Fibrin (also called Factor Ia) is a fibrous protein involved in the clotting of blood, and is non globular. It is a fibrillar protein that is polymerised to form a "mesh" that forms a hemostatic plug or clot (in conjunction with platelets) over a wound site.

Fibrin is made from fibrinogen, a soluble plasma glycoprotein that is synthesised by the liver. Processes in the coagulation cascade activate the zymogen prothrombin to the serine protease thrombin, which is responsible for converting fibrinogen into fibrin. Fibrin is then cross linked by factor XIII to form a clot. FXIIIa stabilizes fibrin further by incorporation of the fibrinolysis inhibitors alpha-2-antiplasmin and TAFI (thrombin activatable fibrinolysis inhibitor, procarboxypeptidase B), and binding to several adhesive proteins of various cells. Both the activation of Factor XIII by thrombin and plasminogen activator (t-PA) are catalyzed by fibrin. Fibrin specifically binds the activated coagulation factors factor Xa and thrombin and entraps them in the network of fibers, thus functioning as a temporary inhibitor of these enzymes which stay active and can be released during fibrinolysis. Recent research has shown that fibrin plays a key role in the inflammatory response and development of rheumatoid arthritis.

Fibrin is involved in the following biological processes: signal transduction, blood coagulation, platelet activation, and protein polymerization.

Role in disease

Excessive generation of fibrin due to activation of the coagulation cascade leads to thrombosis, while ineffective generation or premature lysis of fibrin predisposes to hemorrhage.

Dysfunction or disease of the liver can lead to a decrease in fibrinogen production or the production of abnormal fibrinogen molecules with reduced activity (dysfibrinogenaemia). Hereditary abnormalities of fibrinogen (the gene is carried on chromosome 4) are of both quantitative and qualitative in nature and include; afibrinogenaemia, hypofibrinogenaemia, dysfibrinogenaemia, and hypodysfibrinogenaemia.

Fibrinogen deficiency

Congenital deficiency (afibrinognenemia) or disturbed function of fibrinogen has been described in a few cases.
It can lead to either bleeding, thromboembolic complications or is clinically without pathological findings. More common are acquired deficiency stages which can be detected by laboratory tests in blood plasma or in whole blood by means of thrombelastometry. Acquired deficiency is found after hemodilution, blood losses and/or consumption such as in trauma patients, during some phases of disseminated intravascular coagulation (DIC), and also in sepsis. In patients with fibrinogen deficiency, the correction of bleeding is possible by infusion of fresh frozen plasma (FFP), cryoprecipitate (a fibrinogen rich plasma fraction) or by fibrinogen concentrates. There is increasing evidence that correction of fibrinogen deficiency or fibrinogen polymerization disorders is very important in patients with bleeding.

Diagnostic use

Fibrinogen levels can be measured in venous blood. Normal levels are about 1.5-3.0 g/L, depending on the method which is used. Typically fibrinogen is measured in citrated plasma samples in the laboratory, however the analysis of whole blood samples by use of thrombelastometry (platelet function is inhibited with cytochalasin D) is also possible. Higher levels are, amongst others, associated with cardiovascular disease (>4.6 g/L). It may be elevated in any form of inflammation, as it is an acute phase protein.

It is used in veterinary medicine as an inflammatory marker: in horses a level above the normal range of 1.0-4.0 g/L suggests some degree of systemic inflammatory response.

Low levels of fibrinogen can indicate a systemic activation of the clotting system, with consumption of clotting factors faster than synthesis. This excessive clotting factor consumption condition is known as Disseminated Intravascular Coagulation or "DIC." DIC can be difficult to diagnose, but a strong clue is low fibrinogen levels in the setting of prolonged clotting times (PT or PTT), in the context of acute critical illness such as sepsis or trauma. Besides low fibrinogen level, fibrin polymerization disorders which can be induced by several factors, including plasma expanders, can also lead to severe bleeding problems. Fibrin polymerization disorders can be detected by viscoelastic methods such as thrombelastometry.

Physiology

Fibrinogen (also called factor I) is a 340 KDa glycoprotein synthesised in the liver by hepatocytes and megakaryocytes. The concentration in blood plasma is 1.5-4.0 g/L (normally measured using the Clauss method) or about 7 µM. In its natural form, fibrinogen can form bridges between platelets, by binding to their GpIIb/IIIa surface membrane proteins; however its major function is as the precursor to fibrin.

Fibrinogen, the principal protein of vertebrate blood clotting is a hexamer containing two sets of three different chains (α, β, and γ), linked to each other by disulfide bonds. The N-terminal sections of these three chains contain the cysteines that participate in the cross-linking of the chains. The C-terminal parts of the α, β and γ chains contain a domain of about 225 amino-acid residues, which can function as a molecular recognition unit. In fibrinogen as well as in angiopoietin this domain is implicated in protein-protein interactions. In lectins, such as mammalian ficolins and invertebrate tachylectin 5A, the fibrinogen C-terminal domain binds carbohydrates. On the fibrinogen α and β chains, there is a small peptide sequence (called a fibrinopeptide). It is these small peptides that prevent fibrinogen spontaneously forming polymers with itself.

Structure

The image at the left is a crystal structure of the double-d fragment from human fibrin with two bound ligands. The experimental method used to obtain the image was X-ray diffraction, and it has a resolution of 2.30 Å. The structure is mainly made up of single alpha helices shown in red and beta sheets shown in yellow. The two blue structures are the bound ligands. The chemical structures of the ligands are Ca⁺² ion, alpha-D-mannose (C₆H₁₂O₆), and D-glucosamine (C₈H₁₅NO₆).

See also

• Fibrin Scaffold