Blood Clotting Cascade (brief intro)

Source: Wikipedia and some old Wk. 2 lecture

Definition:

Blood Clotting Cascade: How blood clots (The coagulation process in humans is most extensively researched and therefore best known - and therefore most complicated).

Blood clotting, or coagulation, is an important part of homeostasis (the cessation of blood loss from a damaged vessel) whereby a damaged blood vessel wall is covered by a fibrin clot to stop hemorrhage and aid repair of the damaged vessel. Disorders in coagulation can lead to increased hemorrhage and/or thrombosis and embolism.

In Brief:

The blood clotting cascade consists of a large number of factors, most of which are specialized enzymes called proteases (enzymes that cleave peptide bonds between amino acids of proteins).

It is called a "cascade" because each factor activates the next factor, usually by cleaving it.

Overall, the effect is to activate the enzyme, thrombin, which is responsible for most of the final, visible effects of clotting.

Two major functions of thrombin are the formation of a fibrin clot and the activation of platelets - together these components form a blood clot.

Thrombin:

Thrombin is a coagulation protein that has many effects in the coagulation cascade. It is a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions.

Thrombosis:

Thrombosis is the formation of a clot, or thrombus, inside a blood vessel - obstructing blood flow through the circulation system.

If the clotting cascade is activated inappropriately or in an uncontrolled manner, a thrombosis is formed. This is usually due to a narrowing of an artery or vein.

Venouse thrombosis (deep vein thrombosis - DVT) is usually due to lack of control by anticoagulant factors.

Antithrombin:
(a serine protease inhibitor [serpine] under conformational control)

Antithrombin is a small molecule that inactivates several enzymes of the coagulation system. It is a glycoprotein produced by the liver.

Antithrombin inhibits the serine proteases of the clotting cascade, especially thrombin and factor Xa and thus plays a fundamental role in controlling the blood coagulation cascade.

Serpins:

Lecture: "Serpins - a family of proteinase inhibitors that undergo conformational change"

Wikipedia: Serpins (short for serine protease inhibitor) are a group of structurally related proteins, many of which inhibit peptidases (enzymes that degrade protein, old name: proteases). Although initially simply considered a class of protease inhibitors (proteins that block the action of peptidases), it was discovered later that it has members that do not inhibit any enzymes, but serve as storage proteins (ovalbumin, in egg white), carriage proteins (thyroxine-binding globulin, sex hormone binding globulin) and hormone precursors (angiotensinogen). The term serpin is used for these members as well, despite their noninhibitory function.

Heparin:

Heparin is a highly sulfated glycosaminoglycan widely used as an injectable anticoagulant. It is also used to form an inner anticoagulant surface on various experimental and medical devices such as test tubes and renal dialysis machines. Pharmaceutical grade heparin is commonly derived from mucosal tissues of slaughtered meat animals such as porcine intestine or bovine lung.

Heparin controls the action of antithrombin. For efficient interaction with target proteinases antithrombin requires the cofactor heparin:
- Antithrombin circulates in a relatively inactive form
- Binding heparin dramatically accelerates interaction with target proteinases
- Major anticoagulant effect of heparin occurs by acting through antithrombin

Mutations in antithrombin - a major risk factor for DVT

- Mice completely deficient in antithrombin die in utero due to uncontrolled clotting - antithrombin is important

- Heterozygous mutations in antithrombin (mutation to one allele) can cause it to be ineffective in controlling clotting proteases

- Lack of efficient control of the clotting proteases can lead to venous thrombosis

Causes of antithrombin deficiency:
- Antithrombin, like other serpins, is prone to being unstable
- Certain mutations cna cause it to be unstable because it aggregates or polymerises
- This means there will be lower levels of active antithrombin
- Point mutations to antithrombin may also cause it to be inactive without affecting stability
- These mutations usually affect residues important for binding heparin or the protease target