Development Of Antiplatelet Therapies Research Articles

The rate of platelet activation determines thrombus size and structure at arterial shear

BackgroundThe response of platelets to activating stimuli and pharmaceutical agents varies greatly within the normal population. Current platelet function tests are used to measure end-point levels of platelet activation without taking the speed at which platelets activate into account, potentially missing vital metrics to characterize platelet reactivity. ObjectivesTo identify variability, to agonists and among individuals, in platelet activation kinetics and assess the impact of this on thrombus formation. MethodsWe have developed a bespoke real-time flow cytometry assay and analysis package to measure the rate of platelet activation over time using 2 parameters of platelet activation, fibrinogen binding and P-selectin exposure. ResultsThe rate of platelet activation varied considerably within the normal population but did not correlate with maximal platelet activation, demonstrating that platelet activation rate is a separate and novel metric to describe platelet reactivity. The relative rate of platelet response between agonists was strongly correlated, suggesting that a central control mechanism regulates the rate of platelet response to all agonists. ConclusionFor the first time, we have shown that platelet response rate corresponds to thrombus size and structure, wherein faster responders form larger, more densely packed thrombi at arterial, but crucially not venous, shear. We have demonstrated that the rate of platelet activation is an important metric in stratifying individual platelet responses and will provide a novel focus for the design and development of antiplatelet therapy, targeting high-shear thrombosis without exacerbating bleeding at low shear.

The Development of Antiplatelet Therapy after Percutaneous Coronary Intervention

Coronary artery disease is one of the common cardiovascular diseases and threatens our health. Percutaneous coronary intervention (PCI) is the main treatment for coronary artery disease. Bare-metal stents (BMS) and drug-eluting stents (DES) are popularly applied in clinical practice. With the development of clinic and technology, DES is widely used in coronary artery disease following antiplatelet therapy. Clinical guidelines require dual antiplatelet therapy (DAPT) after PCI in USA and Europe. It is effective to reduce the incident of stent thrombosis, myocardial infarction and major adverse cardiac. However, the risk of major adverse cardiac events and bleeding was increased by DAPT. Therefore, single antiplatelet therapy was induced in various clinical trials. We searched previous research from PubMed, Embase Web of Science published in English from Jan 1, 2000, to Nov 20, 2017 and screened clinical trials in the ClinicalTrials.gov. In this review, we discussed the efficacy of DAPT and prospective investigations of single antiplatelet therapy after PCI.

Perspective on multi-target antiplatelet therapies: high content phenotypic screening as an unbiased source of novel polypharmacological strategies.

Platelets play an important role in cardiovascular thrombosis as well as in many other pathological conditions such as inflammation, atherosclerosis and cancer. While multi-target strategies to treat complex diseases are gaining considerable attention, current development of antiplatelet therapies is mostly oriented towards several single targets, arising from our present understanding of the regulation of platelet activation. Limited efforts to develop multi-target agents or multidrug therapies are mostly due to a lack of a systematic basis to define target combinations with synergistic effects. Here we discuss the perspective to use high content phenotypic screening of in vitro models as a potential source for inference of synergetic multi-target strategies to control platelet activation.

Recent developments in antiplatelet therapy after percutaneus coronary intervention.

Antiplatelet therapy plays an important role in the treatment of patients suffering from acute coronary syndrome (ACS) or undergoing percutaneous coronary intervention (PCI) in order to prevent atherothrombotic events and restenosis or ischemic reocclusion, respectively. Moreover, stent implantation is often performed along with PCI to ensure that the arteries remain open. However, stent thrombosis ST is a possible complication which can occur up to about one year after the procedure. Therefore, it is standard to treat patients with a dual antiplatelet regime whereby aspirin is combined with either clopidogrel, prasugrel or ticagrelor. This review summarizes the characteristics of these P2Y12 antagonists and evaluates the current and future clinical guidelines for antiplatelet therapy in the setting of PCI with or without stenting.

The Future of Antiplatelet Therapy in Cardiovascular Disease

Mechanisms of platelet inhibition are reviewed with emphasis on the pharmacokinetic and pharmacodynamic determinants of clinical efficacy and safety of antiplatelet drugs. Current developments in antiplatelet therapy are discussed in relation to both primary and secondary prevention of atherothrombotic complications. Interindividual variability in response to antiplatelet agents and new drug targets are outlined within the context of optimizing the balance between the cardiovascular benefits and bleeding risks of antiplatelet therapy. Recent advances in the pharmacogenetics of thienopyridines open the realistic prospect of a personalized choice of the most appropriate antiplatelet agent and tailored dose adjustment for an individual patient.

Cangrelor: a novel P2Y12 receptor antagonist

Antiplatelet therapy is critical in the prevention of thrombotic complications of acute coronary syndrome and percutaneous coronary interventions. Current antiplatelet agents (aspirin, clopidogrel and glycoprotein IIb/IIIa antagonists) have demonstrated the capacity to reduce major adverse cardiac events. However, these agents have limitations that compromise their clinical utility. The platelet P2Y12 receptor plays a central role in platelet function and is a focus in the development of antiplatelet therapies. Cangrelor is a potent, competitive inhibitor of the P2Y12 receptor that is administered by intravenous infusion and rapidly achieves near complete inhibition of ADP-induced platelet aggregation. This investigational drug has been studied for use during coronary procedures and the management of patients experiencing acute coronary syndrome and is undergoing evaluation for use in the prevention of perioperative stent thrombosis.

New developments in antiplatelet therapy

The P2Y12 receptor plays a central role in platelet aggregation, and the clinical effectiveness of the thienopyridine clopidogrel, an irreversible P2Y12 antagonist, in preventing thrombosis provides proof that P2Y12 blockade is a sound strategy in reducing thrombotic risk. Drawbacks of clopidogrel treatment include prolonged time to onset and offset of effect and a variable inhibition of platelet aggregation (IPA). New P2Y12 antagonists have been developed to overcome these drawbacks. Prasugrel is a new thienopyridine that is more efficiently metabolized to its active form than clopidogrel, providing more rapid onset of effect and greater and more consistent IPA. AZD6140 is a reversible oral P2Y12 antagonist that does not require metabolic activation. AZD6140 provides more rapid onset and offset of effect than clopidogrel and greater and more consistent IPA, with a level of IPA depending on plasma drug concentrations. Cangrelor is a direct, reversible intravenous P2Y12 antagonist that has rapid onset and offset of action. Phase 2 trials of these agents have provided some evidence of potential clinical benefits in patients at risk of thrombotic events. Recent and ongoing Phase 3 trials will provide important information on how to improve clinical outcomes with P2Y12 inhibition: the TRITON-TIMI 38 trial comparing prasugrel with clopidogrel in 13 608 patients with acute coronary syndromes (ACS) and planned percutaneous coronary intervention (PCI); the PLATO trial comparing AZD6140 with clopidogrel in approximately 18 000 patients with ACS undergoing medical management, PCI, or coronary artery bypass grafting; and the CHAMPION PCI trial of cangrelor vs. clopidogrel in patients with ACS or stable coronary disease undergoing PCI.

Current developments in anti-platelet therapy

Platelets play a life-saving role in hemostasis and blood clotting at sites of vascular injury and consequently are similarly involved in the pathological counterpart, namely thrombosis. Thus, anti-platelet therapy has become a mainstay in treatment and/or prophylaxis of conditions like myocardial infarction, stroke and other cardiovascular diseases. Acetyl-salicylic acid (ASA, aspirin) is still the most widely used agent and considered as the prototype antiplatelet drug. Since platelet activation occurs via several pathways that are not influenced by ASA, several other compounds have been developed to add to its beneficial effect. Currently four main classes of antiplatelet agents are available for clinical use: acetyl-salicylic acid (ASA), phosphodiesterase (PDE) inhibitors, thienopyridines and the intravenous GPIIb/IIIa antagonists. This article gives a concise review of these four classes of anti-platelet agents, using ASA as the reference standard.

Novel inhibitors of factor X for use in cardiovascular diseases.

The complementary roles of platelets and thrombin in the pathophysiology of acute coronary syndromes suggests that for treatment to be effective, both mediators must be targeted. Although great strides have been made in the development of antiplatelet therapies, attempts to inhibit thrombin have been less successful. Unfractionated heparin is limited by a number of pharmacologic shortcomings as well as an inability to meaningfully suppress thrombin generation. The low molecular weight heparins have yielded encouraging results in large-scale clinical trials, but it remains unclear whether their benefit stems from a superior pharmacologic profile to unfractionated heparin or is determined by an enhanced ability to suppress thrombin generation (by virtue of a direct anti-Xa effect). Regardless, investigators have become increasingly interested in factor Xa as a potential target for antithrombotic therapy. A number of naturally occurring Xa antagonists have been identified. Work with recombinant forms of these proteins confirms that factor Xa inhibition can suppress thrombin generation in a variety of animal thrombosis models. Accordingly, a number of synthetic direct and indirect Xa antagonists are under development for the prevention and treatment of thrombotic disorders. The following review summarizes the evolution of factor Xa antagonists.