Hypodysfibrinogenemia

Last updated
Hypodysfibrinogenemia
Other namesCongenital hypodysfibrinogenemia
Specialty Hematology
Causes Mutations in the gene for the fibrinogen alpha chain, fibrinogen beta chain, or fibrinogen gamma chain gene

Hypodysfibrinogenemia, also termed congenital hypodysfibrinogenemia, is a rare hereditary 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. [1] Hypodysfibrinogenemia exhibits reduced penetrance, i.e. only some family members with the mutated gene develop symptoms. [2] [3]

Contents

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. [2] [3]

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. abnormally heavy bleeding during the menstrual period. [1]

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. [2] 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, splanchnic venous thrombosis, and pulmonary thrombosis presumptively secondary to deep vein thrombosis. [1]

Fibrinogen

Circulating fibrinogen is a glycoprotein made of two trimers each of which is composed of three polypeptide chains, Aα (also termed α) encoded by the FGA gene, 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 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. [4] [5]

Pathophysiology

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 fibrinogen alpha chain gene (also termed the FGA gene), 5 in the fibrinogen beta chain gene (also termed the FGB gene), and 17 in the fibrinogen gamma chain gene (also termed the FGG gen). The mutations are mainly missense mutations with nonsense and Frameshift mutations each occurring in 12.5% of cases. [1] 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: [4]

  1. 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.
  2. 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.
  3. 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.
  4. 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.

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. C, T, A, 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 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 or nonsense mutations. [1] [4] 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.

Trivial nameGene: mutationPolypeptide chain: mutationPathophysiologyClinical disorder
fibrinogen OtagoFGA: c.858_859incCAα: Arg268Gln followed by fsimpaired secretion; defective polymerization post-surgical and post-partum bleeding, recurrent miscarriages
fibrinogen MarburgFGA: c.1438A>TAα: Lys461X (PSC)defective polymerization post-partum bleeding, recurrent venous thrombosis
fibrinogen KeokukFGA: c.510 +1 G>T; FGA c.1039C>T (PSC)Aα: splice mutation; Aα: Gln321X (PSC)impaired fibrinogen assembly, poor fibrin clot lysis, defective polymerizationrecurrent venous and arterial thromboses
fibrinogen SfaxFGB: c.679T>CBβ: Cys197Argdefective aggregation of fibrinpost-surgical and postpartum bleeding, metrorrhagia during pregnancy
fibrinogen VlissingenFGG: c.1033_1038delγ: delAsn319-Asp-320impaired secretion, defective calcium binding, defective polymerizationvenous thrombosis
fibrinogen PhiladelphiaFGG: c.1210T>Cγ: Ser378Proimpaired assembly of intracelllar fibrinogen, defective polymerizationpost-surgical, postpartum, and post-trauma bleeding
fibrinogen FreiburgFGG: c.103C>Tγ: Arg16Cysimpaired assembly of intracelllar fibrinogen, defective polymerizationrecurrent venous and arterial thromboses
fibrinogen Leipzig IIFGG: c.323C>G and FGG c.1129G>Aγ: Ala108Gly and λ: Gly377Serimpaired assembly of intracelllar fibrinogen, defective polymerizationrecurrent venous and arterial thromboses

Diagnosis

Hypodysfibrinogenemia is usually diagnosed in individuals who: have a history of abnormal bleeding or thrombosis or are a 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. [1] [2] [6]

Treatment

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. [2]

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. [2] 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. [2] [4] In individuals with a personal or family history of thrombosis, should be considered for long-term anticoagulation drugs such as low molecular weight heparin, coumadin, or rivaroxaban. [2]

Related Research Articles

Factor V Leiden is a variant of human factor V, which causes an increase in blood clotting (hypercoagulability). Due to this mutation, protein C, an anticoagulant protein that normally inhibits the pro-clotting activity of factor V, is not able to bind normally to factor V, leading to a hypercoagulable state, i.e., an increased tendency for the patient to form abnormal and potentially harmful blood clots. Factor V Leiden is the most common hereditary hypercoagulability disorder amongst ethnic Europeans. It is named after the Dutch city of Leiden, where it was first identified in 1994 by Rogier Maria Bertina under the direction of Pieter Hendrick Reitsma. Despite the increased risk of venous thromboembolisms, people with one copy of this gene have not been found to have shorter lives than the general population. It is an autosomal dominant genetic disorder with incomplete penetrance.

<span class="mw-page-title-main">Fibrinogen</span> Soluble protein complex in blood plasma and involved in clot formation

Fibrinogen is a glycoprotein complex, produced in the liver, that circulates in the blood of all vertebrates. During tissue and vascular injury, it is converted enzymatically by thrombin to fibrin and then to a fibrin-based blood clot. Fibrin clots function primarily to occlude blood vessels to stop bleeding. Fibrin also binds and reduces the activity of thrombin. This activity, sometimes referred to as antithrombin I, limits clotting. Fibrin also mediates blood platelet and endothelial cell spreading, tissue fibroblast proliferation, capillary tube formation, and angiogenesis and thereby promotes revascularization and wound healing.

<span class="mw-page-title-main">Thrombin</span> Enzyme involved in blood coagulation in humans

Thrombin is a serine protease, an enzyme that, in humans, is encoded by the F2 gene. Prothrombin is proteolytically cleaved to form thrombin in the clotting process. Thrombin in turn acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions.

von Willebrand disease Medical condition

Von Willebrand disease (VWD) is the most common hereditary blood-clotting disorder in humans. An acquired form can sometimes result from other medical conditions. It arises from a deficiency in the quality or quantity of von Willebrand factor (VWF), a multimeric protein that is required for platelet adhesion. It is known to affect several breeds of dogs as well as humans. The three forms of VWD are hereditary, acquired, and pseudo or platelet type. The three types of hereditary VWD are VWD type 1, VWD type 2, and VWD type 3. Type 2 contains various subtypes. Platelet type VWD is also an inherited condition.

<span class="mw-page-title-main">Thrombophilia</span> Abnormality of blood coagulation

Thrombophilia is an abnormality of blood coagulation that increases the risk of thrombosis. Such abnormalities can be identified in 50% of people who have an episode of thrombosis that was not provoked by other causes. A significant proportion of the population has a detectable thrombophilic abnormality, but most of these develop thrombosis only in the presence of an additional risk factor.

Congenital afibrinogenemia is a rare, genetically inherited blood fibrinogen disorder in which the blood does not clot normally due to the lack of fibrinogen, a blood protein necessary for coagulation. This disorder is autosomal recessive, meaning that two unaffected parents can have a child with the disorder. The lack of fibrinogen expresses itself with excessive and, at times, uncontrollable bleeding.

<span class="mw-page-title-main">Hypoprothrombinemia</span> Medical condition

Hypoprothrombinemia is a rare blood disorder in which a deficiency in immunoreactive prothrombin, produced in the liver, results in an impaired blood clotting reaction, leading to an increased physiological risk for spontaneous bleeding. This condition can be observed in the gastrointestinal system, cranial vault, and superficial integumentary system, affecting both the male and female population. Prothrombin is a critical protein that is involved in the process of hemostasis, as well as illustrating procoagulant activities. This condition is characterized as an autosomal recessive inheritance congenital coagulation disorder affecting 1 per 2,000,000 of the population, worldwide, but is also attributed as acquired.

<span class="mw-page-title-main">Protein C deficiency</span> Medical condition

Protein C deficiency is a rare genetic trait that predisposes to thrombotic disease. It was first described in 1981. The disease belongs to a group of genetic disorders known as thrombophilias. Protein C deficiency is associated with an increased incidence of venous thromboembolism, whereas no association with arterial thrombotic disease has been found.

<span class="mw-page-title-main">Factor X deficiency</span> Medical condition

Factor X deficiency is a bleeding disorder characterized by a lack in the production of factor X (FX), an enzyme protein that causes blood to clot in the coagulation cascade. Produced in the liver FX when activated cleaves prothrombin to generate thrombin in the intrinsic pathway of coagulation. This process is vitamin K dependent and enhanced by activated factor V.

<span class="mw-page-title-main">Factor VII deficiency</span> Medical condition

Factor VII deficiency is a bleeding disorder characterized by a lack in the production of Factor VII (FVII) (proconvertin), a protein that causes blood to clot in the coagulation cascade. After a trauma factor VII initiates the process of coagulation in conjunction with tissue factor in the extrinsic pathway.

<span class="mw-page-title-main">GATA1</span> Protein-coding gene in humans

GATA-binding factor 1 or GATA-1 is the founding member of the GATA family of transcription factors. This protein is widely expressed throughout vertebrate species. In humans and mice, it is encoded by the GATA1 and Gata1 genes, respectively. These genes are located on the X chromosome in both species.

The dysfibrinogenemias consist of three types of fibrinogen disorders in which a critical blood clotting factor, fibrinogen, circulates at normal levels but is dysfunctional. Congenital dysfibrinogenemia is an inherited disorder in which one of the parental genes produces an abnormal fibrinogen. This fibrinogen interferes with normal blood clotting and/or lysis of blood clots. The condition therefore may cause pathological bleeding and/or thrombosis. Acquired dysfibrinogenemia is a non-hereditary disorder in which fibrinogen is dysfunctional due to the presence of liver disease, autoimmune disease, a plasma cell dyscrasias, or certain cancers. It is associated primarily with pathological bleeding. Hereditary fibrinogen Aα-Chain amyloidosis is a sub-category of congenital dysfibrinogenemia in which the dysfunctional fibrinogen does not cause bleeding or thrombosis but rather gradually accumulates in, and disrupts the function of, the kidney.

<span class="mw-page-title-main">Fibrinogen gamma chain</span> Protein-coding gene in the species Homo sapiens

Fibrinogen gamma chain, also known as fibrinogen gamma gene (FGG), is a human gene found on chromosome 4.

<span class="mw-page-title-main">Fibrinogen beta chain</span> Protein-coding gene in the species Homo sapiens

Fibrinogen beta chain, also known as FGB, is a gene found in humans and most other vertebrates with a similar system of blood coagulation.

<span class="mw-page-title-main">Quebec platelet disorder</span> Medical condition

Quebec platelet disorder (QPD) is a rare autosomal dominant bleeding disorder first described in a family from the province of Quebec in Canada. The disorder is characterized by large amounts of the fibrinolytic enzyme urokinase-type plasminogen activator (uPA) in platelets. This causes accelerated fibrinolysis (blood clot breakdown) which can result in bleeding.

Cryofibrinogenemia refers to a condition classified as a fibrinogen disorder in which a person's blood plasma is allowed to cool substantially, causing the (reversible) precipitation of a complex containing fibrinogen, fibrin, fibronectin, and, occasionally, small amounts of fibrin split products, albumin, immunoglobulins and other plasma proteins.

<span class="mw-page-title-main">Factor I deficiency</span> Medical condition

Factor I deficiency, also known as fibrinogen deficiency, is a rare inherited bleeding disorder related to fibrinogen function in the blood coagulation cascade. It is typically subclassified into four distinct fibrinogen disorders: afibrinogenemia, hypofibrinogenemia, dysfibrinogenemia, and hypodysfibrinogenemia.

Congenital hypofibrinogenemia is a rare disorder in which one of the three genes responsible for producing fibrinogen, a critical blood clotting factor, is unable to make a functional fibrinogen glycoprotein because of an inherited mutation. In consequence, liver cells, the normal site of fibrinogen production, make small amounts of this critical coagulation protein, blood levels of fibrinogen are low, and individuals with the disorder may develop a coagulopathy, i.e. a diathesis or propensity to experience episodes of abnormal bleeding. However, individuals with congenital hypofibrinogenemia may also have episodes of abnormal blood clot formation, i.e. thrombosis. This seemingly paradoxical propensity to develop thrombosis in a disorder causing a decrease in a critical protein for blood clotting may be due to the function of fibrin to promote the lysis or disintegration of blood clots. Lower levels of fibrin may reduce the lysis of early fibrin strand depositions and thereby allow these depositions to develop into clots.

Transient myeloproliferative disease (TMD) occurs in a significant percentage of individuals born with the congenital genetic disorder, Down syndrome. It may occur in individuals who are not diagnosed with the syndrome but have some hematological cells containing genetic abnormalities that are similar to those found in Down syndrome. TMD usually develops in utero, is diagnosed prenatally or within ~3 months of birth, and thereafter resolves rapidly and spontaneously. However, during the prenatal-to-postnatal period, the disease may cause irreparable damage to various organs and in ~20% of individuals death. Moreover, ~10% of individuals diagnosed with TMD develop acute megakaryoblastic leukemia at some time during the 5 years following its resolution. TMD is a life-threatening, precancerous condition in fetuses as well as infants in their first few months of life.

References

  1. 1 2 3 4 5 6 Casini A, Brungs T, Lavenu-Bombled C, Vilar R, Neerman-Arbez M, de Moerloose P (2017). "Genetics, diagnosis and clinical features of congenital hypodysfibrinogenemia: a systematic literature review and report of a novel mutation". Journal of Thrombosis and Haemostasis. 15 (5): 876–888. doi: 10.1111/jth.13655 . PMID   28211264.
  2. 1 2 3 4 5 6 7 8 Casini A, de Moerloose P, Neerman-Arbez M (2016). "Clinical Features and Management of Congenital Fibrinogen Deficiencies". Seminars in Thrombosis and Hemostasis. 42 (4): 366–74. doi:10.1055/s-0036-1571339. PMID   27019462. S2CID   12038872.
  3. 1 2 Caimi G, Canino B, Lo Presti R, Urso C, Hopps E (2017). "Clinical conditions responsible for hyperviscosity and skin ulcers complications" (PDF). Clinical Hemorheology and Microcirculation. 67 (1): 25–34. doi:10.3233/CH-160218. hdl: 10447/238851 . PMID   28550239.
  4. 1 2 3 4 Neerman-Arbez M, de Moerloose P, Casini A (2016). "Laboratory and Genetic Investigation of Mutations Accounting for Congenital Fibrinogen Disorders". Seminars in Thrombosis and Hemostasis. 42 (4): 356–65. doi:10.1055/s-0036-1571340. PMID   27019463. S2CID   12693693.
  5. ↑ Duval C, Ariëns RA (2017). "Fibrinogen splice variation and cross-linking: Effects on fibrin structure/function and role of fibrinogen γ' as thrombomobulin II" (PDF). Matrix Biology. 60–61: 8–15. doi:10.1016/j.matbio.2016.09.010. PMID   27784620.
  6. ↑ Casini A, Neerman-Arbez M, Ariëns RA, de Moerloose P (2015). "Dysfibrinogenemia: from molecular anomalies to clinical manifestations and management". Journal of Thrombosis and Haemostasis. 13 (6): 909–19. doi:10.1111/jth.12916. PMID   25816717. S2CID   10955092.
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