Dysfibrinogenemia

Last updated
Dysfibrinogenemia
Other namesDysfibrinogenemia, familial [1]

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. [2] [3] [4] 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. [5] 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. [6]

Contents

Congenital dysfibrinogenemia is the commonest of these three disorders. Some 100 different genetic mutations occurring in more than 400 families have been found to cause it. [5] [7] All of these mutations as well as those causing hereditary fibrinogen Aα-Chain amyloidosis exhibit partial penetrance, i.e. only some family members with one of these mutant genes develop dysfibrinogenemia-related symptoms. [8] [6] While both of these congenital disorders as well as acquired dysfibrinogenemia are considered very rare, it is estimated that ~0.8% of individuals with venous thrombosis have either a congenital or acquired dysfibrinogenemia. Hence, the dysfibrinogenemia disorders may be highly under-diagnosed conditions due to isolated thrombotic events that are not appreciated as reflecting an underlying fibrinogen disorder. [3]

Congenital dysfibrinogenemia is distinguished from a similar inherited disorder, congenital hypodysfibrinogenemia. Both disorders involve the circulation of dysfunctional fibrinogen but in congenital hypodysfibrinogenemia plasma fibrinogen levels are low while in congenital dysfibrinogenemia they are normal. Furthermore, the two disorders involve different gene mutations and inheritance patterns as well as somewhat different symptoms. [3] [9]

Fibrinogen

Fibrinogen is a glycoprotein made and secreted into the blood primarily by liver hepatocyte cells. Endothelium cells also make what appears to be small amounts of fibrinogen but this fibrinogen has not been fully characterized; blood platelets and their precursors, bone marrow megakaryocytes, although once thought to make fibrinogen, are now known to take up and store but not make the glycoprotein. [9] [10] The final secreted, hepatocyte-derived glycoprotein is 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 (i.e. "p") arm of human chromosome 4 (at positions 4q31.3, 4q31.3, and 4q32.1, respectively) and may contain mutations that are the cause of congenital dysfibrinogenemia. The heximer is assembled as a protein in the endoplasmic reticulum of hepatocytes and then transferred to the Golgi where Polysaccharides (i.e. complex sugars) and sialic acid are added by respective glycosylation and sialylation enzyme pathways thereby converting the heximer to a functional fibrinogen glycoprotein. The final circulating glycoprotein (notated as (AαBβγ)2, (αβγ)2, Aα2Bβ2γ2, or α2β2γ2) is arranged as a long flexible rod with nodules at both ends termed D domains and central nodule termed the E domain. [11] [12]

The normal process of blood clot formation involves the coordinated operation of two separate pathways that feed into a final common pathway: 1) primary hemostasis, i.e. the adhesion, activation, and aggregation of circulating blood platelets at sites of vascular injury and 2) secondary hemostasis, i.e. cleavage of the Aα and Bβ chains of fibrinogen by thrombin to form individual fibrin strands plus the respective fibrinopeptides A and B formed from this cleavage. In the final common pathway fibrin is cross-linked by activated clotting factor XIII (termed factor XIIIa) to form mature gel-like fibrin clots. Subsequent fibrinolysis pathways act to limit clot formation and dissolve clots no longer needed. Fibrinogen and its Aα fibrin chain have several functions in this process: [4] [10] [13] [14]

Based on these fibrinogen functions, a fibrinogen mutation may act either to inhibit or promote blood clot formation and/or lysis to thereby produce in individuals a diathesis to develop pathological bleeding, thrombosis, or both conditions. [4]

Congenital dysfibrinogenemia

Presentation

Many cases of congenital dysfibrinogenemia are asymptomatic. Since manifestations of the disorder generally occur in early adulthood or middle-age, younger individuals with a gene mutation causing it may not have had time to develop symptoms while previously asymptomatic individuals of advanced age with such a mutation are unlikely to develop symptoms. Bleeding episodes in most cases of this disorder are mild and commonly involve easy bruising and menorrhagia. Less common manifestations of bleeding may be severe or even life-threatening; these include excessive bleeding after tooth extraction, surgery, vaginal birth, and miscarriage. Rarely, these individuals may suffer hemarthrosis or cerebral hemorrhage. In one study of 37 individuals >50 years old afflicted with this disorder, 19% had a history of thrombosis. Thrombotic complications occur in both arteries and veins and include transient ischemic attack, ischemic stroke, myocardial infarction, retinal artery thrombosis, peripheral artery thrombosis, and deep vein thrombosis. In one series of 33 individuals with a history of thrombosis due to congenital dysfibrinogenemia, five developed chronic pulmonary hypertension due to ongoing pulmonary embolism probably stemming form deep vein thrombosis. About 26% of individuals with the disorder suffer both bleeding and thrombosis complications. [5] [14]

Pathophysiology

Congenital dysfibrinogenemia is most often caused by a single autosomal dominant missense mutation in the Aα, Bβ, or γ gene; rarely, it is caused by a homozygous or compound heterozygous missense mutation, a deletion, frameshift mutation, insert mutation, or splice site mutation in one of these genes. The most frequent sites for these mutations code for the N-terminus of the Aα chain or the C-terminus of the γ chain that lead to defective assembly of fibrin in early clot formation and thereby a bleeding predisposition. [4] Two particular missense mutations represent the majority (74% in one study of 101 individuals) of all mutations associated with dysfibrinogenemia and therefore represent prime sites to examine in the initial testing of individuals having a congenital dysfibrinogenmia bleeding disorder. These mutations alter the codon coded for the amino acid arginine at either the 35th position of FGA (termed Arg35; see fibrinogen Metz1 and fibrinogen Bicetre in the Table below) and or the 301st position of FGG (termed Arg301; see fibrinogen Baltimore IV in the Table below). [11]

The following Table lists examples of mutations causing congenital dysfibrinogenemias. It gives: a) the 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 the names of the nucleotides (i.e. C, T, A, G) at these sites before>after the mutation; c) the altered fibrinogen peptide (Aα, Bβ, or λ) and the amino acids (using standard abbreviations) found in the normal-mutated circulating fibrinogen; d) the cause of the mutated fibrinogen's misfunction(s); e) the clinical consequence(s) of the mutation; and f) comments. Unless noted as a deletion (del), frame shift (fs), or homozygous mutation, all mutations are heterozygous, missense mutations. [5] [15]

Trivial nameGene: site of mutationProtein chain: site mutationPathophysiologyClinical disorderComment
fibrinogen DetroitFGA: c.114G>C/TAα: Arg19Serabnormal Polymerization bleedingrelatively rare; first description of congenital dysfibrinogenmia [16]
fibrinogen Metz1FGA: c.103C>TAα: Arg35Cysdelayed release of fibrinopeptide A bleedingrelatively common
fibrinogen BicetrelFGA: c.104C>GAα: Arg35Hisdelayed release of fibrinopeptide A bleedingrelatively common
fibrinogen PerthFGA: c.1541delCAα: Pro495Leufsthin clot, increased clot strength, impaired plasmin generationbleeding and thrombosisrelatively rare
fibrinogen NaplesFGB: c.292G>ABβ: Ala68thrdefective thrombin bindingthrombosisrelatively rare; homozygous
fibrinogen BaltimoreIVFGG: c.901C>Tλ: Arg301Cysimpaired fiber interactionsthrombosisrelatively common
fibrinogen VlissingenFGG: c.1033_1038delλ: del Asn319-Asp320impaired fiber interactionsthrombosisrelatively rare; nucleotides 1033-1038 and amino acids 319-320 deleted
fibrinogen BarccelonaIVFGG: c.902G>Aλ: Arg301Hisimpaired fiber interactionsthrombosisrelatively common

Diagnosis

The diagnosis of congenital dysfibrinogenmia is made by clinical laboratory studies that find normal levels of plasma fibrinogen but significant excess in the amount of immunologically detected compared to functionally detected (i.e. able to be clotted) fibrinogen. The ratio of functionally-detected to immunologically detected fibrinogen masses in these cases is <0.7. Partial thromboplastin time, activated partial thromboplastin time, thrombin time, and reptilase time tests are usually prolonged regardless of history of bleeding or thrombosis. [11] Where available, laboratory analyses of the fibrinogen genes and peptide chains solidify the diagnosis. Initial examination of these genes or protein chains should search specifically for "hot spot" mutations, i.e. the most common mutations (see Pathophysiology section) that comprise the large bulk of mutations in the disorder. [5] In cases of dysfibrinogenemia in which acquired disease is suspected, diagnosis requires a proper diagnosis of the presence of a causable disease. [4]

Congenital dysfibrinogenmia is initially distinguished form congenital hypodysfibrinogenemia by the finding of normal immunologically-detected levels of fibrinogen in congenital dysfibrinogenemia and sub-normal levels of immunologically-detected fibrinogen in congenital hypodysfibrinogenemia. Both disorders exhibit mass ratios of functionally-detected to immunologically-detected fibrinogen that are below <0.7. Genetic and protein analyses can definitively differentiate the two disorders. [9]

Treatment

In a study of 189 individuals diagnosed with congenital dysfibrinogenemia, ~33% were asymptomatic, ~47% experienced episodic bleeding, and ~20% experienced episodic thromboses. [9] Due to the rareness of this disorder, treatment of individuals with these presentations are based primarily on case reports, guidelines set by the United Kingdom, and expert opinions rather than controlled clinical studies. [5]

Asymptomatic individuals

Treatment of asymptomatic congenital dysfibrinogenemia depends in part on the expectations of developing bleeding and/or thrombotic complications as estimated based on the history of family members with the disorder and, where available, determination of the exact mutation causing the disorder plus the propensity of the particular mutation type to develop these complications. [5] In general, individuals with this disorder require regular follow-up and multidiscipline management prior to surgery, pregnancy, and giving childbirth. Women with the disorder appear to have an increased rate of miscarriages and all individuals with fibrinogen activity in clotting tests below 0.5 grams/liter are prone to bleeding and spontaneous abortions. Women with multiple miscarriages and individuals with excessively low fibrinogen activity levels should be considered for prophylaxis therapy with fibrinogen replacement during pregnancy, delivery, and/or surgery. [5] [9]

Symptomatic individuals

Individuals experiencing episodic bleeding as a result of congenital dysfibrinogenemia should be treated at a center specialized in treating hemophilia. They should avoid all medications that interfere with normal platelet function. During bleeding episodes, treatment with fibrinogen concentrates or in emergencies or when these concentrates are unavailable, infusions of fresh frozen plasma and/or cryoprecipitate (a fibrinogen-rich plasma fraction) to maintain fibrinogen activity levels >1 gram/liter. Tranexamic acid or fibrinogen concentrates are recommended for prophylactic treatment prior to minor surgery while fibrinogen concentrates are recommended prior to major surgery with fibrinogen concentrates usage seeking to maintain fibrinogen activity levels at >1 gram/liter. Women undergoing vaginal or Cesarean child birth should be treated at a hemophilia center with fibrinogen concentrates to maintain fibrinogen activity levels at 1.5 gram/liter. The latter individuals require careful observation for bleeding during their post-partum periods. [5]

Individuals experiencing episodic thrombosis as a result of congenital dysfibrinogenemia should also be treated at a center specialized in treating hemophilia using antithrombotic agents. They should be instructed on antithrombotic behavioral methods fur use in high risk situations such as long car rides and air flights. Venous thrombosis should be treated with low molecular weight heparin for a period that depends on personal and family history of thrombosis events. Prophylactic treatment prior to minor surgery should avoid fibrinogen supplementation and use prophylactic anticoagulation measures; prior to major surgery, fibrinogen supplementation should be used only if serious bleeding occurs; otherwise, prophylactic anticoagulation measures are recommended. [5]

Hereditary fibrinogen Aα-Chain amyloidosis

Presentation

Individuals with hereditary fibrinogen Aα-chain amyloidosis present with evidence ranging from asymptomatic proteinuria to progressive renal impairment and end-stage kidney disease. They do not evidence pathological bleeding or thrombosis and their amyloidosis is non-systemic in that it is restricted to the kidney. In a report on 474 patients with renal amyloidosis, hereditary fibrinogen Aα chain disease represented only 1.3% of all cases whereas aberrant immunoglobulin-induced renal amyloidosis (e.g. AL amyloidosis) represented 86% of the cases). [17] Hereditary fibrinogen Aα-Chain amyloidosis is, however, the most common form of familial renal amyloidosis. [5] [6]

Pathophysiology

Certain mutations in the fibrinogen Aα-chain gene cause a form of familial renal amyloidosis termed hereditary fibrinogen Aα-Chain amyloidosis. [6] The disorder is due to autosomal dominant inheritance of Aα chain mutations the most common of which is hemoglobin Indianapolis, a heterozygous missense (c.1718G>T: Arg554Leu) mutation. Other missense mutations causing this disorder are unnamed; they include 1634A>T: Glu526Val; c.1670C>A: Thr538lys; c.1676A.T:Glu540Val; and c1712C>A:Pro552His. A deletion mutation causing a frameshift viz., c.1622delT: Thr525Leu, is also a cause of the disorder. The fibrinogen bearing these mutant Aα-chains is secreted into the circulation and gradually accumulates in, and causes significant injury to, the kidney. The mutant fibrinogen does not appear to accumulate in, or injure, extra-renal tissues. [5] [6] [17]

Diagnosis

The diagnosis of this disorder depends on demonstrating: 1) a dysfunctional plasma fibrinogen, i.e. significantly less functionally-detected compared to immunologically-detected fibrinogen; b) presence of signs and/or symptoms of kidney disease; and c) histological evidence of often massive obliteration of renal glomeruli by amyloid as detected by Congo red staining. There also should be no evidence for systemic amyloidosis. Specialized centers use immunological and genetic studies to define the nature of the renal amyloid deposits, the presence of FGA gene mutations, and the occurrence of these mutations in family members. The disorder exhibits a highly variable penetrance among family members. [17] [6] Hereditary fibrinogen Aα-Chain amyloidosis shows variable penetrance among family members, a distinctive histological appearance, proteinuria, progressive renal impairment, and markedly better survival rates than other forms of systemic renal amyloidosis. [6]

Treatment

Treatment of hereditary fibrinogen Aα-Chain amyloidosis has relied on chronic maintenance hemodialysis and, where possible, kidney transplantation. While recurrence of amyloidosis in the transplanted kidney occurs and is to be expected, transplant survival rates for this form of amyloidosis are significantly better than those for transplants in other forms of systemic renal amyloidosis. Relatively healthy individuals with hereditary fibrinogen Aα-Chain-related renal amyloidosis may be considered for kidney and liver bi-transplantation with the expectation that survival of the transplanted kidney will be prolonged by replacing the fibrinogen Aα-Chain-producing liver with a non-diseased donor liver. [6]

Acquired dysfibrinogenemia

Presentation

Acquired dysfibrinogenemia commonly present with signs, symptoms, and/or prior diagnoses of the underlying causative disease or drug intake in an individual with an otherwise unexplained bleeding tendency or episode. Bleeding appears to be more prominent in acquired compared to congenital dysfibrinogenemia; pathological thrombosis, while potentially occurring in these individuals as a complication of their underlying disease, is an uncommon feature of the acquired disorder. [4]

Pathophysiology

Acquired dysfibrinogenemia occurs as a known or presumed consequence of an underlying disease which directly or indirectly interferes with the clotting function of fibrinogen. Individuals with acquired dysfibrinogenemias have a greater tendency for bleeding complications than those with congenital fibrinogenemia. [4] [18] [19] The following Table gives some abnormalities, causes, and apparent pathophysiology along with some comments on examples of acquired dysfibrinogenemia. [3] [4]

AbnormalityCausePathophysiologyComment
incorrect post-translational modification of fibrinogensevere liver diseaseabnormal fibrinogen sialylation most common cause of acquired dysfibrinogenemia
monoclonal antibody plasma cell dyscrasias such as multiple myeloma and MGUSmonoclonal antibody interferes with clottinguncommon
polyclonal antibody autoimmune diseases such as systemic lupus erythematosus, rheumatoid arthritis, ulcerative colitis polyclonal antibody interferes with clottinguncommon
production of abnormal fibrinogen by cancer cervical cancer of epithelium, renal cell carcinoma, others paraneoplastic effect of cancerextremely rare
Drug effect mithramycin, isoniazid, direct thrombin inhibitors (e.g. heparin, dabigatran, bivalirudin, argatroban)unclearextremely rare case reports

Diagnosis

Diagnosis of acquired dysfibrinogenemia uses the same laboratory tests that are used for congenital dysfibrinogenemia plus evidence for an underlying causative disease. [4]

Treatment

Treatment of acquired dysfibrinogenemia follows the guidelines recommended for congenital dysfibrinogenemia. [4] In addition, treatment of any disease thought to be responsible for the dysfibrinogenemia might be useful. For example, therapeutic plasma exchange and chemotherapy to reduce monoclonal antibody levels has been used successfully to reverse otherwise uncontrollable bleeding in cases of multiple myeloma-associated dysfibrinogenemia. [20] [21]

Related Research Articles

<span class="mw-page-title-main">Thrombus</span> Blood clot

A thrombus, colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cross-linked fibrin protein. The substance making up a thrombus is sometimes called cruor. A thrombus is a healthy response to injury intended to stop and prevent further bleeding, but can be harmful in thrombosis, when a clot obstructs blood flow through a healthy blood vessel in the circulatory system.

<span class="mw-page-title-main">Coagulation</span> Process of formation of blood clots

Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.

<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

Prothrombin is encoded in the human by the F2 gene. It is proteolytically cleaved during the clotting process by the prothrombinase enzyme complex to form thrombin.

Fibrinolysis is a process that prevents blood clots from growing and becoming problematic. Primary fibrinolysis is a normal body process, while secondary fibrinolysis is the breakdown of clots due to a medicine, a medical disorder, or some other cause.

In biology, hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel. It is the first stage of wound healing. Hemostasis involves three major steps:

<span class="mw-page-title-main">Hemolytic–uremic syndrome</span> Group of blood disorders related to bacterial infection

Hemolytic–uremic syndrome (HUS) is a group of blood disorders characterized by low red blood cells, acute kidney injury, and low platelets. Initial symptoms typically include bloody diarrhea, fever, vomiting, and weakness. Kidney problems and low platelets then occur as the diarrhea progresses. Children are more commonly affected, but most children recover without permanent damage to their health, although some children may have serious and sometimes life-threatening complications. Adults, especially the elderly, may present a more complicated presentation. Complications may include neurological problems and heart failure.

<span class="mw-page-title-main">Thrombophilia</span> Abnormality of blood coagulation increasing the risk of blood clotting (thrombosis)

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.

<span class="mw-page-title-main">Renal vein thrombosis</span> Medical condition

Renal vein thrombosis (RVT) is the formation of a clot in the vein that drains blood from the kidneys, ultimately leading to a reduction in the drainage of one or both kidneys and the possible migration of the clot to other parts of the body. First described by German pathologist Friedrich Daniel von Recklinghausen in 1861, RVT most commonly affects two subpopulations: newly born infants with blood clotting abnormalities or dehydration and adults with nephrotic syndrome.

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">Thrombin time</span>

The thrombin time (TT), also known as the thrombin clotting time (TCT), is a blood test that measures the time it takes for a clot to form in the plasma of a blood sample containing anticoagulant, after an excess of thrombin has been added. It is used to diagnose blood coagulation disorders and to assess the effectiveness of fibrinolytic therapy. This test is repeated with pooled plasma from normal patients. The difference in time between the test and the 'normal' indicates an abnormality in the conversion of fibrinogen to fibrin, an insoluble protein.

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

Fibrinogen alpha chain is a protein that in humans is encoded by the FGA gene.

<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, Canada. The disorder is characterized by large amounts of the fibrinolytic enzyme urokinase-type plasminogen activator (uPA) in platelets. This causes accelerated fibrinolysis which can result in bleeding.

<span class="mw-page-title-main">Familial renal amyloidosis</span> Medical condition

Familial renal amyloidosis is a form of amyloidosis primarily presenting in the kidney.

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

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

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. Hypodysfibrinogenemia exhibits reduced penetrance, i.e. only some family members with the mutated gene develop symptoms.

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.

The platelet plug, also known as the hemostatic plug or platelet thrombus, is an aggregation of platelets formed during early stages of hemostasis in response to one or more injuries to blood vessel walls. After platelets are recruited and begin to accumulate around the breakage, their “sticky” nature allows them to adhere to each other. This forms a platelet plug, which prevents more blood from leaving the body as well as any outside contaminants from getting in. The plug provides a temporary blockage of the break in the vasculature. As such, platelet plug formation occurs after vasoconstriction of the blood vessels but before the creation of the fibrin mesh clot, which is the more permanent solution to the injury. The result of the platelet plug formation is the coagulation of blood. It can also be referred to as primary hemostasis.

References

  1. ↑ "Dysfibrinogenemia". Genetic and Rare Diseases (GARD). NIH. Retrieved 19 March 2019.[ permanent dead link ]
  2. ↑ Dysfibrinogenemia at eMedicine
  3. 1 2 3 4 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 5 6 7 8 9 10 Besser MW, MacDonald SG (2016). "Acquired hypofibrinogenemia: current perspectives". Journal of Blood Medicine. 7: 217–225. doi: 10.2147/JBM.S90693 . PMC   5045218 . PMID   27713652.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 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.
  6. 1 2 3 4 5 6 7 8 Gillmore JD, Lachmann HJ, Rowczenio D, Gilbertson JA, Zeng CH, Liu ZH, Li LS, Wechalekar A, Hawkins PN (2009). "Diagnosis, pathogenesis, treatment, and prognosis of hereditary fibrinogen A alpha-chain amyloidosis". Journal of the American Society of Nephrology. 20 (2): 444–51. doi:10.1681/ASN.2008060614. PMC   2637055 . PMID   19073821.
  7. ↑ McDonagh, J (2001). "Dysfibrinogenemia and other disorders of fibrinogen structure or function". In Colman R, Hirsh J, Marder V, Clowes A, George J (eds.). Hemostasis and Thrombosis (4th ed.). Philadelphia: Lippincott Williams & Wilkins. pp. 855–92. ISBN   978-0-7817-1455-6.
  8. ↑ Hayes, T (2002). "Dysfibrinogenemia and thrombosis". Archives of Pathology & Laboratory Medicine. 126 (11): 1387–90. doi:10.5858/2002-126-1387-DAT. PMID   12421146.
  9. 1 2 3 4 5 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.
  10. 1 2 Repetto O, De Re V (2017). "Coagulation and fibrinolysis in gastric cancer". Annals of the New York Academy of Sciences. 1404 (1): 27–48. Bibcode:2017NYASA1404...27R. doi:10.1111/nyas.13454. PMID   28833193. S2CID   10878584.
  11. 1 2 3 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.
  12. ↑ 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.
  13. ↑ Mosesson MW (2005). "Fibrinogen and fibrin structure and functions". Journal of Thrombosis and Haemostasis. 3 (8): 1894–904. doi: 10.1111/j.1538-7836.2005.01365.x . PMID   16102057. S2CID   22077267.
  14. 1 2 Ruiz-Saez A (2013). "Occurrence of thrombosis in rare bleeding disorders". Seminars in Thrombosis and Hemostasis. 39 (6): 684–92. doi:10.1055/s-0033-1353391. PMID   23929306. S2CID   8840970.
  15. ↑ Tengborn L, Blombäck M, Berntorp E (2015). "Tranexamic acid--an old drug still going strong and making a revival". Thrombosis Research. 135 (2): 231–42. doi:10.1016/j.thromres.2014.11.012. PMID   25559460.
  16. ↑ Blombäck M, Blombäck B, Mammen EF, Prasad AS (1968). "Fibrinogen Detroit--a molecular defect in the N-terminal disulphide knot of human fibrinogen?". Nature. 218 (5137): 134–7. Bibcode:1968Natur.218..134B. doi:10.1038/218134a0. PMID   5645286. S2CID   4165737.
  17. 1 2 3 Said SM, Sethi S, Valeri AM, Leung N, Cornell LD, Fidler ME, Herrera Hernandez L, Vrana JA, Theis JD, Quint PS, Dogan A, Nasr SH (2013). "Renal amyloidosis: origin and clinicopathologic correlations of 474 recent cases". Clinical Journal of the American Society of Nephrology. 8 (9): 1515–23. doi:10.2215/CJN.10491012. PMC   3805078 . PMID   23704299.
  18. ↑ Ashby MA, Lazarchick J (1986). "Acquired dysfibrinogenemia secondary to mithramycin toxicity". The American Journal of the Medical Sciences. 292 (1): 53–5. doi:10.1097/00000441-198607000-00011. PMID   2940861.
  19. ↑ "UpToDate".
  20. ↑ Kotlín R, Sobotková A, Riedel T, Salaj P, Suttnar J, Reicheltová Z, Májek P, Khaznadar T, Dyr JE (2008). "Acquired dysfibrinogenemia secondary to multiple myeloma". Acta Haematologica. 120 (2): 75–81. doi:10.1159/000160182. PMID   18841003. S2CID   45965368.
  21. ↑ Post GR, James L, Alapat D, Guillory V, Cottler-Fox M, Nakagawa M (2013). "A case of acquired dysfibrinogenemia in multiple myeloma treated with therapeutic plasma exchange". Transfusion and Apheresis Science. 48 (1): 35–8. doi:10.1016/j.transci.2012.06.021. PMID   22842111.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.