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.
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 Gq.
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. They act in the formation of blood clots and reduce
blood flow to the site of a clot. Role of A2 in platelet aggregation
Thromboxane A2, 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
are metabolized to produce higher levels of TxA,3 which is relatively less potent
than TxA2 and PGI3; therefore, there is a balance shift toward inhibition of
vasoconstriction and platelet aggregation. It is believed that this
shift in balance lowers the incidence of myocardial infarction and stroke.
Vasoconstriction and, perhaps, various proinflammatory effects exerted by TxA
on tissue microvasculature, is probable reason why the TxA is pathogenic in
various diseases, such as ischemia-reperfusion injury., hepatic
inflammatory processes, acute hepatotoxicity etc. TxB2, a stable
degradation product of TxA2, plays a role in acute hepatoxicity induced by
acetaminophen. 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. 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.
Thromboxane synthase inhibitors inhibit the final enzyme in the synthesis of
thromboxane. Ifetroban is a potent and selective thromboxane receptor
antagonist. Dipyridamole antagonizes this receptor too, but has various other
mechanisms of antiplatelet activity as well.
High-dose naproxen can induce near-complete suppression of platelet
thromboxane throughout the dosing interval and appears not to increase
cardiovascular disease risk, whereas other high-dose NSAID regimens have only
transient effects on platelet COX-1 and have been found to be associated "with a
small but definite vascular hazard". 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. Ridogrel is another example.
References External links
Thromboxanes at the US National Library of Medicine Medical Subject Headings