain), FGB (Bβ chain), or FGG (γ chain), clustered at chromosome 4q28.
Causative mutation classes (PMID:29316703): 1. Null mutations — complete loss of expression from one allele (large deletions, frameshift, nonsense, splice-site variants) 2. Hypomorphic/secretion-impairing missense mutations — protein produced but mis-folded or retained intracellularly, reducing secretion
Because fibrinogen is a heterohexamer (2×Aα + 2×Bβ + 2×γ), loss of one chain prevents normal hexamer assembly from that allele. Heterozygosity reduces hepatic output by approximately 50%, resulting in circulating fibrinogen levels between 0.5–1.5 g/L (normal range: 2–4 g/L).
Fibrinogen is an acute-phase protein synthesized exclusively by hepatocytes (CL:0000182). All three chains are co-expressed, assembled in the ER, and secreted as intact hexamers. In the simple quantitative form, liver morphology is normal (no intracellular aggregation), distinguishing this from HFSD.
Severity correlates directly with residual fibrinogen level (PMID:29316703): - Fg:C ≥1.0 g/L: Generally asymptomatic; most heterozygous carriers fall here - Fg:C 0.7–1.0 g/L: Mild-to-moderate bleeding risk, typically provoked - Fg:C <0.7 g/L: Increased spontaneous bleeding risk; approaches afibrinogenemia spectrum
Hematologic: - Hypofibrinogenemia (obligate, defining) — HP:0011900 - Abnormal bleeding (variable severity) — HP:0001892 - Persistent bleeding after trauma/surgery — HP:0001934
Reproductive (females): - Menorrhagia — HP:0000132 (level-dependent) - Obstetrical complications including recurrent placental abruption — reflects fibrinogen requirement for placental integrity. Fibrinogen is necessary for cytotrophoblast spreading at 4–6 weeks gestation and fetal-maternal vascular development (PMID:29316703).
| Gene | HGNC | Chain | Mutation classes |
|---|---|---|---|
| FGA | hgnc:3661 | Aα | Null and missense; >200 variants described |
| FGB | hgnc:3662 | Bβ | Null and missense |
| FGG | hgnc:3694 | γ | Null and missense (non-polymerization-pocket missense; HFSD-causing γ variants are excluded from this entry) |
Inheritance: Autosomal dominant (heterozygous LOF). Afibrinogenemia (biallelic null) is autosomal recessive. Hypofibrinogenemia is the heterozygous carrier state of autosomal recessive afibrinogenemia alleles, and also arises de novo.
Fibrinogen replacement (on-demand and prophylactic): - Fibrinogen concentrate (e.g., Haemocomplettan/RiaSTAP; NCIT:C81126 Fibrinogen Human) is the therapeutic cornerstone (PMID:36055263) - Targets: Fg:C ≥1.0 g/L (general hemostasis), ≥1.5–2.0 g/L perioperatively, ≥2.0 g/L peripartum - Cryoprecipitate (contains fibrinogen, FVIII, vWF, FXIII) is an alternative where concentrate is unavailable - Antifibrinolytics (tranexamic acid) are useful adjuncts for minor bleeds and dental procedures
Asymptomatic management: - Many patients with Fg:C >1.0 g/L require no prophylactic treatment - Awareness of obstetric risks and perioperative prophylaxis planning are important for female patients
| PMID | Authors | Title | Key content |
|---|---|---|---|
| 29316703 | de Moerloose et al. (2018) | Clinical Consequences and Molecular Bases of Low Fibrinogen Levels | Main review covering pathophysiology, phenotype, obstetric complications |
| 36055263 | Casini et al. (2022) | One Hundred Years of Congenital Fibrinogen Disorders | Classification evolution, fibrinogen concentrate, 100-year review |
| 30076675 | Casini et al. (2018) | Diagnosis and classification of congenital fibrinogen disorders | ISTH SSC classification framework |
This entry models the simple quantitative (Type I, LOF, liver-normal) form of hypofibrinogenemia. Two mechanistically distinct entities in the congenital fibrinogen disorder family are treated separately: - Afibrinogenemia: biallelic null (AR); more severe - Hepatic Fibrinogen Storage Disease (HFSD): gain-of-toxic-function FGG missense → hepatocyte ER aggregation → hepatopathy (see sibling entry)
Tracker issue: #2727.