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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. [1] [2] 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. [3]


Primary hemostasis inducers

One primary function of thromboregulation is the control of primary hemostasis, which is the platelet aggregation process. Some thromboregulators enhance platelet aggregation and some others inhibit the process. Platelet aggregation plays a critical role in the genesis of a resulting thrombus. Adhesion should remain local, but platelet aggregation must grow exponentially to form a platelet thrombus and prevent blood loss. Platelet aggregation factors are the regulators that enhance the adhesion and stimulate the platelets to secrete its granules. It has been shown that collagen, exposed after the injury to the endothelial cover of the vessel, plays as an agonist in platelet adhesion and its activation. The binding of platelets to the sub-endothelial collagen stimulates the secretion of ADP, TXA2, and serotonin present in the platelet granules. [4]

ADP-dependent aggregation is mediated by two receptors: the purinergic P2Y1, coupled to Gαq, mediates the shape in the structure of platelets and triggers the aggregation process. [5] Thromboxane A2 (TX2) has a positive feedback in platelet activation. It is produced by the oxygenation of arachidonic acid by two enzymes: cycloxygenase and thromboxane A2 synthase. TX2 effects are mediated by G protein-coupled receptors, subtypes TPα and TPβ. Both receptors mediate phospholipase C stimulation causing an increase of intracellular levels of inositol 1,4,5-triphosphate and diacylglycerol. Inositol 1,4,5-triphosphate causes an increase in Ca concentration and the release of diacylglycerol activates PKC. TPα stimulates cAMP levels whereas TPβ inhibits the level of intracellular cAMP. [6] Serotonin, 5-HT, is an amine synthesized in the gut and it is released into the bloodstream after the activation of presynaptic neurons or enterochromaffin cells stimulation. Later, it is sequestered by the platelets using antidepressant-sensitive 5-HT transporters (SERTs) and into platelet’s granules by the vesicular monoamine transporter (VMAT). After the secretion, 5-HT increases the effects of prothrombotic agents by its binding with 5-HT2 receptors [7]

Primary hemostasis inhibitors

Thromboregulation is also in charge of regulating the process of clot elimination, called primary hemostasis inhibition. These inhibitors are substances that prevent the clot formation by preventing platelet adhesion. Platelet inhibition is important to prevent thrombotic episodes or the formation of blood clot and consequently preventing heart attacks and strokes. Some primary hemostasis inhibitors are cAMP, prostacyclin, PGE1, and kistrin. cAMP, cyclic adenosine monophosphate, phosphorylate messengers via protein kinase A (PKA). These signaling elements include thromboxane A2, receptor type α, phospholipase Cβ3, and IP3 receptors. Signalization in platelets is very sensitive in cAMP levels. [8] [9] Nitric oxide (NO) stimulates cGMP production and therefore the activation cGMP-dependent protein kinase (G kinase). This kinase inhibits Gαq-phospholipase C-inositol 1,4,5-triphosphate signaling and the mobilization of calcium inside the cell for thromboxane A2. [10] PGI2, prostacyclin, binds to IP receptors that catalyze cAMP formation. This process is mediated via GTP-binding protein Gs and adenylyl cyclase. PGE1 binds to IP receptors. IP receptors bind with ionophores that induce ADP and serotonin secretion. PGE1 inhibits the secretion of factors that stimulate platelet aggregation by competitive inhibition. [11] [12] Kistrin is a protein inhibitor of platelet aggregation. It belongs to the homologous family of glycoprotein IIb-IIa antagonists. Kistrin has an adhesion site that binds to GP IIb-IIIa. [13]

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Prostaglandin Group of physiologically active lipid compounds

The prostaglandins (PG) are a group of physiologically active lipid compounds called eicosanoids having diverse hormone-like effects in animals. Prostaglandins have been found in almost every tissue in humans and other animals. They are derived enzymatically from the fatty acid arachidonic acid. Every prostaglandin contains 20 carbon atoms, including a 5-carbon ring. They are a subclass of eicosanoids and of the prostanoid class of fatty acid derivatives.

An antiplatelet drug (antiaggregant), also known as a platelet agglutination inhibitor or platelet aggregation inhibitor, is a member of a class of pharmaceuticals that decrease platelet aggregation and inhibit thrombus formation. They are effective in the arterial circulation, where anticoagulants have little effect.

Thrombus blood clot

A thrombus, colloquially called a blood clot, is the final product of the blood coagulation step in hemostasis. There are two components to a thrombus: aggregated platelets and red blood cells that form a plug, and a mesh of cross-linked fibrin protein. The substance making up a thrombus is sometimes called cruor. A thrombus is a healthy response to injury intended to prevent bleeding, but can be harmful in thrombosis, when clots obstruct blood flow through healthy blood vessels.

Platelet component of blood aiding in coagulation.

Platelets, also called thrombocytes, are a component of blood whose function is to react to bleeding from blood vessel injury by clumping, thereby initiating a blood clot. Platelets have no cell nucleus: they are fragments of cytoplasm that are derived from the megakaryocytes of the bone marrow, which then enter the circulation. Circulating unactivated platelets are biconvex discoid (lens-shaped) structures, 2–3 µm in greatest diameter. Activated platelets have cell membrane projections covering their surface. Platelets are found only in mammals, whereas in other vertebrates thrombocytes circulate as intact mononuclear cells.

Coagulation The sequential process in which the multiple coagulation factors of the blood interact, ultimately resulting in the formation of an insoluble fibrin clot; it may be divided into three stages: stage 1, the formation of intrinsic and extrinsic prothrom

Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.

Hemostasis or haemostasis is a process to prevent and stop bleeding, meaning to keep blood within a damaged blood vessel. It is the first stage of wound healing. This involves coagulation, blood changing from a liquid to a gel. Intact blood vessels are central to moderating blood's tendency to form clots. The endothelial cells of intact vessels prevent blood clotting with a heparin-like molecule and thrombomodulin and prevent platelet aggregation with nitric oxide and prostacyclin. When endothelial injury occurs, the endothelial cells stop secretion of coagulation and aggregation inhibitors and instead secrete von Willebrand factor which initiate the maintenance of hemostasis after injury. Hemostasis has three major steps: 1) vasoconstriction, 2) temporary blockage of a break by a platelet plug, and 3) blood coagulation, or formation of a fibrin clot. These processes seal the hole until tissues are repaired.

Prostacyclin chemical compound

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 group of lipids known as eicosanoids. The two major thromboxanes are thromboxane A2 and thromboxane B2

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.

Protease-activated receptors (PAR) are a subfamily of related G protein-coupled receptors that are activated by cleavage of part of their extracellular domain. They are highly expressed in platelets, and also on endothelial cells, myocytes and neurons.

Biological crosstalk refers to instances in which one or more components of one signal transduction pathway affects another. This can be achieved through a number of ways with the most common form being crosstalk between proteins of signaling cascades. In these signal transduction pathways, there are often shared components that can interact with either pathway. A more complex instance of crosstalk can be observed with transmembrane crosstalk between the extracellular matrix (ECM) and the cytoskeleton.

P-selectin Cell adhesion molecule (CAM) on the surfaces of activated endothelial cells, which line the inner surface of blood vessels, and activated platelets

P-selectin is a protein that in humans is encoded by the SELP gene.

Thromboxane receptor mammalian protein found in Homo sapiens

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 receptors and was the first eicosanoid receptor cloned. The TP receptor derives its name from its preferred endogenous ligand thromboxane A2.

Phosphodiesterase 3 class of enzymes

PDE3 is a phosphodiesterase. The PDEs belong to at least eleven related gene families, which are different in their primary structure, substrate affinity, responses to effectors, and regulation mechanism. Most of the PDE families are composed of more than one gene. PDE3 is clinically significant because of its role in regulating heart muscle, vascular smooth muscle and platelet aggregation. PDE3 inhibitors have been developed as pharmaceuticals, but their use is limited by arrhythmic effects and they can increase mortality in some applications.

The PDE2 enzyme is one of 21 different phosphodiesterases (PDE) found in mammals. These different PDEs can be subdivided to 11 families. The different PDEs of the same family are functionally related despite the fact that their amino acid sequences show considerable divergence. The PDEs have different substrate specificities. Some are cAMP selective hydrolases, others are cGMP selective hydrolases and the rest can hydrolyse both cAMP and cGMP .
There is only one gene family coding for the PDE2, which is the PDE2A. Three splice variants have been found, the PDE2A1, PDE2A2 and PDE2A3. PDE2A1 is cytosolic whereas -A2 and -A3 are membrane bound. It has been suggested that different localization of PDE2A2 and -A3 is due to a unique N-terminal sequence, which is absent in PDE2A1. Despite the PDE2A splice variants being different, there is no known differences in their kinetic behavior..

Thromboxane A2 chemical compound

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.

Picotamide chemical compound

Picotamide is a platelet aggregation inhibitor. It works as a thromboxane synthase inhibitor and a thromboxane receptor inhibitor, the latter by modifying cellular responses to activation of the thromboxane receptor. Picotamide is licensed in Italy for the treatment of clinical arterial thrombosis and peripheral artery disease.

Prostaglandin EP<sub>3</sub> receptor protein-coding gene in the species Homo sapiens

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.

Vasodilator-stimulated phosphoprotein mammalian protein found in Homo sapiens

Vasodilator-stimulated phosphoprotein is a protein that in humans is encoded by the VASP gene.

Multiple electrode aggregometry

Multiplate multiple electrode aggregometry (MEA) is a test of platelet function in whole blood. The test can be used to diagnose platelet disorders, monitor antiplatelet therapy, and is also investigated as a potential predictor of transfusion requirements and bleeding risk in cardiac surgery.

The platelet plug, also known as the hemostatic plug or platelet thrombus, is an aggregation of platelets formed during the earlier stage of hemostasis in response to blood vessel wall injury. After platelets are recruited and begin to accumulate around the breakage, their “sticky” nature allows them to adhere to each other. This forms a platelet plug, which prevents more blood from leaving the body as well as any outside contaminants from getting in. The plug provides a temporary blockage of the break in the vasculature. As such, platelet plug formation occurs after vasoconstriction of the blood vessels but before the creation of the fibrin mesh clot, which is the more permanent solution to the injury. The result of the platelet plug formation is the coagulation of blood. It can also be referred to as primary hemostasis.


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