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| {{Infobox medical condition (new) | | {{Short description|A rare blood disorder affecting fibrinogen function}} |
| | name = Hypodysfibrinogenemia | |
| | synonyms = Congenital hypodysfibrinogenemia
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| '''Hypodysfibrinogenemia''', also termed '''congenital hypodysfibrinogenemia''', is a rare hereditary [[List of fibrinogen disorders|fibrinogen disorder]] cause by mutations in one or more of the genes that encode a factor critical for [[blood clotting]], [[fibrinogen]]. These mutations result in the production and circulation at reduced levels of fibrinogen at least some of which is dysfunctional.<ref name="pmid28211264">{{cite journal | vauthors = Casini A, Brungs T, Lavenu-Bombled C, Vilar R, Neerman-Arbez M, de Moerloose P | title = Genetics, diagnosis and clinical features of congenital hypodysfibrinogenemia: a systematic literature review and report of a novel mutation | journal = Journal of Thrombosis and Haemostasis | volume = 15 | issue = 5 | pages = 876–888 | year = 2017 | pmid = 28211264 | doi = 10.1111/jth.13655 | url = }}</ref> Hypodysfibrinogenemia exhibits [[Penetrance#Degrees of penetrance|reduced penetrance]], i.e. only some family members with the mutated gene develop symptoms.<ref name="pmid27019462">{{cite journal | vauthors = Casini A, de Moerloose P, Neerman-Arbez M | title = Clinical Features and Management of Congenital Fibrinogen Deficiencies | journal = Seminars in Thrombosis and Hemostasis | volume = 42 | issue = 4 | pages = 366–74 | year = 2016 | pmid = 27019462 | doi = 10.1055/s-0036-1571339 | url = }}</ref><ref name="pmid28550239">{{cite journal | vauthors = Caimi G, Canino B, Lo Presti R, Urso C, Hopps E | title = Clinical conditions responsible for hyperviscosity and skin ulcers complications | journal = Clinical Hemorheology and Microcirculation | volume = 67| issue = 1| pages = 25–34| year = 2017 | pmid = 28550239 | doi = 10.3233/CH-160218 | url =https://iris.unipa.it/bitstream/10447/238851/1/CHM%20160218.pdf }}</ref>
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| The disorder is similar to a form of [[dysfibrinogenemia]] termed congenital dysfibrinogenemia. However, congenital dysfibrinogenemia differs form hypodysfibrinogenemia in four ways. Congenital dysfibrinogenemia involves: the circulation at normal levels of fibrinogen at least some of which is dysfunctional; a different set of causative gene mutations; a somewhat different mix of clinical symptoms; and a much lower rate of penetrance.<ref name="pmid27019462"/><ref name="pmid28550239"/>
| | '''Hypodysfibrinogenemia''' is a rare [[coagulation disorder]] characterized by the presence of abnormal [[fibrinogen]] molecules in the blood. Fibrinogen is a crucial [[glycoprotein]] involved in the blood clotting process, and abnormalities in its structure or function can lead to bleeding or thrombotic complications. |
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| Hypodysfibrinogenemia causes episodes of pathological bleeding and thrombosis due not only to low levels of circulating fibrinogen but also to the dysfunction of a portion of the circulating fibrinogen. The disorder can lead to very significant bleeding during even minor surgical procedures and women afflicted with the disorderoften suffer significant bleeding during and after giving child birth, higher rates of miscarriages, and [[menorrhagia]], i.e. [[abnormal uterine bleeding|abnormally heavy bleeding]] during the [[menstruation|menstrual period]].<ref name="pmid28211264"/>
| | ==Pathophysiology== |
| | Fibrinogen is synthesized in the [[liver]] and plays a vital role in hemostasis. It is converted by [[thrombin]] into [[fibrin]], which forms a mesh that stabilizes the initial platelet plug during the clotting process. In hypodysfibrinogenemia, mutations in the [[fibrinogen gene]] lead to the production of structurally abnormal fibrinogen molecules. These abnormalities can affect the molecule's ability to be converted into fibrin or to form a stable clot, resulting in a bleeding tendency or, paradoxically, an increased risk of thrombosis. |
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| == Presentation == | | ==Clinical Presentation== |
| In a study of 32 individuals diagnosed with hypodysfibrinogenemia, 41% presented with episodic bleeding, 43% presented with episodic thrombosis, and 16% were asymptomatic, being detected by abnormal blood tests.<ref name="pmid27019462"/> Bleeding and thrombosis generally begin in adulthood with the average age at the time of presentation and diagnosis being 32 years. Bleeding is more frequent and severe in women of child-bearing age; these women may suffer miscarriages, [[menometrorrhagia]], and excessive bleeding during child birth and/or the [[postpartum]] period. Excessive bleeding following major or minor surgery, including dental extractions, occurs in both females and males with the disorder. Thrombotic complications of the disorder are often (~50%) recurrent and can involve central and peripheral arteries, deep and superficial veins. Thrombotic events may be serious and involve occlusion of a [[cerebral artery]] leading to [[stroke]], [[Hepatic portal systems|splanchnic venous thrombosis]], and [[pulmonary thrombosis]] presumptively secondary to [[deep vein thrombosis]].<ref name="pmid28211264"/>
| | Patients with hypodysfibrinogenemia may present with a variety of symptoms, ranging from mild to severe bleeding episodes. Common manifestations include: |
| | * Easy bruising |
| | * [[Epistaxis]] (nosebleeds) |
| | * [[Menorrhagia]] (heavy menstrual bleeding) |
| | * Prolonged bleeding after surgery or trauma |
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| == Fibrinogen ==
| | In some cases, patients may also experience thrombotic events, such as [[deep vein thrombosis]] or [[pulmonary embolism]], due to the abnormal fibrinogen's impact on clot stability and dissolution. |
| Circulating fibrinogen is a [[glycoprotein]] made of two [[Protein trimer|trimers]] each of which is composed of three polypeptide chains, [[Fibrinogen alpha chain|Aα]] (also termed α) encoded by the ''FGA'' gene, [[Fibrinogen beta chain|Bβ]] (also termed β) encoded by the ''FGB'' gene, and γ encoded by the ''FGG'' gene. All three genes are located on the long or "q" arm of human chromosome 4 (at [[Locus (genetics)#Nomenclature|positions]] 4q31.3, 4q31.3, and 4q32.1, respectively) and are the sites where mutations occur that code for a dysfunctional fibrinogen and/or reduced fibrinogen levels which are the cause of congenital hypodysfibrinogenemia.<ref name="pmid27019463">{{cite journal | vauthors = Neerman-Arbez M, de Moerloose P, Casini A | title = Laboratory and Genetic Investigation of Mutations Accounting for Congenital Fibrinogen Disorders | journal = Seminars in Thrombosis and Hemostasis | volume = 42 | issue = 4 | pages = 356–65 | year = 2016 | pmid = 27019463 | doi = 10.1055/s-0036-1571340 | url = }}</ref><ref name="pmid27784620">{{cite journal | vauthors = Duval C, Ariëns RA | title = Fibrinogen splice variation and cross-linking: Effects on fibrin structure/function and role of fibrinogen γ' as thrombomobulin II | journal = Matrix Biology | volume = 60-61 | issue = | pages = 8–15 | year = 2017 | pmid = 27784620 | doi = 10.1016/j.matbio.2016.09.010 | url = }}</ref>
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| == Pathophysiology == | | ==Diagnosis== |
| Congenital hypodysfibrinogenemia is inherited as an [[autosomal dominant]] disorder caused by at least 32 different types of single mutations. Ten of these mutations are in the ''FGA'' gene, 5 in the ''FGB'' gene, and 17 in the FGG gene. The mutations are mainly [[missense mutations]] with [[nonsense mutation|nonsense]] and [[Frameshift mutation]]s each occurring in 12.5% of cases.<ref name="pmid28211264"/> The causes of two fibrinogen abnormalities that characterize hypodysfibrinogenemia, i.e. circulation at reduced levels of fibrinogen at least some of which is dysfunctional, reflect different molecular mechanisms:<ref name="pmid27019463"/>
| | The diagnosis of hypodysfibrinogenemia involves a combination of clinical evaluation and laboratory testing. Key diagnostic tests include: |
| # A [[heterozygous]] mutation in one of the two copies of either the ''FGA, FGB,'' or ''FGG'' gene leads to production of a fibrinogen that is both dysfunctional and poorly secreted into the blood stream, e.g. fibrinogen Vlissingen, fibrinogen Philadelphia, and fibrinogen Freiburg.
| | * [[Coagulation profile]]: Prolonged [[prothrombin time]] (PT) and [[activated partial thromboplastin time]] (aPTT) may be observed. |
| # A [[homozygous]] mutation in both copies of one of the cited genes leads to production of a fibrinogen that is both dysfunctional and poorly secreted into the blood stream, e.g. fibrinogen Otago, fibrinogen Marburg, and fibrinogen Sfax.
| | * Fibrinogen activity assay: Measures the functional activity of fibrinogen in the blood. |
| # Two different mutations (see [[Compound heterozygosity]]) occur in each of the two copies of one of the cited genes, with one mutation coding for reduced formation of a functionally normal circulating fibrinogen and the second mutation coding for the circulation of a dysfunctional fibrinogen, e.g. fibrinogen Leipzig.
| | * Fibrinogen antigen assay: Quantifies the amount of fibrinogen present. |
| # Two different mutations occur in one copy of the cited genes, with one mutation causing hypofibrinogenemia and the other mutation coding for a dysfunctional fibrinogen, e.g. fibrinogen Keokuk.
| | * Genetic testing: Identifies mutations in the fibrinogen gene that are responsible for the disorder. |
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| The following Table adds further information on the just cited examples of hypodysfibrinogenemias. The Table gives: '''a)''' each mutated protein's trivial name; '''b)''' the gene mutated (i.e. ''FGA, FGB,'' or ''FGG''), its mutation site (i.e. numbered nucleotide in the [[cloned]] gene), and name of the nucleotides (i.e. [[cytosine|C]], [[thymine|T]], [[adenine|A]], [[guanine|G]]) at these sites before>after the mutation; '''c)''' the name of the altered fibrinogen peptide (Aα, Bβ, or λ) and the amino acids (using [[amino acid#Table of standard amino acid abbreviations and properties|standard abbreviations]]) occurring before-after the mutation at the numbered amino acid(s) sites in the circulating mutated fibrinogen; '''d)''' the [[pathophysiology]] for the mutated fibrinogen's misfunction(s); and '''e)''' the clinical consequence(s) of the mutation. Unless noted as a deletion (del) or frame shift (fs), all mutations are [[missense mutation|missense]] or [[nonsense mutation]]s.<ref name="pmid28211264"/><ref name="pmid27019463"/> A [[nonsense mutation]] causing a premature [[stop codon]] and thereby a shorten polypeptide chain is notated by an X (PSC) after the altered amino acid codon. | | ==Management== |
| | The management of hypodysfibrinogenemia focuses on preventing and treating bleeding episodes. Treatment options may include: |
| | * [[Fibrinogen concentrate]]: Used to replace deficient or dysfunctional fibrinogen during bleeding episodes or prophylactically before surgery. |
| | * [[Fresh frozen plasma]]: Contains fibrinogen and other clotting factors, used in acute bleeding situations. |
| | * [[Antifibrinolytic agents]]: Such as [[tranexamic acid]], to prevent the breakdown of clots. |
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| {| class="wikitable"
| | Patients with a history of thrombotic events may require [[anticoagulation therapy]] under careful monitoring. |
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| ! Trivial name !! Gene: mutation !! Polypeptide chain: mutation !! Pathophysiology !! Clinical disorder
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| | fibrinogen Otago || ''FGA'': c.858_859incC || Aα: Arg268Gln followed by fs || impaired secretion; defective [[polymerization]] || post-surgical and post-[[partum]] bleeding, recurrent [[Miscarriage|miscarriages]]
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| | fibrinogen Marburg || ''FGA'': c.1438A>T || Aα: Lys461X (PSC) || defective [[polymerization]] || post-[[partum]] bleeding, recurrent venous thrombosis
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| | fibrinogen Keokuk || ''FGA'': c.510 +1 G>T; ''FGA'' c.1039C>T (PSC) || Aα: [[Splice site mutation|splice mutation]]; Aα: Gln321X (PSC) || impaired fibrinogen assembly, poor fibrin clot lysis, defective polymerization || recurrent venous and arterial thromboses
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| | fibrinogen Sfax || ''FGB'': c.679T>C || Bβ: Cys197Arg|| defective aggregation of fibrin || post-surgical and [[postpartum]] bleeding, [[metrorrhagia]] during pregnancy
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| | fibrinogen Vlissingen || ''FGG'': c.1033_1038del || γ: delAsn319-Asp-320 || impaired secretion, defective calcium binding, defective polymerization || venous thrombosis
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| | fibrinogen Philadelphia || ''FGG'': c.1210T>C || γ: Ser378Pro || impaired assembly of intracelllar fibrinogen, defective polymerization || post-surgical, postpartum, and post-trauma bleeding
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| | fibrinogen Freiburg || ''FGG'': c.103C>T || γ: Arg16Cys || impaired assembly of intracelllar fibrinogen, defective polymerization || recurrent venous and arterial thromboses
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| | fibrinogen Leipzig II || ''FGG'': c.323C>G and ''FGG'' c.1129G>A || γ: Ala108Gly and λ: Gly377Ser || impaired assembly of intracelllar fibrinogen, defective polymerization || recurrent venous and arterial thromboses
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| |}
| | ==Prognosis== |
| | The prognosis for individuals with hypodysfibrinogenemia varies depending on the severity of the condition and the presence of complications. With appropriate management, many patients can lead normal lives, although they may require ongoing monitoring and treatment to prevent bleeding or thrombotic events. |
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| == Diagnosis == | | ==Related pages== |
| Hypodysfibrinogenemia is usually diagnosed in individuals who: have a history of abnormal bleeding or thrombosis or are a [[Consanguinity|close blood relative]] of such an individual. Initial laboratory findings include a decrease in serum fibrinogen mass levels as measured by [[immunoassay]] plus a reduction in inducible blood clot formation so that the ratio of functionally-detected fibrinogen mass (i.e. detected in induced clots) to immunoassay-detected fibrinogen mass is abnormally low, i.e. <0.7. This contrast with individuals with congenital dysfibrinogenemia who exhibit normal levels of fibrinogen as measured by immunoassay but low functionally-detected to immunoassay-detected fibrinogen mass ratios, i.e. <0.7. Where available, specialized laboratories can conduct studies to define the exact gene mutation(s) and fibrinogen abnormalities underlying the disorder.<ref name="pmid28211264"/><ref name="pmid27019462"/><ref name="pmid25816717">{{cite journal | vauthors = Casini A, Neerman-Arbez M, Ariëns RA, de Moerloose P | title = Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management | journal = Journal of Thrombosis and Haemostasis | volume = 13 | issue = 6 | pages = 909–19 | year = 2015 | pmid = 25816717 | doi = 10.1111/jth.12916 | url = }}</ref>
| | * [[Coagulation disorders]] |
| | * [[Fibrinogen]] |
| | * [[Thrombosis]] |
| | * [[Bleeding disorders]] |
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| == Treatment ==
| | [[Category:Coagulation disorders]] |
| Blood relatives of the [[proband]] case should be evaluated for the presence of hypodysfibrinogenemia. Individuals with the disorder need to be advised on its inheritance, complications, and preventative measures that can be taken to avoid bleeding and/or thrombosis. Since >80% of individuals may develop bleeding or thrombosis complications of the disorder, asymptomatic individuals diagnosed with hydposyfibrinogenemia are best handled at a specialized center in order to benefit from multidisciplinary management.<ref name="pmid27019462"/>
| | [[Category:Hematology]] |
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| Measures to prevent and/or treat complications of hypodysfibrinogenemia should be tailored to the personal and family history of the individual by a specialized center. Individuals with a personal or family history of bleeding are considered to be of low risk of bleeding when their functional fibrinogen levels are >1 gram/liter for major surgery, >0.5 gram/liter for minor surgery, >0.5 to 1-2 gram/liter for spontaneous bleeding (depending on its severity), >0.5 to > 1 gram/liter for the first two trimesters of pregnancy, and >1 to <2 gram/liter for the last trimester of pregnancy and postpartum period. Functional fibrinogen below these levels should be treated preferably with fibrinogen concentrate or if not available, fibrinogen-rich [[cryoprecipitate]] or plasma to attain low risk levels of functional fibrinogen.<ref name="pmid27019462"/> [[Antifibrinolytic]] drugs such as [[tranexamic acid]] or (ε-aminocaproic acid) may be considered as an alternative preventative or therapeutic treatments in cases of minor surgery, dental extractions, mucosal bleeding, or other episodes of mild bleeding.<ref name="pmid27019462"/><ref name="pmid27019463"/> In individuals with a personal or family history of thrombosis, should be considered for long-term [[Anticoagulant|anticoagulation drugs]] such as [[low molecular weight heparin]], [[Warfarin|coumadin]], or [[rivaroxaban]].<ref name="pmid27019462"/>
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| ==References==
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| {{reflist}}
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| [[Category:Medical condition not in Wikidata]]
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| [[Category:Coagulopathies]] | |
| [[Category:Autosomal dominant disorders]]
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| [[Category:Rare diseases]] | |
| [[Category:Genetic diseases and disorders]]
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A rare blood disorder affecting fibrinogen function
Hypodysfibrinogenemia is a rare coagulation disorder characterized by the presence of abnormal fibrinogen molecules in the blood. Fibrinogen is a crucial glycoprotein involved in the blood clotting process, and abnormalities in its structure or function can lead to bleeding or thrombotic complications.
Pathophysiology
Fibrinogen is synthesized in the liver and plays a vital role in hemostasis. It is converted by thrombin into fibrin, which forms a mesh that stabilizes the initial platelet plug during the clotting process. In hypodysfibrinogenemia, mutations in the fibrinogen gene lead to the production of structurally abnormal fibrinogen molecules. These abnormalities can affect the molecule's ability to be converted into fibrin or to form a stable clot, resulting in a bleeding tendency or, paradoxically, an increased risk of thrombosis.
Clinical Presentation
Patients with hypodysfibrinogenemia may present with a variety of symptoms, ranging from mild to severe bleeding episodes. Common manifestations include:
- Easy bruising
- Epistaxis (nosebleeds)
- Menorrhagia (heavy menstrual bleeding)
- Prolonged bleeding after surgery or trauma
In some cases, patients may also experience thrombotic events, such as deep vein thrombosis or pulmonary embolism, due to the abnormal fibrinogen's impact on clot stability and dissolution.
Diagnosis
The diagnosis of hypodysfibrinogenemia involves a combination of clinical evaluation and laboratory testing. Key diagnostic tests include:
- Coagulation profile: Prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT) may be observed.
- Fibrinogen activity assay: Measures the functional activity of fibrinogen in the blood.
- Fibrinogen antigen assay: Quantifies the amount of fibrinogen present.
- Genetic testing: Identifies mutations in the fibrinogen gene that are responsible for the disorder.
Management
The management of hypodysfibrinogenemia focuses on preventing and treating bleeding episodes. Treatment options may include:
Patients with a history of thrombotic events may require anticoagulation therapy under careful monitoring.
Prognosis
The prognosis for individuals with hypodysfibrinogenemia varies depending on the severity of the condition and the presence of complications. With appropriate management, many patients can lead normal lives, although they may require ongoing monitoring and treatment to prevent bleeding or thrombotic events.
Related pages
