scholarly journals Identification of a new congenital defect of platelet function characterized by severe impairment of platelet responses to adenosine diphosphate

Blood ◽  
1992 ◽  
Vol 80 (11) ◽  
pp. 2787-2796 ◽  
Author(s):  
M Cattaneo ◽  
A Lecchi ◽  
AM Randi ◽  
JL McGregor ◽  
PM Mannucci
Keyword(s):  
Monoclonal Antibody ◽  
Platelet Function ◽  
Signal Transduction Pathway ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Adenosine Diphosphate ◽  
Fibrin Clot ◽  
Clot Retraction ◽  
Release Reaction ◽  
Function Defect

Abstract This study characterizes a congenital hemorrhagic disorder caused by a platelet function defect with the following features: (1) severely impaired platelet aggregation and fibrinogen or von Willebrand factor (vWF) binding induced by adenosine diphosphate (ADP); (2) defective aggregation, release reaction, and fibrinogen or vWF binding induced by other agonists; (3) normal aggregation and release reaction induced by high concentrations of thrombin or collagen; (4) no further inhibition by ADP scavengers of aggregation, release reaction, and fibrinogen or vWF binding, comparable with those observed for normal platelets in the presence of ADP scavengers; (5) normal membrane glycoprotein (GP) composition and normal binding of the anti-GP IIb/IIIa monoclonal antibody 10E5; (6) no acceleration by ADP of binding of the anti-GP IIb/IIIa monoclonal antibody 7E3; (7) normal platelet-fibrin clot retraction if induced by thrombin or reptilase plus epinephrine, absent if induced by reptilase plus ADP; (8) no inhibition by ADP of the prostaglandin E1-induced increase in platelet cyclic adenosine monophosphate, but normal inhibition by epinephrine; (9) defective mobilization of cytoplasmic Ca2+ by ADP; (10) normal binding of 14C-ADP to fresh platelets, but defective binding of [2–3H]-ADP to formalin- fixed platelets. This congenital platelet function defect is characterized by selective impairment of platelet responses to ADP, caused by either decreased number of platelet ADP receptors or abnormalities of the signal-transduction pathway of platelet activation by ADP.

scholarly journals Identification of a new congenital defect of platelet function characterized by severe impairment of platelet responses to adenosine diphosphate

Blood ◽  
1992 ◽  
Vol 80 (11) ◽  
pp. 2787-2796 ◽  
Author(s):  
M Cattaneo ◽  
A Lecchi ◽  
AM Randi ◽  
JL McGregor ◽  
PM Mannucci
Keyword(s):  
Monoclonal Antibody ◽  
Platelet Function ◽  
Signal Transduction Pathway ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Adenosine Diphosphate ◽  
Fibrin Clot ◽  
Clot Retraction ◽  
Release Reaction ◽  
Function Defect

This study characterizes a congenital hemorrhagic disorder caused by a platelet function defect with the following features: (1) severely impaired platelet aggregation and fibrinogen or von Willebrand factor (vWF) binding induced by adenosine diphosphate (ADP); (2) defective aggregation, release reaction, and fibrinogen or vWF binding induced by other agonists; (3) normal aggregation and release reaction induced by high concentrations of thrombin or collagen; (4) no further inhibition by ADP scavengers of aggregation, release reaction, and fibrinogen or vWF binding, comparable with those observed for normal platelets in the presence of ADP scavengers; (5) normal membrane glycoprotein (GP) composition and normal binding of the anti-GP IIb/IIIa monoclonal antibody 10E5; (6) no acceleration by ADP of binding of the anti-GP IIb/IIIa monoclonal antibody 7E3; (7) normal platelet-fibrin clot retraction if induced by thrombin or reptilase plus epinephrine, absent if induced by reptilase plus ADP; (8) no inhibition by ADP of the prostaglandin E1-induced increase in platelet cyclic adenosine monophosphate, but normal inhibition by epinephrine; (9) defective mobilization of cytoplasmic Ca2+ by ADP; (10) normal binding of 14C-ADP to fresh platelets, but defective binding of [2–3H]-ADP to formalin- fixed platelets. This congenital platelet function defect is characterized by selective impairment of platelet responses to ADP, caused by either decreased number of platelet ADP receptors or abnormalities of the signal-transduction pathway of platelet activation by ADP.

scholarly journals Effect of alteplase on platelet function and receptor expression

2019 ◽  
Vol 47 (4) ◽  
pp. 1731-1739 ◽  
Author(s):  
Jun Lu ◽  
Peng Hu ◽  
Guangyu Wei ◽  
Qi Luo ◽  
Jianlin Qiao ◽  
...  
Keyword(s):  
Arachidonic Acid ◽  
Platelet Aggregation ◽  
Platelet Activation ◽  
Platelet Function ◽  
Adenosine Diphosphate ◽  
Receptor Expression ◽  
Light Transmittance ◽  
Dependent Manner ◽  
Clot Retraction ◽  
Platelet Receptors

Objective To investigate the role of alteplase, a widely-used thrombolytic drug, in platelet function. Methods Human platelets were incubated with different concentrations of alteplase followed by analysis of platelet aggregation in response to adenosine diphosphate (ADP), collagen, ristocetin, arachidonic acid or epinephrine using light transmittance aggregometry. Platelet activation and surface levels of platelet receptors GPIbα, GPVI and αIIbβ3 were analysed using flow cytometry. The effect of alteplase on clot retraction was also examined. Results This study demonstrated that alteplase significantly inhibited platelet aggregation in response to ADP, collagen and epinephrine in a dose-dependent manner, but it did not affect ristocetin- or arachidonic acid-induced platelet aggregation. Alteplase did not affect platelet activation as demonstrated by no differences in P-selectin levels and PAC-1 binding being observed in collagen-stimulated platelets after alteplase treatment compared with vehicle. There were no changes in the surface levels of the platelet receptors GPIbα, GPVI and αIIbβ3 in alteplase-treated platelets. Alteplase treatment reduced thrombin-mediated clot retraction. Conclusions Alteplase inhibits platelet aggregation and clot retraction without affecting platelet activation and surface receptor levels.

scholarly journals Mutants in the ADP-ribosyltransferase Cleft of Cholera Toxin Lack Diarrheagenicity but Retain Adjuvanticity

1997 ◽  
Vol 185 (7) ◽  
pp. 1203-1210 ◽  
Author(s):  
Shingo Yamamoto ◽  
Yoshifumi Takeda ◽  
Masafumi Yamamoto ◽  
Hisao Kurazono ◽  
Koichi Imaoka ◽  
...  
Keyword(s):  
Cholera Toxin ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Adenosine Diphosphate ◽  
Site Directed Mutagenesis ◽  
T Helper ◽  
Th2 Cell ◽  
A Subunit ◽  
Adp Ribosyltransferase ◽  
Type Response

Cholera toxin (CT), the most commonly used mucosal adjuvant in experimental animals, is unsuitable for humans because of potent diarrhea-inducing properties. We have constructed two CT-A subunit mutants, e.g., serine→ phenylalanine at position 61 (S61F), and glutamic acid→ lysine at 112 (E112K) by site-directed mutagenesis. Neither mutant CT (mCT), in contrast to native CT (nCT), induced adenosine diphosphate-ribosylation, cyclic adenosine monophosphate formation, or fluid accumulation in ligated mouse ileal loops. Both mCTs retained adjuvant properties, since mice given ovalbumin (OVA) subcutaneously with mCTs or nCT, but not OVA alone developed high-titered serum anti-OVA immunoglobulin G (IgG) antibodies (Abs) which were largely of IgG1 and IgG2b subclasses. Although nCT induced brisk IgE Ab responses, both mCTs elicited lower anti-OVA IgE Abs. OVA-specific CD4+ T cells were induced by nCT and by mCTs, and quantitative analysis of secreted cytokines and mRNA revealed a T helper cell 2 (Th2)-type response. These results now show that the toxic properties of CT can be separated from adjuvanticity, and the mCTs induce Ab responses via a Th2 cell pathway.

scholarly journals Role of AC-cAMP-PKA Cascade in Antidepressant Action of Electroacupuncture Treatment in Rats

2012 ◽  
Vol 2012 ◽  
pp. 1-7 ◽  
Author(s):  
Jian-hua Liu ◽  
Zhi-feng Wu ◽  
Jian Sun ◽  
Li Jiang ◽  
Shuo Jiang ◽  
...  
Keyword(s):  
Signal Transduction ◽  
Antidepressant Treatment ◽  
Signal Transduction Pathway ◽  
Cyclic Adenosine Monophosphate ◽  
Chronic Mild Stress ◽  
Adenosine Monophosphate ◽  
Mild Stress ◽  
Transduction Pathway ◽  
Antidepressant Action

Adenylyl cyclase (AC)-cyclic adenosine monophosphate (cAMP)-cAMP-dependent protein kinase A (PKA) cascade is considered to be associated with the pathogenesis and treatment of depression. The present study was conducted to explore the role of the cAMP cascade in antidepressant action of electroacupuncture (EA) treatment for chronic mild stress (CMS)-induced depression model rats. The results showed that EA improved significantly behavior symptoms in depression and dysfunction of AC-cAMP-PKA signal transduction pathway induced by CMS, which was as effective as fluoxetine. Moreover, the antidepressant effects of EA rather than Fluoxetine were completely abolished by H89, a specific PKA inhibitor. Consequently, EA has a significant antidepressant treatment in CMS-induced depression model rats, and AC-cAMP-PKA signal transduction pathway is crucial for it.

scholarly journals The effect of pharmacologic inhibition of phospholipid methylation on human platelet function

Blood ◽  
1982 ◽  
Vol 59 (5) ◽  
pp. 906-912
Author(s):  
SJ Shattil ◽  
JA Montgomery ◽  
PK Chiang
Keyword(s):  
Platelet Activation ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Adenosine Diphosphate ◽  
Human Platelets ◽  
Serotonin Release ◽  
Platelet Phospholipid ◽  
Biochemical Effect ◽  
Methylation Pathway ◽  
Pharmacologic Inhibition

Human platelets are capable of synthesizing their major membrane phospholipid, phosphatidylcholine, by a methylation pathway. This involves the sequential transfer of methyl groups from S-adenosyl-L- methionine (AdoMet) to phosphatidylethanolamine, and in the process, AdoMet is converted to S-adenosylhomocysteine (AdoHcy). The activity of this methylation pathway is decreased upon stimulation of platelets by various agonists. We inhibited methylation reactions pharmacologically to see whether this inhibition plays any role in the process of platelet activation. Two inhibitors of AdoHcy hydrolase, 3-deaza- adenosine and 3-deaza-(+/-)aristeromycin (500 microM each), were effective in increasing platelets levels of AdoHcy and preventing turnover of AdoMet. Also, these compounds were equipotent in inhibiting platelet phospholipid methylation. However, while 3-deaza-adenosine potentiated platelet aggregation and 14C-serotonin release induced by epinephrine or adenosine diphosphate (ADP) (p less than 0.01), 3-deaza- aristeromycin had no such effect. Neither compound affected platelet responses to thrombin or collagen. Inhibition of methylation reactions was not the only biochemical effect of 3-deaza-adenosine since it also blunted significantly the elevation of platelet cyclic adenosine monophosphate (AMP) levels induced by prostaglandin E1 (p less than 0.02). Therefore, these studies demonstrate that inhibition of platelet phospholipid methylation, per se, has no discernable effect on the function of human platelets. The methylation pathway, though active in platelets, does not appear to be primarily involved in membrane events responsible for platelet activation.

Effect of Lidoflazine (R 7904) on Human Platelet Function in Vitro

1972 ◽  
Vol 28 (02) ◽  
pp. 228-236 ◽  
Author(s):  
F De Clerck
Keyword(s):  
Platelet Function ◽  
Mode Of Action ◽  
Human Platelet ◽  
Platelet Rich Plasma ◽  
Serotonin Release ◽  
Clot Retraction ◽  
Plasma Coagulation ◽  
Release Reaction ◽  
Platelet Release

SummaryThe effect of lidoflazine and of cinnarizine on human platelet function in vitro was compared to that of dipyridamole.Pre-incubation for 30 min at 37° C of platelet rich plasma with lidoflazine or with dipyridamole 5 ×10–4 M resulted in an appreciable inhibition of collagen aggregation in particular and to a lesser extent of ADP aggregation; cinnarizine was marginally active only.Clot retraction was inhibited by lidoflazine and by dipyridamole. Experiments on biphasic ADP aggregation and C14-serotonin release during aggregation show that lidoflazine reduces the platelet release reaction.The possible mode of action of the compound is discussed.Plasma coagulation and PF – 3 availability were not affected.

scholarly journals Differential requirements for platelet aggregation and inhibition of adenylate cyclase by epinephrine. Studies of a familial platelet alpha 2-adrenergic receptor defect

Blood ◽  
1988 ◽  
Vol 71 (2) ◽  
pp. 494-501 ◽  
Author(s):  
AK Rao ◽  
J Willis ◽  
MA Kowalska ◽  
YT Wachtfogel ◽  
RW Colman
Keyword(s):  
Platelet Aggregation ◽  
Adenylate Cyclase ◽  
Adrenergic Receptors ◽  
Adrenergic Receptor ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Adenosine Diphosphate ◽  
Normal Subjects ◽  
Camp Levels ◽  
Epinephrine Concentration

Abstract We describe a family whose members have impaired platelet aggregation and secretion responses to epinephrine with normal responses to adenosine diphosphate and collagen. Platelet alpha 2-adrenergic receptors (measured using 3H methyl-yohimbine) were diminished in the propositus (78 sites per platelet), his two sisters (70 and 27 sites per platelet), and parents (37 and 63 sites per platelet), but not in two maternal aunts (12 normal subjects, 214 +/- 18 sites per platelet; mean +/- SE). However, the inhibition of cyclic adenosine monophosphate (cAMP) levels by epinephrine in platelets exposed to 400 nmol/L PGI2 was similar in the patients and five normal subjects (epinephrine concentration for 50% inhibition, 0.04 +/- 0.01 mumol/L v 0.03 +/- 0.01 mumol/L; P greater than .05). In normal platelets, the concentration of yohimbine (0.18 mumol/L) required for half maximal inhibition of aggregation induced by 2 mumol/L epinephrine was lower than that for inhibition of its effect on adenylate cyclase (1.6 mumol/L). In quin2 loaded platelets, thrombin (0.1 U/mL) stimulated rise in cytoplasmic Ca2+ concentration, [Ca2+]i, was normal in the two patients studied. The PGI2 analog ZK 36,374 completely inhibited thrombin-induced rise in [Ca2+]i; the reversal of this inhibition by epinephrine was normal in the two patients. Thus, despite the impaired aggregation response to epinephrine, platelets from these patients have normal ability to inhibit PGI2-stimulated cAMP levels. These patients with an inherited receptor defect provide evidence that fewer platelet alpha 2-adrenergic receptors are required for epinephrine-induced inhibition of adenylate cyclase than for aggregation.

scholarly journals Adenosine and Forskolin Inhibit Platelet Aggregation by Collagen but not the Proximal Signalling Events

2019 ◽  
Vol 119 (07) ◽  
pp. 1124-1137 ◽  
Author(s):  
Joanne C. Clark ◽  
Deirdre M. Kavanagh ◽  
Stephanie Watson ◽  
Jeremy A. Pike ◽  
Robert K. Andrews ◽  
...  
Keyword(s):  
Adenylyl Cyclase ◽  
G Protein ◽  
Platelet Activation ◽  
Cyclic Adenosine Monophosphate ◽  
Adenosine Monophosphate ◽  
Adenosine Diphosphate ◽  
Receptor Activation ◽  
Inhibitory Effect ◽  
Human Platelets ◽  
Adenosine Receptor Agonist

Background The G protein-coupled receptor, adenosine A2A, signals through the stimulatory G protein, Gs, in platelets leading to activation of adenylyl cyclase and elevation of cyclic adenosine monophosphate (cAMP) and inhibition of platelet activation. Objective This article investigates the effect of A2A receptor activation on signalling by the collagen receptor glycoprotein (GP) VI in platelets. Methods Washed human platelets were stimulated by collagen or the GPVI-specific agonist collagen-related peptide (CRP) in the presence of the adenosine receptor agonist, 5′-N-ethylcarboxamidoadenosine (NECA) or the adenylyl cyclase activator, forskolin and analysed for aggregation, adenosine triphosphate secretion, protein phosphorylation, spreading, Ca2+ mobilisation, GPVI receptor clustering, cAMP, thromboxane B2 (TxB2) and P-selectin exposure. Results NECA, a bioactive adenosine analogue, partially inhibits aggregation and secretion to collagen or CRP in the absence or presence of the P2Y12 receptor antagonist, cangrelor and the cyclooxygenase inhibitor, indomethacin. The inhibitory effect in the presence of the three inhibitors is largely overcome at higher concentrations of collagen but not CRP. Neither NECA nor forskolin altered clustering of GPVI, elevation of Ca2+ or spreading of platelets on a collagen surface. Further, neither NECA nor forskolin, altered collagen-induced tyrosine phosphorylation of Syk, LAT nor PLCγ2. However, NECA and forskolin inhibited platelet activation by the TxA2 mimetic, U46619, but not the combination of adenosine diphosphate and collagen. Conclusion NECA and forskolin have no effect on the proximal signalling events by collagen. They inhibit platelet activation in a response-specific manner in part through inhibition of the feedback action of TxA2.

scholarly journals Effect of propranolol on platelet function

Blood ◽  
1977 ◽  
Vol 49 (2) ◽  
pp. 185-196 ◽  
Author(s):  
BB Weksler ◽  
M Gillick ◽  
J Pink
Keyword(s):  
Platelet Aggregation ◽  
Platelet Function ◽  
Direct Action ◽  
Blood Platelets ◽  
Adenosine Diphosphate ◽  
Ionophore A23187 ◽  
Atherosclerotic Vascular Disease ◽  
Clot Retraction

Abstract Excessive reactivity of blood platelets may contribute to atherosclerotic vascular disease. Hence drugs which alter platelet function may be protective. Prompted by findings that propranolol therapy normalized hyperactive platelet aggregation in patients with coronary artery disease, we studied propranolol in vitro to assess its action on platelets. At concentrations similar to those achieved in vivo (0.1–1 muM), propranolol raised the thresholds for aggregation of some normal paltelets by adenosine diphosphate (ADP). At higher concentrations (10-50 muM), propranolol abolished the second wave of platelet aggregation induced by ADP and epinephrine, and inhibited aggregation induced by collagen, thrombin, and the ionophore A23187. Propanolol blocked the release of 14C-serotonin from platelets, inhibited platelet adhesion to collagen, and interfered with clot retraction. Propranolol blocked ionophore-induced uptake of 45Ca by platelets. Inhibition appeared unrelated to beta-adrenergic blockage, as d(+) propranolol (which lacks beta-blocking activity) was equipotent with 1(-) propranolol. Moreover, practolol, a beta-blockading drug which is nonlipophilic, did not inhibit platelet function. These studies suggested that propranolol, like local anesthetics, decreased platelet responsiveness by a direct action on the platelet membrane, possibly by interfering with calcium availability. Modulation of platelet function by propranolol may occur at concentrations achieved at usual clinical doses of the drug.

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