What Is Thrombin?

Thrombin is a serine protease, an enzyme that, in humans, is encoded by the F2 gene[1]. Prothrombin (coagulation factor II) is proteolytically cleaved to form thrombin in the clotting process. Thrombin in turn acts as a serine protease that converts soluble fibrinogen into insoluble strands of fibrin, as well as catalyzing many other coagulation-related reactions.

In blood coagulation, thrombin acts to convert factor XI to XIa, VIII to VIIIa, V to Va, fibrinogen to fibrin, and XIII to XIIIa.

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. Thrombin interacts with thrombomodulin.

As part of its activity in the coagulation cascade, thrombin also promotes platelet activation and aggregation via activation of protease-activated receptors on the cell membrane of the platelet.

Synthesis Of Thrombin

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 co-translationally modified in a vitamin K-dependent reaction that converts 10-12 glutamic acids in the N terminus of the molecule to gamma-carboxyglutamic acid (Gla).[2] In the presence of calcium, the Gla residues promote the binding of prothrombin 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.

In human adults, the normal blood level of antithrombin activity has been measured to be around 1.1 units/mL. Newborn levels of thrombin steadily increase after birth to reach normal adult levels, from a level of around 0.5 units/mL 1 day after birth, to a level of around 0.9 units/mL after 6 months of life.


Activation of prothrombin is crucial in physiological and pathological coagulation. Various rare diseases involving prothrombin have been described (e.g., hypoprothrombinemia). Anti-prothrombin antibodies in autoimmune disease may be a factor in the formation of the lupus anticoagulant (also known as antiphospholipid syndrome). Hyperprothrombinemia can be caused by the G20210A mutation.

Thrombin, a potent vasoconstrictor and mitogen, is implicated as a major factor in vasospasm following subarachnoid hemorrhage. Blood from a ruptured cerebral aneurysm clots around a cerebral artery, releasing thrombin. This can induce an acute and prolonged narrowing of the blood vessel, potentially resulting in cerebral ischemia and infarction (stroke).

Beyond its key role in the dynamic process of thrombus formation, thrombin has a pronounced pro-inflammatory character, which may influence the onset and progression of atherosclerosis. Acting via its specific cell membrane receptors (protease activated receptors: PAR-1, PAR-3 and PAR-4), which are abundantly expressed in all arterial vessel wall constituents, thrombin has the potential to exert pro-atherogenic actions such as inflammation, leukocyte recruitment into the atherosclerotic plaque, enhanced oxidative stress, migration and proliferation of vascular smooth muscle cells, apoptosis and angiogenesis.

Thrombin is implicated in the physiology of blood clots. Its presence indicates the existence of a clot. In 2013 a system for detecting the presence of thrombin was developed in mice. It combines peptide-coated iron oxide attached to “reporter chemicals”. When a peptide binds to a thrombin molecule, the report is released and appears in the urine where it can be detected. Human testing has not been conducted.

Medicine And Surgery

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). The direct thrombin inhibitors, a newer class of medication, directly inhibit thrombin by binding to its active site.

Recombinant thrombin is available as a powder for reconstitution into aqueous solution. It can be applied topically during surgery, as an aid to hemostasis. It can be useful for controlling minor bleeding from capillaries and small venules, but ineffective and not indicated for massive or brisk arterial bleeding[3].


The thrombin (prothrombin) gene is located on the eleventh chromosome (11p11-q12).

There are an estimated 30 people in the world that have been diagnosed with the congenital form of Factor II deficiency, which should not be confused with the prothrombin G20210A mutation, which is also called the factor II mutation. Prothrombin G20210A is congenital.

Prothrombin G20210A is not usually accompanied by other factor mutations (i.e., the most common is factor V Leiden). The gene may be inherited heterozygous (1 pair), or much more rarely, homozygous (2 pairs), and is not related to gender or blood type.

Homozygous mutations increase the risk of thrombosis more than heterozygous mutations, but the relative increased risk is not well documented. Other potential risks for thrombosis, such as oral contraceptives may be additive. The previously reported relationship of inflammatory bowel disease (i.e., Crohn’s disease or ulcerative colitis) and prothrombin G20210A or factor V Leiden mutation have been contradicted by research.

[1] Royle NJ, Irwin DM, Koschinsky ML, MacGillivray RT, Hamerton JL (May 1987). Human genes encoding prothrombin and ceruloplasmin map to 11p11-q12 and 3q21-24, respectively. Somatic Cell and Molecular Genetics.

[2] Knorre DG, Kudryashova NV, Godovikova TS (October 2009). Chemical and functional aspects of posttranslational modification of proteins. Acta Naturae. 1 (3): 29–51. doi:10.32607/20758251-2009-1-3-29-51

[3] Greenhalgh DG, Gamelli RL, Collins J, Sood R, Mozingo DW, Gray TE, Alexander WA (2009). Recombinant thrombin: safety and immunogenicity in burn wound excision and grafting. Journal of Burn Care & Research. 30 (3): 371–9. doi:10.1097/BCR.0b013e3181a28979

Top Image: Crystal structure of thrombin with an inhibitor.