Thromboregulation
Thromboregulationis the series of mechanisms in how a primary clot is regulated. These mechanisms include, competitive inhibition or negative feedback. It includes primaryhemostasis,which is the process of how blood platelets adhere to the endothelium of an injured blood vessel.[1][2]Plateletaggregation 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
[edit]One primary function of thromboregulation is the control of primaryhemostasis,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 resultingthrombus.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 ofADP,TXA2,andserotoninpresent in the platelet granules.[4]
ADP-dependent aggregation is mediated by two receptors: the purinergicP2Y1,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:cycloxygenaseand thromboxane A2 synthase. TX2 effects are mediated by G protein-coupled receptors, subtypes TPα and TPβ. Both receptors mediatephospholipase Cstimulation causing an increase of intracellular levels ofinositol 1,4,5-triphosphateanddiacylglycerol.Inositol 1,4,5-triphosphate causes an increase in Ca concentration and the release of diacylglycerol activatesPKC.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 orenterochromaffin cellsstimulation. Later, it is sequestered by the platelets using antidepressant-sensitive 5-HT transporters (SERTs) and into platelet’s granules by thevesicular 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
[edit]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 includethromboxane 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 activationcGMP-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 andadenylyl cyclase.PGE1binds to IP receptors. IP receptors bind withionophoresthat 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]
References
[edit]- ^Marcus, Aaron; Safier, Lenore (April 1993)."Thromboregulation: multicellular modulation of platelet reactivity in hemostasis and thrombosis".The FASEB Journal.7(6): 516–522.doi:10.1096/fasebj.7.6.8472890.PMID8472890.S2CID43022341.
- ^Ruiz Argüelles, Guillermo J. (2009).Fundamentos de Hematología(in Spanish) (4 ed.). Editorial Médica Panamericana.
- ^Brass, Lawrence (September 2003)."Thrombin and Platelet activation".Chest.125(3 Suppl): 18S–25S.doi:10.1378/chest.124.3_suppl.18S.PMID12970120.
- ^Furie, Bruce; Barbara, Furie (December 2005)."Thrombus formation in vivo".The Journal of Clinical Investigation.115(12): 3355–3362.doi:10.1172/jci26987.PMC1297262.PMID16322780.
- ^Marcus, Aaron; Safier, Lenore (April 1993)."Thromboregulation: multicellular modulation of platelet reactivity in hemostasis and thrombosis".The FASEB Journal.7(6): 516–522.doi:10.1096/fasebj.7.6.8472890.PMID8472890.S2CID43022341.
- ^Marcus, Aaron; Safier, Lenore (April 1993)."Thromboregulation: multicellular modulation of platelet reactivity in hemostasis and thrombosis".The FASEB Journal.7(6): 516–522.doi:10.1096/fasebj.7.6.8472890.PMID8472890.S2CID43022341.
- ^Ruiz Argüelles, Guillermo J. (2009).Fundamentos de Hematología(in Spanish) (4 ed.). Editorial Médica Panamericana.
- ^Maurice, D H; Haslam, RJ (May 1990)."Molecular basis of the synergistic inhibition of platelet function by nitrovasodilators and activators of adenylate cyclase: inhibition of cyclic AMP breakdown by cyclic GMP".Molecular Pharmacology.37(5): 671–681.PMID2160060.
- ^Siess, Wolfgang; Eduardo, Lapetina (1990)."Functional relationship between cyclic AMP-dependent protein phosphorylation and platelet inhibition".Biochemical Journal.271(3): 815–819.doi:10.1042/bj2710815.PMC1149637.PMID1700902.
- ^Wang, Guand-Rong; Yan, Zhu; Halushka, Perry; Lincoln, Thomas; Mendelshon, Michael (1998)."Mechanism of platelet inhibition by nitric oxide: In vivo phosphorylation of thromboxane by cyclic GMP-dependent protein kinase".Proceedings of the National Academy of Sciences of the United States of America.95(9): 4888–4893.doi:10.1073/pnas.95.9.4888.PMC20183.PMID9560198.
- ^Iyú, David; Jüttner, Madlen; Glenn, Jackie R.; White, Ann E.; Johnson, Andrew J.; Fox, Susan C.; Heptinstall, Stan (2011). "PGE1 and PGE2 modify platelet function through different prostanoid receptors".Prostaglandins & Other Lipid Mediators.94(1–2): 9–16.doi:10.1016/j.prostaglandins.2010.11.001.PMID21095237.
- ^Fenstein, MB; Fraser, C (1975)."Human platelet secretion and aggregation induced by calcium ionophores. Inhibition by PGE1 and dibutyryl cyclicl AMP".The Journal of General Physiology.66(5): 561–581.CiteSeerX10.1.1.283.2493.doi:10.1085/jgp.66.5.561.PMC2226221.PMID172596.
- ^Adler, M; Lazaurs, RA; MS, Dennis; G, Wagner (July 1991). "Solution structure of kistrin, a potent platelet aggregation inhibitor GP IIb-IIa antagonist".Science.253(5018): 445–448.doi:10.1126/science.1862345.PMID1862345.