Advances in antiplatelet therapy

Cardiovascular diseases (CVDs) are the leading cause of morbidity and mortality in the western world. These disorders share a common pathophysiology – atherosclerosis, which affects various arterial beds, leading to protean manifestations (coronary artery disease [CAD], stroke, peripheral arterial disease [PAD]). The platelet plays a pivotal role in the perpetuation and clinical expression of these disorders. The platelet, once believed to have a role confined to modulation of thrombosis and haemostasis, also plays an active role in vascular inflammation. Antiplatelet agents have become first-line therapy for CVD, and their unequivocal benefits are demonstrated in various basic and experimental models and supported by overwhelming evidence from clinical trials. Search is underway for more effective and safer antiplatelet therapy. Novel therapies are emerging to target the redundant pathways of platelet adhesion, activation and aggregation. Efforts are also ongoing to enhance implementation of existent therapy, target therapy selectively to high-risk patients and to those likely to respond (pharmacogenomics), and study the incremental benefits and safety of various antiplatelet combinations and their interaction with other medications in patients with CVD treated with polypharmacy.     

New antiplatelet drugs

Many clinical trials and pathologic analyses have clearly demonstrated a central role for platelets in the pathophysiology of major cardiovascular disorders, including unstable angina pectoris, acute myocardial infarction (MI), transient ischaemia, and stroke following thrombolytic therapy [1,2]. A meta-analysis of 25 randomised trials of various antiplatelet agents that included 29,000 patients revealed a highly significant decrease in non-fatal MI, stroke, total cardiovascular death, and overall mortality in patients treated with antiplatelet agents compared with placebo [3]. These data have triggered intense efforts over the past 10 years in studying the role of the platelet in cardiovascular disorders, and in developing more potent and selective antiplatelet agents. This discussion summarises recent advances in the development and evaluation of these newer agents with particular emphasis on antagonists of the glycoprotein (GP) IIb/IIIa receptor, since this protein plays a key role in the final common pathway of platelet aggregation.     

Potentiation and priming of platelet activation: a potential target for antiplatelet therapy

Ischemic cardiovascular events represent the leading cause of mortality and morbidity worldwide, and platelet aggregation and thrombus formation are the main effectors of acute arterial ischemic events. Although antiplatelet therapy is the cornerstone of antithrombotic treatment of ischemic cardiovascular disorders, available antiplatelet agents have less than satisfactory efficacy; thus, the identification of novel potential target candidates for antiplatelet therapy is highly warranted. Recent evidence suggests that several molecules that amplify the aggregation response of platelets to activating stimuli, which are either released by platelets (potentiating molecules) or present in the milieu before platelets get activated (primers), play a major role in pathologic thrombus formation without being significantly involved in primary haemostasis. These molecules appear to be a particularly appealing novel potential pharmacologic target for antiplatelet therapy. Here, we review the present knowledge on some molecules acting as potentiators or primers of platelet activation and discuss their possible pharmacologic modulation for antithrombotic purposes.     

Antiplatelet drugs in arterial thrombosis: a review.

The thrombotic process, basic mechanisms of action of antiplatelet drugs, and clinical trials with platelet inhibitors are reviewed. The role of prostaglandins in platelet reactions and the mechanisms of aspirin's, dipyridamole's and sulfinpyrazone's inhibition of platelet function are discussed. Clinical studies of the use of these three drugs, alone or in combination with each other or with anticoagulants, for the treatment of thrombotic disorders associated with valvular heart disease, prosthetic heart valves, cerebral vascular disease (e.g., transient ischemic attacks), coronary artery diseases (including myocardial infarction), peripheral vascular disease, renal disease and renal allograft rejection are reviewed and evaluated. Clinical evidence suggests that antiplatelet drugs are useful in preventing thromboembolism associated with coronary and cerebral vascular disorders. In peripheral vascular and renal diseases and in renal allografts, their benefits have not been proved. Further controlled clinical studies of the preventive use of these drugs for arterial thrombosis are needed.     

Antiplatelet therapies: platelet GPIIb/IIIa antagonists and beyond

Cardiovascular and cerebrovascular diseases continue to be leading causes of death throughout the world. Blood platelets play a pivotal role not only in haemostasis but also in the pathogenesis of thrombosis and atherosclerosis, platelet aggregation being an essential step in the formation of either an effective haemostatic plug or an intravascular thrombus. The benefits of various antiplatelet therapies ranging from aspirin, ticlopidine, Clopidogrel, and intravenous platelet GPIIb/IIIa antagonists in various thromboembolic disorders are well documented. Despite of the success of intravenous acute GPIIb/IIIa blockade when given in conjunction with heparin, chronic oral GPIIb/IIIa antagonists with or without aspirin failed in various cardiovascular settings. This review highlights the role of the various antiplatelet therapies in thrombotic disorders as well as future directions.     

Antiplatelet therapy: present status and future prospects

The excessive accumulation of platelets at sites of vascular injury is a key event in the development of arterial thrombosis, the principal pathogenic mechanism underlying the acute coronary syndromes and ischaemic stroke. In combination, these disorders are the leading causes of morbidity and mortality in the industrialised world and, as a consequence, the platelet is a major therapeutic target in the management of cardiovascular disease. This perspective focuses on the present state of antiplatelet therapy and potential future strategies to improve the safety and efficacy of antiplatelet agents.     

Pharmacologic Inhibition of Platelet Function

Atherothrombosis continues to be a leading cause of death and disability despite advances in pharmacologic and procedural therapies. Antiplatelet agents have been extensively studied and validated to improve outcomes in multiple settings of cardiovascular disease. The emergence of the phenomenon of resistance to antiplatelet therapy resulted in the availability of platelet function tests to assess the effectiveness of these agents. Subsequent evaluations have shown considerable inter-individual variability in platelet inhibition in patients receiving antiplatelet agents. Several small studies showed that patients who were deemed 'resistant' to antiplatelet therapy by platelet function testing had adverse clinical outcomes. It is essential that ongoing investigations help delineate a standard definition of 'resistance' to antiplatelet therapy, which test of platelet function should be the gold standard, and what therapy, once identified, can help overcome resistance to the currently available antiplatelet agents. Data are needed to determine if outcomes can be improved by changes to existing antiplatelet therapy based on the results of platelet function tests. Alternatively, newer antiplatelet agents may prove effective in overcoming resistance; however, these agents also await validation in large-scale clinical trials.     

Genetic factors underlying differential blood platelet sensitivity to inhibitors

Blood platelets are not only the primary defence mechanism involved in physiological hemostasis, but also their disorders constitute a crucial risk factor in arterial thrombosis. As arterial thrombi are composed of predominantly platelets formed under conditions of elevated shear stress at sites of atherosclerotic vascular injury and disturbed blood flow, the prevention of arterial thrombosis has been for years the main target for antiplatelet therapy. Individual differences in the rate of platelet activation and reactivity markedly influence normal hemostasis and the pathological outcome of thrombosis. Such an individual variability is largely determined by environmental and genetic factors. These are known to either hamper platelets' response to agonists, and thereby mimic the pharmacological modulation of platelet function or mask therapy effect and sensitize platelets. Some clinical studies have indicated that platelet glycoprotein polymorphisms are genetic factors contributing to arterial thrombosis. In spite of some discrepancies between different studies, there is substantial evidence that the integrin beta3 P1(A2) allele, the variants GPIbalpha Met145 and GPIbalpha (-5C) haplotype or the integrin alpha2 haplotype 1 (807T) each contribute to the risk for and morbidity of thrombotic disease. In this article, we reviewed a role of the aforementioned polymorphisms in modulating platelet function and platelet response to inhibitors. The paper focuses on the association between Pl(A1/A2) polymorphism and sensitivity (or resistance) to aspirin and the inhibitory efficacy of GPIIb-IIIa antagonists. Additionally, a potential role of 807C/T polymorphism (GPIa), polymorphisms of GPIb and platelet purinoreceptor P2Y12 in affecting platelet sensitivity to blocking agents is discussed.     

Antiplatelet therapy in patients with diabetes mellitus

Platelets are key players in arterial thrombosis, and oral antiplatelet therapy is a cornerstone in the treatment and prevention of cardiovascular events. However, although currently approved antiplatelet drugs have proved successful in reducing cardiovascular events, platelet-dependent thrombosis remains an important cause of morbidity and mortality in patients with coronary artery disease. It is well-known that patients with diabetes mellitus (DM) have an increased risk of cardiovascular events and, therefore, understanding the mechanism of action and safety profile of antiplatelet drugs in this high-risk population is of particular interest. There is considerable inter-individual variation in the efficacy of established antiplatelet drugs, and high on-treatment platelet reactivity is associated with an increased risk of cardiovascular events, thus prompting the search for novel drugs against platelet-dependent thrombosis. New antiplatelet treatment strategies include drugs with more efficient and reversible platelet inhibition. This review discusses selective inhibitors of the platelet cyclooxygenase enzyme, thienopyridine and non-thienopyridine inhibitors of the platelet adenosine diphosphate receptor, phosphodiesterase inhibitors, and protease-activated receptor antagonists. An overview of currently available antiplatelet drugs is provided, focusing on benefits and limitations in patients with DM. Furthermore, the rationale for new oral antiplatelet drugs under development is discussed with particular focus on the potential role of these drugs to improve cardiovascular outcomes in patients with DM.     

Oral Antiplatelet Therapy in the Secondary Prevention of Atherothrombotic Events

Atherothrombosis is the leading cause of death worldwide and has a large economic impact. It is a pathologic process related to atherosclerosis, which leads to adverse clinical manifestations, including acute coronary syndrome, cerebrovascular disease, and peripheral arterial disease. Patients with atherothrombosis are at heightened risk for recurrent ischemic events or death, and therefore, secondary prevention is an important goal in the treatment of these patients. Antiplatelet therapies available for long-term secondary prevention include aspirin (acetylsalicylic acid), extended-release dipyridamole plus aspirin, and clopidogrel. A number of clinical trials have demonstrated the benefit of combined antiplatelet therapy in secondary prevention, supporting the recommendations made in current published guidelines. Although the efficacy and safety of antiplatelet agents is well established and supported by clinical trials, their utilization rate in patients with atherothrombosis remains suboptimal. Quality improvement initiatives have demonstrated effectiveness in promoting the awareness and implementation of treatment guidelines. This article reviews the benefits and risks of antiplatelet therapy in patients with cardiovascular disease with the aim of spurring greater adherence to treatment recommendations and, thereby, better patient outcomes.     

New perspectives in antiplatelet therapy

Platelet activation is a complex mechanism of response to vascular injury and atherothrombotic disease, leading to thrombus formation. A wide variety of surface receptors -integrins, leucine-rich family receptors, G protein coupled receptors, tyrosine kinase receptors- and intraplatelet molecules support and regulate platelet activation. They are potential targets of antiplatelet therapy for the prevention and treatment of arterial thrombosis. Despite the overall clinical benefit of established antiplatelet drugs targeting cyclooxigenase-1 (COX-1), glycoprotein integrin αIIbβ3, and the purinergic P2Y(12) receptor of adenosine diphosphate, a significant proportion of treated patients continue to experience recurrent ischaemic events. This may be in partly attributed to insufficient inhibition of platelet activation. In addition, it should not be underestimated that these drugs are not immune from bleeding complications. The substantial progress in understating the regulation of platelet activation has played a key role in the development of novel antiplatelet agents. Current examples of drug under development and evaluation include: novel P2Y(12) receptor inhibitors (prasugrel, ticagrelor, cangrelor, and elinogrel), thrombin receptor PAR-1 antagonists (vorapaxar, atopaxar), new integrin glycoprotein IIb/IIIa inhibitors, and inhibitors targeting the thromboxane receptor (TP), phosphodiesterases, the collagen receptor glycoprotein VI, and intraplatelet signalling molecules. This review summarizes the mechanisms of action and current clinical evaluation of these novel antiplatelet agents.     

Ticlopidine. An updated review of its pharmacology and therapeutic use in platelet-dependent disorders

Ticlopidine inhibits platelet aggregation induced by adenosine diphosphate (ADP) and most other platelet agonists in ex vivo studies of human platelets. The drug also improves other abnormalities of platelet function seen in patients with cerebrovascular disease, peripheral arterial disease, ischaemic heart disease or other conditions involving platelet hyperaggregation. Abnormal platelet activity has been implicated in a variety of clinical conditions in which patients are at high risk of thromboembolic events, and thus the effectiveness of ticlopidine has been investigated in such patients. Since the initial review of the drug appeared in the Journal, data from several large multicentre studies have shown that ticlopidine has a substantial benefit to offer patients who have experienced transient ischaemic attacks or stroke, and in those with peripheral arterial disease or ischaemic heart disease. Ticlopidine reduces the incidence of further stroke, myocardial infarction or vascular death, and is superior to placebo and aspirin in this regard in studies of patients with recent stroke or transient ischaemic attacks, or intermittent claudication. Ticlopidine is equally effective in both men and women and also improves symptoms of claudication in patients with peripheral arterial disease, and appears to reduce anginal pain. Patients with subarachnoid haemorrhage and sickle cell disease have shown some improvement with ticlopidine administration. The drug reduces thromboembolic events and re-stenosis in patients undergoing haemodialysis and cardiac surgery, and appears to prevent the progression of nonproliferative diabetic retinopathy. Ticlopidine in large clinical trials is associated with a higher incidence of adverse effects than placebo and an overall incidence similar to aspirin. Most adverse effects do not require withdrawal of treatment. Gastrointestinal symptoms (particularly diarrhoea) are most common, occurring almost twice as frequently with ticlopidine as with aspirin. Other adverse effects associated with ticlopidine include skin rash, haemorrhagic disorders, and haematological effects; these latter effects require careful monitoring of patients during the initial weeks of therapy. In conclusion, ticlopidine is a valuable addition to the prophylactic treatments available for the management of patients with cerebrovascular disease, peripheral arterial disease or ischaemic heart disease, who present a high risk of thromboembolic events. Although tolerability may be a problem for some patients, the overall benefit conferred by the drug would appear to outweigh this potential disadvantage. Because of its antiplatelet activity, ticlopidine has a promising role in other disorders mediated by platelet dysfunction. However, the precise role of the drug in these additional therapeutic indications awaits clarification with wider clinical experience.     

Clopidogrel and aspirin in cardiovascular medicine: responders or not--current best available evidence

Dual antiplatelet therapy represents an important advance for patients with established coronary artery disease. It is an important strategy for patients with acute coronary syndromes and those undergoing percutaneous transcatheter coronary interventions. Clopidogrel effectively inhibits ADP-induced platelet activation and aggregation by selectively and irreversibly blocking the P2Y(12) receptor on the platelet membrane. Aspirin works by irreversibly acetylating the cyclooxygenase (COX-1) enzyme, thus suppressing the production of thromboxane A(2) (TxA(2)) and inhibiting platelet activation and aggregation. Variable platelet response and potential resistance to therapy has emerged with aspirin and clopidogrel. The definitions of antiplatelet agents variability in responsiveness and nonresponsiveness are discussed. Clopidogrel and aspirin responsiveness as they are measured in the laboratory by various techniques (platelet aggregometry and point-of-care assays such as platelet function analyzer [PFA-100] and rapid platelet function assay [RPFA]) are evaluated. The mechanisms responsible for variations in responsiveness to antiplatelet agents such as clinical, cellular and genetic factors are defined. Aspirin and clopidogrel resistance are emerging clinical entities with potentially severe consequences such as myocardial infarction, stroke or death. The therapeutic interventions to deal with nonresponsiveness are reported, although specific recommendations are not clearly established. In the future, routine measurement of platelet function in patients with cardiovascular disease may become the standard of care. Personalized antithrombotic treatment strategies may be determined by ex-vivo measurements that identify critical pathways influencing thrombotic risk in the individual patient.     

Efficacy of clopidogrel treatment and platelet responsiveness in peripheral arterial procedures

Introduction: Long-term antiplatelet therapy with clopidogrel has been recommended in patients undergoing peripheral arterial procedures. Poor antiplatelet effect of clopidogrel or high on-clopidogrel platelet reactivity (HCPR) has been recently identified in patients with peripheral arterial disease (PAD).

Areas covered: This review focuses on the use of clopidogrel and the phenomenon of HCPR in PAD patients treated for intermittent claudication or critical limb ischaemia (CLI). The authors summarize current guidelines and recommendations for use of clopidogrel following peripheral arterial procedures and explore the prevalence and clinical impact of HCPR in the PAD population. Underlying mechanisms of HCPR and relevant clinical and genetic factors are analyzed with particular attention to the potential utility of point-of-care platelet function testing (PFT).

Expert opinion: Clopidogrel is a safe, effective and well-tolerated antiplatelet agent in PAD patients following peripheral arterial revascularization. Dual-antiplatelet therapy could also be considered after complex endovascular procedures. HCPR has been identified in more than 50% of PAD patients on clopidogrel and has been related with significantly increased re-intervention rates. Incidence of HCPR is significantly higher in patients with CLI, diabetes mellitus and chronic renal disease. Personalized antiplatelet therapy on the basis of PFT is an elegant emerging concept for optimization of platelet inhibition and potential identification of patients at increased risk of bleeding and warrants investigation in future large-scale trials.     

Triple antiplatelet therapy in acute coronary syndromes

Heightened platelet activity plays a critical role in thrombus formation, which is central to acute coronary syndromes (ACS), including non-ST-segment elevation (NSTE)-ACS (comprising unstable angina pectoris and non-ST-segment elevation myocardial infarction [NSTEMI]) and ST-segment elevation myocardial infarction (STEMI), and has been implicated in poor clinical outcome. Platelets not only impact coronary thrombus but are major contributors to microcirculatory dysfunction and vascular inflammation. Efforts to inhibit platelet function, including antiplatelet therapy, are paramount to the management of ACS; thus, a growing recognition of the various pathways driving platelet activity has given rise to the need for multiple agents that impart complimentary mechanisms of action. While only inhibiting platelet activation will still allow for aggregation, i.e. the binding of glycoprotein (GP) IIb/IIIa receptors to fibrinogen, solely blocking aggregation may leave platelet-activating pathways free to sustain the production and release of various pro-inflammatory and pro-thrombotic compounds. The benefit of 'triple antiplatelet therapy', referring to the combination of aspirin, a thienopyridine or non-thienopyridine adenosine diphosphate (ADP)/P2Y12 receptor blocker and a GPIIb/IIIa inhibitor (GPI), has been demonstrated in patients with NSTE-ACS who ultimately undergo percutaneous coronary intervention (PCI) and are determined to be at an elevated risk for ischaemic events, and in patients undergoing primary PCI. It is therefore recommended by the European Society of Cardiology (ESC) and American College of Cardiology/American Heart Association. Furthermore, the rationale for adding a GPI, particularly in patients with STEMI, is backed by studies that have shown negligible effects of a 600?mg clopidogrel loading dose, despite being administered 4 hours prior to PCI. Moreover, it has been observed that the physiological state of STEMI may deem dual antiplatelet therapy ineffective, because during an acute event the absorption of clopidogrel may be impaired. Nonetheless, there is still considerable variability with respect to the use of triple antiplatelet therapy such as that documented in the Euro Heart Survey. The perception that the mortality benefit afforded by adding a GPI to dual oral antiplatelet therapy does not outweigh the risk is a likely factor. This may be fuelled by results of trials such as BRAVE-3, which, inconsistent with those for On-TIME 2, failed to prove the value of adding a GPI to dual oral antiplatelet therapy in patients with STEMI. Subsequent analyses have indeed demonstrated the positive benefit-risk ratio associated with adding a GPI and determined that the timing of GPI administration could have an impact on clinical outcome related to its impact on infarct size in patients with STEMI. Additionally, it has been presumed that a synergistic effect exists between P2Y12 inhibitors and GPIs. Triple antiplatelet therapy has a significant role to play in the management of patients with ACS managed with PCI. An understanding of patient risk status and timing of symptoms and bleeding risk is crucial to patient selection and ensuring that this therapy is optimized. Though no interaction has been noted in trials of newer, more potent antiplatelet agents, future studies are key to determining the role of this strategy in the era of these more potent agents.     

Targeting von Willebrand factor as a novel anti-platelet therapy; Application of ARC1779, an Anti-vWF aptamer, against thrombotic risk

Excessive activation of platelets is a causative factor for thrombotic diseases such as acute coronary syndrome or stroke, and various anti-platelet drugs were developed. Aspirin and clopidogrel have been used as gold standards for anti-platelet therapies, however, their clinical limitations including bleeding problem have increased the demand driving development of novel anti-platelet drugs with new targets. Among several activating pathways leading to platelet aggregation, the interaction between von Willebrand factor (vWF) and glycoprotein Ib, which mainly occurs under high shear stress in arterioles, is recently suggested to be a new promising target. The anti-thrombotic efficacy of anti-vWF agents, such as ARC1779, has been proved in several preclinical and clinical studies. Here, we will discuss the potential benefits of targeting vWF as a novel antiplatelet therapy, providing an insight into the role of vWF in increased thrombotic risk.     

Pharmacodynamic properties of antiplatelet agents: current knowledge and future perspectives

Platelets play an important role in atherothrombotic disease. The currently available antiplatelet drugs target key steps of platelet activation including thromboxane A(2) synthesis, ADP-mediated signaling, and glycoprotein IIb/IIIa-mediated platelet aggregation. The improvement of our understanding on the pharmacokinetic and pharmacodynamic characteristics of these drugs enables the tailoring of the most appropriate anti-thrombotic therapy to the individual patient and risk situation in the daily clinical practice. However, current antiplatelet therapies are associated with increased bleeding risk. Thus, further research on platelet functions may give rise to numerous new antiplatelet agents with high anti-thrombotic efficiency and low adverse hemorrhagic side effects.     

Platelet function and antiplatelet therapy in cardiovascular disease: implications of genetic polymorphisms

Platelets play a crucial role in thrombosis, inflammation, immunity and atherogenesis. Antiplatelet agents are widely used in patients with acute coronary syndrome and other cardiovascular disorders. Aspirin and clopidogrel are the most commonly prescribed antiplatelet agents, with a relatively safe profile and efficiency in a variety of clinical conditions. Numerous prospective studies have revealed variability of antiplatelet efficacy. The so called "antiplatelet resistance" prompted a search for mechanisms implicated in poor responsiveness to aspirin and clopidogrel therapy. In this regard, genetic polymorphisms in the platelet receptor genes attracted considerable interest. Specific genetic variants in platelet receptors such as the P2Y12, glycoprotein (GP) IIb/IIIa, GPIa/IIa, GPIb/IX/V and the cytochrome P450 (CYP) family of genes are associated with variable response to antiplatelet therapy and cardiovascular events. Genetic polymorphisms and haplotypes that comprehensively capture the genetic information encoded within the platelet receptor genes can, to some extent, predict response to the antiplatelet drug better than any single genotype. Genotyping for multiple receptor variants in patients on antiplatelet therapy, complemented by standardized quantification of platelet function, can provide useful information for future drug design studies and possibly for personalized antiplatelet therapy and prevention of thrombotic events. Additional information is, however, needed to evaluate the cost-effectiveness of complex genetic and platelet function testing.     

Platelets in atherothrombosis--diagnostic and prognostic value of platelet activation in patients with atherosclerotic diseases

Platelets and their activation have a pivotal role in the development of atherosclerotic diseases such as acute myocardial infarction (AMI), stroke and peripheral arterial occlusion. Biomarkers of platelet activation are making inroads into clinical studies and may serve as promising agents upstream to established downstream markers of myocardial necrosis such as troponin and creatin kinase. Targeting the degree of platelet activation assessed by the key collagen receptor of platelet activation, glycoprotein VI (GPVI), may have diagnostic and prognostic value for the assessement of high-risk groups of patients with symptomatic coronary artery disease and ischemic stroke and may be worthwhile to help to facilitate clinical decision-making and to rapidly initiate adequate therapy. The concert of platelet count, platelet activation, platelet aggregation and subsequent inflammation has had a significant impact on the clinical outcome in patients with atherosclerotic diseases. For a therapeutical approach to ameliorate prognosis, the use of antiplatelet treatment in particular in AMI patients with low response to clopidogrel has partly been overcome by novel second antiplatelet drugs on top of aspirin such as prasugrel and ticagrelor. Antiplatelet therapy may be adapted according to a GPVI-based platelet activity monitoring along with aggregometry of residual platelet aggregation. Other approaches using protease-activated receptor- 1 antagonists vorapaxar or atopaxar, which inhibit the platelet thrombin receptor, soluble GPVI called Revacept?, which blocks the collagen binding sites at the vascular lesion and anopheline saliva protein derived from the malaria vector mosquito, a platelet adhesion inhibitor independent of a GPVI mechanism, still wait for their breakthrough.     

G13-mediated signaling as a potential target for antiplatelet drugs

The activation of platelets at sites of vascular injury is essential for primary hemostasis, but also underlies arterial thrombosis leading to myocardial infarction or stroke. The inhibition of platelet function is therefore a major strategy to prevent and treat arterial thrombosis. Platelet stimuli like ADP, thrombin or thromboxane A(2) activate receptors that are coupled to heterotrimeric G proteins to regulate intracellular signaling pathways. Activation of platelets through these receptors has been shown to involve signaling through various heterotrimeric G proteins. The G protein G(13), which is able to link receptors to the Rho/Rho-kinase pathway, has recently been shown to be critically involved in platelet activation and to play an important role in platelet-dependent arterial thrombosis. The G(13)-mediated signaling pathway may therefore be an interesting new target for antiplatelet drugs.