Thromboxane

Thromboxane is a member of the family of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2. The distinguishing feature of thromboxanes is a 6-membered ether-containing ring.

Thromboxane is named for its role in clot formation (thrombosis).

Production

Thromboxane-A synthase, an enzyme found in platelets, converts the arachidonic acid derivative prostaglandin H₂ to thromboxane.

Mechanism

Thromboxane acts by binding to any of the thromboxane receptors, G-protein-coupled receptors coupled to the G protein G_q.^[1]

Functions

Thromboxane is a vasoconstrictor and a potent hypertensive agent, and it facilitates platelet aggregation.

It is in homeostatic balance in the circulatory system with prostacyclin, a related compound. The mechanism of secretion of thromboxanes from platelets is still unclear.

Role of A2 in platelet aggregation

Thromboxane A₂ (TXA₂), produced by activated platelets, has prothrombotic properties, stimulating activation of new platelets as well as increasing platelet aggregation.

Platelet aggregation is achieved by mediating expression of the glycoprotein complex GP IIb/IIIa in the cell membrane of platelets. Circulating fibrinogen binds these receptors on adjacent platelets, further strengthening the clot.

Pathology

It is believed that the vasoconstriction caused by thromboxanes plays a role in Prinzmetal's angina. Omega-3 fatty acids have higher levels of TxA,₃ which is relatively less potent than TxA₂ and PGI₃; therefore, there is a balance shift toward vasoconstriction and platelet aggregation inhibition. It is believed that this shift in balance lowers the incidence of myocardial infarction and stroke.

Inhibitors

Thromboxane inhibitors are broadly classified as either those that inhibit the synthesis of thromboxane, or those that inhibit the target effect of it.

Thromboxane synthesis inhibitors, in turn, can be classified regarding which step in the synthesis they inhibit:

• The widely used drug aspirin acts by inhibiting the ability of the COX enzyme to synthesize the precursors of thromboxane within platelets. Low-dose, long-term aspirin use irreversibly blocks the formation of thromboxane A₂ in platelets, producing an inhibitory effect on platelet aggregation. This anticoagulant property makes aspirin useful for reducing the incidence of heart attacks.^[2] 40 mg of aspirin a day is able to inhibit a large proportion of maximum thromboxane A₂ release provoked acutely, with the prostaglandin I2 synthesis being little affected; however, higher doses of aspirin are required to attain further inhibition.^[3]
• Thromboxane synthase inhibitors inhibit the final enzyme (thromboxane synthase) in the synthesis of thromboxane. Ifetroban is a potent and selective thromboxane receptor antagonist.^[4] Dipyridamole antagonizes this receptor too, but has various other mechanisms of antiplatelet activity as well.

The inhibitors of the target effects of thromboxane are the thromboxane receptor antagonist, including terutroban.

Picotamide has activity both as a thromboxane synthase inhibitor and as a thromboxane receptor antagonist.^[5]

Terminology

Thromboxane synthetase is a misnomer for thromboxane synthase but is often found in the literature.

References

1. ^ Rat kidney thromboxane receptor: molecular cloning, signal ...
2. ^ [1] American Heart Association: Aspirin in Heart Attack and Stroke Prevention "The American Heart Association recommends aspirin use for patients who've had a myocardial infarction (heart attack), unstable angina, ischemic stroke (caused by blood clot) or transient ischemic attacks (TIAs or "little strokes"), if not contraindicated. This recommendation is based on sound evidence from clinical trials showing that aspirin helps prevent the recurrence of such events as heart attack, hospitalization for recurrent angina, second strokes, etc. (secondary prevention). Studies show aspirin also helps prevent these events from occurring in people at high risk (primary prevention)."
3. ^ Tohgi, H; S Konno, K Tamura, B Kimura and K Kawano (1992). "Effects of low-to-high doses of aspirin on platelet aggregability and metabolites of thromboxane A2 and prostacyclin". Stroke 23 (10): 1400–1403. doi:10.1161/01.STR.23.10.1400. PMID 1412574. 
4. ^ Dockens, R.; Santone, K.; Mitroka, J.; Morrison, R.; Jemal, M.; Greene, D.; Barbhaiya, R. (2000). "Disposition of radiolabeled ifetroban in rats, dogs, monkeys, and humans". Drug metabolism and disposition: the biological fate of chemicals 28 (8): 973–980. PMID 10901709.  edit
5. ^ Ratti, S; Quarato, P; Casagrande, C; Fumagalli, R; Corsini, A (1998). "Picotamide, an antithromboxane agent, inhibits the migration and proliferation of arterial myocytes". European Journal of Pharmacology 355 (1): 77–83. doi:10.1016/S0014-2999(98)00467-1. PMID 9754941. 

External links

• MeSH Thromboxanes