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Home >> Molecular Biology Dictionary >> Fibrinogen
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Fibrinogen
The major clot forming substrate in the blood plasma of vertebrates. Though fibrinogen represents a small fraction of plasma proteins (normal human plasma has a fibrinogen content of 2 4 mg/ml ofa total of70 mg protein / ml), its conversion to fibrin causes a dramatic gelation which blocks the flow of blood. Upon injury, sufficient amounts of the clotting enzyme, thrombin, are generate in about 5 min clotting time to produce a gel.
Although clotting in the circulation(thrombosis) can be extremely dangerous, clotting is an essential and normal response (hemostasis) for preventing the loss of blood. Individuals born with the hereditary absence of fibrinogen (afibrinogenemia) suffer from severe bleeding, which can be counteracted by transfusing normal plasma or purified fibrinogen.
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There are also rare cases ofabnormal fibrinogens (dysfibrinogenemia) which may be associated with tendency for bleeding. Depletion offibrinogen might occur by disseminated intravascular coagulation when substances which promote clotting enter the circulation (as in placenta abruption). Premature degradation of fibrinogen by the proteolytic enzymethe plasmin could also lower the fibrinogen concentration of plasma to levels where life threatening hemorrhage might ensue. Malignant cells produce large amounts of activators of this fibrinolytic system, and the problem is often compounded by the fact that the fibrinogen-degradation products themselves interfere with clotting.
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Drugs such as e aminocaproic acid, which inhibit the conversion ofplasminogen to plasmin, might be useful in such a situation. Fibrinogen is synthesized by the hepatocytes in the liver, and the synthetic rate can be stimulated by hormones. Significant amounts of carbohydrates become attached to the protein before it is secreted into the circulation; fibrinogen is a plasma glycoprotein. Alterations in its carbohydrate composition as found in some liver diseases can give rise to abnormal fibrinogens with defective clotting properties.
In electron micrographs, fibrinogen has a length of about 45 nanometers, and the molecule appears to be symmetrical. The structure can be represented best by a model comprising globular as well as rodlike regions (Fig. la). The diameters of the nodular domains (starting from either end) are 4.8,4.8,3.4, and 4.5 nm. The rods are 2.2 nm thick.
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Though not shown in Fig. 1, there are also two flexible appendages (a short and along one) protruding from both ends of the molecule. The longer appendages are highly exposed, and they can be easily removed by proteolytic enzymes.
Fibrinogen
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During clotting, an end to end association ensues' (Fig. 1b), followed by a side to side aggregation of the filaments (Fig. 1c), producing a half staggered overlap of individual molecules with a characteristic cross striation of about 22.5 nm. In this array, the central nodule of one molecule interacts with the two end to end associated, terminal globules in the neighboring filament.
Composition
As far as chemical composition is concerned, human fibrinogen, with a molecular weight of 337,897, comprises two sets of three open polypeptide chains (Aa, Bb, and Y) held together by disulfide bonds; thus, the composition can be expressed as(Aa2 Bb2 Y2 Only the Bb and rchains carry carbohydrate residues.
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Each of the three polypeptides is encoded by a distinct messenger ribonucleic acid, which indicates that the of fibrinogen is the result of the concerted expression of three genes. The Aa chain is the largest (mol wt 66,026), followed by Bb (mol wt 54,358) and Y chain (mol wt48,529). Though the exact mode of assembly of these constituent chains in the model given in Fig 1 is not yet known, they are arranged such known, they arranged such that all N termini are located in the central globular region and all C termini are found on the outermost structures.
The long, flexible appendages protruding from each end of the molecule comprise the C terminal regions of the Aa chains and the short appendages the C termini ofY chains. The complete amino acid sequences of all chains of human fibrinogen are known. Considerable evolutionary variations exist in vertebrates with regard to the sequences of N terminal peptides in the Aa Bb chains (called fibrinopeptides A and B) and in the exposed C terminal half of the Aa chain. Clotting mechanism.
It is now possible to reconstruct with reasonable certainty the sequence ofevents surrounding the clotting offibrinogen in normal plasma, and each of the reaction steps in the scheme in Fig. 2 can be studied separately with the use of purified components. Clotting is regulated by two enzymes, thrombin and factor XIIIa (fibrinoligase, activated fibrin stabilizing factor, transglutaminase). Thrombin is a protease similar to trypsin but ofmuch greater specificity. It exerts a dual control by regulating the rate of fibrin formation as well as producing factor XIIIa by processes of limited proteolysis.
In the fibrinogen fibrin conversion, about 97% ofthe parent protein fibrin and 3% appears as fibrinopeptides A and B; in the reaction of thrombin with factor XIII, activation fragments are released from the N termini of the a subunits of factor XIII.The presence of fibrinogen greatly accelerates the latter reaction so that the production of fibrin and the activation of factor XIII are harmonized. In the plasma milieu, the fibrin molecules readily aggregate into a clot. In order to obtain a clot structure of a strength sufficient to stem bleeding, it is necessary for the thrombin-modified factor XIII (indicated as XIII in Fig. 2) to be activated to XIIIa This is promoted by fibrinogen and is accomplished by the action of Ca2+ ions which dissociate the catalytic subunits (a*2) from the inert, carrier subunits (b2). Factor XIIIa acts as a transamidating enzyme which strengthens the fibrin clot by creating a few r glutamyl e Iysine cross links (Fig. 3). Without such cross links, a clot structure would be like a brick wall without mortar.
Physiological pathway Clothing of Fibrinogen
Enzyme Catalyzed Reaction in Blood Clotting
Individuals with the hereditary absence of factor XIII often suffer from severe bleeding, even though their clotting times are in the normal range. In addition, various molecular disorders of fibrin stabilization are known in which some acquired inhibitor suddenly makes its appearance in the circulation, directed either against the activation of factor XIII or against the cross linking of fibrin by XIIIa. Several such inhibitors were found to be autoimmune IgG antibodies. Primary amines also specifically inhibit cross linking without interfering with fibrin formation.
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