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1
Poelstra, K., JF Baller, MJ Hardonk, and WW Bakker. "Demonstration of antithrombotic activity of glomerular adenosine diphosphatase [published erratum appears in Blood 1991 Oct 15;78(8):2163]." Blood 78, no. 1 (July 1, 1991): 141–48. http://dx.doi.org/10.1182/blood.v78.1.141.bloodjournal781141.
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We have demonstrated that reduced glomerular adenosine diphosphatase (ADPase) activity within the rat kidney is associated with an increased thrombotic tendency. To establish a possible causal relationship between these intraglomerular events, experiments were conducted to inhibit adenosine diphosphate (ADP) degradation without influencing other glomerular prothrombotic or antithrombotic mechanisms. Concurrently, we studied intraglomerular platelet aggregation. Two ways of selective inhibition of glomerular ADPase activity were applied: (1) by competitive substrates (ie, uridine diphosphate [UDP]), and (2) by the nondegradable ADP analogue ADP-beta-S. Both strategies were used during ex vivo alternate perfusion of kidneys with platelets and ADP (to test intraglomerular thrombotic tendency). Each group (n = 6) received different substrates or a combination of substrates. A significant increase in platelet aggregation was observed in kidneys after perfusion with platelets and ADP together with the competitive substrate UDP as compared to perfusions with platelets and ADP alone (78.5% +/- 9.8% v 27.9% +/- 11.4% glomeruli staining positive for platelets, P less than .005). In contrast, UDP alone had no effect on platelet aggregation. Other nucleoside polyphosphates (guanosine diphosphate and inosine triphosphate) were also effective as competitive substrates in the ex vivo perfusion model (n = 4). None of these substrates was capable of increasing ADP-induced aggregation when studied in vitro. In addition, ADP- beta-S also increased platelet aggregation in the perfusion model as compared with native ADP (P less than .005). These results show that selective reduction of ADP degradation in intact kidneys strongly promotes the intraglomerular proaggregatory condition. It can be concluded that glomerular ADPase exerts potent antithrombotic activity within the normal rat kidney.
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Poelstra, K., JF Baller, MJ Hardonk, and WW Bakker. "Demonstration of antithrombotic activity of glomerular adenosine diphosphatase [published erratum appears in Blood 1991 Oct 15;78(8):2163]." Blood 78, no. 1 (July 1, 1991): 141–48. http://dx.doi.org/10.1182/blood.v78.1.141.141.
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Abstract We have demonstrated that reduced glomerular adenosine diphosphatase (ADPase) activity within the rat kidney is associated with an increased thrombotic tendency. To establish a possible causal relationship between these intraglomerular events, experiments were conducted to inhibit adenosine diphosphate (ADP) degradation without influencing other glomerular prothrombotic or antithrombotic mechanisms. Concurrently, we studied intraglomerular platelet aggregation. Two ways of selective inhibition of glomerular ADPase activity were applied: (1) by competitive substrates (ie, uridine diphosphate [UDP]), and (2) by the nondegradable ADP analogue ADP-beta-S. Both strategies were used during ex vivo alternate perfusion of kidneys with platelets and ADP (to test intraglomerular thrombotic tendency). Each group (n = 6) received different substrates or a combination of substrates. A significant increase in platelet aggregation was observed in kidneys after perfusion with platelets and ADP together with the competitive substrate UDP as compared to perfusions with platelets and ADP alone (78.5% +/- 9.8% v 27.9% +/- 11.4% glomeruli staining positive for platelets, P less than .005). In contrast, UDP alone had no effect on platelet aggregation. Other nucleoside polyphosphates (guanosine diphosphate and inosine triphosphate) were also effective as competitive substrates in the ex vivo perfusion model (n = 4). None of these substrates was capable of increasing ADP-induced aggregation when studied in vitro. In addition, ADP- beta-S also increased platelet aggregation in the perfusion model as compared with native ADP (P less than .005). These results show that selective reduction of ADP degradation in intact kidneys strongly promotes the intraglomerular proaggregatory condition. It can be concluded that glomerular ADPase exerts potent antithrombotic activity within the normal rat kidney.
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Cattaneo, Marco, Christian Gachet, Jeanne-Pierre Cazenave, and Marian A. Packham. "Adenosine diphosphate (ADP) does not induce thromboxane A2 generation in human platelets." Blood 99, no. 10 (May 15, 2002): 3868–70. http://dx.doi.org/10.1182/blood-2002-01-0313.
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Darlington, Daniel N., Xiaowu Wu, Kevin L. Chang, James Bynum, and Andrew P. Cap. "Regulation of Platelet Function By Adenosine Receptors." Blood 134, Supplement_1 (November 13, 2019): 2348. http://dx.doi.org/10.1182/blood-2019-131129.
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Introduction: We have recently shown that severe trauma and hemorrhage lead to inhibition of platelet aggregation and an elevation in cyclic adenosine monophosphate (cAMP). Adenosine is one of the few humoral agents known to stimulate cAMP in platelets. Because adenosine is released from damaged tissue, it may contribute to the platelet dysfunction seen after severe trauma. Platelets have four adenosine receptors (A1, A2a, A2b and A3). These receptors are G-Protein Coupled Receptors and have been proposed to stimulate adenylyl cyclase and increase intracellular cAMP. Although studies have shown that stimulate A2a can inhibit platelet aggregation and elevate cAMP, there is little data elucidating the function of the other receptors. Objective: Define which adenosine receptors affects platelet aggregation and cAMP production. Methods: Platelet-rich plasma (PRP) was isolated from whole blood of human volunteers, and centrifuged at 200g for 10min. Light transmission aggregometry was performed using a plate reader (Synergy Neo2 Multimode Reader, BioTek) with constant agitation. PRP was stimulated with adenosine diphosphate (ADP) with or without various adenosine agonists or antagonists, including the non-metabolizable adenosine agonist 5-(N-ethyl-carboxamido) adenosine (NECA), antagonists to receptors A1 (DPCPX), A2a (Sch 58261), A2b (GS 6201) and A3 (MRS 1220), or agonists for A2a (CGS 21680) A2b (BAY 60-6583) or agonist A1 (CCPA), A2a (CGS 21680), A2b (Bay 60-6583), A3 (2-Cl-IB-Meca). Cyclic AMP was extracted from 100ul of PRP after adding 1ml of EtOH, 10mM ammonium formate, with 10ug/ml cGMP-Br as an internal control. Samples were centrifuged at 20K g for 10min, and supernatant dried. Samples were brought up in 200ul of 0.1% formic acid for analysis by Reverse Phase liquid chromatography/ Tandem Mass Spectroscopy (Quantiva, ThrermoFisher). N-8/group. Results: Adenosine diphosphate (100uM) leads to platelet aggregation (change in mAbsorbance units, Table 1). The adenosine agonist NECA inhibited aggregation to ADP and elevated cAMP in a dose dependent manner (pg/ml per 1000 plt, Table 1). Platelet aggregation was inhibited and cAMP was elevated after stimulation with agonists for adenosine receptor A2a agonist, but not A1, A2b, or A3 (Table 2). Antagonists for A2a, but not A1, A2b, A3, blocked NECA inhibition of ADP aggregation (Table 3). Agonist for adenosine receptor A2a inhibited the ADP-induced aggregation and elevated cAMP in a dose response manner (Table 4). Discussion: Adenosine inhibits platelet aggregation to ADP. The mechanism appears to be due to elevation in intracellular cAMP, and works through the A2a receptor. These data suggest that the A2a receptor could be potential target for a resuscitation strategy that could attenuate or prevent platelet dysfunction after trauma by preventing stimulation of adenylate cyclase and synthesis of cAMP. This study was funded by the US Army medical Research and Development Command. Disclosures No relevant conflicts of interest to declare.
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Cattaneo, Marco. "The platelet P2Y12 receptor for adenosine diphosphate: congenital and drug-induced defects." Blood 117, no. 7 (February 17, 2011): 2102–12. http://dx.doi.org/10.1182/blood-2010-08-263111.
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Abstract P2Y12, the Gi-coupled platelet receptor for adenosine diphosphate (ADP), plays a central role in platelet function. Patients with congenital P2Y12 defects display a mild to moderate bleeding diathesis, characterized by mucocutaneous bleedings and excessive post-surgical and post-traumatic blood loss. Defects of P2Y12 should be suspected when ADP, even at high concentrations (≥ 10μM), is unable to induce full, irreversible platelet aggregation. Tests that evaluate the degree of inhibition of adenylyl cyclase by ADP should be used to confirm the diagnosis. Drugs that inhibit P2Y12 are potent antithrombotic drugs, attesting the central role played by P2Y12 in platelet thrombus formation. Clopidogrel, the most widely used drug that inhibits P2Y12, is effective both in monotherapy and in combination with acetylsalicylic acid. The most important drawback of clopidogrel is its inability to inhibit adequately P2Y12-dependent platelet function in approximately one-third of patients who are therefore not protected from major cardiovascular events. New drugs, such as prasugrel and ticagrelor, which effectively inhibit P2Y12 in the majority of patients, proved to be more efficacious than clopdidogrel in preventing major cardiovascular events. Although they increase the incidence of major bleedings, the net clinical benefit is in favor of the new P2Y12 inhibitors.
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Goto, Shinya, Noriko Tamura, and Shunnosuke Handa. "Effects of adenosine 5′-diphosphate (ADP) receptor blockade on platelet aggregation under flow." Blood 99, no. 12 (June 15, 2002): 4644–46. http://dx.doi.org/10.1182/blood-2001-12-0284.
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Muhsin, A., M. T. Eusni Raha, M. N. Sabariah, A. K. Faraizah, H. Roshida, and M. S. Salmiah. "Impaired Platelet Aggregation to Adenosine Diphosphate (ADP) Agonist in National Blood Centre, Malaysia." Asian Journal of Epidemiology 5, no. 4 (September 15, 2012): 114–22. http://dx.doi.org/10.3923/aje.2012.114.122.
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Koessler, Juergen, Philipp Klingler, Marius Niklaus, Katja Weber, Angela Koessler, Markus Boeck, and Anna Kobsar. "The Impact of Cold Storage on Adenosine Diphosphate-Mediated Platelet Responsiveness." TH Open 04, no. 03 (July 2020): e163-e172. http://dx.doi.org/10.1055/s-0040-1714254.
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Abstract Introduction Cold storage of platelets is considered to contribute to lower risk of bacterial growth and to more efficient hemostatic capacity. For the optimization of storage strategies, it is required to further elucidate the influence of refrigeration on platelet integrity. This study focused on adenosine diphosphate (ADP)-related platelet responsiveness. Materials and Methods Platelets were prepared from apheresis-derived platelet concentrates or from peripheral whole blood, stored either at room temperature or at 4°C. ADP-induced aggregation was tested with light transmission. Activation markers, purinergic receptor expression, and P2Y12 receptor function were determined by flow cytometry. P2Y1 and P2X1 function was assessed by fluorescence assays, cyclic nucleotide concentrations by immunoassays, and vasodilator-stimulated phosphoprotein (VASP)-phosphorylation levels by Western blot analysis. Results In contrast to room temperature, ADP-induced aggregation was maintained under cold storage for 6 days, associated with elevated activation markers like fibrinogen binding or CD62P expression. Purinergic receptor expression was not essentially different, whereas P2Y1 function deteriorated rapidly at cold storage, but not P2Y12 activity. Inhibitory pathways of cold-stored platelets were characterized by reduced responses to nitric oxide and prostaglandin E1. Refrigeration of citrated whole blood also led to the attenuation of induced inhibition of platelet aggregation, detectable within 24 hours. Conclusion ADP responsiveness is preserved under cold storage for 6 days due to stable P2Y12 activity and concomitant disintegration of inhibitory pathways enabling a higher reactivity of stored platelets. The ideal storage time at cold temperature for the highest hemostatic effect of platelets should be evaluated in further studies.
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Rinder, CS, LA Student, JL Bonan, HM Rinder, and BR Smith. "Aspirin does not inhibit adenosine diphosphate-induced platelet alpha- granule release." Blood 82, no. 2 (July 15, 1993): 505–12. http://dx.doi.org/10.1182/blood.v82.2.505.505.
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Abstract The involvement of metabolites of arachidonic acid in platelet-dense granule secretion and secondary platelet-platelet interactions is well characterized. However, their role in heterotypic interactions dependent on alpha-granule secretion is less well understood. Using platelet-surface expression of P-selectin as a marker of alpha-granule secretion, we have shown that: (1) aspirin treatment of platelets at doses that block dense granule secretion does not inhibit alpha-granule secretion to adenosine diphosphate (ADP); (2) synergism between epinephrine and ADP in the induction of P-selectin expression is similarly unaffected by aspirin; and (3) the ability of P-selectin to mediate adhesion of activated platelets to monocytes and polymorphonuclear lymphocytes in whole blood is also unchanged by aspirin treatment. To further explore the mechanisms responsible for platelet alpha-granule secretion, we have shown that inhibition of Na+/H+ exchange by either acidification of the extracellular medium or amiloride treatment blocked ADP-induced P-selectin expression. In contrast, incubation with the platelet lipoxygenase inhibitor 5,8,11- eicosatrynoic acid, by itself and with aspirin, did not decrease ADP- induced P-selectin expression. We conclude that platelet alpha-granule secretion in response to ADP is dependent on intact Na+/H+ exchange but is independent of the lipoxygenase- and cyclooxygenase-dependent metabolites of arachidonic acid.
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Rinder, CS, LA Student, JL Bonan, HM Rinder, and BR Smith. "Aspirin does not inhibit adenosine diphosphate-induced platelet alpha- granule release." Blood 82, no. 2 (July 15, 1993): 505–12. http://dx.doi.org/10.1182/blood.v82.2.505.bloodjournal822505.
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The involvement of metabolites of arachidonic acid in platelet-dense granule secretion and secondary platelet-platelet interactions is well characterized. However, their role in heterotypic interactions dependent on alpha-granule secretion is less well understood. Using platelet-surface expression of P-selectin as a marker of alpha-granule secretion, we have shown that: (1) aspirin treatment of platelets at doses that block dense granule secretion does not inhibit alpha-granule secretion to adenosine diphosphate (ADP); (2) synergism between epinephrine and ADP in the induction of P-selectin expression is similarly unaffected by aspirin; and (3) the ability of P-selectin to mediate adhesion of activated platelets to monocytes and polymorphonuclear lymphocytes in whole blood is also unchanged by aspirin treatment. To further explore the mechanisms responsible for platelet alpha-granule secretion, we have shown that inhibition of Na+/H+ exchange by either acidification of the extracellular medium or amiloride treatment blocked ADP-induced P-selectin expression. In contrast, incubation with the platelet lipoxygenase inhibitor 5,8,11- eicosatrynoic acid, by itself and with aspirin, did not decrease ADP- induced P-selectin expression. We conclude that platelet alpha-granule secretion in response to ADP is dependent on intact Na+/H+ exchange but is independent of the lipoxygenase- and cyclooxygenase-dependent metabolites of arachidonic acid.
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Gachet, Christian, and Beatrice Hechler. "Platelet Purinergic Receptors in Thrombosis and Inflammation." Hämostaseologie 40, no. 02 (May 2020): 145–52. http://dx.doi.org/10.1055/a-1113-0711.
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AbstractIt took approximately 40 years from the seminal identification of adenosine diphosphate (ADP) as the factor R, an agent derived from red blood cells inducing platelet adhesion to glass, to the completion of the repertoire of its receptors on platelets and its importance in haemostasis and thrombosis. ADP, either derived from red blood cells or released by platelets themselves, stimulates platelets via two G protein-coupled receptors, P2Y1 and P2Y12. In addition, adenosine triphosphate, also contained in the platelet dense granules, activates the P2X1 cation channel. Each of these receptors plays a specific role during platelet activation and aggregation, with relevance to haemostasis, thrombosis and various inflammatory processes where platelets are involved including chronic responses such as atherosclerosis or acute responses such as sepsis, endotoxaemia or allergic asthma. Finally, platelets also express P2Y14, a receptor activated by released uridine diphosphate glucose. Although devoid of any known role in haemostasis, this receptor seems to play a specific role in neutrophil chemotaxis.
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Kim, Phyo, James D. Jones, and Thoralf M. Sundt. "High-energy phosphate levels in the cerebral artery during chronic vasospasm after subarachnoid hemorrhage." Journal of Neurosurgery 76, no. 6 (June 1992): 991–96. http://dx.doi.org/10.3171/jns.1992.76.6.0991.
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✓ High-energy phosphate levels were measured in the canine cerebral artery during chronic vasospasm. Subarachnoid hemorrhage and vasospasm were induced by percutaneous injections of autologous venous blood into the cisterna magna. Narrowing of the artery was confirmed by angiography 7 days later. Levels of adenosine phosphates (adenosine triphosphate (ATP), adenosine diphosphate (ADP), and adenosine monophosphate (AMP)), guanosine phosphates (guanosine triphosphate (GTP) and guanosine diphosphate (GDP)), and creatine phosphate (CrP) in the basilar artery were quantified using high-performance liquid chromatography. The total creatine (Crtotal) content was measured by a spectrophotometric method after acid hydrolysis of CrP. Levels of ATP, GTP, and CrP were markedly reduced in the spastic arteries, and ratios of ATP:ADP, GTP:GDP, and CrP:Crtotal were significantly decreased. The results indicate a serious disturbance in the energy metabolism that takes place in the cerebral artery during chronic vasospasm.
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Vial, Catherine, Samantha J. Pitt, Jon Roberts, Michael G. Rolf, Martyn P. Mahaut-Smith, and Richard J. Evans. "Lack of evidence for functional ADP-activated human P2X1 receptors supports a role for ATP during hemostasis and thrombosis." Blood 102, no. 10 (November 15, 2003): 3646–51. http://dx.doi.org/10.1182/blood-2003-06-1963.
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AbstractPurine nucleotides acting through P2 receptors play key roles in platelet signaling. The P2X1 receptor is an adenosine triphosphate (ATP)-gated ion channel that mediates a rapid calcium influx signal, but can also synergize with subsequent adenosine diphosphate (ADP)-evoked P2Y1 receptor-mediated responses and thus may contribute to platelet activation during hemostasis. Recent studies have shown that P2X1 receptors contribute to the formation of platelet thrombi, particularly under conditions of high shear stress. Based on intracellular Ca2+ measurements a previous report has suggested that a splice variant of the P2X1 receptor, P2X1del, is expressed in platelets and, in contrast to the full-length P2X1WT receptor, is activated by ADP. In the present study we show that the P2X1del receptor fails to form functional ion channels and is below the limit of detection in human platelets. Furthermore, ADP does not contribute to the rapid ionotropic P2X receptor-mediated response in platelets. These results support the notion that ATP is the principal physiologic agonist at P2X1 receptors and that it plays a role in the activation of platelets. (Blood. 2003;102:3646-3651)
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Kajita, Yasukazu, Hans H. Dietrich, and Ralph G. Dacey. "Effects of oxyhemoglobin on local and propagated vasodilatory responses induced by adenosine, adenosine diphosphate, and adenosine triphosphate in rat cerebral arterioles." Journal of Neurosurgery 85, no. 5 (November 1996): 908–16. http://dx.doi.org/10.3171/jns.1996.85.5.0908.
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✓ After subarachnoid hemorrhage (SAH), cerebral arteries display impaired vasomotor control, resulting in decreased regional cerebral blood flow. Recently, propagation of vasomotor responses has been recognized as an important regulatory mechanism in microcirculation. In this study, the authors tested the hypothesis that oxyhemoglobin (OxyHb) inhibits the vasodilatory effect of chemical mediators such as adenosine and adenine nucleotides at a local and/or propagated site. Penetrating intracerebral arterioles were surgically isolated from the middle cerebral arteries of rat brains, cannulated, and observed videomicroscopically in an organ bath under an inverted microscope. The effects of 10−5 M OxyHb on vasoactive responses to adenosine, adenosine diphosphate (ADP), and adenosine triphosphate (ATP) were examined. The drugs were extraluminally applied either to the bath (10−10−10−3 M) or, using pressure microejection (pipette concentration 10−2 M), locally. The ATP and ADP initially constricted and then significantly dilated the vessels after both extraluminal application and microapplication. Furthermore, local microstimulation by these drugs produced conducted vasodilation. Adenosine elicited significant vasodilation after both extraluminal and local stimulation. Again, conducted vasodilation was observed. The vasomotor responses that were induced by a maximum local stimulation corresponded in magnitude to those observed at bath concentrations of 10−5 to 10−4 M of the same drug. Pretreatment with OxyHb constricted arterioles to an average of 87% of control and blunted extraluminally induced dilation at low concentrations (10−10−10−8) of ATP and ADP, but did not affect vasodilation induced by 10−4 M or greater concentrations of ATP, ADP, or adenosine. Although the local response to local microstimulation was unaltered, propagated vasodilation as a response to ATP, ADP, and adenosine was significantly attenuated by OxyHb. These findings indicate that vasodilatory propagation plays an important role in the regulation of brain microcirculation and that its impairment by OxyHb could, in part, explain the cerebral hypoperfusion that is observed after SAH.
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Eltzschig, Holger K., Linda F. Thompson, Jorn Karhausen, Richard J. Cotta, Juan C. Ibla, Simon C. Robson, and Sean P. Colgan. "Endogenous adenosine produced during hypoxia attenuates neutrophil accumulation: coordination by extracellular nucleotide metabolism." Blood 104, no. 13 (December 15, 2004): 3986–92. http://dx.doi.org/10.1182/blood-2004-06-2066.
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Abstract Hypoxia is a well-documented inflammatory stimulus and results in tissue polymorphonuclear leukocyte (PMN) accumulation. Likewise, increased tissue adenosine levels are commonly associated with hypoxia, and given the anti-inflammatory properties of adenosine, we hypothesized that adenosine production via adenine nucleotide metabolism at the vascular surface triggers an endogenous anti-inflammatory response during hypoxia. Initial in vitro studies indicated that endogenously generated adenosine, through activation of PMN adenosine A2A and A2B receptors, functions as an antiadhesive signal for PMN binding to microvascular endothelia. Intravascular nucleotides released by inflammatory cells undergo phosphohydrolysis via hypoxia-induced CD39 ectoapyrase (CD39 converts adenosine triphosphate/adenosine diphosphate [ATP/ADP] to adenosine monophosphate [AMP]) and CD73 ecto-5′-nucleotidase (CD73 converts AMP to adenosine). Extensions of our in vitro findings using cd39- and cd73-null animals revealed that extracellular adenosine produced through adenine nucleotide metabolism during hypoxia is a potent anti-inflammatory signal for PMNs in vivo. These findings identify CD39 and CD73 as critical control points for endogenous adenosine generation and implicate this pathway as an innate mechanism to attenuate excessive tissue PMN accumulation. (Blood. 2004;104:3986-3992)
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Cho, Moon J., Junling Liu, Tamara I. Pestina, Shirley A. Steward, Dennis W. Thomas, Thomas M. Coffman, Demin Wang, Carl W. Jackson, and T. Kent Gartner. "The roles of αIIbβ3-mediated outside-in signal transduction, thromboxane A2, and adenosine diphosphate in collagen-induced platelet aggregation." Blood 101, no. 7 (April 1, 2003): 2646–51. http://dx.doi.org/10.1182/blood-2002-05-1363.
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Collagen-induced activation of platelets in suspension leads to αIIbβ3-mediated outside-in signaling, granule release, thromboxane A2 (TxA2) production, and aggregation. Although much is known about collagen-induced platelet signaling, the roles of TxA2 production, adenosine diphosphate (ADP) and dense-granule secretion, and αIIbβ3-mediated outside-in signaling in this process are unclear. Here, we demonstrate that TxA2 and ADP are required for collagen-induced platelet activation in response to a low, but not a high, level of collagen and that αIIbβ3-mediated outside-in signaling is required, at least in part, for this TxA2 production and ADP secretion. A high level of collagen can activate platelets deficient in PLCγ2, Gαq, or TxA2 receptors, as well as platelets treated with a protein kinase C inhibitor, Ro31-8220. Thus, activation of αIIbβ3 in response to a high level of collagen does not require these signaling proteins. Furthermore, a high level of collagen can cause weak TxA2 and ADP-independent aggregation, but maximal aggregation induced by a high level of collagen requires TxA2 or secretion.
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Benedikter, Hermann, Gisela Knopki, and Paul Renz. "Phosphatidylinositol-Specific Phospholipase C from Bovine Blood Platelets. Inhibition by Calmodulin-Inhibitors — Activation by ATP and ADP." Zeitschrift für Naturforschung C 40, no. 1-2 (February 1, 1985): 68–72. http://dx.doi.org/10.1515/znc-1985-1-214.
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The phospholipase C-activity in crude extracts of bovine blood platelets is strongly inhibited by the calmodulin-inhibitors fluphenazine and calmidazolium in the mᴍ range, and activated by ATP and ADP. but not by AMP. The activating effect is also shown by the nonhydrolysable ATP- and ADP-analogs α,β- and β,γ-methyleneadenosine 5′-triphosphate and α,β-methylene- adenosine 5′-diphosphate, thus indicating that it is an allosteric effect. The stimulation of the phospholipase C-activity by ATP is also detectable in some partially purified fractions of the crude platelet extract, but it is abolished on further purification of the enzyme.
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Nagaoka, S., H. Shinbara, M. Okubo, T. Kawakita, K. Hino, and E. Sumiya. "Contributions of Adp and Atp to the Increase in Skeletal Muscle Blood Flow after Manual Acupuncture Stimulation in Rats." Acupuncture in Medicine 34, no. 3 (June 2016): 229–34. http://dx.doi.org/10.1136/acupmed-2015-010959.
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Objective To investigate the contributions of adenosine triphosphate (ATP) and adenosine diphosphate (ADP) to the increase in skeletal muscle blood flow (MBF) observed following manual acupuncture (MA) stimulation in rats. Methods Male Sprague-Dawley rats were used as experimental animals (300–370 g, n=40). MA was applied to the right tibialis anterior muscle (TA) for 1 min using a stainless steel acupuncture needle. In eight rats, high-performance liquid chromatography with the microdialysis technique was used to measure local extracellular concentrations of ATP, ADP, adenosine monophosphate (AMP), and adenosine in the TA. In the remaining 32 rats, fluorescent microspheres (15 µm in diameter) were used to measure MBF in the TA following pre-treatment with either the P2 receptor antagonist suramin (100 mg/kg intra-arterially) or saline (control) (n=16 each). Rats receiving MA (Suramin+MA and Saline+MA groups, n=8 each) were compared with untreated rats (Suramin and Saline groups, n=8). Results MA significantly increased the local extracellular concentration of ATP, ADP, and adenosine (p<0.05, before MA vs 30 min after MA). In addition, MA significantly increased MBF in rats pre-treated with saline or suramin (p<0.01, Saline vs Saline+MA; p<0.05, Suramin vs Suramin+MA, respectively). However, suramin significantly suppressed this MA-induced increase in MBF (p<0.05, Saline+MA vs Suramin+MA). Conclusions These results suggest that both ATP and ADP partially contribute to the MA-induced increase in MBF via P2 receptors. However, further studies are needed to clarify the contributions of other vasodilators.
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Sukeksi, Andri, and Rizqi Yogania Rahmawati. "Potensi Ekstrak Etanol Daun Sirih (Piper Betle L.) Sebagai Pengganti ADP (Adenosine Diphosphate) Pada Pemeriksaan Agregasi Trombosit." Lontara 2, no. 1 (June 16, 2021): 11–17. http://dx.doi.org/10.53861/lontarariset.v2i1.184.
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Adenosine diphosphate (ADP) reagent is often used in the examination of platelet aggregation, yet has limitations in terms of price and availability. Natural source namely betel leaf (Piper betle L.) are believed to be used as a substitute for ADP because betel leaf have the characteristics of styptic (to resist bleeding), vulnerary (to heal skin wounds), and anti-inflammatory (to preserve inflammation) (Moeljanto & Mulyono, 2003). The aim of this study was to determine the potential of betel leaf on the examination of platelet aggregation. The method used in this research included the betel leaf extraction using ethanol as solvent with an evaporator. The extract obtained was used as a substitute for the ADP reagent in platelet examination in the form of determining the percentage of platelet aggregation in 16 human blood samples, with a population of students at the University of Muhammadiyah Semarang. The final results showed that the addition of betel leaf extraction to the 16 blood samples examined gave an average value of platelet aggregation percentage which was higher (65%) than the mean value of platelet aggregation using ADP reagent mixing (57%). Both results fall within the normal value range, namely 50-70%. It can be concluded that betel leaf extract has the potential to be used as a replacement reagent for ADP in the process of examining platelets, especially in determining the percentage value of platelet aggregation.
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Turner, Nancy A., Joel L. Moake, and Larry V. McIntire. "Blockade of adenosine diphosphate receptors P2Y12 and P2Y1 is required to inhibit platelet aggregation in whole blood under flow." Blood 98, no. 12 (December 1, 2001): 3340–45. http://dx.doi.org/10.1182/blood.v98.12.3340.
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Abstract Using heparinized whole blood and flow conditions, it was shown that adenosine 5′-diphosphate (ADP) receptors P2Y12 and P2Y1 are both important in direct shear-induced platelet aggregation and platelet aggregation subsequent to initial adhesion onto von Willebrand factor (vWf)–collagen. In the viscometer, whole blood was subjected to shear rates of 750, 1500, and 3000 s−1 for 30 seconds at room temperature. The extent of aggregation was determined by flow cytometry. The P2Y12antagonist AR-C69 931MX (ARMX) reduced shear-induced aggregation at these rates by 56%, 54%, and 16%, respectively, compared to control samples. Adenosine 3′,5′-diphosphate (A3P5P; P2Y1antagonist) inhibited shear-induced aggregation by 40%, 30% and 29%, respectively, compared to control samples. Blockade of both ADP receptors at 3000 s−1 with ARMX plus A3P5P further reduced the platelet aggregation by 41% compared to the addition of ARMX alone (57% compared to control samples). Using a parallel-plate flow chamber, whole blood was perfused over bovine collagen type 1 at a wall shear rate of 3000 s−1 for 60 seconds. Platelet deposition was quantified with epifluorescence video microscopy and digital image processing. Blockade of P2Y12 alone or blockade of P2Y1 alone did not reduce thrombus formation on vWf–collagen. In contrast, blockade of both P2Y12 and P2Y1 reduced platelet deposition by 72%. These results indicate that combinations of antagonists of the ADP receptors P2Y12 and P2Y1 are effective inhibitors of direct shear-induced platelet aggregation and of platelet aggregation subsequent to initial adhesion under flow conditions. Inhibitors of these pathways are potentially useful as antiarterial thrombotic agents.
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Leon, Catherine, Meike Alex, Antje Klocke, Eberhard Morgenstern, Christine Moosbauer, Anita Eckly, Michael Spannagl, Christian Gachet, and Bernd Engelmann. "Platelet ADP receptors contribute to the initiation of intravascular coagulation." Blood 103, no. 2 (January 15, 2004): 594–600. http://dx.doi.org/10.1182/blood-2003-05-1385.
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Abstract While the adenosine 5′-diphosphate (ADP) pathway is known to enhance thrombus formation by recruiting platelets and leukocytes to the primary layer of collagen-adhering platelets, its role for the initiation of coagulation has not been revealed. Ex vivo inhibition of the P2Y12 ADP receptor by clopidogrel administration diminished the rapid exposure of tissue factor (TF), the major initiator of coagulation, in conjugates of platelets with leukocytes established by the contact of whole blood with fibrillar collagen. Under in vitro conditions, the P2Y12 and P2Y1 ADP receptors were both found to be implicated in the exposure of TF in collagen-activated whole blood. Immunoelectron-microscopy revealed that collagen elicited the release of TF from its storage pools within the platelets. Functional activation of the intravascular TF was reduced by inhibition of the ADP receptors, partially due to the disruption of the platelet-neutrophil adhesions. Injection of collagen into the venous system of mice increased the number of thrombin-antithrombin complexes, indicative for the formation of thrombin in vivo. In P2Y1-deficient mice, the ability of collagen to enhance the generation of thrombin was impaired. In conclusion, the platelet ADP pathway supports the initiation of intravascular coagulation, which is likely to contribute to the concomitant formation of fibrin at the site of the growing thrombus.
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Agarwal, Ashok K., Narendra N. Tandon, Nicholas J. Greco, Noel J. Cusack, and G. A. Jamieson. "Evaluation of the Binding to Fixed Platelets of Agonists and Antagonists of ADP-Induced Aggregation." Thrombosis and Haemostasis 62, no. 04 (1989): 1103–6. http://dx.doi.org/10.1055/s-0038-1647126.
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SummarySteady state binding of eleven different ADP analogues to formaldehyde-fixed platelets has been determined in a competitive binding assay using 3H-ADP. The compounds tested were the inactive analogues L-ADP and L-ATP; the agonists 2-chloroadenosine 5’-diphosphate, adenosine 5’-O-(2-thiodiphosphate)and the diastereoisomeric pair Sp-adenosine 5’-(1-thiodiphosphate) (Sp-ADP-α-S) and Rp-adenosine 5’-(1-thiodiphosphate) (Rp-ADP-α-S); and the antagonists adenosine 5’-O-thiomonophosphate, 2-chloroadenosine 5’-O-thiomonophosphate, 2-chloroadenosine 5’-triphoshate, and the diastereoisomeric pair 5’-(1-thiotriphosphate) (Sp-ATP-α-S) and Rp-adenosine 5’-(1-thiotriphosphate) (Rp-ATP-α-S). All compounds tested competed at the high affinity binding sites for ADP previously identified (Blood 1988; 71: 110-6) but in some cases competition could not be demonstrated at the low affinity sites because of the high nucleotide concentrations required. As a group, C2-substituted analogues bound less strongly (Ki >2 μM) than did the analogues without substituents in the purine ring (Ki <0.7 μM). With the pair of diastereoisomeric agonists Sp-ADP-α-S and Rp-ADP-α-S the Ki values at the high affinity site (210 nM and 560 nM) were of the same relative magnitude and in the same direction as their reported potencies as agonists (Ki 4 μM and 20 μM). With the diastereoisomeric antagonists Sp-ATP-α-S and Rp-ATP-α-S a similar relationship was seen between affinity (17 nM and 156 nM) and inhibitory potency (Ki 4 μM and 20 μM). These results may help to differentiate possible mechanisms in the interaction of ADP with its receptors.
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Behrend, EN, GF Grauer, DS Greco, BJ Rose, and MA Thrall. "Comparison of the effects of diltiazem and aspirin on platelet aggregation in cats." Journal of the American Animal Hospital Association 32, no. 1 (January 1, 1996): 11–18. http://dx.doi.org/10.5326/15473317-32-1-11.
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Platelet aggregation in response to collagen (1 or 3 micrograms/ml), arachidonic acid (10(-2) M), and adenosine diphosphate (ADP, 2 microM) was compared in healthy cats treated with diltiazem (approximately 2 mg/kg body weight, q 8 hrs for 10 doses), aspirin (approximately 21 mg/kg body weight [1 baby aspirin], q 72 hrs for three doses), or a combination of diltiazem and aspirin. Baseline values obtained prior to treatment served as controls. Addition of arachidonic acid to blood resulted in an impedance change (i.e., aggregation) with time in samples from the nontreated cats and the cats treated with diltiazem, but the addition had no effect in blood from cats treated with aspirin alone or with a combination of diltiazem and aspirin. Platelet aggregation in response to either concentration of collagen or to ADP was not altered by any treatment. Secretion of adenosine triphosphate (ATP) from the platelets was measured when the aggregating agent was 3 micrograms/ml collagen; secretion was not affected by any treatment.
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Tolhurst, Gwen, Catherine Vial, Catherine Léon, Christian Gachet, Richard J. Evans, and Martyn P. Mahaut-Smith. "Interplay between P2Y1, P2Y12, and P2X1 receptors in the activation of megakaryocyte cation influx currents by ADP: evidence that the primary megakaryocyte represents a fully functional model of platelet P2 receptor signaling." Blood 106, no. 5 (September 1, 2005): 1644–51. http://dx.doi.org/10.1182/blood-2005-02-0725.
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Abstract The difficulty of conducting electrophysiologic recordings from the platelet has restricted investigations into the role of ion channels in thrombosis and hemostasis. We now demonstrate that the well-established synergy between P2Y1 and P2Y12 receptors during adenosine diphosphate (ADP)–dependent activation of the platelet αIIbβ3 integrin also exists in murine marrow megakaryocytes, further supporting the progenitor cell as a bona fide model of platelet P2 receptor signaling. In patch clamp recordings, ADP (30 μM) stimulated a transient inward current at –70 mV, which was carried by Na+ and Ca2+ and was amplified by phenylarsine oxide, a potentiator of certain transient receptor potential (TRP) ion channels by phosphatidylinositol 4,5-bisphosphate depletion. This initial current decayed to a sustained phase, upon which repetitive transient inward cation currents with pre-dominantly P2X1-like kinetics were super-imposed. Abolishing P2X1-receptor activity prevented most of the repetitive currents, consistent with their activation by secreted adenosine triphosphate (ATP). Recordings in P2Y1-receptor–deficient megakaryocytes demonstrated an essential requirement of this receptor for activation of all ADP-evoked inward currents. However, P2Y12 receptors, through the activation of PI3-kinase, played a synergistic role in both P2Y1 and P2X1-receptor–dependent currents. Thus, direct stimulation of P2Y1 and P2Y12 receptors, together with autocrine P2X1 activation, is responsible for the activation of nonselective cation currents by the platelet agonistADP.
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Coleman, Leon G., Renata K. Polanowska-Grabowska, Marek Marcinkiewicz, and Adrian R. L. Gear. "LDL oxidized by hypochlorous acid causes irreversible platelet aggregation when combined with low levels of ADP, thrombin, epinephrine, or macrophage-derived chemokine (CCL22)." Blood 104, no. 2 (July 15, 2004): 380–89. http://dx.doi.org/10.1182/blood-2003-08-2961.
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Abstract The in vitro oxidation of low-density lipoprotein (LDL) by hypochlorous acid produces a modified form (HOCl-LDL) capable of stimulating platelet function. We now report that HOCl-LDL is highly effective at inducing platelet function, causing stable aggregation and α-granule secretion. Such stimulation depended on the presence of low levels of primary agonists such as adenosine diphosphate (ADP) and thrombin, or others like epinephrine (EPI) and macrophage-derived chemokine (MDC, CCL22). Agonist levels, which by themselves induced little or reversible aggregation, caused strong stable aggregation when combined with low levels of HOCl-LDL. Platelet activation by HOCl-LDL and ADP (1 μM) caused P-selectin (CD62P) exposure, without serotonin or adenosine triphosphate (ATP) secretion. Intracellular calcium levels rose slowly (from 100 to 200 nM) in response to HOCl-LDL alone and rapidly when combined with ADP to about 300 nM. p38 mitogen-activated protein kinase (MAPK) became phosphorylated in response to HOCl-LDL alone. This phosphorylation was not blocked by the protein kinase C (PKC) inhibitor bisindolylmaleimide, which reduced the extent of aggregation and calcium increase. However, the p38 MAPK inhibitor SB203580 blocked platelet aggregation and phosphorylation of p38 MAPK. These findings suggest that HOCl-LDL exposed during atherosclerotic plaque rupture, coupled with low levels of primary agonists, can rapidly induce extensive and stable thrombus formation. (Blood. 2004;104:380-389)
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Jedlitschky, Gabriele, Konstanze Tirschmann, Lena E. Lubenow, Hendrik K. Nieuwenhuis, Jan W. N. Akkerman, Andreas Greinacher, and Heyo K. Kroemer. "The nucleotide transporter MRP4 (ABCC4) is highly expressed in human platelets and present in dense granules, indicating a role in mediator storage." Blood 104, no. 12 (December 1, 2004): 3603–10. http://dx.doi.org/10.1182/blood-2003-12-4330.
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Platelet aggregation is initiated by the release of mediators as adenosine diphosphate (ADP) stored in platelet granules. Possible candidates for transport proteins mediating accumulation of these mediators in granules include multidrug resistance protein 4 (MRP4, ABCC4), a transport pump for cyclic nucleotides and nucleotide analogs. We investigated the expression of MRP4 in human platelets by immunoblotting, detecting a strong signal at 170 kDa. Immunofluorescence microscopy using 2 MRP4-specific antibodies revealed staining mainly in intracellular structures, which largely colocalized with the accumulation of mepacrine as marker for delta-granules and to a lower extent at the plasma membrane. Furthermore, an altered distribution of MRP4 was observed in platelets from a patient with Hermansky-Pudlak syndrome with defective delta-granules. Adenosine triphosphate (ATP)–dependent cyclic guanosine monophosphate (cGMP) transport codistributed with MRP4 detection in subcellular fractions, with highest activities in the dense granule and plasma membrane fractions. This transport was inhibited by dipyramidole, indomethacin, and MK571 with median inhibitory concentration (IC50) values of 12, 22, and 43 μM, and by ibuprofen. Transport studies with [3H]ADP indicated the presence of an orthovanadate-sensitive ADP transporting system, inhibited by dipyramidole, MK571, and cyclic nucleotides. The results indicate a function of MRP4 in platelet mediator storage and inhibition of MRP4 may represent a novel mechanism for inhibition of platelet function by some anti-inflammatory drugs.
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Pero, Ronald W., Leif G. Salford, Lars-Göran Strömblad, and Christina Andersson. "Mononuclear leukocyte ADP-ribosylation as an indicator of immune function in malignant-glioma patients treated with betamethasone for cerebral edema." Journal of Neurosurgery 77, no. 4 (October 1992): 601–6. http://dx.doi.org/10.3171/jns.1992.77.4.0601.
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✓ Glioma patients receiving corticosteroids (16 mg/day betamethasone) were examined for evidence of immune cell dysfunction by using quantitative estimates of adenosine diphosphate (ADP)-ribosylation in peripheral mononuclear leukocytes as the physiological indicator. The duration of daily treatment with corticosteroids varied from 0 to 35 days at the time of collection of the blood samples. Even after adjustment for covariate factors such as age, sex, smoking habits, alcohol use, antiepileptic medications, and tumor grade, there still remained a highly significant dose-dependent inverse relationship between constitutive and hydrogen peroxide-induced mononuclear leukocyte ADP-ribosylation levels and the duration of corticosteroid treatment (beta coefficients −0.40 and −0.29, respectively; p < 0.03). No other variable under consideration significantly influenced ADP-ribosylation levels after statistical adjustment. These data support a mutual interdependence of mononuclear leukocyte ADP-ribosylation and corticosteroid-induced immune cell dysfunction in vivo.
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Driessens, MH, EA van Rijthoven, G. La Riviere, and E. Roos. "Expression of pertussis toxin adenosine diphosphate-ribosyltransferase in a T-cell hybridoma reduces metastatic capacity." Blood 88, no. 8 (October 15, 1996): 3116–23. http://dx.doi.org/10.1182/blood.v88.8.3116.bloodjournal8883116.
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T-cell hybridomas are highly metastatic, and their in vitro invasiveness correlates with metastatic capacity. Invasion is blocked by pertussis toxin (PT), which adenosine diphosphate (ADP)-ribosylates G1-proteins, and we have provided evidence that the PT-sensitive signal stimulates leukocyte function-associated antigen-1 (LFA-1)-mediated adhesion required for invasion. PT pretreatment of TAM2D2 T-cell hybridoma cells reduced metastasis, but only to a limited extent. In the present study, we have transfected the cDNA of the PT ADP-ribosyltransferase S1 subunit into TAM2D2 cells to abrogate G1-protein function permanently. We report here a substantial reduction in the metastatic capacity of two transfectants, S05 and S09, in which 88% and 95% of the G1-proteins was ADP-ribosylated. Two-thirds of the mice injected with S09 cells were tumor-free. Metastasis to the liver was almost completely prevented and less metastases were formed in the spleen and kidneys. Metastasis formation by S05 cells in liver and spleen was much reduced, but in lymph nodes and peritoneal tissues, metastases occurred with a frequency similar to that of controls. We conclude that G1-proteins play an important role in T-cell hybridoma metastasis. We propose that the reduction in metastasis is due to diminished entry of tumor cells from the blood into tissues.
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Brzoska, Tomasz, Egemen Tutuncuoglu, Stevan P. Tofovic, Edwin K. Jackson, Mark T. Gladwin, and Prithu Sundd. "CD39 As a Master Regulator of Pulmonary Thrombosis in Sickle Cell Disease." Blood 134, Supplement_1 (November 13, 2019): 2266. http://dx.doi.org/10.1182/blood-2019-130882.
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Acute systemic painful vaso-occlusive crisis (VOC) often serves as an antecedent to acute chest syndrome (ACS), which is a type of acute lung injury and the leading cause of mortality among sickle cell disease (SCD) patients. Thrombocytopenia secondary to pulmonary thrombosis is major risk factor for ACS, however, only 20% of ACS patients are diagnosed with pulmonary thrombosis as an underlying cause of ACS. Although clinical evidence supports the presence of prothrombotic state in subset of SCD patients, the molecular, cellular and genetic mechanisms that selectively render subset of SCD patients at either higher or lower risk of developing pulmonary thrombosis remains elusive. Adenosine diphosphate (ADP) released from lysed erythrocytes can activate platelets by stimulating their purinergic P2Y1 and P2Y12 receptors, however, P2Y12 receptor antagonists have not shown any benefit in clinical trials, justifying the need for better understanding of purinergic signaling in SCD. Here, we use intravital lung microscopy in transgenic humanized SCD mice to show that intravenous administration of ADP triggered pulmonary thrombosis in control mice but failed to trigger pulmonary thrombosis in SCD mice. In contrast, collagen evoked pulmonary thrombosis identically in both control and SCD mice. Identical to intravital findings, IV ADP administration also evoked transient thrombocytopenia in control but not SCD mice, while, IV collagen led to comparable drop in platelet count in both SCD and control mice. ADP is metabolized by the ecto-nucleoside-tri-phosphate-diphosphohydrolase-1 (E-NTPDase1) CD39. IV administration of fluorescent analogue of ADP, N⁶- ethenoadenosine- 5'- O- diphosphate (ε-ADP) followed by invivo microdialysis and HPLC analysis revealed impaired ε-ADP degradation in SCD mice, suggestive of decreased CD39 activity. Our current findings suggest that loss of CD39 activity in SCD possibly prevents ADP-mediated pulmonary thrombosis. Currently, experiments are underway to identify pathways contributing to loss of CD39 activity in SCD, how that affects purinergic signaling and whether selective activation vs deactivation of this pathway is responsible for risk of pulmonary thrombosis in only 20% of ACS patients. Disclosures Gladwin: Globin Solutions, Inc: Patents & Royalties: Provisional patents for the use of recombinant neuroglobin and heme-based molecules as antidotes for CO poisoning; United Therapeutics: Patents & Royalties: Co-inventor on an NIH government patent for the use of nitrite salts in cardiovascular diseases ; Bayer Pharmaceuticals: Other: Co-investigator.
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Jones, Chris I., Sarah Bray, Stephen F. Garner, Jonathan Stephens, Bernard de Bono, Will G. J. Angenent, David Bentley, et al. "A functional genomics approach reveals novel quantitative trait loci associated with platelet signaling pathways." Blood 114, no. 7 (August 13, 2009): 1405–16. http://dx.doi.org/10.1182/blood-2009-02-202614.
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AbstractPlatelet response to activation varies widely between individuals but shows interindividual consistency and strong heritability. The genetic basis of this variation has not been properly explored. We therefore systematically measured the effect on function of sequence variation in 97 candidate genes in the collagen and adenosine-diphosphate (ADP) signaling pathways. Resequencing of the genes in 48 European DNA samples nearly doubled the number of known single nucleotide polymorphisms (SNPs) and informed the selection of 1327 SNPs for genotyping in 500 healthy Northern European subjects with known platelet responses to collagen-related peptide (CRP-XL) and ADP. This identified 17 novel associations with platelet function (P < .005) accounting for approximately 46% of the variation in response. Further investigations with platelets of known genotype explored the mechanisms behind some of the associations. SNPs in PEAR1 associated with increased platelet response to CRP-XL and increased PEAR1 protein expression after platelet degranulation. The minor allele of a 3′ untranslated region (UTR) SNP (rs2769668) in VAV3 was associated with higher protein expression (P = .03) and increased P-selectin exposure after ADP activation (P = .004). Furthermore the minor allele of the intronic SNP rs17786144 in ITPR1 modified Ca2+ levels after activation with ADP (P < .004). These data provide novel insights into key hubs within platelet signaling networks.
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Gubin, Alexander N., J. Muthoni Njoroge, Urszula Wojda, Svetlana D. Pack, Maria Rios, Marion E. Reid, and Jeffery L. Miller. "Identification of the Dombrock blood group glycoprotein as a polymorphic member of the ADP-ribosyltransferase gene family." Blood 96, no. 7 (October 1, 2000): 2621–27. http://dx.doi.org/10.1182/blood.v96.7.2621.
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Abstract Identification of the 25 known human blood group molecules is of fundamental importance for the fields of erythroid cell biology and transfusion medicine. Here we provide the first molecular description of the “Dombrock” blood group system. A candidate gene was identified by in silico analyses of approximately 5000 expressed sequence tags (ESTs) from terminally differentiating human erythroid cells. Transfection experiments demonstrated specific binding of anti-Dombrock and confirmed glycosylphosphatidylinositol membrane attachment. Dombrock expression is developmentally regulated during erythroid differentiation and occurs at highest levels in the fetal liver. Homology studies suggest that the Dombrock molecule is a member of the adenosine 5′-diphosphate (ADP)–ribosyltransferase ectoenzyme gene family. Genotypic comparisons suggest Doa versus Dob antigenicity results from a single amino acid substitution within an encoded arginine-glycine-aspartic acid (RGD) motif of the molecule.
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Gubin, Alexander N., J. Muthoni Njoroge, Urszula Wojda, Svetlana D. Pack, Maria Rios, Marion E. Reid, and Jeffery L. Miller. "Identification of the Dombrock blood group glycoprotein as a polymorphic member of the ADP-ribosyltransferase gene family." Blood 96, no. 7 (October 1, 2000): 2621–27. http://dx.doi.org/10.1182/blood.v96.7.2621.h8002621_2621_2627.
Full textAbstract:
Identification of the 25 known human blood group molecules is of fundamental importance for the fields of erythroid cell biology and transfusion medicine. Here we provide the first molecular description of the “Dombrock” blood group system. A candidate gene was identified by in silico analyses of approximately 5000 expressed sequence tags (ESTs) from terminally differentiating human erythroid cells. Transfection experiments demonstrated specific binding of anti-Dombrock and confirmed glycosylphosphatidylinositol membrane attachment. Dombrock expression is developmentally regulated during erythroid differentiation and occurs at highest levels in the fetal liver. Homology studies suggest that the Dombrock molecule is a member of the adenosine 5′-diphosphate (ADP)–ribosyltransferase ectoenzyme gene family. Genotypic comparisons suggest Doa versus Dob antigenicity results from a single amino acid substitution within an encoded arginine-glycine-aspartic acid (RGD) motif of the molecule.
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Cristalli, G., and D. C. B. Mills. "Identification of a receptor for ADP on blood platelets by photoaffinity labelling." Biochemical Journal 291, no. 3 (May 1, 1993): 875–81. http://dx.doi.org/10.1042/bj2910875.
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The synthesis of a new analogue of ADP, 2-(p-azidophenyl)-ethythioadenosine 5′-diphosphate (AzPET-ADP), is described. This compound contains a photolabile phenylazide group attached to the ADP molecule by a thioether link at the purine 2 position. It has been prepared in radioactive form with 32P in the beta-phosphate at a specific radioactivity of 100 mCi/mumol. The reagent activated platelets, causing shape change and aggregation, with somewhat lower affinity than ADP. On photolysis the affinity was increased. The reagent also inhibited platelet adenylate cyclase stimulation by prostaglandin E1, with considerably higher affinity than ADP. On photolysis the affinity was decreased. AzPET-ADP competitively inhibited the binding of 2-methylthio[beta-32P]ADP, a ligand for the receptor by which ADP causes inhibition of adenylate cyclase. In the dark, AzPET-[beta-32P]ADP bound reversibly and with high affinity to a single population of sites similar in number to the sites that bind 2-methylthio[beta-32P]ADP. Binding was inhibited by ADP and by ATP and by p-chloromercuribenzenesulphonic acid (pCMBS). On exposure to u.v. light in the presence of platelets, AzPET-[beta-32P]ADP was incorporated covalently but non-specifically into several platelet proteins, although prominent intracellular proteins were not labelled. Specific labelling was confined to a single region of SDS/polyacrylamide gels, overlying but not comigrating with actin. Incorporation of radioactivity into this region was inhibited by ADP and by ATP as well as by ADP beta S, ATP alpha S and pCMBS, but not by adenosine, GDP or AMP. Inhibition of AzPET-[beta-32P]ADP incorporation was closely correlated with inhibition of equilibrium binding of 2-methylthio[beta-32P]ADP. These results suggests that the labelled protein, which migrates with an apparent molecular mass of 43 kDa in reduced gels, is the receptor through which ADP inhibits adenylate cyclase.
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Podczasy, John J., James Lee, and Ivana Vucenik. "Evaluation of Whole-Blood Lumiaggregation." Clinical and Applied Thrombosis/Hemostasis 3, no. 3 (July 1997): 190–95. http://dx.doi.org/10.1177/107602969700300307.
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An evaluation of whole-blood lumiaggregation was conducted in a normal population. Platelet aggregation and adenosine triphosphate (ATP) secretion were monitored in a three-phase study that analyzed sample dilution, agonist dose response, and method comparison. In the first phase, the blood:saline ratio was varied; in the second phase, the concentration of the agonists was varied ; and in the last phase, a comparison of impedance aggregation and ATP release in whole blood to optical aggregation and ATP release in platelet-rich plasma (PRP) was performed. Five common platelet agonists— collagen, adenosine diphosphate (ADP), arachidonic acid, thrombin, and ristocetin—were used in this evaluation of the lumiaggregometer (Chrono-Log Corp., Havertown, PA, U.S.A.). The data revealed that the optimum blood:saline ratio for conducting platelet antigen studies is 1:1, although with some agonists other dilutions can be used. The agonist dose-response phase basically confirmed the manufacturer's concentration recommendations. Additionally, it was determined that platelet aggregation using the whole-blood impedance technique compared to the PRP optical method yielded similar information. Furthermore, the advantages of whole-blood impedance aggregation include its use in microsamples and more timely results due to minimal sample preparation. Key Words: Platelet aggregation—Lumiaggregation—Whole blood—Platelet-rich ptasma—ATP.
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Sharp, Dan S., Neal L. Benowitz, P. M. W. Bath, John F. Martin, Andrew D. Beswick, and Peter C. Elwood. "Cigarette Smoking Sensitizes and Desensitizes Impedance-measured ADP-induced Platelet Aggregation in Whole Blood." Thrombosis and Haemostasis 74, no. 02 (1995): 730–35. http://dx.doi.org/10.1055/s-0038-1649805.
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SummaryThe effect of smoking on platelet aggregation appears to produce conflicting results, with some studies indicating an enhancement and others a decrease of aggregation. This epidemiological study of 120 male smokers, a subset of the Caerphilly Heart Disease Study, examined the relationship of two dimensions of smoking (time proximity of last cigarette before venepuncture and serum nicotine concentration) with threshold dose of adenosine diphosphate (ADP) necessary to induce platelet aggregation in whole blood. Means (range) of ADP threshold dose and nicotine concentration were 1.66 (0.5-2.5, censored) μM and 12.2 (0-35.2) ng/ml. Men smoking within 30 min of venepuncture demonstrated lower ADP threshold doses (-0.48 μM lower [95% C. I.: -0.95, -0.02]) – reflecting increased sensitivity. Men with higher nicotine concentration had higher ADP threshold doses (Regression Coefficient: +0.032 μM per ng/ml [95% C. I.: 0.003, 0.062]) – reflecting decreased sensitivity. Men smoking 30 min or more before venepuncture who also had high nicotine concentration (25-30 ng/ml) demonstrated the highest ADP threshold doses compared to never smokers and to men smoking the previous day (≈2.20 vs 1.86 and 1.81 μM). Relations involving nicotine concentration do not necessarily reflect a pharmacological effect although the potential for a short term nicotine mediated tolerance effect cannot be dismissed. These observations support an hypothesis suggesting a temporal sequence of platelet sensitization and desensitization during smoking.
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Jones, GD, and AR Gear. "Subsecond calcium dynamics in ADP- and thrombin-stimulated platelets: a continuous-flow approach using indo-1." Blood 71, no. 6 (June 1, 1988): 1539–43. http://dx.doi.org/10.1182/blood.v71.6.1539.1539.
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Abstract The regulation and kinetics (less than 5 seconds) of cytosolic calcium changes ([Ca2+]i) in stimulated blood platelets have been investigated under physiological blood flow conditions. Using a newly-developed continuous-flow approach with indo-1-loaded human platelets, adenosine diphosphate (ADP, 10 mumol/L) and thrombin (5 U/mL) were equally effective in significantly increasing [Ca2+]i by 0.5 seconds. ADP induced a transient [Ca2+]i peak of 1 to 2 mumol/L near 2 seconds, whereas thrombin caused a sustained and larger response. The first phase (less than 2 seconds) was not influenced by a lack of extracellular Ca2+, in contrast to the subsequent [Ca2+]i increase that only reached about 0.7 mumol/L for either ADP or thrombin. The shear rates used in our continuous-flow apparatus were physiological (less than 1,258 sec-1) and only slightly increased the basal [Ca2+]i of 0.1 mumol/L. Platelet aggregation (less than 5 seconds), assessed by single- particle counting, was not altered in platelets loaded with indo-1/AM (2.5 mumol/L).
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Jones, GD, and AR Gear. "Subsecond calcium dynamics in ADP- and thrombin-stimulated platelets: a continuous-flow approach using indo-1." Blood 71, no. 6 (June 1, 1988): 1539–43. http://dx.doi.org/10.1182/blood.v71.6.1539.bloodjournal7161539.
Full textAbstract:
The regulation and kinetics (less than 5 seconds) of cytosolic calcium changes ([Ca2+]i) in stimulated blood platelets have been investigated under physiological blood flow conditions. Using a newly-developed continuous-flow approach with indo-1-loaded human platelets, adenosine diphosphate (ADP, 10 mumol/L) and thrombin (5 U/mL) were equally effective in significantly increasing [Ca2+]i by 0.5 seconds. ADP induced a transient [Ca2+]i peak of 1 to 2 mumol/L near 2 seconds, whereas thrombin caused a sustained and larger response. The first phase (less than 2 seconds) was not influenced by a lack of extracellular Ca2+, in contrast to the subsequent [Ca2+]i increase that only reached about 0.7 mumol/L for either ADP or thrombin. The shear rates used in our continuous-flow apparatus were physiological (less than 1,258 sec-1) and only slightly increased the basal [Ca2+]i of 0.1 mumol/L. Platelet aggregation (less than 5 seconds), assessed by single- particle counting, was not altered in platelets loaded with indo-1/AM (2.5 mumol/L).
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Alkhamis, TM, RL Beissinger, and JR Chediak. "Artificial surface effect on red blood cells and platelets in laminar shear flow." Blood 75, no. 7 (April 1, 1990): 1568–75. http://dx.doi.org/10.1182/blood.v75.7.1568.1568.
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Abstract Red blood cell (RBC) effects on platelet adhesion to a nonbiologic test surface (tetrafluoroethylene propylene copolymer) and platelet aggregation during laminar shear flow for shear rates to 5,680 s-1 (corresponding to shear stress to 200 dyne/cm2) were investigated. Results on hemoglobin (Hb) and adenosine diphosphate (ADP) release from RBCs, percent decrease of single platelets in the bulk, and percent of test surface covered with platelets were obtained in a cone-and-plate (CP) viscometer for samples of whole blood, suspensions of RBC ghosts in platelet-rich plasma (PRP), and suspensions of RBCs in either PRP or platelet-poor plasma. Results obtained over the shear rate range studied for samples of normal hematocrit indicated that low-stress shearing led to ADP and Hb release from intact RBCs; shear-induced release of ADP from RBCs was about twice that of platelets, and of the total ADP released, the ADP released from RBCs contributed about six times that of the platelets to single platelet reduction in the bulk and about twice that of the platelets to platelet adhesion, ie, coverage of the test surface with platelets. Results obtained for various hematocrits showed that above a threshold hematocrit of about 25% to 35% the RBCs (suspended in PRP) had a greater contribution to ADP release, platelet adhesion, and platelet aggregation than the platelets themselves. Single platelet reduction for samples of RBC ghosts suspended in PRP correlated with shear rate level and not with shear stress.
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Alkhamis, TM, RL Beissinger, and JR Chediak. "Artificial surface effect on red blood cells and platelets in laminar shear flow." Blood 75, no. 7 (April 1, 1990): 1568–75. http://dx.doi.org/10.1182/blood.v75.7.1568.bloodjournal7571568.
Full textAbstract:
Red blood cell (RBC) effects on platelet adhesion to a nonbiologic test surface (tetrafluoroethylene propylene copolymer) and platelet aggregation during laminar shear flow for shear rates to 5,680 s-1 (corresponding to shear stress to 200 dyne/cm2) were investigated. Results on hemoglobin (Hb) and adenosine diphosphate (ADP) release from RBCs, percent decrease of single platelets in the bulk, and percent of test surface covered with platelets were obtained in a cone-and-plate (CP) viscometer for samples of whole blood, suspensions of RBC ghosts in platelet-rich plasma (PRP), and suspensions of RBCs in either PRP or platelet-poor plasma. Results obtained over the shear rate range studied for samples of normal hematocrit indicated that low-stress shearing led to ADP and Hb release from intact RBCs; shear-induced release of ADP from RBCs was about twice that of platelets, and of the total ADP released, the ADP released from RBCs contributed about six times that of the platelets to single platelet reduction in the bulk and about twice that of the platelets to platelet adhesion, ie, coverage of the test surface with platelets. Results obtained for various hematocrits showed that above a threshold hematocrit of about 25% to 35% the RBCs (suspended in PRP) had a greater contribution to ADP release, platelet adhesion, and platelet aggregation than the platelets themselves. Single platelet reduction for samples of RBC ghosts suspended in PRP correlated with shear rate level and not with shear stress.
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Battinelli, Elisabeth M., Beth A. Markens, and Joseph E. Italiano. "Release of angiogenesis regulatory proteins from platelet alpha granules: modulation of physiologic and pathologic angiogenesis." Blood 118, no. 5 (August 4, 2011): 1359–69. http://dx.doi.org/10.1182/blood-2011-02-334524.
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Abstract An association between platelets, angiogenesis, and cancer has long been recognized, but the mechanisms linking them remains unclear. Platelets regulate new blood vessel growth through numerous stimulators and inhibitors of angiogenesis by several pathways, including differential exocytosis of angiogenesis regulators. Herein, we investigated the differential release of angiogenesis stimulators and inhibitors from platelets. Activation of human platelets with adenosine diphosphate (ADP) stimulated the release of VEGF, but not endostatin whereas, thromboxane A2 (TXA2) released endostatin but not VEGF. Platelet releasates generated by activation with ADP promoted migration and formation of capillary structures by human umbilical vein endothelial cells (HUV-EC-Cs) in in vitro angiogenesis models. Conversely, TXA2-stimulated platelet releasate inhibited migration and formation of capillary structures. Because tumor growth beyond 1-2 mm3 is angiogenesis-dependent, we hypothesized that cancer cells preferentially stimulate platelets to secrete their pro-angiogenic payload. In support of this, the breast cancer cell line MCF-7 stimulated secretion of VEGF and a pro-angiogenic releasate from platelets. Furthermore, the antiplatelet agent aspirin inhibited platelet–mediated angiogenesis after exposure to ADP or MCF-7 cells providing a potential mechanism for how aspirin may impact malignancy. Manipulation of differentially mediated release of angiogenic factors from platelets may provide a new modality for cancer treatment.
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Purvis, Jeremy E., Manash S. Chatterjee, Lawrence F. Brass, and Scott L. Diamond. "A molecular signaling model of platelet phosphoinositide and calcium regulation during homeostasis and P2Y1 activation." Blood 112, no. 10 (November 15, 2008): 4069–79. http://dx.doi.org/10.1182/blood-2008-05-157883.
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Abstract To quantify how various molecular mechanisms are integrated to maintain platelet homeostasis and allow responsiveness to adenosine diphosphate (ADP), we developed a computational model of the human platelet. Existing kinetic information for 77 reactions, 132 fixed kinetic rate constants, and 70 species was combined with electrochemical calculations, measurements of platelet ultrastructure, novel experimental results, and published single-cell data. The model accurately predicted: (1) steady-state resting concentrations for intracellular calcium, inositol 1,4,5-trisphosphate, diacylglycerol, phosphatidic acid, phosphatidylinositol, phosphatidylinositol phosphate, and phosphatidylinositol 4,5-bisphosphate; (2) transient increases in intracellular calcium, inositol 1,4,5-trisphosphate, and Gq-GTP in response to ADP; and (3) the volume of the platelet dense tubular system. A more stringent test of the model involved stochastic simulation of individual platelets, which display an asynchronous calcium spiking behavior in response to ADP. Simulations accurately reproduced the broad frequency distribution of measured spiking events and demonstrated that asynchronous spiking was a consequence of stochastic fluctuations resulting from the small volume of the platelet. The model also provided insights into possible mechanisms of negative-feedback signaling, the relative potency of platelet agonists, and cell-to-cell variation across platelet populations. This integrative approach to platelet biology offers a novel and complementary strategy to traditional reductionist methods.
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Patel, Yatin M., Kirti Patel, Salman Rahman, Mark P. Smith, Gillian Spooner, Rushika Sumathipala, Michael Mitchell, Geraldine Flynn, Alexandra Aitken, and Geoffrey Savidge. "Evidence for a role for Gαi1 in mediating weak agonist-induced platelet aggregation in human platelets: reduced Gαi1 expression and defective Gi signaling in the platelets of a patient with a chronic bleeding disorder." Blood 101, no. 12 (June 15, 2003): 4828–35. http://dx.doi.org/10.1182/blood-2002-10-3080.
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AbstractWe have examined platelet functional responses and characterized a novel signaling defect in the platelets of a patient suffering from a chronic bleeding disorder. Platelet aggregation responses stimulated by weak agonists such as adenosine diphosphate (ADP) and adrenaline were severely impaired. In comparison, both aggregation and dense granule secretion were normal following activation with high doses of collagen, thrombin, or phorbol-12 myristate-13 acetate (PMA). ADP, thrombin, or thromboxane A2 (TxA2) signaling through their respective Gq-coupled receptors was normal as assessed by measuring either mobilization of intracellular calcium, diacylglycerol (DAG) generation, or pleckstrin phosphorylation. In comparison, Gi-mediated signaling induced by either thrombin, ADP, or adrenaline, examined by suppression of forskolin-stimulated rise in cyclic AMP (cAMP) was impaired, indicating dysfunctional Gαi signaling. Immunoblot analysis of platelet membranes with specific antiserum against different Gα subunits indicated normal levels of Gαi2,Gαi3,Gαz, and Gαq in patient platelets. However, the Gαi1level was reduced to 25% of that found in normal platelets. Analysis of platelet cDNA and gDNA revealed no abnormality in either the Gαi1 or Gαi2 gene sequences. Our studies implicate the minor expressed Gαi subtype Gαi1 as having an important role in regulating signaling pathways associated with the activation of αIIbβ3 and subsequent platelet aggregation by weak agonists.
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Pospieszna, Barbara, Krzysztof Kusy, Ewa Maria Słomińska, Wioleta Dudzinska, Monika Ciekot-Sołtysiak, and Jacek Zieliński. "The Effect of Training on Erythrocyte Energy Status and Plasma Purine Metabolites in Athletes." Metabolites 10, no. 1 (December 19, 2019): 5. http://dx.doi.org/10.3390/metabo10010005.
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This study aimed to assess the changes in red blood cell (RBC) energy status and plasma purine metabolites concentration over a one-year training cycle in endurance-trained (EN; n = 11, 20–26 years), and sprint-trained (SP; n = 11, 20–30 years) competitive athletes in comparison to recreationally-trained individuals (RE; n = 11, 20–26 years). Somatic, physiological, and biochemical variables were measured in four training phases differing in exercise load profile: transition, general, specific, and competition. Significantly highest values of RBC adenylate energy charge (AEC; p ≤ 0.001), ATP-to-ADP and ADP-to-AMP ratios (p ≤ 0.05), and plasma levels of adenosine (Ado; p ≤ 0.05) were noted in the competition phase in the EN and SP, but not in the RE group. Significantly lowest plasma levels of adenosine diphosphate (ADP; p ≤ 0.05), adenosine monophosphate (AMP; p ≤ 0.001), inosine (Ino; p ≤ 0.001), and hypoxanthine (Hx; p ≤ 0.001) accompanied by higher erythrocyte hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity (p ≤ 0.001), were observed in the competition phase in both athletic groups. No significant alterations were found in the erythrocyte concentration of guanine nucleotides in any group. In conclusion, periodized training of competitive athletes’ results in a favorable adaptation of RBC metabolism. The observed changes cover improved RBC energy status (increased AEC and ATP/ADP ratio) and reduced purine loss with more efficient erythrocyte purine pool recovery (increased HGPRT activity and plasma levels of Ado; decreased Hx and Ino concentration).
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Weiss, HJ, B. Lages, T. Hoffmann, and VT Turitto. "Correction of the platelet adhesion defect in delta-storage pool deficiency at elevated hematocrit--possible role of adenosine diphosphate." Blood 87, no. 10 (May 15, 1996): 4214–22. http://dx.doi.org/10.1182/blood.v87.10.4214.bloodjournal87104214.
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Previous studies on patients with storage pool deficiency (SPD) who are specifically deficient in platelet dense granules (delta-SPD) have suggested a role for dense granule substances, in all likelihood adenosine diphosphate (ADP), in mediating thrombus formation on subendothelium at high shear rates. The role of dense granule substances in mediating platelet adhesion appears to be more complicated Previous studies in delta-SPD suggested an adhesion defect that was strongly influenced by the patient's hematocrit (Hct) value. To explore further the possibility that red blood cells (RBCs) may influence the role that platelet storage granules play in mediating adhesion at high shear rates, we have measured adhesion (and thrombus formation) throughout a preselected range of Hct values (30% to 60%) in normal subjects and in patients with delta-SPD. The present studies confirm the defect in platelet adhesion in patients with delta-SPD, most significantly at Hct values of 30% to 40%. This defect (but not that of thrombus formation) can be completely corrected by the addition of RBCs. The correction of the platelet adhesion defect by RBCs was specific for delta-SPD; it was not observed in either von Willebrand's disease or thrombasthenia. Studies performed on normal blood under conditions that could be expected to block any effect of ADP on adhesion and an analysis of the type of adhesion defect in delta-SPD suggest that ADP may be involved in the process required for platelet spreading on the subendothelium. The corrective effect of RBCs on platelet adhesion in delta-SPD appears to be chemical rather than physical in nature, possibly due to shear-induced release of RBC ADP or to other recently described properties of RBCs that enhance collagen- induced platelet interactions.
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Bult, Hidde, Hermine R. L. Fret, François H. Jordaens, and Arnold G. Herman. "Dipyridamole Potentiates Platelet Inhibition by Nitric Oxide." Thrombosis and Haemostasis 66, no. 03 (1991): 343–49. http://dx.doi.org/10.1055/s-0038-1646418.
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SummaryIn a placebo-controlled double blind cross-over experiment the adenosine uptake inhibitor dipyridamole (400 mg/day) did not affect ex vivo platelet aggregation induced by collagen or adenosine-diphosphate (ADP) in an electronic whole blood aggregometer (WBA). Dipyridamole was also inactive in vitro, unless red blood cell injury was deliberately enhanced, thereby increasing the level of free adenine nucleotides. Since dipyridamole also inhibits cyclic guanosine monophosphate (GMP) phosphodiesterase (PDE), we used platelet rich plasma (PRP) to study its interaction with authentic and endothelium-derived nitric oxide (NO). The latter inhibits platelets by increasing cyclic GMP. Dipyridamole (1 to 30 εM), either alone or in combination with a subthreshold concentration of prostacyclin (PGI2), was inactive. However, when combined with a subthreshold concentration of NO, dipyridamole caused a concentration-dependent platelet suppression, which became more pronounced when PGI2 was present as well. It is concluded that dipyridamole could reduce the threshold for platelet suppression by NO through inhibition of cyclic GMP PDE.
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Funaro, Ada, Erika Ortolan, Bruna Ferranti, Lucia Gargiulo, Rosario Notaro, Lucio Luzzatto, and Fabio Malavasi. "CD157 is an important mediator of neutrophil adhesion and migration." Blood 104, no. 13 (December 15, 2004): 4269–78. http://dx.doi.org/10.1182/blood-2004-06-2129.
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Abstract CD157, a glycosylphosphatidylinositol (GPI)–anchored protein encoded by a member of the CD38 NADase/ADP-ribosyl cyclase gene family, is expressed on the surface of most human circulating neutrophils. This work demonstrates that CD157 is a receptor that induces reorganization of the cytoskeleton and significant changes in cell shape, and that signals mediated by CD157 act through modulation of cytosolic Ca2+ concentration. These signals are independent of the products of CD157's enzymatic activities (ie, cyclic adenosine diphosphate [ADP]–ribose and ADP-ribose). Indeed, the enzymatic activities of CD157 in circulating neutrophils as well as in dimethyl sulfoxide (DMSO)–differentiated (CD157+/CD38-) HL-60 cells, are hardly detectable. This work also shows that the receptorial activity relies on cross-talk between CD157 and β2 integrin. CD157 localizes in GM1-enriched lipid rafts and, upon activation, it migrates to the uropod, a structure specialized in motility and adhesive functions. Indeed, CD157 is involved in adhesion to extracellular matrix proteins and in chemotaxis induced in vitro by formyl-methionyl-leucyl-phenylalanine (fMLP). These findings were consistent with the results obtained in neutrophils from patients with paroxysmal nocturnal hemoglobinuria (PNH), in which CD157 is deficient. These neutrophils showed constant defects in adhesion and migration. Our data attribute specific and crucial roles to CD157 in the regulation of innate immunity during inflammation.
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Pengo, V., M. Boschello, P. Prandoni, L. Schivazappa, and A. Girolami. "Beta-thromboglobulin (β-TG) and platelet factor 4 (PF4) release by adenosine diphosphate (ADP) contact with native whole blood." Thrombosis Research 39, no. 5 (September 1985): 645–50. http://dx.doi.org/10.1016/0049-3848(85)90247-6.
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Mazzucato, Mario, Paola Pradella, Maria Rita Cozzi, Luigi De Marco, and Zaverio M. Ruggeri. "Sequential cytoplasmic calcium signals in a 2-stage platelet activation process induced by the glycoprotein Ibα mechanoreceptor." Blood 100, no. 8 (October 15, 2002): 2793–800. http://dx.doi.org/10.1182/blood-2002-02-0514.
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We found that the interaction of platelets with immobilized von Willebrand factor (VWF) under flow induces distinct elevations of cytosolic Ca++ concentration ([Ca++]i) that are associated with sequential stages of integrin αIIbβ3 activation. Fluid-dynamic conditions that are compatible with the existence of tensile stress on the bonds between glycoprotein Ibα (GPIbα) and the VWF A1 domain led to Ca++ release from intracellular stores (type α/β peaks), which preceded stationary platelet adhesion. Raised levels of cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate, as well as membrane-permeable calcium chelators, inhibited these [Ca++]ioscillations and prevented stable adhesion without affecting the dynamic characteristics of the typical platelet translocation on VWF mediated by GPIbα. Once adhesion was established through the integrin αIIbβ3, new [Ca++]i oscillations (type γ) of greater amplitude and duration, and involving a transmembrane ion flux, developed in association with the recruitment of additional platelets into aggregates. Degradation of released adenosine diphosphate (ADP) to AMP or inhibition of phosphatidylinositol 3-kinase (PI3-K) prevented this response without affecting stationary adhesion and blocked aggregation. These findings indicate that an initial signal induced by stressed GPIbα-VWF bonds leads to αIIbβ3 activation sufficient to support localized platelet adhesion. Then, additional signals from ADP receptors and possibly ligand-occupied αIIbβ3, with the contribution of a pathway involving PI3-K, amplify platelet activation to the level required for aggregation. Our conclusions modify those proposed by others regarding the mechanisms that regulate signaling between GPIbα and αIIbβ3 and lead to platelet adhesion and aggregation on immobilized VWF.
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Refaai, Majed A., Kelly F. Henrichs, Sherry L. Spinelli, Richard P. Phipps, Edward Masel, Brian H. Smith, Charles W. Francis, and Neil Blumberg. "Platelet Activation Following Exposure to Anti-ABO Antibodies— An In Vitro Study." Oncology & Hematology Review (US) 07, no. 01 (2011): 72. http://dx.doi.org/10.17925/ohr.2011.07.1.72.
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Since platelets possess A and B antigen, mismatched ABO platelets could, theoretically, become activated or hypofunctional by exposure to anti-A or anti-B antibodies found in transfused or recipient plasma. Following normal baseline platelet aggregation to adenosine diphosphate (ADP), platelets from normal donors of different blood types were incubated at 37°C for 10 minutes with 50μl of normal saline (NS), O plasma, or AB plasma. Aggregation was then induced with ADP. No significant changes from baseline were seen in platelet aggregation studies following incubation with NS. However, platelet aggregations of type A and type B platelets were significantly inhibited when incubated with O plasma (mean of 41 and 22%, respectively). Our findings indicate that mediators in group O plasma, very likely anti-A and anti-B antibodies, cause impaired platelet aggregation of ABO non-identical platelets.
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Cattaneo, Marco. "Bleeding manifestations of congenital and drug-induced defects of the platelet P2Y12 receptor for adenosine diphosphate." Thrombosis and Haemostasis 105, S 06 (2011): S67—S74. http://dx.doi.org/10.1160/ths10-11-0742.
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SummaryP2Y12, one of the two platelet receptors for adenosine diphosphate (ADP), plays a central role in platelet function. Defects of P2Y12 should be suspected when ADP, even at high concentrations (≥10 μM), is unable to induce full, irreversible platelet aggregation. Patients with congenital P2Y12 defects display a mild-to-moderate bleeding diathesis of variable severity, characterised by mucocutaneous bleeding and excessive post-surgical and post-traumatic blood loss. Drugs that inhibit P2Y12 are potent antithrombotic drugs, attesting the central role played by P2Y12 in platelet thrombus formation. Clopidogrel, the most widely used drug that inhibits P2Y12, is effective both in monotherapy and in combination with acetylsalicylic acid (ASA). Its most important drawback is the inability to inhibit adequately P2Y12-dependent platelet function in about 1/3 of patients, at the recommended therapeutic doses. The incidence of bleeding events is similar in ASA-treated and clopidogrel-treated patients; however, the combination of ASA and clopidogrel causes more bleeding than each drug in monotherapy. Compared to clopidogrel, new drugs inhibiting P2Y12, such as prasugrel and ticagrelor, decrease the risk of cardiovascular events and increase the risk of bleeding complications, because they adequately inhibit P2Y12-dependent platelet function in the vast majority of treated patients.