Thrombin

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(Redirected from Prothrombin)

Image:2c93.png
Thrombin in complex with an inhibitor
coagulation factor II
Identifiers
Symbol(s)	F2
Entrez	2147
OMIM	176930
RefSeq	NM_000506
UniProt	P00734
Other data
EC number	3.4.21.5
Locus	Chr. 11 p11-q12

Thrombin (activated Factor II (IIa)) is a coagulation protein that has many effects in the coagulation cascade. It is a serine protease (EC 3.4.21.5) that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions.

1 Gene
2 Physiology
3 Role in disease
4 Pharmacology
5 References

[edit] Gene

The prothrombin gene is located on the eleventh chromosome (11p11-q12). The molecular weight of prothrombin is approximately 72000. Once activated, the catalytic domain of prothrombin (i.e. thrombin, molecular weight 36000) is released from prothrombin fragment 1.2. There are an estimated 30 people in the world who have been diagnosed with the congenital form of Factor II. The prothrombin gene is called a Factor II mutation. Most people who have a Factor II mutation acquire it later on in life, unlike the few who have obtained it congenitally. The Factor II mutated gene is not always accompanied by other factors (i.e. the most common Factor V). In most cases, it is viewed as a homozygous gene (unless otherwise) diagnosed as heterozygous. If you are on oral contraceptives or you have accompanying conditions (i.e. Crohn's disease or Ulcerative Colitis) it is best to be tested for all clotting factors.

[edit] Physiology

[edit] Generation

Thrombin is produced by the enzymatic cleavage of two sites on prothrombin by activated Factor X (Xa). The activity of factor Xa is greatly enhanced by binding to activated Factor V (Va), termed the prothrombinase complex. Prothrombin is produced in the liver and is post-translationally modified in a vitamin K-dependent reaction that converts ten glutamic acids on prothrombin to gamma-carboxyglutamic acid (Gla). In the presence of calcium, the gamma-carboxyglutamic acid residues promote the binding of thrombin to phospholipid bilayers. Deficiency of vitamin K or administration of the anticoagulant warfarin inhibits the production of gamma-carboxyglutamic acid residues, slowing the activation of the coagulation cascade.

[edit] Action

Thrombin converts fibrinogen to an active form that assembles into fibrin. Thrombin also activates factor XI, factor V and factor VIII. This positive feedback accelerates the production of thrombin.

Factor XIII is also activated by thrombin. Factor XIIIa is a transglutaminase that catalyzes the formation of covalent bonds between lysine and glutamine residues in fibrin. The covalent bonds increase the stability of the fibrin clot.

[edit] Platelets

In addition to its activity in the coagulation cascades, thrombin also promotes platelet activation, via activation of protease-activated receptors on the platelet.

[edit] Negative feedback

Thrombin activates protein C, an inhibitor of the coagulation cascade. The activation of protein C is greatly enhanced following the binding of thrombin to thrombomodulin, an integral membrane protein expressed by endothelial cells. Activated protein C inactivates factors Va and VIIIa. Binding of activated protein C to protein S leads to a modest increase in its activity.

[edit] Role in disease

Activation of prothrombin is crucial in physiological and pathological coagulation. Various rare diseases involving prothrombin have been described (e.g. hypoprothrombinemia).

An apparently quite common disorder (up to 5% in Western patients) is the substitution of adenine for guanine at position 20210 of the prothrombin gene. Although this falls outside the reading frame for the protein, it leads to high levels of prothrombin and a possibly increased risk of thrombosis (Poort et al 1996).

[edit] Pharmacology

Prothrombin complex concentrate and fresh frozen plasma are prothrombin-rich coagulation factor preparations that can be used to correct deficiencies (usually due to medication) of prothrombin. Indications include intractable bleeding due to warfarin.

Manipulation of prothrombin is central to the mode of action of most anticoagulants. Warfarin and related drugs inhibit vitamin K-dependent carboxylation of several coagulation factors, including prothrombin. Heparin increases the affinity of antithrombin to thrombin (as well as factor Xa). A newer class of medication, the direct thrombin inhibitors, directly inhibit thrombin by binding to its active site.

[edit] References

Poort SR, Rosendaal FR, Reitsma PH, Bertina RM. A common genetic variation in the 3' untranslated region of the prothrombin gene is associated with elevated plasma prothrombin levels and an increase in venous thrombosis. Blood 1996;88:3698-703. PMID 8916933.

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Coagulation