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]
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 inhibitorsedit
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]
Referencesedit
^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. PMID 8472890. S2CID 43022341.
^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. PMID 12970120.
^Furie, Bruce; Barbara, Furie (December 2005). "Thrombus formation in vivo". The Journal of Clinical Investigation. 115 (12): 3355–3362. doi:10.1172/jci26987. PMC1297262. PMID 16322780.
^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. PMID 8472890. S2CID 43022341.
^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. PMID 8472890. S2CID 43022341.
^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. PMID 2160060.
^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. PMID 1700902.
^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. PMID 9560198.
^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. PMID 21095237.
^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. PMID 172596.
^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. PMID 1862345.
April 11, 2024
thromboregulation, series, mechanisms, primary, clot, regulated, these, mechanisms, include, competitive, inhibition, negative, feedback, includes, primary, hemostasis, which, process, blood, platelets, adhere, endothelium, injured, blood, vessel, platelet, ag. 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 Contents 1 Primary hemostasis inducers 2 Primary hemostasis inhibitors 3 ReferencesPrimary hemostasis inducers editOne 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 Gaq 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 TPa and TPb 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 TPa stimulates cAMP levels whereas TPb 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 editThromboregulation 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 a phospholipase Cb3 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 Gaq 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 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 PMID 8472890 S2CID 43022341 Ruiz Arguelles Guillermo J 2009 Fundamentos de Hematologia in Spanish 4 ed Editorial Medica Panamericana Brass Lawrence September 2003 Thrombin and Platelet activation Chest 125 3 Suppl 18S 25S doi 10 1378 chest 124 3 suppl 18S PMID 12970120 Furie Bruce Barbara Furie December 2005 Thrombus formation in vivo The Journal of Clinical Investigation 115 12 3355 3362 doi 10 1172 jci26987 PMC 1297262 PMID 16322780 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 PMID 8472890 S2CID 43022341 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 PMID 8472890 S2CID 43022341 Ruiz Arguelles Guillermo J 2009 Fundamentos de Hematologia in Spanish 4 ed Editorial Medica 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 PMID 2160060 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 PMC 1149637 PMID 1700902 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 PMC 20183 PMID 9560198 Iyu David Juttner 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 amp Other Lipid Mediators 94 1 2 9 16 doi 10 1016 j prostaglandins 2010 11 001 PMID 21095237 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 CiteSeerX 10 1 1 283 2493 doi 10 1085 jgp 66 5 561 PMC 2226221 PMID 172596 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 PMID 1862345 Retrieved from https en wikipedia org w index php title Thromboregulation amp oldid 1216232153, wikipedia, wiki, book, books, library,
