Physiology, Thromboxane A2


Thromboxane A2 (TxA2) is in the family of lipids known as eicosanoids, which are metabolites of arachidonic acid generated by the sequential action of three enzymes – phospholipase A2, COX-1/COX-2 and TxA2 Synthase (TXAS). TxA2 was originally described as being released from platelets and is now known to be released by a variety of other cells including macrophages, neutrophils, and endothelial cells. Named after its role in thrombosis, TxA2 has prothrombotic properties, as it stimulates the activation of platelets and platelet aggregation. TxA2 is also a known vasoconstrictor and gets activated during times of tissue injury and inflammation. While the prostaglandin counterbalances its thrombotic and vasoconstrictor properties prostacyclin (PGI2), there are various physiological and pathological situations where this balanced becomes dysregulated.[1] Increased activity of TxA2 may play a role in the pathogenesis of myocardial infarction, stroke, atherosclerosis, and bronchial asthma.[2] Increased action of TxA2 also has implications in pulmonary hypertension, kidney injury, hepatic injury, allergies, angiogenesis, and metastasis of cancer cells.[3][4][5][6][7][8]

Issues of Concern

TxA2 is a potent platelet activator and vasoconstrictor that may have pathological consequences when activation is uncontrolled.


TxA2 is involved in multiple biological processes via its cell surface receptor, termed the TP. The TP is a G protein-coupled receptor (GPCR) expressed in a variety of tissues and cells including platelets, vasculature (smooth muscle and endothelial cells), lungs, kidneys, heart, thymus, and spleen. There are two highly related isoforms of the TP (alpha and beta) that arise through differential mRNA splicing, a characteristic that is exclusive to the human receptor.[9] In most tissues, both isoforms express; however, only the TP-alpha form is in platelets. The TP not only undergoes activation by TxA2 but also isoprostanes, which are free radical-catalyzed peroxidation products of arachidonic acid without the direct action of COX enzymes.


The production of TxA2 is via a sequential process that begins with arachidonic acid (AA). Arachidonic acid is a polyunsaturated fatty acid present in the phospholipid membrane of the body’s cells. In the setting of inflammation, phospholipase A2 cleaves arachidonic acid from the cell’s membrane and, through one pathway, is converted to prostaglandin H2 (PGH2) via the action of the enzyme COX. There are two evolutionarily conserved COX isoforms, including COX-1 and COX-2. COX-1 is constitutively expressed in platelets, and COX-2 is an inducible form found only in a small fraction of circulating platelets under normal conditions. COX-2 is shown to have increased expression in newly formed platelets and during times of inflammation and other provoked settings compared to normal conditions. PGH2 ultimately converts into the product TxA2 via the enzyme TXAS.[10]


TxA2 serves as a positive-feedback mediator during platelet activation. Because of its short half-life of about 30 seconds, TxA2 acts in an autocrine or paracrine matter to activate adjacent platelets and generate more TxA2 and amplify the action of other, more potent, platelet agonists. When TxA2 binds to TP, there is platelet activation leading to platelet-shape change, activation of phospholipase A2, platelet degranulation of dense granules and alpha granules, and platelet aggregation. TxA2 also induces vasoconstriction of smooth muscle.[11]


When platelets circulate through vessels with intact endothelium, the platelets remain in their inactivated state. This inactivated state is supported by the release of prostacyclin (PGI2) from the intact endothelium as well as the absence of various activating factors. When a platelet encounters a break in the endothelium, however, it encounters molecules such as collagen, ADP, thrombin, and TxA2 that trigger its activation.[12]

Platelet Activation

The predominant activators of platelets are diffusible stimuli such as ADP, TxA2, and thrombin. They all work by initiating the aggregation of platelets into a growing thrombus through the action of various G protein-mediated signaling pathways. These pathways converge to induce platelet-shape change, degranulation, and integrin Glycoprotein (GP) IIb/IIIa mediated aggregation. Each stimulus uses a distinct mechanism, but ultimately all of the mechanisms are involved in full platelet activation. TxA2 activates mainly Gq and G12/G13 via the TP. Gq family members of heterotrimeric G protein activate beta isoforms of phospholipase C (PLC) that hydrolyzes phosphatidylinositol phosphate (PIP) to diacylglycerol (DAG) and inositol trisphosphate (IP3), leading to protein kinase C (PKC) activation as well as intracellular Ca(2+) accumulation, respectively.  G12/13 signaling of GPCRs has recently been shown to involve activation of RhoGTPase nucleotide exchange factors (RhoGEFs).[13]

Because all mediators can, in turn, multiply the formation and release of thrombin, TxA2, and ADP, their effects are amplified, and ultimately, all major G protein-mediated signaling pathways are activated. This grouped activation inherently makes specific pathways challenging to isolate. However, research has proven that an increase in the free cytosolic [Ca] and activation of PKC are necessary for platelet activation, and this is precisely what occurs when TxA2 activates the Gq pathway.[14] 

Platelet-Shape Change

A change in shape is the initial response of platelets to activators such as TxA2. It is an extremely rapid process caused by a reorganization of the cytoskeleton. The mediation of platelet-shape change is mostly by myosin light chain (MLC) phosphorylation. MLC phosphorylation can be controlled through a Ca2+/calmodulin-dependent regulation of MLC kinase, controlled by the activation of Gq and through a Rho/Rho-kinase-mediated regulation of myosin phosphatase, controlled by the activation of G12/G13.[15] During platelet-shape change, new actin filaments are formed, leading to the formation of a submembranous actin filament network and the extension of filopodia. Also, the actomyosin-based contractile processes are stimulated, resulting in the centralization of dense and alpha granules. Finally, the circumferential microtubule coil depolymerizes, which allows the platelet to change from a discoid to a spherical shape. The platelet shape change, which is induced by agonist concentrations lower than those required for degranulation and aggregation, is believed to be a prerequisite for efficient secretion of granule contents and to greatly facilitate adhesion of platelets to each other and components of the extracellular matrix.[16][17]

Platelet Degranulation

A variety of mediators can induce platelet degranulation. TxA2 induces platelet degranulation via the Gq/PLC-beta pathway. Secretion from platelets is an important mechanism that amplifies platelet activation and results in the release of mediators that act on the vessel wall as well as on other blood cells. It occurs in two waves, the first consists of the release of dense core granules and alpha-granules which is followed by the release of lysosomes. Dense granules contain small molecules such as nucleotides (ADP, ATP) or serotonin, whereas alpha granules contain various proteins including growth factors, chemokines, adhesive molecules such as Von Willebrand Factor (vWF), and coagulation factors. The central role of the Gq/PLC-beta pathway in agonist-induced platelet granule secretion is supported by the finding that various platelet activators failed to induce secretion in platelets lacking Galpha-q and by the fact that secretion in response to TxA2 is reduced in PLC-beta–deficient platelets.[18]

Platelet Aggregation

While the exact signaling mechanisms that link receptors of platelet activators to the cytoplasmic domains of GP IIb/IIIa are incompletely understood, there is good evidence that activation of PLC-beta through Gq, which results in the formation of IP3 and DAG, plays a role in mediating GP IIb/IIIa activation. IP3-mediated increases in cytosolic-free Ca as well as activated PKC appears to be necessary for activation of the integrin GP IIb/IIIa. This intracellular signaling pathway results in a conformational change of GP IIb/IIIa to an active form and is referred to as “inside-out” signaling. It results in fibrinogen/vWF-mediated platelet aggregation.[19]


Since finding TxA2 to be a rabbit aorta-contracting substance, TxA2 has a potent contractile activity towards vascular smooth muscle cells. In addition to vascular smooth muscle, TxA2 causes contraction of bronchial smooth muscle, intestinal smooth, uterus, and urinary bladder muscles.[11] When TxA2 binds to its receptor, there is an influx of calcium ions which directly increase contraction of smooth muscle cells.[20] The vasoconstriction caused by TxA2 aids in the platelet aggregation because platelets are close to each other, which leads to greater clot formation.


The pathophysiology of TxA2 includes increased production in the setting of injury and inflammation. Increased production leads to increased activation of the TP, which increases platelets activation, aggregation, and vasoconstriction. These all result in thrombosis and thus, decreased blood flow to various parts of the body. Furthermore, pathological states can disturb the physiologic redox state of cells, leading to increased ROS. Exposure of these ROS to membrane lipids can induce nonenzymatic peroxidation reactions leading to the production of isoprostanes, which also activate the TP and increase rates of thrombosis.[21]

Clinical Significance

Cardiovascular Disease: The biosynthesis of TxA2 and isoprostanes is elevated in numerous cardiovascular and inflammatory diseases, as is the expression of the receptor itself.

Myocardial Infarction

Myocardial infarction occurs when there is complete occlusion of blood flow to an area of the heart. Thrombus formation mediated by TxA2-induced platelet aggregation and vascular constriction sometimes causes myocardial infarction (as well as infarctions of other organs).[10]


Atherosclerosis is a chronic disease of the vasculature that is influenced by multiple factors that involve a complex interplay between components of the blood and the arterial wall. TxA2 and isoprostanes, as well as PGI2, are known to promote the initiation and progression of atherogenesis through control of platelet activation and leukocyte-endothelial cell interaction.[22]

Variant (Prinzmetal) Angina 

Studies have also indicated that increased TxA2 in circulating plasma is closely correlated with the hypersensitivity of coronary arteries to ergonovine maleate in patients with variant angina, suggesting a possible role of augmented TxA2 production in the enhancement of coronary vascular spasticity.[23]

Treatment in Cardiovascular Disease

Irreversible inhibition of COX-1-derived TxA2 with low-dose aspirin affords prophylaxis against both primary and secondary vascular thrombotic events, which underscores the central role of TxA2 as a platelet agonist in cardiovascular disease. However, COX-1 inhibitors have correlations with adverse effects such as GI toxicity and bleeding.[10] Furthermore, selective COX-2 inhibitors cause cardiotoxicity, which may be related to the inhibition of PGI2 production, while maintaining the production of TxA2 via COX-1; this makes TP and TXAS antagonists potential therapeutic targets for treatment and prevention of CVD.


TxA2-induced contraction of bronchial smooth muscles may contribute to asthma, which has been improved by TP antagonists.[24] TxA2 is also involved in bronchial muscle hyperplasia and airway remodeling in asthma.[25]  Studies have also shown that pulmonary hypertension associated with ischemia-reperfusion results in part from the pulmonary release of TxA2.[3]


TxA2 is involved in nephritis and nephrotic syndrome of the kidney.[4] TP stimulation of mesangial cells causes cell contraction, promotes proliferation, changes cellular ion fluxes, increases the mRNA levels of fibronectin, laminin, collagen, tissue plasminogen activator (tPA), plasminogen activator inhibitor-1 (PAI-1) and accelerates transforming growth factor synthesis.[11]


Hepatic injury after hepatic stress results from several mechanisms, including inflammation and microcirculatory disturbance. Levels of thromboxane have been shown to increase in the systemic circulation after different types of hepatic stress such as endotoxemia, hepatic ischemia-reperfusion, hepatectomy, liver transplantation, hemorrhagic shock and resuscitation, hepatic cirrhosis, and alcoholic liver injury. The production of thromboxane from the liver also becomes enhanced under these stresses. Thromboxane induces hepatic damage through vasoconstriction, platelet aggregation, induction of leukocyte adhesion, up-regulation of proinflammatory cytokines, and release of other vasoconstrictors.[5]

Allergy and Inflammation

Research shows that TxA2 contributes to the pathogenesis of asthma, rhinitis and atopic dermatitis. Allergic inflammation is the fundamental pathophysiology of allergic diseases and closely correlates with disease progression and exacerbation.[6]

Angiogenesis and Metastasis of Cancer Cells 

TxA2 is implicated in modulating angiogenesis during tumor growth and chronic inflammation and is involved in angiotensin II-induced neovascularization.[7] Basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) stimulate endothelial cell migration mediated by TxA2. Additionally, TxA2 is involved in metastasis of cancer cells.[8]

Article Details

Article Author

Dane Rucker

Article Editor:

Amit Dhamoon


9/13/2020 1:37:15 PM



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