1,722,550 research outputs found
Light transmission aggregometry and ATP release for the diagnostic assessment of platelet function
No full textLight transmission aggregometry (LTA) is the gold standard for the study of patients with defects of platelet function. Use of LTA in clinical practice for predicting the risk of thrombosis or monitoring the pharmacologic effects of antiplatelet agents should be discouraged, because not only is the monitoring of treatment with antiplatelet agents (with any laboratory test) not indicated at present, but also the lack of standardization of the technique for LTA makes it additionally unsuitable for this purpose. The need for standardization of LTA has recently been emphasized by the results of four surveys, which showed that there is a wide variation in the methodology used worldwide. A modification of the traditional LTA is the lumiaggregometer, which measures platelet secretion in parallel with platelet aggregation. This technique is probably preferable to traditional LTA in the diagnostic workup of patients with inherited defects of platelet function, because it is more sensitive to the most common disorders, which are characterized by abnormalities of platelet secretion. LTA (or lumiaggregometry) is useful as a first screening test of patients with the clinical suspicion of defects of platelet function because it helps to provide an interim diagnostic hypothesis, which can then be confirmed or discounted using appropriate and specific tests. Copyrigh
New P2Y(12) inhibitors
No full textAdenosine diphosphate (ADP) plays a key role in the
genesis of physiological platelet-rich hemostatic plugs
and of pathological arterial thrombi.1 The transduction of the
ADP signal involves its interaction with 2 platelet receptors,
the Gq-coupled P2Y1 receptor and the Gi-coupled P2Y12
receptor, which belong to the family of purinergic P2 receptors.
Concomitant activation of both the Gq and Gi pathways
by ADP is necessary to elicit normal platelet aggregation.2 In
addition to its role in ADP-induced platelet aggregation,
P2Y12 (Figure 1) also mediates the potentiation of platelet
secretion induced by strong agonists, which is independent of
the formation of large aggregates and thromboxane A2 synthesis2;
the stabilization of thrombin-induced platelet aggregates2;
shear-induced platelet aggregation2; and the inhibition
of the antiplatelet effects of the natural regulator of platelet
function, prostacyclin.3 In contrast to P2Y1, P2Y12 has a very
selective tissue distribution, making it an attractive molecular
target for therapeutic intervention. Indeed, P2Y12 is the target
of efficacious antithrombotic agent
Are the bleeding time and PFA-100((R)) useful in the initial screening of patients with mucocutaneous bleedings of hereditary nature?
No full textHyperhomocysteinemia, atherosclerosis and thrombosis
No full textHigh plasma levels of homocysteine are the results of the interplay between congenital and environmental factors. In the last two decades, a growing amount of interest has focused on mild-to-moderate hyperhomocysteinemia as a risk factor of thromboembolic diseases. Case-control and cross-sectional studies clearly indicated that mild-to-moderate hyperhomocysteinemia is associated with heightened risk of both arterial and venous thrombosis. On the other hand, prospective studies did not unequivocally show that hyperhomocysteinemia is associated with a high thrombotic risk. Therefore, additional studies are needed to define whether hyperhomocysteinemia is a risk factor for thrombosis, especially of the venous circulation. Among these, prospective cohort studies will clarify better the temporal relationship between high homocysteine levels and the thrombotic event. Most importantly, however, randomized, placebo-controlled, double-blind trials of the effects of homocysteine-lowering vitamins on the thrombotic risk are urgently needed. Not only will they help in defining whether the relationship between hyperhomocysteinemia and thrombosis is causal, they will also have a potential dramatic impact in the prevention of thromboembolic events
The P2 receptors and congenital platelet function defects
No full textPlatelets possess three P2 receptors: two (P2Y (1) and P2Y (12)) are receptors for adenosine diphosphate (ADP), and one (P2X1) is a receptor for adenosine triphosphate (ATP). The P2Y (1) receptor, which is coupled to Gq and phospholipase C-beta, is responsible for mobilization of ionized calcium from internal stores and mediates the ADP-induced platelet shape change and initial wave of rapidly reversible aggregation. The other ADP receptor, P2Y (12), is negatively coupled to adenylyl cyclase through Gi and mediates a progressive and sustained ADP-induced aggregation not preceded by shape change. In addition, this receptor plays an important role in the potentiation of platelet secretion induced by several platelet agonists. The combined action of P2Y (1) and P2Y (12) is necessary for the full platelet aggregation response to ADP. Four patients with severe deficiency of P2Y (12) have been described so far. Sequence analysis of the P2Y (12) locus of three of these patients revealed homozygous mutations that produced a frame shift mutation and premature truncation of the protein. The fourth patient had an allele with a frame shift mutation and a normal allele, which could be silenced by an additional, as yet unknown, mutation. More recently, we described a patient with a congenital bleeding disorder and a dysfunctional P2Y (12). The patient is a compound heterozygote, in whom one allele contained a G to A transition resulting in an Arg (256) to Gln codon substitution (R256Q) and the other allele contained a C to T transition resulting in an Arg (265) to Trp codon substitution (R265W). The two substitutions are located in TM6 and EL3 of the receptor. Stable Chinese hamster ovaries (CHO) cell lines were established expressing either wild-type P2Y (12) and P2Y (12)(R256Q) or P2Y (12)(R265W). Neither mutation blocked the ability of the P2Y (12) receptor to translocate to the CHO cell surface. ADP at all tested concentrations (0.1 to 10 muM) greatly inhibited the forskolin-induced increase of cyclic adenosine monophosphate (cAMP) in CHO cells transfected with wild-type P2Y (12), whereas CHO cells transfected with either mutant protein were only partially inhibited by ADP. Thus, the molecular basis for the patient's dysfunctional platelet phenotype is explained by missense mutations and the expression of a dysfunctional P2Y (12) receptor. The localization of both mutations in TM6 and EL3 identifies this region of P2Y (12) as a structurally and functionally critical region of the receptor
ADP receptors : inhibitory strategies for antiplatelet therapy
No full textThe interaction of adenosine-5′-diphosphate (ADP) with its platelet receptors (P2Y1 and P2Y12) plays a very important role in thrombogenesis. The thienopyridine ticlopidine was the first specific antagonist of the platelet P2Y12 ADP receptor to be tested in randomized clinical trials for the prevention of arterial thrombotic events. Although ticlopidine reduces the incidence of vascular events in patients at risk, it also unfortunately has some significant drawbacks: a relatively high incidence of toxic effects, which may be fatal in some cases; delayed onset of action; and a high interindividual variability in response. A second thienopyridine, clopidogrel, has superseded ticlopidine, because it is also an efficacious antithrombotic drug and is less toxic than ticlopidine. However, clopidogrel is not completely free from faults: severe toxic effects, albeit occurring much less frequently than with ticlopidine, may still complicate its administration to patients; the onset of pharmacologic action can be accelerated by the use of large loading doses, but may still not be optimal; the high interpatient variability in response remains an important issue. These concerns justify the continued search for agents that can further improve the clinical outcome of patients with atherosclerosis through greater efficacy and/or safety. A new thienopyridyl compound, prasugrel, which is characterized by higher potency and faster onset of action compared with clopidogrel, is currently under clinical evaluation. Two direct and reversible P2Y12 antagonists, cangrelor and AZD6140, feature very rapid onset and reversal of platelet inhibition, which make them attractive alternatives to thienopyridines, especially when rapid inhibition of platelet aggregation or its quick reversal are required. Along with new the P2Y12 antagonists, inhibitors of the other platelet receptor for ADP, the antagonists P2Y1, are under development and may prove to be effective antithrombotic agents
Laboratory detection of 'aspirin resistance' : what test should we use (if any)?
No full textAspirin is widely used to decrease the risk of occlusive arterial
events in patients at risk. It irreversibly inhibits the
cyclooxygenase-1 (COX-1)-dependent synthesis of thromboxane
A2 (TxA2), which is essential for the full aggregation
response of platelets.
In the last years, the issue of ‘aspirin resistance’ has been
emphasized in the medical literature.1–4 Despite several
studies published on this subject, its definition, diagnosis,
prevalence, causes, and clinical consequences are still
uncertai
Several platelet receptors and their ligands are involved in platelet- dependent thrombus formation
No full textComment on:
Pathways of platelet activation and unexplained clopidogel variability: causes of poor response to clopidogrel.
Kounis NG, Grapsas N.
Thromb Res. 2013 Aug; 132(2):312. Epub 2013 May 26.
Mechanisms of variability in antiplatelet agents response. [Thromb Res. 2012
Resistance to antiplatelet drugs : molecular mechanisms and laboratory detection
No full textSummary. The definition resistance to antiplatelet drugs
should be limited to situations in which failure of the drug to
hit its pharmacological target has been documented by specific
laboratory tests. Aspirin resistance, as determined by specific
tests (e.g. serum thromboxane B2), appears to be rare (1–2%)
and, in most instances, is caused by poor compliance. In
contrast to aspirin, studies that used specific tests tomeasure the
pharmacological effect of thienopyridines [e.g. vasodilatorstimulated
phosphoprotein (VASP)] showed a wide variability
of responses to these drugs, with significant proportions of
subjects (15–30%) who are very poor responders. Interindividual
differences in the extent of metabolism of thienopyridines
to their active metabolites is the most plausible
mechanism for the observed inter-individual variability in
platelet inhibition. The demonstration that some patients may
be resistant or poor responders to the pharmacological effect
of antiplatelet drugs, has prompted the need of laboratory
monitoring of antiplatelet therapy. However, many published
studies have been performed using unspecific tests of platelet
function, which identify patients on antiplatelet treatment with
high residual platelet reactivity, which is not necessarily because
of resistance to antiplatelet drugs. Despite this drawback,
identification of patients with high residual platelet reactivity
may be useful to predict their risk of atherothrombotic events.
However,many studies still need to be carried out to identify the
ideal laboratory test and to answer basic questions on its clinical
utility and cost-effectiveness, before monitoring antiplatelet
therapy can be recommended in the clinical practise.Until then,
monitoring of antiplatelet therapy should be considered for
investigational purposes only
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