Fibrinogen

Fibrin and Cancer

Malignant tumours can initiate inflammation, with fibrinogen forming part of the tumour inflammatory response. Fibrinogen that is localised to tumours appears to be converted to fibrin polymers, possibly as a result of the inflammatory response by leukocytes that accumulate and infiltrate the tumour mass. The fibrin polymers appear to accumulate within the tumour stroma and to envelop the tumour cells, possibly by binding to the integrin-like receptors on the tumour cell surface. The fibrin matrix may help promote angiogenesis within the tumour, which is necessary for its growth and propagation. This process may occur because of fibrin’s role in inflammation.

Atherosclerosis

Atherosclerosis is the clogging, narrowing and hardening of the arteries, which can lead to stroke, heart attack, eye problems and kidney problems. Atherosclerosis is characterised by the deposition of plaques, which consist of hydrophobic lipids, macrophages, smooth muscle cells and proteins beneath the endothelial lining of large arteries. Plaques also appear to contain fibrin and its degradation products, which may be involved in the growth and development of plaques, possibly through its role in inflammation. As a result, high levels of blood fibrinogen may be a risk factor for atherosclerosis.

Dysfibrogenaemia

Mutational changes in any of the three genes (FGA, FGB, and FGG) that encode the three fibrinogen polypeptides (Aa, Bb and g) can result in structural changes in fibrinogen that can affect its properties, such as its ability to form clots. The general term, dysfibrinogenaemia, relates to congenital defects in the fibrinogen molecule that lead to recurrent thrombosis. Patients with dysfibrogenaemia can show prolonged clot formation, or, in the most sever cases, no clot formation at all. Dysfibrinogenaemia can lead to abnormal clotting, increased bleeding and wound splitting. Defects can occur in the conversion of fibrinogen to fibrin, though in the majority of cases, defects occur in the aggregation of fibrin into a polymer clot.

Fibrinogen binding by Pathogens

The pathogenic bacteria Streptococcus agalactiae is responsible for causing pneumonia, sepsis, andmeningitis in newborns, as well as cellulitis,arthritis, urinary tract infections, and endocarditis in immune-compromised adults. These bacteria carry a receptor, FbsA, which is capable of binding to fibrinogen. This binding results in the fibrinogen-dependent aggregation of platelets, permitting the bacteria to adhere to the extracellular matrix and invade the pulmonary epithelium, which is thought to be necessary for infection.

Snake Bites, Fibrinolysis and Clinical Drugs

Several different snake species, including Viperidae (vipers and rattlesnakes) and Elapidae (cobras, kraits and coral snakes), can produce venoms containing fibrin(ogen)olytic enzymes. These enzymes attack fibrin to degrade blood clots, as well as fibrinogen to prevent further clot formation. Some of these enzymes can also attack basement membrane proteins to induce haemorrhaging. There are different types of fibrin(ogen)olytic enzymes, some attacking a specific chain, such as a-fibrin(ogen)ase and b-fibrin(ogen)ase, which preferentially attack the Aa or Bb polypeptide of fibrin(ogen, respectively. Two general classes of fibrinolytic enzymes have been characterised, metalloproteinases and serine proteinases, which differ in their mechanism of action.

Snake venom fibrinolytic enzymes have potential use as clinical drugs for the treatment of occlusive thrombi - for example, fibrolase, a fibrinolytic metalloproteinase from Agkistrodon contortrix contortrix, and the serine b-fibrinogenolytic proteinase from Vipera lebetina. Recombinant enzymes have also been produced for clinical trials, such as alfimeprase, a structurally altered fibrolase.