Thromboxane: What is it? Production, Functions, Pathology and Inhibitors

It is a member of the lipid family known as eicosanoids.

The two main thromboxanes are thromboxane A2 and thromboxane B2. The distinctive feature of thromboxanes is a ring containing 6-membered ethers.

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

Thromboxane A2 (TXA2), the primary product of the COX-1-dependent metabolism of arachidonic acid, mediates its biological actions through the TXA2 receptor, called the TP receptor.

The irreversible inhibition of TXA2 derived from COX-1 of platelets with low doses of aspirin provides protection against primary and secondary vascular thrombotic events, underscoring the central role of TXA2 as a platelet agonist in cardiovascular disease.

The limitations associated with the use of aspirin include significant gastrointestinal toxicity, hemorrhagic complications, potential interindividual response variability, and poor efficacy in some disease states.

This, together with the broad role of TXA2 in cardiovascular disease beyond platelets, has refocused the interest towards additional pharmacological targets associated with TXA2, in particular the TXA2 synthase and the TP receptor.

The superiority of these agents against low doses of aspirin, in terms of clinical efficacy, tolerability and commercial viability, remain open questions that are the focus of ongoing research.

Thromboxane production

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

Thromboxane A2 (TXA2) is a member of the prostanoid family of arachidonic acid metabolites generated by the sequential action of three enzymes: phospholipase A2, COX-1 or COX-2 and TXA2 synthase (TXAS).

TXA2 directs multiple biological processes through its cell surface receptor, called the TP receptor.

The biosynthesis of TXA2 as well as isoprostanes, non-enzymatic products derived from free radicals of arachidonic acid that can activate the TP receptor in vivo, is elevated in numerous cardiovascular and inflammatory diseases, as is the expression of the receptor itself.

The irreversible inhibition of platelet TXA2 derived from COX-1 with low doses of aspirin is currently used as an antiplatelet therapy for the prevention of primary and secondary vascular thrombotic events, reflecting the central role of TXA2 as a platelet agonist in cardiovascular disease.

TXA2 also affects vasoconstriction, the expression of the endothelial adhesion molecule and cell migration, proliferation and hypertrophy, in accordance with its role in cardiovascular disease beyond platelets.

This article describes the current understanding of TXA2 and the TP receptor in cardiovascular diseases and examines new potential drugs targeted to this pathway.


They act in the formation of blood clots and reduce the flow of blood to the site of a clot.

If the lid of a vulnerable plaque erodes or ruptures, as in myocardial ischemia, the platelets adhere to the damaged lining of the vessel and to each other in seconds and form a plug.

These “sticky platelets” secrete various chemicals, including thromboxane A2 that stimulates vasoconstriction and reduces blood flow at the site.


Omega-3 fatty acids are metabolized to produce higher levels of TxA, 3 which is relatively less potent than TxA2 and PGI3; therefore, there is a displacement of the equilibrium towards the inhibition of vasoconstriction and platelet aggregation.

The vasoconstriction and, perhaps, several proinflammatory effects exerted by TxA in the tissue microvasculature, is a probable reason why the TxA is pathogenic in various diseases, such as ischemia-reperfusion injury, hepatic inflammatory processes, acute hepatotoxicity, etc.

TxB2, a product of stable degradation of TxA2, plays a role in the acute hepatotoxicity induced by paracetamol.

Thromboxane inhibitors

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

This anticoagulant property makes aspirin useful in reducing the incidence of heart attacks.

The thromboxane synthase inhibitors inhibit the final enzyme (thromboxane synthase) in the synthesis of thromboxane. Ifetroban is a potent and selective thromboxane receptor antagonist.

High doses of naproxen can induce an almost complete suppression of platelet thromboxane throughout the dosing interval and does not appear to increase the risk of cardiovascular disease (CVD).

While other high-dose NSAID regimens (non-steroidal anti-inflammatory drugs) have only transient effects on COX-1 platelets and have been found to be associated “with a small but defined vascular hazard”.

Thromboxane A2 has been unequivocally involved in a variety of cardiovascular diseases, due to its acute and chronic effects in the promotion of platelet aggregation, vasoconstriction and proliferation.

The documented success of low doses of aspirin in the prevention of atherothrombosis can be fully explained by the inhibition of TXA2 biosynthesis through platelet COX-1.

The limitations associated with the use of aspirin, which include significant GI toxicity, unwanted bleeding, potential interindividual response variability and poor efficacy in some disease states, together with the broad role of TXA2 in CVD and the mechanical opportunities that exist beyond of the COX-1 platelet pathway, reoriented interest in additional TXA2-associated drug targets, in particular TXAS and the TP receptor.

Ongoing research will indicate whether these efforts will produce drugs that are clinically superior to low doses of aspirin in terms of clinical efficacy and commercial viability.