Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.5 (thrombin)
 33,306 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. The 2',3'-dialdehyde derivative of ADP (oADP) at concentrations approaching the millimolar range induces human blood platelets to undergo the transition from discoid to globular morphology (the 'shape change') but is incapable of inducing aggregation. 2. When incubated with platelets for 1 min before addition of the agonist, oADP acts as a competitive inhibitor of shape change and aggregation induced by ADP. Under these conditions secretion and hence aggregation induced by low concentrations of collagen; and secretion and hence secondary aggregation induced by adrenaline, thrombin and vasopressin are also inhibited by this analogue. In addition, oADP stimulates the rate of primary aggregation induced by adrenaline and causes partial inhibition of primary aggregation induced by thrombin or vasopressin. When longer preincubation times are employed the extent of inhibition with respect to all agonists, except for high concentrations of collagen, is increased and the competitive character of the inhibition with respect to ADP is no longer apparent. 3. Incubation of human platelets with the 2',3'-dialdehyde derivative of ATP (oATP) causes effects similar to those described for oADP except that the analogue neither induces platelet shape change, nor stimulates the rate of primary aggregation induced by adrenaline. In addition oATP fails to cause significant inhibition of platelet shape change induced by serotonin. The extent and character of inhibition caused by addition of oATP is not a function of the time of incubation. 4. The 2',3'-dialcohol derivatives of ADP and ATP and orATP) effect the aggregation properties of human blood platelets in a manner generally resembling those observed for the 2',3'-dialdehyde analogues. However, orADP is only weakly effective in causing platelet shape change and stimulating the rate of primary aggregation induced by adrenaline and does not inhibit secretion induced by adrenaline, collagen, thrombin and vasopressin. The extent of inhibition by orADP increases only slightly with increased time of incubation. 5. The data suggest that oADP acts as a partial agonist, and oATP as an antagonist, at the platelet ADP receptor, but that platelet membrane stabilisation also results from interaction with these dialdehyde analogues. Such membrane stabilisation does not complicate the interaction of platelets with orADP, which appears to act as a classical antagonist for the ADP receptor.
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PMID:Interaction of human blood platelets with the 2',3'-dialdehyde and 2',3'-dialcohol derivatives of adenosine 5'-diphosphate and adenosine 5'-triphosphate. 68 37

The molecular basis for heparin-induced thrombocytopenia (HIT), a relatively common complication of heparin therapy, is not yet fully understood. We found that pretreatment of platelets with AR-C66096 (formerly FPL 66096), a specific platelet adenosine diphosphate (ADP) receptor antagonist, at a concentration of 100 to 200 nmol/L that blocked ADP-dependent platelet aggregation, resulted in complete loss of platelet aggregation responses to HIT sera. AR-C66096 also totally inhibited HIT serum-induced dense granule release, as judged by measurement of adenosine triphosphate (ATP) release. Apyrase, added to platelets at a concentration that had only minor effects on thrombin- or arachidonic acid-induced aggregation, also blocked completely HIT serum-induced platelet aggregation. Furthermore, AR-C66096 inhibited platelet aggregation and ATP release induced by cross-linking Fc gamma RIIA with specific antibodies. These data show that released ADP and the platelet ADP receptor play a pivotal role in HIT serum-induced platelet activation/aggregation. The thromboxane receptor inhibitor, Daltroban, had no effect on HIT serum-induced platelet activation whereas GPIIb-IIIa antagonists blocked platelet aggregation but had only a moderate effect on HIT serum-induced dense granule release. Pretreatment of platelets with chondroitinases but not with heparinases resulted in concentration dependent inhibition of HIT serum-induced platelet aggregation. These novel data relating to the mechanism of platelet activation induced by HIT sera suggest that the possibility should be examined that ADP receptor antagonists or compounds that inhibit ADP release may be effective as therapeutic agents for the prevention or treatment of complications associated with heparin therapy.
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PMID:Adenosine diphosphate (ADP) and ADP receptor play a major role in platelet activation/aggregation induced by sera from heparin-induced thrombocytopenia patients. 942 8

Previous studies have shown that platelets are activated during atrial fibrillation (AF). However, prophylactic therapy with aspirin is not associated with a reduction of thromboembolic complications in patients with AF. Stimulation of platelet thrombin and ADP receptors causes a release of P-selectin, which is not affected by aspirin. The purpose of this study was to assess the influence of AF on platelet P-selectin expression. Blood samples from 30 patients were studied ex vivo. Nineteen patients had chronic AF (> 3 months), 11 patients were in sinus rhythm (SR). P-selectin expression was determined by flow cytometry (antibody binding capacity [BC]) at baseline and after platelet stimulation with adenosine diphosphate (ADP) and thrombin receptor activating peptide (TRAP). To determine the effect of heart rate and atrial pressure (RAP), measurements were repeated after 10 minutes of ventricular pacing (120 beats/min) in patients with SR. P-selectin expression was increased in patients with AF at baseline (AF: 1329 +/- 81 BC vs SR: 968 +/- 108 BC; P < 0.05) and after stimulation with ADP (AF: 1445 +/- 101 BC vs SR: 1061 +/- 109 BC; P < 0.05) and TRAP (AF: 13,783 +/- 2442 BC vs SR: 5977 +/- 800 BC; P < 0.05). RAP (2.0 +/- 0.5 vs 6.0 +/- 0.8 mmHg; P < 0.01) and atrial rate (75 +/- 5 vs 114 +/- 5 beats/min; P < 0.001) increased during ventricular pacing. However, P-selectin levels remained stable. AF was accompanied by increased P-selectin expression. In contrast, increased ventricular rate and elevated atrial pressure alone had no effect on platelet activity. Further studies are needed to determine if platelet ADP receptor inhibitors offer a therapeutic benefit in patients with AF.
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PMID:Increased expression of P-selectin in patients with chronic atrial fibrillation. 1113 46

The intracellular signaling pathways by which G protein-coupled receptors on the platelet surface initiate aggregation, a critical process for hemostasis and thrombosis, are not well understood. In particular, the contribution of the G(i) pathway has not been directly addressed. We have investigated the activation of platelets from mice in which the gene for the predominant platelet G alpha(i) subtype, G alpha(i2), has been disrupted. In intact platelets from G alpha(i2)-deficient mice, the inhibition of adenylyl cyclase by ADP was found to be partially impaired compared with wild-type platelets. Moreover, both ADP-dependent platelet aggregation and the activation of the integrin alpha IIb beta 3 (GPIIb-IIIa) were strongly reduced in platelets from G alpha(i2)-deficient mice. In addition, G alpha(i2)-deficient platelets displayed impaired activation at low thrombin concentrations. This defect was mimicked by blocking the adenylyl cyclase--coupled platelet ADP receptor (P2Y(12)) on wild-type platelets with a selective antagonist. These observations suggest that G alpha(i2) is involved in the inhibition of platelet adenylyl cyclase in vivo and is a critical component of the signaling pathway for integrin activation by ADP, resulting in platelet aggregation. In addition, thrombin-dependent activation of mouse platelets is mediated, at least in part, by secreted ADP acting on the G alpha(i2)-linked ADP receptor.
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PMID:Impaired activation of murine platelets lacking G alpha(i2). 1148 41

Circulating platelets are constantly exposed to nitric oxide (NO) released from the vascular endothelium. This NO acts to reduce platelet reactivity, and in so doing blunts platelet aggregation and thrombus formation. For successful hemostasis, platelet activation and aggregation must occur at sites of vascular injury despite the constant presence of NO. As platelets aggregate, they release secondary mediators that drive further aggregation. Particularly significant among these secondary mediators is ADP, which, acting through platelet P2Y12 receptors, strongly amplifies aggregation. Platelet P2Y12 receptors are the targets of very widely used antithrombotic drugs such as clopidogrel, prasugrel, and ticagrelor. Here we show that blockade of platelet P2Y12 receptors dramatically enhances the antiplatelet potency of NO, causing a 1,000- to 100,000-fold increase in inhibitory activity against platelet aggregation and release reactions in response to activation of receptors for either thrombin or collagen. This powerful synergism is explained by blockade of a P2Y12 receptor-dependent, NO/cGMP-insensitive phosphatidylinositol 3-kinase pathway of platelet activation. These studies demonstrate that activation of the platelet ADP receptor, P2Y12, severely blunts the inhibitory effects of NO. The powerful antithrombotic effects of P2Y12 receptor blockers may, in part, be mediated by profound potentiation of the effects of endogenous NO.
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PMID:Blockade of the purinergic P2Y12 receptor greatly increases the platelet inhibitory actions of nitric oxide. 2400 63