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Fibrinogen (coagulation factor I) is a
glycoprotein Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
complex Complex commonly refers to: * Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe ** Complex system, a system composed of many components which may interact with each ...
, produced in the liver, that circulates in the blood of all
vertebrate Vertebrates () are animals with a vertebral column (backbone or spine), and a cranium, or skull. The vertebral column surrounds and protects the spinal cord, while the cranium protects the brain. The vertebrates make up the subphylum Vertebra ...
s. During tissue and vascular injury, it is converted
enzymatically An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as produc ...
by
thrombin Prothrombin (coagulation factor II) 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. Thrombin (Factor IIa) (, fibrose, thrombase, throm ...
to
fibrin Fibrin (also called Factor Ia) is a fibrous protein, fibrous, non-globular protein involved in the Coagulation, clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerization, polymerize. ...
and then to a fibrin-based
blood clot A thrombus ( thrombi) is a solid or semisolid aggregate from constituents of the blood (platelets, fibrin, red blood cells, white blood cells) within the circulatory system during life. A blood clot is the final product of the blood coagulatio ...
. Fibrin clots function primarily to occlude blood vessels to stop
bleeding Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethr ...
. Fibrin also binds and reduces the activity of thrombin. This activity, sometimes referred to as antithrombin I, limits clotting. Fibrin also mediates blood
platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...
and
endothelial cell The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and th ...
spreading, tissue
fibroblast A fibroblast is a type of cell (biology), biological cell typically with a spindle shape that synthesizes the extracellular matrix and collagen, produces the structural framework (Stroma (tissue), stroma) for animal Tissue (biology), tissues, and ...
proliferation, capillary tube formation, and
angiogenesis Angiogenesis is the physiological process through which new blood vessels form from pre-existing vessels, formed in the earlier stage of vasculogenesis. Angiogenesis continues the growth of the vasculature mainly by processes of sprouting and ...
and thereby promotes
revascularization In medical and surgical therapy, revascularization is the restoration of perfusion to a body part or organ that has had ischemia. It is typically accomplished by surgical means. Vascular bypass and angioplasty are the two primary means of r ...
and
wound healing Wound healing refers to a living organism's replacement of destroyed or damaged tissue by newly produced tissue. In undamaged skin, the epidermis (surface, epithelial layer) and dermis (deeper, connective layer) form a protective barrier again ...
. Reduced and/or dysfunctional fibrinogens occur in various congenital and acquired human fibrinogen-related disorders. These disorders represent a group of rare conditions in which individuals may present with severe episodes of pathological bleeding and
thrombosis Thrombosis () is the formation of a Thrombus, blood clot inside a blood vessel, obstructing the flow of blood through the circulatory system. When a blood vessel (a vein or an artery) is injured, the body uses platelets (thrombocytes) and fib ...
; these conditions are treated by supplementing blood fibrinogen levels and inhibiting blood clotting, respectively. These disorders may also be the cause of certain liver and kidney diseases. Fibrinogen is a "positive"
acute-phase protein Acute-phase proteins (APPs) are a class of proteins whose concentrations in blood plasma either increase (positive acute-phase proteins) or decrease (negative acute-phase proteins) in response to inflammation. This response is called the ''acute-p ...
, i.e. its blood levels rise in response to systemic inflammation, tissue injury, and certain other events. It is also elevated in various
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
s. Elevated levels of fibrinogen in
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
as well as cancer and other conditions have been suggested to be the cause of thrombosis and vascular injury that accompanies these conditions.


Genes

Fibrinogen is made and secreted into the blood primarily by liver
hepatocyte A hepatocyte is a cell of the main parenchymal tissue of the liver. Hepatocytes make up 80% of the liver's mass. These cells are involved in: * Protein synthesis * Protein storage * Transformation of carbohydrates * Synthesis of cholesterol, bi ...
cells.
Endothelium The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the r ...
cells are also reported to make small amounts of fibrinogen, but this fibrinogen has not been fully characterized; blood
platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...
s and their precursors, bone marrow
megakaryocytes A megakaryocyte () is a large bone marrow cell with a lobated nucleus that produces blood platelets (thrombocytes), which are necessary for normal clotting. In humans, megakaryocytes usually account for 1 out of 10,000 bone marrow cells, but ca ...
, while once thought to make fibrinogen, are now known to take up and store but not make the glycoprotein. The final secreted, hepatocyte-derived glycoprotein is composed of two trimers, with each trimer composed of three different polypeptide chains, the
fibrinogen alpha chain Fibrinogen alpha chain is a protein that in humans is encoded by the ''FGA'' gene. Function The protein encoded by this gene is the alpha component of fibrinogen, a blood-borne glycoprotein composed of three pairs of nonidentical polypeptide ...
(also termed the Aα or α chain) encoded by the ''FGA'' gene, the
fibrinogen beta chain Fibrinogen beta chain, also known as FGB, is a gene found in humans and most other vertebrate Vertebrates () are animals with a vertebral column (backbone or spine), and a cranium, or skull. The vertebral column surrounds and protects the sp ...
(also termed the Bβ or β chain) encoded by the ''FGB'' gene, and the fibrinogen gamma chain (also termed the γ chain) 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).
Alternate splicing Alternative splicing, alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to produce different splice variants. For example, some exons of a gene may be included ...
of the ''FGA'' gene produces a minor expanded
isoform A protein isoform, or "protein variant", is a member of a set of highly similar proteins that originate from a single gene and are the result of genetic differences. While many perform the same or similar biological roles, some isoforms have uniqu ...
of Aα termed AαE which replaces Aα in 1–3% of circulating fibrinogen; alternate splicing of ''FGG'' produces a minor isoform of γ termed γ' which replaces γ in 8–10% of circulating fibrinogen; ''FGB'' is not alternatively spliced. Hence, the final fibrinogen product is composed principally of Aα, Bβ, and γ chains with a small percentage of it containing AαE and/or γ' chains in place of Aα and/or γ chains, respectively. The three genes are transcribed and translated in co-ordination by a mechanism(s) which remains incompletely understood. The coordinated transcription of these three fibrinogen genes is rapidly and greatly increased by systemic conditions such as inflammation and tissue injury. Cytokines produced during these systemic conditions, such as
interleukin 6 Interleukin 6 (IL-6) is an interleukin that acts as both a pro-inflammatory cytokine and an anti-inflammatory myokine. In humans, it is encoded by the ''IL6'' gene. In addition, osteoblasts secrete IL-6 to stimulate osteoclast formation. Smoo ...
and interleukin 1β, appear responsible for up-regulating this transcription.


Structure

The Aα, Bβ, and γ chains are transcribed and translated coordinately on the
endoplasmic reticulum The endoplasmic reticulum (ER) is a part of a transportation system of the eukaryote, eukaryotic cell, and has many other important functions such as protein folding. The word endoplasmic means "within the cytoplasm", and reticulum is Latin for ...
(ER), with their peptide chains being passed into the ER while their
signal peptide A signal peptide (sometimes referred to as signal sequence, targeting signal, localization signal, localization sequence, transit peptide, leader sequence or leader peptide) is a short peptide (usually 16–30 amino acids long) present at the ...
portions are removed. Inside the ER, the three chains are assembled initially into Aαγ and Bβγ dimers, then to AαBβγ trimers, and finally to (AαBβγ)2 heximers, i.e. two AαBβγ trimers joined by numerous
disulfide bonds In chemistry, a disulfide (or disulphide in British English) is a compound containing a functional group or the anion. The linkage is also called an SS-bond or sometimes a disulfide bridge and usually derived from two thiol groups. In in ...
. The heximer is transferred to the Golgi where it is
glycosylated Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
, hydroxylated,
sulfated Sulfation (sometimes spelled sulphation in British English) is the chemical reaction that entails the addition of SO3 group. In principle, many sulfations would involve reactions of sulfur trioxide (SO3). In practice, most sulfations are effected ...
, and
phosphorylated In biochemistry, phosphorylation is described as the "transfer of a phosphate group" from a donor to an acceptor. A common phosphorylating agent (phosphate donor) is ATP and a common family of acceptor are alcohols: : This equation can be writt ...
to form the mature fibrinogen glycoprotein that is secreted into the blood. Mature fibrinogen is arranged as a long flexible protein array of three nodules held together by a very thin thread which is estimated to have a diameter between 8 and 15 
angstrom The angstrom (; ) is a unit of length equal to m; that is, one ten-billionth of a metre, a hundred-millionth of a centimetre, 0.1 nanometre, or 100 picometres. The unit is named after the Swedish physicist Anders Jonas Ångström (1814–18 ...
s (Å). The two end nodules (termed D regions or domains) are alike in consisting of Bβ and γ chains, while the center slightly smaller nodule (termed the E region or domain) consists of two intertwined Aα alpha chains. Measurements of shadow lengths indicate that nodule diameters are in the range 50 to 70 Å. The length of the dried molecule is 475 ± 25 Å. The fibrinogen molecule circulates as a soluble plasma
glycoprotein Glycoproteins are proteins which contain oligosaccharide (sugar) chains covalently attached to amino acid side-chains. The carbohydrate is attached to the protein in a cotranslational or posttranslational modification. This process is known a ...
with a typical
molecular weight A molecule is a group of two or more atoms that are held together by Force, attractive forces known as chemical bonds; depending on context, the term may or may not include ions that satisfy this criterion. In quantum physics, organic chemi ...
of ~340 – ~420  kDa (kilodaltons) (depending on its content of Aα verses AαE, γ versus γ' chains, and carbohydrate 4 – ~10%w/w. It has a rod-like shape with dimensions of 9 × 47.5 × 6 nm and has a negative net charge at physiological pH (its
isoelectric point The isoelectric point (pI, pH(I), IEP), is the pH at which a molecule carries no net electric charge, electrical charge or is electrically neutral in the statistical mean. The standard nomenclature to represent the isoelectric point is pH(I). Howe ...
~5.5 – ~6.5, e.g. pH 5.8). The normal concentration of fibrinogen in
blood plasma Blood plasma is a light Amber (color), amber-colored liquid component of blood in which blood cells are absent, but which contains Blood protein, proteins and other constituents of whole blood in Suspension (chemistry), suspension. It makes up ...
is 150–400 mg/dl, with levels appreciably below or above this range associated with pathological bleeding and/or thrombosis. Fibrinogen has a circulating
half-life Half-life is a mathematical and scientific description of exponential or gradual decay. Half-life, half life or halflife may also refer to: Film * Half-Life (film), ''Half-Life'' (film), a 2008 independent film by Jennifer Phang * ''Half Life: ...
of ~4 days.


Blood clot formation

During blood clotting,
thrombin Prothrombin (coagulation factor II) 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. Thrombin (Factor IIa) (, fibrose, thrombase, throm ...
attacks the
N-terminus The N-terminus (also known as the amino-terminus, NH2-terminus, N-terminal end or amine-terminus) is the start of a protein or polypeptide, referring to the free amine group (-NH2) located at the end of a polypeptide. Within a peptide, the amin ...
of the Aα and Bβ chains in fibrinogen to form individual fibrin strands plus two small
polypeptide Peptides are short chains of amino acids linked by peptide bonds. A polypeptide is a longer, continuous, unbranched peptide chain. Polypeptides that have a molecular mass of 10,000 Da or more are called proteins. Chains of fewer than twenty ...
s, fibrinopeptides A and B derived from these respective chains. The individual fibrin strands then polymerize and are
crosslinked In chemistry and biology, a cross-link is a bond or a short sequence of bonds that links one polymer chain to another. These links may take the form of covalent bonds or ionic bonds and the polymers can be either synthetic polymers or natural ...
with other fibrin strands by blood
factor XIII Factor XIII, or fibrin stabilizing factor, is a plasma protein and zymogen. It is activated by thrombin to factor XIIIa which crosslinks fibrin in coagulation. Deficiency of XIII worsens clot stability and increases bleeding tendency. Huma ...
a to form an extensive interconnected fibrin network that is the basis for the formation of a mature fibrin clot. In addition to forming fibrin, fibrinogen also promotes blood clotting by forming bridges between, and activating, blood
platelet Platelets or thrombocytes () are a part of blood whose function (along with the coagulation#Coagulation factors, coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus, blood clot. Platelets have no ...
s through binding to their GpIIb/IIIa surface membrane fibrinogen receptor. Fibrin participates in limiting blood clot formation and degrading formed blood clots by at least two important mechanisms. First, it possesses three low affinity binding sites (two in fibrin's E domain; one in its D domain) for thrombin; this binding sequesters thrombin from attacking fibrinogen. Second, fibrin's Aα chain accelerates by at least 100-fold the amount of
plasmin Plasmin is an important enzyme () present in blood that degrades many blood plasma proteins, including fibrin thrombus, clots. The degradation of fibrin is termed fibrinolysis. In humans, the plasmin protein (in the zymogen form of plasminogen) i ...
activated by
tissue plasminogen activator Tissue-type plasminogen activator, short name tPA, is a protein that facilitates the breakdown of blood clots. It acts as an enzyme to convert plasminogen into its active form plasmin, the major enzyme responsible for clot breakdown. It is a s ...
; plasmin breaks-down blood clots. Plasmin's attack on fibrin releases
D-dimer D-dimer (or D dimer) is a dimer that is a fibrin degradation product (FDP), a small protein fragment present in the blood after a blood clot is degraded by fibrinolysis. It is so named because it contains two D fragments of the fibrin protein ...
s (also termed DD dimers). The detection of these dimers in blood is used as a clinical test for fibrinolysis.


Fibrinogen disorders

Several disorders in the quantity and/or quality of fibrinogen cause pathological bleeding, pathological blood clotting, and/or the deposition of fibrinogen in the liver, kidneys, and other tissues.


Congenital afibrinogenemia

Congenital afibrinogenemia is a rare and generally
autosomal recessive In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
inherited disorder in which blood does not clot due to a lack of fibrinogen (plasma fibrinogen levels typically) but sometimes detected at extremely low levels, e.g. <10 mg/dl. This severe disorder is usually caused by mutations in both the maternal and paternal copies of either the ''FGA, FGB,'' or ''FBG'' gene. The mutations have virtually complete genetic
penetrance Penetrance in genetics is the proportion of individuals carrying a particular variant (or allele) of a gene (genotype) that also expresses an associated trait (phenotype). In medical genetics, the penetrance of a disease-causing mutation is the pr ...
with essentially all
homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mos ...
bearers experiencing frequent and sometimes life-threatening episodes of bleeding and/or thrombosis. Pathological bleeding occurs early in life, for example often being seen at birth with excessive hemorrhage from the
navel The navel (clinically known as the umbilicus; : umbilici or umbilicuses; also known as the belly button or tummy button) is a protruding, flat, or hollowed area on the abdomen at the attachment site of the umbilical cord. Structure The u ...
.


Congenital hypofibrinogenemia

Congenital hypofibrinogenemia is a rare inherited disorder in which blood may not clot normally due to reduced levels of fibrinogen (plasma fibrinogen typically <150 but >50 mg/dl). The disorder reflects a disruptive mutation in only one of the two parental ''FGA, FGB,'' or ''FBG'' genes and has a low degree of genetic penetrance, i.e. only some family members with the defective gene ever exhibit symptoms. Symptoms of the disorder, which more often occurs in individuals with lower plasma fibrinogen levels, include episodic bleeding and thrombosis that typically begin in late childhood or adulthood.


Fibrinogen storage disease

Fibringogen storage disease is an extremely rare disorder. It is a form of congenital hypofibrinogenemia in which certain specific hereditary mutations in one copy of the ''FGG'' gene causes its fibrinogen product to accumulate in, and damage, liver cells. The disorder has not reported with ''FGA'' or ''FGB'' mutations. Symptoms of these ''FGG'' mutations have a low level of penetrance. The plasma fibrinogen levels (generally <150 but >50 mg/dl) detected in this disorder reflect the fibrinogen made by the normal gene. Fibrinogen storage disease may lead to abnormal bleeding and thrombosis but is distinguished by also sometimes leading to liver
cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...
.


Congenital dysfibrinogenemia

Congenital dysfibrinogenemia is a rare
autosomal dominant In genetics, dominance is the phenomenon of one variant (allele) of a gene on a chromosome masking or overriding the Phenotype, effect of a different variant of the same gene on Homologous chromosome, the other copy of the chromosome. The firs ...
inherited disorder in which plasma fibrinogen is composed of a dysfunctional fibrinogen made by a mutated ''FGA, FGB,'' or ''FBG'' gene inherited from one parent plus a normal fibrinogen made by a normal gene inherited from the other parent. As a reflection of this duality, plasma fibrinogen levels measured by immunological methods are normal (>150 mg/dl) but are c. 50% lower when measured by clot formation methods. The disorder exhibits reduced penetrance, with only some individuals with the abnormal gene showing symptoms of abnormal bleeding and thrombosis.


Hereditary fibrinogen Aα-Chain amyloidosis

Hereditary fibrinogen Aα-Chain amyloidosis is an autosomal dominant extremely rare inherited disorder caused by a mutation in one of the two copies of the ''FGA'' gene. It is a form of congenital dysfibrinogenemia in which certain mutations lead to the production of an abnormal fibrinogen that circulates in the blood while gradually accumulating in the kidney. This accumulation leads over time to one form of
familial renal amyloidosis Familial renal amyloidosis is a form of amyloidosis primarily presenting in the kidney. It is associated most commonly with congenital mutations in the fibrinogen alpha chain and classified as a dysfibrinogenemia (see Hereditary Fibrinogen Aα-C ...
. Plasma fibrinogen levels are similar to that seen in other forms of congenital dysfibrinogenemia. Fibrinogen Aα-Chain amyloidosis has not associated with abnormal bleeding or thrombosis.


Acquired dysfibrinogenemia

Acquired dysfibrinogenemia is a rare disorder in which circulating fibrinogen is composed at least in part of a dysfunctional fibrinogen due to various acquired diseases. One well-studied cause of the disorder is severe
liver disease Liver disease, or hepatic disease, is any of many diseases of the liver. If long-lasting it is termed chronic liver disease. Although the diseases differ in detail, liver diseases often have features in common. Liver diseases File:Ground gla ...
including hepatoma, chronic active
hepatitis Hepatitis is inflammation of the liver parenchyma, liver tissue. Some people or animals with hepatitis have no symptoms, whereas others develop yellow discoloration of the skin and whites of the eyes (jaundice), Anorexia (symptom), poor appetite ...
,
cirrhosis Cirrhosis, also known as liver cirrhosis or hepatic cirrhosis, chronic liver failure or chronic hepatic failure and end-stage liver disease, is a chronic condition of the liver in which the normal functioning tissue, or parenchyma, is replaced ...
, and
jaundice Jaundice, also known as icterus, is a yellowish or, less frequently, greenish pigmentation of the skin and sclera due to high bilirubin levels. Jaundice in adults is typically a sign indicating the presence of underlying diseases involving ...
due to biliary tract obstruction. The diseased liver synthesizes a fibrinogen which has a normally functional
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although over 500 amino acids exist in nature, by far the most important are the 22 α-amino acids incorporated into proteins. Only these 22 a ...
sequence but is incorrectly
glycosylated Glycosylation is the reaction in which a carbohydrate (or ' glycan'), i.e. a glycosyl donor, is attached to a hydroxyl or other functional group of another molecule (a glycosyl acceptor) in order to form a glycoconjugate. In biology (but not ...
(i.e. has a wrong amount of sugar residues) added to it during its passage through the Golgi. The incorrectly glycosalated fibrinogen is dysfunctional and may cause pathological episodes of bleeding and/or blood clotting. Other, less well understood, causes are plasma cell dyscrasias and
autoimmune disorders An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
in which a circulating abnormal immunoglobulin or other protein interferes with fibrinogen function, and rare cases of cancer and medication (
isotretinoin Isotretinoin, also known as 13-''cis''-retinoic acid and sold under the brand name Accutane among others, is a medication used to treat skin diseases like harlequin-type ichthyosis, and lamellar ichthyosis, and severe cystic acne or moderat ...
,
glucocorticoids Glucocorticoids (or, less commonly, glucocorticosteroids) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor that is present in almost every vertebra ...
, and antileukemic drugs) toxicities.


Congenital hypodysfibrinogenemia

Congenital hypodysfibrinogenemia is a rare inherited disorder in which low levels (i.e. <150 mg/dl) of immunologically detected plasma fibrinogen are composed at least in part of a dysfunctional fibrinogen. The disorder reflects mutations typically in both inherited fibrinogen genes, one of which produces a dysfunctional fibrinogen, while the other produces low amounts of fibrinogen. The disorder, while having reduced penetrance, is usually more severe than congenital dysfibrinogenemia, but like the latter disorder, causes pathological episodes of bleeding and/or blood clotting.


Cryofibrinogenemia

Cryofibrinogenemia is an acquired disorder in which fibrinogen precipitates at cold temperatures and may lead to the intravascular precipitation of fibrinogen,
fibrin Fibrin (also called Factor Ia) is a fibrous protein, fibrous, non-globular protein involved in the Coagulation, clotting of blood. It is formed by the action of the protease thrombin on fibrinogen, which causes it to polymerization, polymerize. ...
, and other circulating proteins, thereby causing the
infarction Infarction is tissue death (necrosis) due to Ischemia, inadequate blood supply to the affected area. It may be caused by Thrombosis, artery blockages, rupture, mechanical compression, or vasoconstriction. The resulting lesion is referred to as a ...
of various tissues and bodily extremities. Cryoglobulonemia may occur without evidence of an underlying associated disorders, i.e. primary cryoglobulinemia (also termed essential cryoglobulinemia) or, far more commonly, with evidence of an underlying disease, i.e. secondary cryoglobulonemia. Secondary cryofibrinoenemia can develop in individuals with infection (% of cases),
malignant Malignancy () is the tendency of a medical condition to become progressively worse; the term is most familiar as a characterization of cancer. A ''malignant'' tumor contrasts with a non-cancerous benign tumor, ''benign'' tumor in that a malig ...
or premalignant disorders (21%),
vasculitis Vasculitis is a group of disorders that destroy blood vessels by inflammation. Both artery, arteries and veins are affected. Lymphangitis (inflammation of lymphatic vessels) is sometimes considered a type of vasculitis. Vasculitis is primarily c ...
(25%), and
autoimmune disease An autoimmune disease is a condition that results from an anomalous response of the adaptive immune system, wherein it mistakenly targets and attacks healthy, functioning parts of the body as if they were foreign organisms. It is estimated tha ...
s (42%). In these cases, cryofibinogenema may or may not cause tissue injury and/or other symptoms and the actual cause-effect relationship between these diseases and the development of cryofibrinogenmia is unclear. Cryofibrinogenemia can also occur in association with the intake of certain drugs.


Acquired hypofibrinogenemia

Acquired hypofibrinogenemia is a deficiency in circulating fibrinogen due to excessive consumption that may occur as a result of trauma, certain phases of
disseminated intravascular coagulation Disseminated intravascular coagulation (DIC) is a condition in which blood clots form throughout the body, blocking Microvessel, small blood vessels. Symptoms may include chest pain, shortness of breath, leg pain, problems speaking, or problems ...
, and
sepsis Sepsis is a potentially life-threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. This initial stage of sepsis is followed by suppression of the immune system. Common signs and s ...
. It may also occur as a result of hemodilution as a result of blood losses and/or transfusions with
packed red blood cells Red blood cell concentrates, also known as red cell concentrates or packed red blood cells, are red blood cells that have been separated for blood transfusion. A red blood cell concentrate typically has a haematocrit of 0.50 – 0.70 L/L and ...
or other fibrinogen-poor whole blood replacements.


Laboratory tests

Clinical analyses of the fibrinogen disorders typically measure blood clotting using the following successive steps: Higher levels are, amongst others, associated with
cardiovascular disease Cardiovascular disease (CVD) is any disease involving the heart or blood vessels. CVDs constitute a class of diseases that includes: coronary artery diseases (e.g. angina, heart attack), heart failure, hypertensive heart disease, rheumati ...
(>3.43 g/L). It may be elevated in any form of
inflammation Inflammation (from ) is part of the biological response of body tissues to harmful stimuli, such as pathogens, damaged cells, or irritants. The five cardinal signs are heat, pain, redness, swelling, and loss of function (Latin ''calor'', '' ...
, as it is an
acute-phase protein Acute-phase proteins (APPs) are a class of proteins whose concentrations in blood plasma either increase (positive acute-phase proteins) or decrease (negative acute-phase proteins) in response to inflammation. This response is called the ''acute-p ...
; for example, it is especially apparent in human gingival tissue during the initial phase of periodontal disease. *Blood clotting is measured using standard tests, e.g.
prothrombin time The prothrombin time (PT) – along with its derived measures of prothrombin ratio (PR) and international normalized ratio (INR) – is an assay for evaluating the Coagulation#Extrinsic pathway, extrinsic pathway and Coagulation#Common pathway, ...
,
partial thromboplastin time The partial thromboplastin time (PTT), also known as the activated partial thromboplastin time (aPTT or APTT), is a blood test that characterizes coagulation of the blood. A historical name for this measure is the Kaolin-cephalin clotting time ...
,
thrombin time 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 ...
, and/or reptilase time. Low fibrinogen levels and dysfunctional fibrinogens usually prolong these times, whereas the lack of fibrinogen (i.e. afibrinogenemia) renders these times infinitely prolonged. *Fibrinogen levels are measured in the plasma isolated from
venous Veins () are blood vessels in the circulatory system of humans and most other animals that carry blood towards the heart. Most veins carry deoxygenated blood from the tissues back to the heart; exceptions are those of the pulmonary and fetal c ...
blood by immunoassays, or through clotting assays such as the Clauss fibrinogen assay or
prothrombin Prothrombin (coagulation factor II) 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. Thrombin (Factor IIa) (, fibrose, thrombase, throm ...
based methods. Normal levels being about 1.5-3 g/L, depending on the method used. These levels are normal in dysfibrinogenemia (i.e. 1.5-3 g/L), decreased in hypofibrinogenemia and hypodysfibrinogenemia (i.e. <1.5 g/L), and absent (i.e. <0.02 g/L) in afibrinogenemia. *Functional levels of fibrinogen are measured on plasma induced to clot. The levels of clotted fibrinogen in this test should be decreased in hypofibrinogenemia, hypodysfibrinogenemia, and dysfibrinogenemia and undetectable in afibrinogenemia. *Functional fibrinogen/antigenic fibrinogen levels are <0.7 g/L in hypofibrinogenemia, hypodysfibrinogenemia, and dysfibrogenemia, and not applicable in afibrinogenemia. *Fibrinogen analysis can also be tested on whole-blood samples by thromboelastometry. This analysis investigates the interaction of coagulation factors, their inhibitors, anticoagulant drugs, and blood cells (specifically, platelets), during clotting and subsequent fibrinolysis as it occurs in whole blood. The test provides information on hemostatic efficacy and maximum clot firmness to give additional information on fibrin-platelet interactions and the rate of fibrinolysis (see
Thromboelastometry Thromboelastometry (TEM), previously named rotational thromboelastography (ROTEG) or rotational thromboelastometry (ROTEM), is an established viscoelastic method for hemostasis testing in whole blood. It is a modification of traditional thrombo ...
). *Scanning electron microscopy and confocal laser scanning microscopy of in vitro-formed clots can give information on fibrin clot density and architecture. *The fibrinogen uptake test or fibrinogen scan was formerly used to detect
deep vein thrombosis Deep vein thrombosis (DVT) is a type of venous thrombosis involving the formation of a blood clot in a deep vein, most commonly in the legs or pelvis. A minority of DVTs occur in the arms. Symptoms can include pain, swelling, redness, and enl ...
. In this method, radioactively labeled fibrinogen, typically with
radioiodine There are 40 known isotopes of iodine (53I) from 108I to 147I; all undergo radioactive decay except 127I, which is stable. Iodine is thus a monoisotopic element. Its longest-lived radioactive isotope, 129I, has a half-life of 16.14 million ye ...
, is given to individuals, incorporated into a
thrombus A thrombus ( thrombi) is a solid or semisolid aggregate from constituents of the blood (platelets, fibrin, red blood cells, white blood cells) within the circulatory system during life. A blood clot is the final product of the blood coagulatio ...
, and detected by
scintigraphy Scintigraphy (from Latin ''scintilla'', "spark"), also known as a gamma scan, is a diagnostic test in nuclear medicine, where radioisotopes attached to drugs that travel to a specific organ or tissue (radiopharmaceuticals) are taken internally a ...
.


Hyperfibrinogenemia

Levels of functionally normal fibrinogen increase in
pregnancy Pregnancy is the time during which one or more offspring gestation, gestates inside a woman's uterus. A multiple birth, multiple pregnancy involves more than one offspring, such as with twins. Conception (biology), Conception usually occurs ...
to an average of 4.5 gram/liter (g/L) compared to an average of 3 g/L in non-pregnant people. They may also increase in various forms of cancer, particularly gastric,
lung The lungs are the primary Organ (biology), organs of the respiratory system in many animals, including humans. In mammals and most other tetrapods, two lungs are located near the Vertebral column, backbone on either side of the heart. Their ...
,
prostate The prostate is an male accessory gland, accessory gland of the male reproductive system and a muscle-driven mechanical switch between urination and ejaculation. It is found in all male mammals. It differs between species anatomically, chemica ...
, and
ovarian cancer Ovarian cancer is a cancerous tumor of an ovary. It may originate from the ovary itself or more commonly from communicating nearby structures such as fallopian tubes or the inner lining of the abdomen. The ovary is made up of three different ...
s. In these cases, the ''hyperfibrinogenemia'' may contribute to the development of pathological thrombosis. A particular pattern of migratory
superficial vein Superficial veins are veins that are close to the surface of the body, as opposed to deep veins, which are far from the surface. Superficial veins are not paired with an artery, unlike the deep veins, which are typically associated with an art ...
thrombosis, termed trousseau's syndrome, occurs in, and may precede all other signs and symptoms of, these cancers. Hyperfibrinogenemia has also been linked as a cause of persistent pulmonary hypertension of the newborn and post-operative thrombosis. High fibrinogen levels had been proposed as a predictor of hemorrhagic complications during catheter-directed thrombolysis for acute or subacute peripheral native artery and arterial bypass occlusions. However, a systematic review of the available literature until January 2016 found that the predictive value of plasma fibrinogen level for predicting hemorrhagic complications after catheter-directed thrombolysis is unproven.


History

Paul Morawitz in 1905 described fibrinogen.


References


External links

* Jennifer McDowall/Interpro
Protein of the Month: ''Fibrinogen''.
* Peter D'Eustachio/reactome:
fibrinogen → fibrin monomer + 2 fibrinopeptide A + 2 fibrinopeptide B
' * Khan Academy Medicine (on YouTube):
Clotting 1 - How do we make blood clots?
' * * * {{Acute phase proteins Acute-phase proteins Blood proteins Coagulation system Precursor proteins