The Role of Cyclic Nucleotides in Platelets

Mills, D. C. B.

doi:10.1007/978-3-642-68393-0_20

Cited by 16 publications

(6 citation statements)

References 221 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…CTAD inhibits platelet activation by several mechanisms. Theophylline and dipyridamole have been shown to inhibit phosphodiesterase, resulting in an increase of platelet cyclic AMP and a decrease of platelet responsiveness (20,21). Adenosine is an inhibitor of platelet aggregation, preventing thrombin-induced platelet aggregation and rise in intracellular calcium (22).…”

Section: Discussionmentioning

confidence: 99%

Assessment of platelet activation in several different anticoagulants by the Advia 120 Hematology System, fluorescence flow cytometry, and electron microscopy

Ahnadi¹,

Chapman²,

Lépine³

et al. 2003

Thromb Haemost

View full text Add to dashboard Cite

In vivo platelet activation results are often confounded by activation induced in vitro during the preparative procedures. We measured ex vivo (basal) and in vitro (thrombin-induced) platelet activation in sodium citrate, ethylenediaminetetraacetic acid (EDTA), and Citrate Theophylline Dipyridamole Adenosine (CTAD) whole blood specimens. Determinations were made by measurements of platelet density (mean platelet component: MPC concentration) on the Advia 120 Hematology System. The MPC has been previously shown to correlate with a fluorescence flow cytometric method, also determined in this study, using the surface expression of CD62P. Moreover, platelet shape and structure changes in EDTA and CTAD anticoagulated whole blood specimens were characterized by transmission electron microscopy (TEM). Observations made using the Advia 120 Hematology System platelet density parameter, MPC, in the absence of thrombin were 25.7 +/- 0.9 g/dl, 27.9 +/- 0.9 g/dl and 24.8 +/- 1.2 g/dl in sodium citrate, EDTA and CTAD whole blood specimens, respectively. Addition of thrombin induced a significant change in platelet MPC for sodium citrate (21.9 +/- 1.9 g/dl; p<0.0001) and EDTA (23.2 +/- 0.9 g/dl; p<0.0001) whole blood specimens. In contrast, thrombin had no effect on MPC measured in whole blood taken into CTAD tubes. In vitro fluorescence flow cytometric platelet activation experiments measuring the percentage of platelets expressing anti-CD62P showed increase in sodium citrate specimens from 9.2 +/- 7.0 to 55.5 +/- 23.1 % (p<0.0001) and in EDTA specimens from 1.9 +/- 1.7 to 64.6 +/- 12.4 % (p<0.0001) after addition of thrombin. However, in blood taken into CTAD tubes, there was no significant change. Studies on platelets isolated from whole blood in CTAD showed activation by thrombin indicating that platelets in CTAD, while protected in its presence remained functional upon its removal. When observed by TEM over time, platelets in EDTA appear more activated and contain fewer granules than platelets in CTAD. We conclude that CTAD demonstrates in vitro platelet activation inhibition and may be useful in stabilizing ex vivo platelet activation. The novel platelet activation parameter, MPC, measured by an automated routine hematology system, using customized proprietary software, may be used in conjunction with CTAD, a stabilizing anticoagulant, to measure the ex vivo platelet activation state in whole blood specimens. TEM studies verify shape modifications and simultaneous retention of intracellular granules at early post-venipuncture time periods in CTAD specimens.

show abstract

Section: Discussionmentioning

confidence: 99%

Assessment of platelet activation in several different anticoagulants by the Advia 120 Hematology System, fluorescence flow cytometry, and electron microscopy

Ahnadi¹,

Chapman²,

Lépine³

et al. 2003

Thromb Haemost

View full text Add to dashboard Cite

show abstract

“…Elevation of the cAMP level in platelets, by activation of adenylyl cyclase and/or inhibition of cyclic nucleotide phosphodiesterase, causes inhibition of responses induced by platelet agonists such as thrombin [1], but not collagen [2]. Thrombin, together with other agonists sensitive to cAMP, activates phospholipase C β1 (PLC β1 ) via a trimeric G protein, which then cleaves phosphatidylinositol 4,5‐ bis phosphate (PtdIns(4,5) P 2 ) to diacylglycerol and inositol 1,4,5‐ tris phosphate (Ins(1,4,5) P 3 ).…”

mentioning

confidence: 99%

Role of autocrine stimulation on the effects of cyclic AMP on protein  and lipid phosphorylation in collagen‐activated and thrombin‐activated platelets

Ryningen

Jensen

Holmsen

1999

European Journal of Biochemistry

View full text Add to dashboard Cite

We compared several responses in thrombin-stimulated and collagen (type I)-stimulated platelets with and without forskolin and inhibitors of autocrine stimulation (IAS: an ADP-removing system of creatine phosphate/creatine phosphokinase, Arg-Gly-Asp-Ser peptide to prevent fibrinogen/fibronectin binding to GPIIb/IIIa, SQ 29.548 as a thromboxane A 2 receptor antagonist, cyproheptadine as a serotonin receptor antagonist, BN 52021 as a plateletactivating factor receptor antagonist). The pattern of tyrosine-phosphorylated proteins, the phosphorylation of lipids in the polyphosphoinositide cycle and phosphorylation of pleckstrin (P47) were studied as markers for signaltransducing responses, exposure of CD62 (P-selectin) and CD63 (Glycoprotein 53), as well as secretion of ADP + ATP and b-N-acetyl-glycosaminidase were studied as final activation responses. Clear differences between thrombin-stimulated and collagen-stimulated platelets were observed. First, practically all protein-tyrosine phosphorylation induced by thrombin was inhibited by IAS, while a partial inhibition was observed for collagen; the phosphorylation due to collagen alone was apparently stimulated by elevation of cAMP. Secondly, the other responses to thrombin were inhibited by increased levels of cAMP, independent of autocrine stimulation. In contrast, only the autocrine part of the collagen-induced responses was inhibited by elevation of cAMP. Thus, the inhibition by elevated cAMP seen in collagen-stimulated platelets seems to be due to removal of the G-protein-mediated activation from secreted autocrine stimulators either by IAS or forskolin. The remaining activity is a pure collagen effect which is not affected by elevated levels of cAMP.Keywords: autocrine inhibition; collagen; cAMP; platelet responses; thrombin.Elevation of the cAMP level in platelets, by activation of adenylyl cyclase and/or inhibition of cyclic nucleotide phosphodiesterase, causes inhibition of responses induced by platelet agonists such as thrombin [1], but not collagen [2]. Thrombin, together with other agonists sensitive to cAMP, activates phospholipase C b1 (PLC b1 ) via a trimeric G protein, which then cleaves phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P 2 ) to diacylglycerol and inositol 1,4,5-trisphosphate (Ins(1,4,5)P 3 ). Diacylglycerol remains bound to the plasma membrane and activates protein kinase C (PKC) together with phosphatidylserine (PtdS) and Ca 2+ . Being cytosolic, Ins(1,4,5)P 3 mobilizes calcium from intracellular stores which carries the signal further, culminating in the execution of final responses such as shape change [3], aggregation (i.e. exposure of the fibrinogen receptor, integrin a IIb /b 3 ) [4±6] and secretion of the contents of plateletstorage granules [7,8].Collagen is an important primary stimulus of platelets during hemostasis. As with most other platelet agonists, collagen signal transduction involves polyphosphoinositide (PPIns) hydrolysis, protein phosphorylation and secretion, but the exact mechanisms underlying these events are...

show abstract

“…Dipyridamole inhibits the activity of phosphodiesterase leading to the degradation of cAMP. The increased intraplatelet cAMP concentration prevents platelet aggregation 24. Furthermore, it has been argued that dipyridamole exerts an antithrombotic effect by modulating the action of platelet inhibiting eicosanoids such as prostacyclin and prostaglandin D2 25.…”

Section: Discussionmentioning

confidence: 99%

Intracoronary dipyridamole reduces the incidence of abrupt vessel closure following PTCA: a prospective randomised trial

Heintzen

Heidland

Klimek

et al. 2000

Heart

View full text Add to dashboard Cite

Objectives-To investigate the eVect of intracoronary dipyridamole on the incidence of abrupt vessel closure, myocardial infarction, necessity for bypass grafting, and death following percutaneous transluminal coronary angioplasty (PTCA). Patients-Patients were randomly allocated to receive either conventional pretreatment (heparin 15 000 IU and aspirin 500 mg intravenously) or additional intracoronary dipyridamole (0.5 mg/ kg bodyweight). Dipyridamole was administered in 550 PTCA procedures (455 interventions in men, mean (SD) age 59.2 (8.4) years; 74 acute coronary syndromes), while conventional pretreatment was administered in 544 interventions (444 interventions in men 58.3 (7.9) years old; 81 acute coronary syndromes). In 53 interventions bail out stenting was performed for threatened abrupt vessel closure. Results-Intracoronary dipyridamole significantly reduced the incidence of abrupt vessel closure (odds ratio 0.42. 95% confidence interval (CI) 0.22 to 0.79). While abrupt vessel closure occurred in 6.1% of interventions following conventional pretreatment, dipyridamole reduced the incidence to 2.5%. Restricting the analysis to balloon angioplasty, this reduction was observed in patients with stable angina (odds ratio 0.49, 95% CI 0.23 to 0.96) as well as in those with acute coronary syndromes (odds ratio 0.29, 95% CI 0.09 to 0.87). Reduction of secondary end points in the dipyridamole treated patients failed to reach significance in the PTCA group. Conclusions-Intracoronary dipyridamole before PTCA reduces the incidence of abrupt vessel closure following PTCA for stable angina and acute coronary syndromes. (Heart 2000;83:551-556)

show abstract

The Role of Cyclic Nucleotides in Platelets

Cited by 16 publications

References 221 publications

Assessment of platelet activation in several different anticoagulants by the Advia 120 Hematology System, fluorescence flow cytometry, and electron microscopy

Assessment of platelet activation in several different anticoagulants by the Advia 120 Hematology System, fluorescence flow cytometry, and electron microscopy

Role of autocrine stimulation on the effects of cyclic AMP on protein  and lipid phosphorylation in collagen‐activated and thrombin‐activated platelets

Intracoronary dipyridamole reduces the incidence of abrupt vessel closure following PTCA: a prospective randomised trial

Contact Info

Product

Resources

About

The Role of Cyclic Nucleotides in Platelets

Cited by 16 publications

References 221 publications

Assessment of platelet activation in several different anticoagulants by the Advia 120 Hematology System, fluorescence flow cytometry, and electron microscopy

Assessment of platelet activation in several different anticoagulants by the Advia 120 Hematology System, fluorescence flow cytometry, and electron microscopy

Role of autocrine stimulation on the effects of cyclic AMP on protein and lipid phosphorylation in collagen‐activated and thrombin‐activated platelets

Intracoronary dipyridamole reduces the incidence of abrupt vessel closure following PTCA: a prospective randomised trial

Contact Info

Product

Resources

About

Role of autocrine stimulation on the effects of cyclic AMP on protein  and lipid phosphorylation in collagen‐activated and thrombin‐activated platelets