|, BDPLT13, TXA2-R, thromboxane A2 receptor|
The thromboxane receptor (TP) also known as the prostanoid TP receptor is a protein that in humans is encoded by the TBXA2R gene, The thromboxane receptor is one among the five classes of prostanoid receptorsand was the first eicosanoid receptor cloned. The TP receptor derives its name from its preferred endogenous ligand thromboxane A2.
The gene responsible for directing the synthesis of the thromboxane receptor, TBXA2R, is located on chromosome 19 at position p13.3, spans 15 kilobases, and contains 5 exons.TBXA2R codes for a member of the G protein-coupled super family of seven-transmembrane receptors.
Molecular biology findings have provided definitive evidence for two human TP receptor subtypes.The originally cloned TP from placenta (343 amino acids in length) is known as the α isoform and the splice variant cloned from endothelium (with 407 amino acids), termed the β isoform. The first 328 amino acids are the same for both isoforms, but the β isoform exhibits an extended C-terminal cytoplasmic domain. Both isoforms stimulate cells in part by activating the Gq family of G proteins. In at least certain cell types, however, TPα also stimulates cells by activating the Gs family of G proteins while TPβ also stimulates cells by activating the Gi class of G proteins. This leads to the stimulation or inhibition, respectively, of adenylate cyclase activity and thereby very different cellular responses. Differences in their C-terminal tail sequence also allow for significant differences in the two receptors internalization and thereby desensitization (i.e. loss of G protein- and therefore cell-stimulating ability) after activation by an agonist; TPβ but not TPα undergoes agonist-induced internalization.
The expression of α and β isoforms is not equal within or across different cell types.For example, platelets express high concentrations of the α isoform (and possess residual RNA for the β isoform), while expression of the β isoform has not been documented in these cells. The β isoform is expressed in human endothelium. Furthermore, each TP isoform can physically combine with: a) another of its isoforms to make TPα-TPα or TPβ-TPβ homodimers that promote stronger cell signaling than achieved by their monomer counterparts; b) their opposite isoform to make TPα-TPβ heterodimers that activate more cell signaling pathways than either isoform or homodimer; and c) with the prostacyclin receptor (i.e. IP receptor) to form TP-IP heterodimers that, with respect to TPα-IP heterodimers, trigger particularly intense activation of adenyl cyclase. The latter effect on adenyl cyclase may serve to suppress TPα's cell stimulating actions and thereby some of its potentially deleterious actions.
Mice and rats express only the TPα isoform. Since these rodents are used as animal models to define the functions of genes and their products, their failure to have two TP isoforms has limited understanding of the individual and different functions of each TP receptor isoform.
Historically, TP receptor involvement in blood platelet function has received the greatest attention. However, it is now clear that TP receptors exhibit a wide distribution in different cell types and among different organ systems.For example, TP receptors have been localized in cardiovascular, reproductive, immune, pulmonary and neurological tissues, among others.
|TP Receptor Distribution||Lung, Spleen, Uterus, Placenta, Aorta, Heart, Intestine, Liver, Eye, Thymus, Kidney, Spinal Cord, Brain||Platelets, Blood Monocytes, Glomerular mesangial cells, Oligodendrocytes, Cardiac myocytes, Afferent Sympathetic Nerve Endings in the Heart, Epithelial cells, Hela cells, Smooth muscle cells, Endothelial cells, Trophoblasts, Schwann cells, Astrocytes, Megakaryocytes, Kupffer cells, Human erythroleukemic megakaryocyte (HEL), K562 (Human chronic myelogenous leukemia) cells, Hepatoblastoma HepG2 cells, Immature thymocytes, EL-4 (mouse T cell line), astrocytoma cells|
Standard prostanoids have the following relative efficacies as receptor ligands in binding to and activating TP: TXA2=PGH2>>PGD2=PGE2=PGF2alpha=PGI2. Since TXA2 is highly unstable, receptor binding and biological studies on TP are conducted with stable TXA2 analogs such as I-BOP and U46619. These two analogs have one-half of their maximal binding capacity and cell-stimulating potency at ~1 and 10-20 nanomolar, respectively; it is assumed that TXA2 and PGH2 (which also is unstable) have binding and cell-stimulating potencies within this range. PGD2, PGE2, PGF2alpha, and PGI2 have binding and stimulating potencies that are >1,000-fold weaker than I-BOP and therefore are assumed not to have appreciable ability to stimulate TP in vivo. 20-Hydroxyeicosatetraenoic acid (20-HETE) is a full agonist and certain isoprostanes, e.g. 8-iso-PGF2 alpha and 8-iso-PGE2, are partial agonists of the TP receptor. In animal models and human tissues, they act through TP to promote platelet responses and stimulate blood vessel contraction.Synthetic analogs of TXA2 that activate TP but are relatively resistant to spontaneous and metabolic degradation include SQ 26655, AGN192093, and EP 171, all of which have binding and activating potencies for TP similar to I-BOP.
Several synthetic compounds bind to, but do not activate, TP and thereby inhibit its activation by activating ligands. These receptor antagonists include I-SAP, SQ-29548, S-145, domitroban, and vapiprost, all of which have affinities for binding TP similar to that of I-BOP. Other notable TP receptor antagonists are Seratrodast (AA-2414), Terutroban (S18886), PTA2, 13-APA, GR-32191, Sulotroban (BM-13177), SQ-29,548, SQ-28,668, ONO-3708, Bay U3405, EP-045, BMS-180,291, and S-145.Many of these TP receptor antagonists have been evaluated as potential therapeutic agents for asthma, thrombosis and hypertension. These evaluations indicate that TP receptor antagonists can be more effective than drugs which selectively block the production of TXA2 thromboxane synthase inhibitors. This seemingly paradoxical result may reflect the ability of PGH2, whose production is not blocked by the inhibitors, to substitute for TXA2 in activating TP. Novel TP receptor antagonists that also have activity in reducing TXA2 production by inhibiting cyclooxygenases have been discovered and are in development for testing in animal models.
TP is classified as a contractile type of prostenoid receptor based on its ability to contract diverse types of smooth muscle-containing tissues such as those of the lung, intestines, and uterus.TP contracts smooth muscle and stimulates various response in a wide range of other cell tytes by coupling with and mobilizing one or more families of the G protein class of receptor-regulated cell signaling molecules. When bound to TXA2, PGH2, or other of its agonists, TP mobilizes members of the:
Following its activation of these pathways, the TP receptors's cell-stimulating ability rapidly reverses by a process termed homologous desensitization, i.e. TP is no longer able to mobilize its G protein targets or further stimulate cell function. Subsequently, the β but not α isoform of TP undergoes receptor internalization. These receptor down regulating events are triggered by the G protein-coupled receptor kinases mobilized during TP receptor activation. TP receptor-independent agents that stimulate cells to activate protein kinases C or protein kinases A can also down-regulate TP in a process termed heterologous desensitization. For example, prostacyclin I2 (PGI2)-induced activation of its prostacyclin receptor (IP) and prostaglandin D2-induced activation of its prostaglandin DP1 receptor cause TP receptor desensitization by activating protein kinases A while prostaglandin F2alpha-induced activation of its prostaglandin F receptor and prostaglandin E2-induced activation of its prostaglandin EP1 receptor receptor desensitizes TP by activating protein kinases C. These desensitization responses serve to limit the action of receptor agonists as well as the overall extent of cell excitation.
In addition to its ability to down-regulate TPα, the IP receptor activates cell signaling pathways that counteract those activated by TP. Furthermore, the IP receptor can physically unite with the TPα receptor to form an IP-TPα heterodimer complex which, when bound by TXA2, activates predominantly IP-coupled cell signal pathways. The nature and extent of many cellular responses to TP receptor activation are thereby modulated by the IP receptor and this modulation may serve to limit the potentially deleterious effects of TP receptor activation (see following section on Functions).
Studies using animals genetically engineered to lack the TP receptor and examining the actions of this receptor's agonists and antagonists in animals and on animal and human tissues indicate that TP has various functions in animals and that these functions also occur, or serve as a paradigm for further study, in humans.
Human and animal platelets stimulated by various agents such as thrombin produce TXA2. Inhibition of this production greatly reduces the platelets final adhesion aggregation and degranulation (i.e. secretion of its granule contents) responses to the original stimulus. In addition, the platelets of mice lacking TP receptors have similarly defective adhesion, aggregation, and degranulation responses and these TP deficient mice cannot form stable blood clots and in consequence exhibit bleeding tendencies. TP, as studies show, is part of a positive feedback loop that functions to promote platelet adhesion, aggregation, degranulation, and platelet-induced blood clotting-responses in vitro and in vivo. The platelet-directed functions of TP are in many respects opposite to those of the IP receptor. This further indicates (see previous section) that the balance between the TXA2-TP and PGI2-IP axes contribute to regulating platelet function, blood clotting, and bleeding.
Animal model studies indicate that TP receptor activation contracts vascular smooth muscle cells and acts on cardiac tissues to increase heart rate, trigger Cardiac arrhythmias, and produce myocardial ischemia. These effects may underlie, at least in part, the protective effects of TP gene knockout in mice. TP(-/-) mice are: a) resistant to the cardiogenic shock caused by infusion of the TP agonist, U46619, or the prostaglandin and thromboxane A2 precursor, arachidonic acid; b) partially protected from the cardiac damage caused by hypertension in IP-receptor deficient mice feed a high salt diet; c) prevented from developing angiotensin II-induced and N-Nitroarginine methyl ester-induced hypertension along with associated cardiac hypertrophy; d) resistant to the vascular damage caused by balloon catheter-induced injury of the external carotid artery; e) less likely to develop severe hepatic microcirculation dysfunction caused by TNFα as well as kidney damage caused by TNFα or bacteria-derived endotoxin; and f) slow in developing vascular atherosclerosis in ApoE gene knockout mice.In addition, TP receptor antagonists lessen myocardial infarct size in various animal models of this disease and block the cardiac dysfunction caused by extensive tissue ischemia in animal models of remote ischemic preconditioning. TP thereby has wide-ranging functions that tend to be detrimental to the cardiovascular network in animals and, most likely, humans. However, TP functions are not uniformly injurious to the cardiovascular system: TP receptor-depleted mice show an increase in cardiac damage as well as mortality due to trypanosoma cruzi infection. The mechanism[s) behind this putative protective effect and its applicability to humans is not yet known.
20-Hydroxyeicosatetraenoic acid (20-HETE), a product of arachidonic acid formed by Cytochrome P450 omega hydroxylases,and certain isoprostanes, which form by non-enzymatic free radical attack on arachidonic acid, constrict rodent and human artery preparations by directly activating TP. While significantly less potent than thromboxane A2 in activating this receptor, studies on rat and human cerebral artery preparations indicate that increased blood flow through these arteries triggers production of 20-HETE which in turn binds TP receptors to constrict these vessels and thereby reduce their blood blow. Acting in the latter capacity, 20-HETE, it is proposed, functions as a TXA2 analog to regulate blood flow to the brain and possibly other organs. Isoprostanes form in tissues undergoing acute or chronic oxidative stress such as occurs at sites of inflammation and the arteries of diabetic patients. High levels of isoprostanes form in ischemic or otherwise injured blood vessels and acting through TP, can stimulate arterial inflammation and smooth muscle proliferation; this isoprostane-TP axis is proposed to contribute to the development of atherosclerosis and thereby heart attacks and strokes in humans.
TP receptor activation contracts bronchial smooth muscle preparations obtained from animal models as well as humans and contracts airways in animal models.In a mouse model of asthma (i.e. hypersensitivity to ovalabumin), a TP receptor antagonist decreased the number of eosinophils infiltrating lung as judged by their content in Bronchoalveolar lavage fluid and in a mouse model of dust mite-induced astha, deletion of TBXA2R prevented the development of airways contraction and pulmonary eosinophilia responses to allergen. Another TP receptor agonists likewise reduced airway bronchial reactivity to allergen as well as symptoms in volunteers with asthma. The TP receptor appears to play and essential role in the pro-asthmatic actions of leukotriene C4 (LTC4): in ovalbumin-sensitized mice, leukotriene C4 increased the number of eosinophils in bronchoalveolar lavage fluid and simultaneously decreased the percentages of eosinophils in blood but these responses did not occur in TBXA2R-deficient mice. LTC4 also stimulated lung expression of the pro-inflammatory intracellular adhesion molecules, ICAM-1 and VCAM-1 by a TP receptor-dependent mechanism. These findings suggest that TP contributes to asthma in animal models at least in part by mediating the actions of LTC4. Further studies are required to determine if TP receptor antagonists might be useful for treating asthma and other airway constriction syndromes such as chronic obstructive lung diseases in humans.
Along with PGF2α acting through its FP receptor, TXA2 acting through TP contracts uterine smooth muscle preparations from rodents and humans. Since the human uterous loses its sensitivity to PGP2α but not to TXA2 during the early stages of labor in vaginal childbirth, TP agonists, it is suggested, might be useful for treating preterm labor failures.
Activation of TP receptors stimulates vascular endothelial cell pro-inflammatory responses such as increased expression of cell surface adhesion proteins (i.e. ICAM-1, VCAM-1, and E-selectin); stimulates apoptosis (i.e. cell death) of CD4+ and CD8+ lymphocytes; causes the chemokinesis (i.e. cell movement) of native T cells; and impairs the adhesion of dendritic cells to T cells thereby inhibiting dendritic cell-dependent proliferation of T cells. TP deficient mice exhibit an enhanced contact hypersensitivity response to DNFB thymocytes in the thymus of these deficient mice are resistant to lipopolysaccharide-induced apoptosis. TP receptor-depleted mice also gradually develop with age extensive lymphadenopathy and, associated with this, increased immune responses to foreign antigens. These studies indicate that TXA2-TP signaling functions as a negative regulator of DC-T cell interactions and possibly thereby the acquisition of acquired immunity in mice. Further studies are needed to translate these mouse studies to humans.
Increased expression of cyclooxygenases and their potential involvement in the progression of various human cancers have been described. Some studies suggest that the TXA2 downstream metabolite of these cyclooxygenases along with its TP receptor contribute to mediating this progression. TP activation stimulates tumor cell proliferation, migration, neovascularization, invasiveness, and metastasis in animal models, animal and human cell models, and/or human tissue samples in cancers of the prostate, breast, lung, colon, brain, and bladder.These findings, while suggestive, need translational studies to determine their relevancy to the cited human cancers.
Isolated cases of humans with mild to moderate bleeding tendencies have been found to have mutations in TP that are associated with defects in this receptors binding of TXA2 analogs, activating cell signal pathways, and/or platelet functional responses not only to TP agonists but also to agents that stimulate platelets by TP-independent mechanisms (see Genomics section below).
TP receptor antagonist Seratrodast is marketed in Japan and China for the treatment of asthma. Picotamide, a dual inhibitor of TP and TXA2 synthesis, is licensed in Italy for the treatment of clinical arterial thrombosis and peripheral artery disease.These drugs are not yet licensed for use in other countries.
While functional roles for TP receptor signaling in diverse homeostatic and pathological processes have been demonstrated in animal models, in humans these roles have been demonstrated mainly with respect to platelet function, blood clotting, and hemostasis. TP has also been proposed to be involved in human: blood pressure and organ blood flow regulation; essential and pregnancy-induced hypertension; vascular complications due to sickle cell anemia; other cardiovascular diseases including heart attack, stroke, and peripheral artery diseases; uterine contraction in childbirth; and modulation of innate and adaptive immune responses including those contributing to various allergic and inflammatory diseases of the intestine, lung, and kidney.However, many of the animal model and tissue studies supporting these suggested functions have yet to be proven directly applicable to human diseases. Studies to supply these proofs rest primarily on determining if TP receptor antagonists are clinically useful. However, these studies face issues that drugs which indirectly target TP (e.g. Nonsteroidal anti-inflammatory drugs that block TXA2 production) or which circumvent TP (e.g. P2Y12 antagonists that inhibit platelet activation and corticosteroids and cysteinyl leukotriene receptor 1 antagonists that suppress allergic and/or inflammatory reactions) are effective treatments for many putatively TP-dependent diseases. These drugs are likely to be cheaper and may prove to have more severe side effects that TP-targeting drugs. These considerations may help to explain why relatively few studies have examinted the clinical usefulness of TP-targeting drugs. The following translation studies on TP antagonists have been conducted or are underway:
In addition to the above TP antagonists, drugs that have dual inhibitory actions in that they block not only TP but also block the enzyme responsible for making TXA22, Thromboxane-A synthase, are in clinical development. These dual inhibitor studies include:
Several isolated and/or inherited cases of patients suffering a mild to moderately severe bleeding diathesis have been found to be associated with mutations in 'the 'TBXA2R gene that lead to abnormalities in the expression, subcellular location, or function of its TP product. These cases include:
Single nucleotide polymorphism (SNP) variations in the TBXA2R gene have been associated with allergic and cardiovascular diseases; these include:
Prostacyclin (also called prostaglandin I2 or PGI2) is a prostaglandin member of the eicosanoid family of lipid molecules. It inhibits platelet activation and is also an effective vasodilator.
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 A synthase 1 , also known as TBXAS1, is a cytochrome P450 enzyme that, in humans, is encoded by the TBXAS1 gene.
Most of the eicosanoid receptors are integral membrane protein G protein-coupled receptors (GPCRs) that bind and respond to eicosanoid signaling molecules. Eicosanoids are rapidly metabolized to inactive products and therefore are short-lived. Accordingly, the eicosanoid-receptor interaction is typically limited to a local interaction: cells, upon stimulation, metabolize arachidonic acid to an eicosanoid which then binds cognate receptors on either its parent cell or on nearby cells to trigger functional responses within a restricted tissue area, e.g. an inflammatory response to an invading pathogen. In some cases, however, the synthesized eicosanoid travels through the blood to trigger systemic or coordinated tissue responses, e.g. prostaglandin (PG) E2 released locally travels to the hypothalamus to trigger a febrile reaction. An example of a non-GPCR receptor that binds many eicosanoids is the PPAR-γ nuclear receptor.
Prostaglandin receptors or prostanoid receptors represent a sub-class of cell surface membrane receptors that are regarded as the primary receptors for one or more of the classical, naturally occurring prostanoids viz., prostaglandin D2,, PGE2, PGF2alpha, prostacyclin (PGI2), thromboxane A2 (TXA2), and PGH2. They are named based on the prostanoid to which they preferentially bind and respond, e.g. the receptor responsive to PGI2 at lower concentrations than any other prostanoid is named the Prostacyclin receptor (IP). One exception to this rule is the receptor for thromboxane A2 (TP) which binds and responds to PGH2 and TXA2 equally well.
Thromboxane A2 (TXA2) is a type of thromboxane that is produced by activated platelets during hemostasis and has prothrombotic properties: it stimulates activation of new platelets as well as increases platelet aggregation. This is achieved by activating the thromboxane receptor, which results in platelet-shape change, inside-out activation of integrins, and degranulation. Circulating fibrinogen binds these receptors on adjacent platelets, further strengthening the clot. Thromboxane A2 is also a known vasoconstrictor and is especially important during tissue injury and inflammation. It is also regarded as responsible for Prinzmetal's angina.
The Prostaglandin D2 receptor 1 (DP1), a G protein-coupled receptor encoded by the PTGDR1 gene (also termed PTGDR), is primarily a receptor for prostaglandin D2 (PGD2). The receptor is a member of the Prostaglandin receptors belonging to the Subfamily A14 of rhodopsin-like receptors. Activation of DP1 by PGD2 or other cognate receptor ligands is associated with a variety of physiological and pathological responses in animal models.
Cyclopentenone prostaglandins are a subset of prostaglandins (PGs) or prostanoids that has 15-deoxy-Δ12,14-prostaglandin J2 (15-d-Δ12,14-PGJ2), Δ12-PGJ2, and PGJ2 as its most prominent members but also including PGA2, PGA1, and, while not classified as such, other PGs. 15-d-Δ12,14-PGJ2, Δ12-PGJ2, and PGJ2 share a common mono-unsaturated cyclopentenone structure as well as a set of similar biological activities including the ability to suppress inflammation responses and the growth as well as survival of cells, particularly those of cancerous or neurological origin. Consequently, these three cyclopentenone-PGs and the two epoxyisoprostanes are suggested to be models for the development of novel anti-inflammatory and anti-cancer drugs. The cyclopenentone prostaglandins are structurally and functionally related to a subset of isoprostanes viz., two cyclopentenone isoprostanes, 5,6-epoxyisoprostane E2 and 5,6-epoxisoprostane A2.
Prostaglandin E2 receptor 4 (EP4) is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the PTGER4 gene in humans; it is one of four identified EP receptors, the others being EP1, EP2, and EP3, all of which bind with and mediate cellular responses to PGE2 and also, but generally with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors). EP4 has been implicated in various physiological and pathological responses in animal models and humans.
Guanine nucleotide-binding protein G(q) subunit alpha is a protein that in humans is encoded by the GNAQ gene. Together with GNA11, it functions as a Gq alpha subunit.
Prostaglandin D2 receptor 2 (DP2 or CRTH2) is a human protein encoded by the PTGDR2 gene and GPR44. DP2 has also been designated as CD294 (cluster of differentiation 294). It is a member of the class of prostaglandin receptors which bind with and respond to various prostaglandins. DP2 along with Prostaglandin DP1 receptor are receptors for prostaglandin D2 (PGD2). Activation of DP2 by PGD2 or other cognate receptor ligands has been associated with certain physiological and pathological responses, particularly those associated with allergy and inflammation, in animal models and certain human diseases.
Prostaglandin E2 receptor 1 (EP1) is a 42kDa prostaglandin receptor encoded by the PTGER1 gene. EP1 is one of four identified EP receptors, EP1, EP2, EP3, and EP4 which bind with and mediate cellular responses principally to prostaglandin E2) (PGE2) and also but generally with lesser affinity and responsiveness to certain other prostanoids (see Prostaglandin receptors). Animal model studies have implicated EP1 in various physiological and pathological responses. However, key differences in the distribution of EP1 between these test animals and humans as well as other complicating issues make it difficult to establish the function(s) of this receptor in human health and disease.
Prostaglandin E2 receptor 2, also known as EP2, is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the human gene PTGER2: it is one of four identified EP receptors, the others being EP1, EP3, and EP4, which bind with and mediate cellular responses to PGE2 and also, but with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors). EP has been implicated in various physiological and pathological responses.
Prostaglandin EP3 receptor (53kDa), also known as EP3, is a prostaglandin receptor for prostaglandin E2 (PGE2) encoded by the human gene PTGER3; it is one of four identified EP receptors, the others being EP1, EP2, and EP4, all of which bind with and mediate cellular responses to PGE2 and also, but generally with lesser affinity and responsiveness, certain other prostanoids (see Prostaglandin receptors). EP has been implicated in various physiological and pathological responses.
Prostaglandin F receptor (FP) is a receptor belonging to the prostaglandin (PG) group of receptors. FP binds to and mediates the biological actions of Prostaglandin F2α (PGF2α). It is encoded in humans by the PTGFR gene.
The Prostacyclin receptor , also termed the prostaglandin I2 receptor or just IP, is a receptor belonging to the prostaglandin (PG) group of receptors. IP binds to and mediates the biological actions of prostacyclin (also termed Prostaglandin I2, PGI2, or when used as a drug, epoprostenol). IP is encoded in humans by the PTGIR gene. While possessing many functions as defined in animal model studies, the major clinical relevancy of IP is as a powerful vasodilator: stimulators of IP are used to treat severe and even life-threatening diseases involving pathological vasoconstriction.
Seratrodast (development name, AA-2414; marketed originally as Bronica) is a thromboxane A2 (TXA2) receptor (TP receptor) antagonist used primarily in the treatment of asthma. It was the first TP receptor antagonist that was developed as an anti-asthmatic drug and received marketing approval in Japan in 1997. As of 2017 seratrodast was marketed as Bronica in Japan, and as Changnuo, Mai Xu Jia, Quan Kang Nuo in China.
U46619 is a stable synthetic analog of the endoperoxide prostaglandin PGH2 first prepared in 1975, and acts as a thromboxane A2 (TP) receptor agonist. It potently stimulates TP receptor-mediated, but not other prostaglandin receptor-mediated responses in various in vitro preparations. and exhibits many properties similar to thromboxane A2, including shape change and aggregation of platelets and smooth muscle contraction. U46619 is a vasoconstrictor that mimics the hydroosmotic effect of vasopressin.
Thromboregulation is the series of mechanisms in how a primary clot is regulated. These mechanisms include, competitive inhibition or negative feedback. It includes primary hemostasis, which is the process of how blood platelets adhere to the endothelium of an injured blood vessel. Platelet aggregation is fundamental to repair vascular damage and the initiation of the blood thrombus formation. The elimination of clots is also part of thromboregulation. Failure in platelet clot regulation may cause hemorrhage or thrombosis. Substances called thromboregulators control every part of these events.
12-Hydroxyheptadecatrenoic acid is a 17 carbon metabolite of the 20 carbon polyunsaturated fatty acid, arachidonic acid. It was first detected and structurally defined by P. Wlodawer, Bengt I. Samuelsson, and M. Hamberg as a product of arachidonic acid metabolism made by microsomes isolated from sheep seminal vesicle glands and by intact human platelets. 12-HHT is less ambiguously termed 12-(S)-hydroxy-5Z,8E,10E-heptadecatrienoic acid to indicate the S stereoisomerism of its 12-hydroxyl residue and the Z, E, and E cis-trans isomerism of its three double bonds. The metabolite was for many years thought to be merely a biologically inactive byproduct of prostaglandin synthesis. More recent studies, however, have attached potentially important activity to it.