Antiplatelet therapy in cardiovascular disease: Current status and future directions.

Antiplatelet medications remain a cornerstone of therapy for atherosclerotic cardiovascular and cerebrovascular diseases. In primary prevention (patients with cardiovascular risk factors but no documented events, symptoms or angiographic disease), there is little evidence of benefit of any antiplatelet therapy, and such therapy carries the risk of excess bleeding. Where there is documented disease (secondary prevention), stable patients benefit from long-term antiplatelet monotherapy, aspirin being first choice in those with coronary heart disease and clopidogrel in those with cerebrovascular disease; moreover, recent evidence shows that low-dose rivaroxaban in combination with aspirin confers added benefit, in patients with stable cardiovascular and peripheral arterial disease. In patients with acute cerebrovascular disease, aspirin combined with clopidogrel reduces subsequent risk, while in acute coronary syndrome, dual antiplatelet therapy comprising aspirin and a P2Y12 inhibitor (clopidogrel, prasugrel or ticagrelor) confers greater protection than aspirin monotherapy, with prasugrel and ticagrelor offering greater antiplatelet efficacy with faster onset of action than clopidogrel. Although greater antiplatelet efficacy is advantageous in preventing thrombotic events, this must be tempered by increased risk of bleeding, which may be a particular issue in certain patient groups, as will be discussed. We will also discuss possible future approaches to personalisation of antiplatelet therapy.

SNO-MLP (S-Nitrosylation of Muscle LIM Protein) Facilitates Myocardial Hypertrophy Through TLR3 (Toll-Like Receptor 3)-Mediated RIP3 (Receptor-Interacting Protein Kinase 3) and NLRP3 (NOD-Like Receptor Pyrin Domain Containing 3) Inflammasome Activation.

BACKGROUND: S-nitrosylation (SNO), a prototypic redox-based posttranslational modification, is involved in the pathogenesis of cardiovascular disease. The aim of this study was to determine the role of SNO of MLP (muscle LIM protein) in myocardial hypertrophy, as well as the mechanism by which SNO-MLP modulates hypertrophic growth in response to pressure overload. METHODS: Myocardial samples from patients and animal models exhibiting myocardial hypertrophy were examined for SNO-MLP level using biotin-switch methods. SNO sites were further identified through liquid chromatography-tandem mass spectrometry. Denitrosylation of MLP by the mutation of nitrosylation sites or overexpression of S-nitrosoglutathione reductase was used to analyze the contribution of SNO-MLP in myocardial hypertrophy. Downstream effectors of SNO-MLP were screened through mass spectrometry and confirmed by coimmunoprecipitation. Recruitment of TLR3 (Toll-like receptor 3) by SNO-MLP in myocardial hypertrophy was examined in TLR3 small interfering RNA-transfected neonatal rat cardiomyocytes and in a TLR3 knockout mouse model. RESULTS: SNO-MLP level was significantly higher in hypertrophic myocardium from patients and in spontaneously hypertensive rats and mice subjected to transverse aortic constriction. The level of SNO-MLP also increased in angiotensin II- or phenylephrine-treated neonatal rat cardiomyocytes. S-nitrosylated site of MLP at cysteine 79 was identified by liquid chromatography-tandem mass spectrometry and confirmed in neonatal rat cardiomyocytes. Mutation of cysteine 79 significantly reduced hypertrophic growth in angiotensin II- or phenylephrine-treated neonatal rat cardiomyocytes and transverse aortic constriction mice. Reducing SNO-MLP level by overexpression of S-nitrosoglutathione reductase greatly attenuated myocardial hypertrophy. Mechanistically, SNO-MLP stimulated TLR3 binding to MLP in response to hypertrophic stimuli, and disrupted this interaction by downregulating TLR3-attenuated myocardial hypertrophy. SNO-MLP also increased the complex formation between TLR3 and RIP3 (receptor-interacting protein kinase 3). This interaction in turn induced NLRP3 (nucleotide-binding oligomerization domain-like receptor pyrin domain containing 3) inflammasome activation, thereby promoting the development of myocardial hypertrophy. CONCLUSIONS: Our findings revealed a key role of SNO-MLP in myocardial hypertrophy and demonstrated TLR3-mediated RIP3 and NLRP3 inflammasome activation as the downstream signaling pathway, which may represent a therapeutic target for myocardial hypertrophy and heart failure.

Advanced Glycation Endproducts Impair Endothelial Progenitor Cell Migration and Homing via Syndecan 4 Shedding.

Endothelial progenitor cells (EPCs) are a subtype of bone marrow-derived progenitor cells. Stromal cell-derived factor 1 (SDF-1)-mediated EPC mobilization from bone marrow to areas of ischemia plays an important role in angiogenesis. Previous studies have reported that advanced glycation endproducts (AGEs), which are important mediators of diabetes-related vascular pathology, may impair EPC migration and homing, but the mechanism is unclear. Syndecan-4 (synd4) is a ubiquitous heparan sulfate proteoglycan receptor on the cell surface, involved in SDF-1-dependent cell migration. The extracellular domain of synd4 (ext-synd4) is shed in the context of acute inflammation, but the shedding of ext-synd4 in response to AGEs is undefined. Here we investigated changes in ext-synd4 on EPCs in response to AGEs, focusing on the influence of impaired synd4 signaling on EPC migration and homing. We found decreased full length and increased residue of synd4 in cells incubated with AGEs, with concomitant increase in the soluble fragment of ext-synd4 in the cell medium. EPCs from patients with type 2 diabetes expressed less ext-synd4 as assessed by Western blotting. Flow cytometry analysis showed less ext-synd4 on circulating CD34+ peripheral blood mononuclear cells, of which EPCs form a subgroup. We then explored the role of synd4 in EPC migration and homing. Impaired migration of synd4-deficient EPCs was observed by a 2D-chemotaxis slide. Furthermore, poor homing of synd4-/- EPCs was observed in a mouse model of lower limb ischemia. This study demonstrates that the shedding of synd4 from EPCs plays a key role in AGE-mediated dysfunction of EPC migration and homing. Stem Cells 2017;35:522-531.

Gender differences in cardiovascular prophylaxis: Focus on antiplatelet treatment.

Cardiovascular disease (CVD) represents the leading cause of death worldwide, and equally affects both sexes although women develop disease at an older age than men. A number of clinical evidence has identified the female sex as an independent factor for poor prognosis, with the rate of mortality and disability following an acute cardiovascular (CV) event being higher in women than men. It has been argued that the different level of platelet reactivity between sexes may account for a different responsiveness to anti-platelet therapy, with consequent important implications on clinical outcomes. However, conclusive evidence supporting the concept of a gender-dependent effectiveness of platelet inhibitors are lacking. On the contrary, sex-related dissimilarities have been evidenced in cardiovascular patients in terms of age of presentation, comorbidities such as obesity, diabetes and renal disease, and a different pharmacological approach to and effectiveness in controlling classical cardiovascular risk factors such as hypertension, glucose profile and lipid dysmetabolism. All these factors could place women at an increased level of cardiovascular risk compared to men, and may concur to an enhanced pro-thrombogenic profile. The purpose of this manuscript is to provide an overview of gender-related differences in cardiovascular treatment, in order to highlight the need to improve the pharmacological prophylaxis adopted in women through a more accurate evaluation of the overall cardiovascular risk profile with consequent establishment of a more effective and targeted anti-thrombotic strategy which is not limited to the use of anti-platelet agents.

Traditional Chinese medicines in the management of cardiovascular diseases: a comprehensive systematic review.

AIMS: The aim was to perform a systematic review of the efficacy of traditional Chinese medicines (TCM) in cardiovascular disease. METHODS: Electronic databases were searched up to 11 November 2015 for all randomized-controlled trials evaluating the effect of TCM in hypertension, ischaemic stroke, heart failure, coronary heart disease and type 2 diabetes mellitus. Pooled odds ratios (ORs) were calculated using a fixed-effects model. RESULTS: Four hypertension studies were eligible for statistical analysis and included 133 patients receiving TCM and 130 control patients. There were significant reductions in systolic blood pressure in patients receiving TCM, comparable to results achieved with pharmaceutical medicines. An OR of 3.781 (95% confidence interval 2.392, 5.977; P = 0.000) was observed for the anti-hypertensive effect of TCM. Significant heterogeneity was present (P = 0.011), with a tendency towards publication bias that did not reach significance (P = 0.05275). Outcome measures for other cardiovascular diseases were inconsistent. CONCLUSIONS: Certain TCM compounds appear to have significant anti-hypertensive effects, and although some are associated in some studies with improved outcomes in coronary heart disease, heart failure and type 2 diabetes mellitus, the data are inconsistent and will require large-scale randomized-controlled trials to allow full evaluation of any potential therapeutic benefit in these areas.

Achieving the World Health Organization's vision for clinical pharmacology.

Clinical pharmacology is a medical specialty whose practitioners teach, undertake research, frame policy, give information and advice about the actions and proper uses of medicines in humans and implement that knowledge in clinical practice. It involves a combination of several activities: drug discovery and development, training safe prescribers, providing objective and evidence-based therapeutic information to ethics, regulatory and pricing bodies, supporting patient care in an increasingly subspecialized arena where co-morbidities, polypharmacy, altered pharmacokinetics and drug interactions are common and developing and contributing to medicines policies for Governments. Clinical pharmacologists must advocate drug quality and they must also advocate for sustainability of the Discipline. However for this they need appropriate clinical service and training support. This Commentary discusses strategies to ensure the Discipline is supported by teaching, training and policy organizations, to communicate the full benefits of clinical pharmacology services, put a monetary value on clinical pharmacology services and to grow the clinical pharmacology workforce to support a growing clinical, academic and regulatory need.

Antiplatelet therapy as a modulator of stroke aetiology: a meta-analysis.

AIMS: Antiplatelet therapy reduces the incidence of ischaemic stroke. Platelet-mediated thrombosis contributes variably to the major subtypes of stroke as defined by the TOAST criteria: large artery atherosclerosis (LAA), cardioembolic (CE) and small vessel occlusion (SVO). The effect of antiplatelet therapy on the incidence of each subtype is unknown and is the subject of this meta-analysis. METHODS: Electronic databases were searched for articles comparing the effect of antiplatelet therapy on the incidence of stroke according to aetiological subtype. Studies containing subjects prescribed anticoagulant therapy or solely investigating subjects with atrial fibrillation were excluded. Pooled odds ratios (ORs) were calculated using a fixed effects model. RESULTS: Nine studies were included (n = 5739). In patients who had an ischaemic stroke, pre-event antiplatelet therapy was associated with significantly decreased incidence of LAA (OR 0.88, 95% CI 0.79, 0.99; P = 0.026), increased incidence of CE (OR 1.23, 95% CI 1.08, 1.41; P = 0.002) and no effect on SVO (OR 0.99, 95% CI 0.88, 1.11; P = 0.806). Concordant non-significant trends were observed in primary prevention populations (n = 751): LAA (OR 0.81, 95% CI 0.57, 1.15; P = 0.240), CE (OR 1.29, 95% CI 0.89, 1.87; P = 0.179) and SVO (OR 0.99, 95% CI 0.73, 1.36; P = 0.970). Subgroup analysis of aspirin monotherapy (n = 3786) demonstrated a significant reduction in LAA (OR 0.87, 95% CI 0.76, 1.00; P = 0.046), but non-significant effects on the incidence of CE (OR 1.17, 95% CI 0.99, 1.39; P = 0.068) and SVO (OR 1.04, 95% CI 0.91, 1.20; P = 0.570). Probability of publication bias was low (P > 0.05). CONCLUSIONS: Antiplatelet therapy preferentially reduces the incidence of LAA stroke compared with CE and SVO subtypes.

Antiplatelet drug resistance: Molecular insights and clinical implications.

Antiplatelet drugs are prescribed to patients with cardiovascular disease in order to reduce their risk of clinically important atherothrombotic events. However, a proportion of patients fail to appropriately respond to these drugs in a heterogeneous phenomenon known as 'antiplatelet drug resistance'. Individuals who are identified as being resistant have a higher cardiovascular risk, but currently there is no clinically validated approach to identify and treat these individuals. Large randomised control trials have attempted to personalise antiplatelet therapy based on platelet function testing, but these have failed to demonstrate improved clinical outcomes. An alternative approach to this non-specific assessment of platelet function is to consider whether antiplatelet therapy may be personalised based on the identification of molecular mechanisms that are known to confer resistance. Here we present molecular insights into the mechanisms for aspirin and clopidogrel resistance, with a discussion of their clinical implications.

The PlA1/A2 polymorphism of glycoprotein IIIa in relation to efficacy of antiplatelet drugs: a systematic review and meta-analysis.

AIM: The PlA1/A2 polymorphism of glycoprotein IIIa (GPIIIa) has been associated with both antiplatelet drug resistance and increased cardiovascular events. The aim of this study was to conduct the first meta-analysis investigating the association between carriage of the PlA2 allele and resistance to currently licensed antiplatelet drugs. METHODS: Electronic databases (MEDLINE and EMBASE) were searched for all articles evaluating genetic polymorphisms of GPIIIa. For studies where antiplatelet resistance was measured using validated techniques, pooled odds ratios (ORs) were calculated using fixed effects and random effects models. RESULTS: Sixteen studies were eligible for statistical analysis and included 1650 PlA1 homozygous subjects and 668 carriers of the PlA2 allele. For carriers of the PlA2 allele, OR 0.924 (n = 2318; 95% CI 0.743, 1.151; P = 0.481) was observed for resistance to any antiplatelet drug, OR 0.862 (n = 2085; 95% CI 0.685, 1.086; P = 0.208) for resistance to aspirin and OR 1.429 (n = 233; 95% CI 0.791, 2.582; P = 0.237) for resistance to clopidogrel. In the aspirin cohort, sub-group analysis revealed no statistical association in either healthy subjects or those with cardiovascular disease. PlA2 carriage was marginally associated with aspirin sensitivity using the fixed effects model when identified by the PFA-100 assay (n = 1151; OR 0.743, 95% CI 0.558, 0.989; P = 0.041) but with significant heterogeneity (I(2) = 55%; P = 0.002). Significance was lost with analysis using a random effects model. CONCLUSIONS: The totality of published data does not support an association between carriage of the PlA2 allele and antiplatelet drug resistance. Significant heterogeneity indicates the need for larger studies using validated and standardized assays.

Increased platelet expression of glycoprotein IIIa following aspirin treatment in aspirin-resistant but not aspirin-sensitive subjects.

AIMS: Aspirin is widely used as an anti-platelet agent for cardiovascular prophylaxis. Despite aspirin treatment, many patients experience recurrent thrombotic events, and aspirin resistance may contribute to this. We examined the prevalence of aspirin resistance in a healthy population, and investigated whether the platelet proteome differed in aspirin-resistant subjects. METHODS: Ninety-three healthy subjects received aspirin 300 mg daily for 28 days. Before and at the end of treatment, urine was taken to determine 11-dehydrothromboxane B2 , and blood was taken to measure arachidonic acid (AA)-induced aggregation of platelet-rich plasma and to interrogate the platelet proteome by mass spectrometric analysis with further confirmation of findings using Western blotting. RESULTS: In two of the 93 subjects, neither AA-induced aggregation nor urinary 11-dehydrothromboxane B2 was effectively suppressed by aspirin, despite measurable plasma salicylate concentrations, suggesting the presence of true aspirin resistance. Despite no detectable differences in the platelet proteome at baseline, following aspirin a marked increase was seen in platelet glycoprotein IIIa expression in the aspirin-resistant but not aspirin-sensitive subjects. An increase in platelet glycoprotein IIIa expression with aspirin resistance was confirmed in a separate cohort of 17 patients with stable coronary artery disease on long term aspirin treatment, four of whom exhibited aspirin resistance. CONCLUSIONS: In a healthy population, true aspirin resistance is uncommon but exists. Resistance is associated with an increase in platelet glycoprotein IIIa expression in response to aspirin. These data shed new light on the mechanism of aspirin resistance, and provide the potential to identify aspirin-resistant subjects using a novel biomarker.

Serum amyloid A-A potential therapeutic target for hyper-inflammatory syndrome associated with COVID-19.

Serum amyloid-A (SAA) is associated with inflammatory disorders such as rheumatoid arthritis, Familial Mediterranean Fever, sarcoidosis, and vasculitis. There is accumulating evidence that SAA is a reliable biomarker for these autoinflammatory and rheumatic diseases and may contribute to their pathophysiology. Hyperinflammatory syndrome associated with COVID-19 is a complex interaction between infection and autoimmunity and elevation of SAA is strongly correlated with severity of the inflammation. In this review we highlight the involvement of SAA in these different inflammatory conditions, consider its potential role and discuss whether it could be a potential target for treatment of the hyperinflammatory state of COVID-19 with many potential advantages and fewer adverse effects. Additional studies linking SAA to the pathophysiology of COVID-19 hyper-inflammation and autoimmunity are needed to establish the causal relationship and the therapeutic potential of inhibitors of SAA activity.

Increased Expression Levels of Netrin-1 in Visceral Adipose Tissue during Obesity Favour Colon Cancer Cell Migration.

Netrin (NTN)-1, an extracellular matrix protein with a crucial role in inflammation, is dysregulated during obesity (OB) and influences colon cancer (CC) progression. To decipher the mechanisms underlying CC development during obesity, we examined the expression of NTN1 and its receptors in the visceral adipose tissue (VAT) of 74 (25 normal weight (NW)) (16 with CC) and 49 patients with OB (12 with CC). We also evaluated the effect of caloric restriction (CR) on the gene expression levels of Ntn1 and its receptors in the colon from a rat model fed a normal diet. The impact of adipocyte-conditioned media (ACM) from patients with OB and NTN-1 was assessed on the expression levels of neogenin 1(NEO1), deleted in colorectal carcinomas (DCC) and uncoordinated-5 homolog B (UNC5B) in Caco-2 and HT-29 human colorectal cell lines, as well as on Caco-2 cell migration. Increased NTN1 and NEO1 mRNA levels in VAT were due to OB (p < 0.05) and CC (p < 0.001). In addition, an upregulation in the expression levels of DCC and UNC5B in patients with CC (p < 0.01 and p < 0.05, respectively) was observed. Decreased (p < 0.01) Ntn1 levels in the colon from rats submitted to CR were found. In vitro experiments showed that ACM increased DCC (p < 0.05) and NEO1 (p < 0.01) mRNA levels in HT-29 and Caco-2 cell lines, respectively, while UNC5B decreased (p < 0.01) in HT-29. The treatment with NTN-1 increased (p < 0.05) NEO1 mRNA levels in HT-29 cells and DCC (p < 0.05) in both cell lines. Finally, we revealed a potent migratory effect of ACM and NTN-1 on Caco-2 cells. Collectively, these findings point to increased NTN-1 during OB and CC fuelling cancer progression and exerting a strong migratory effect on colon cancer cells.

Syndecan-4 over-expression preserves cardiac function in a rat model of myocardial infarction.

Syndecan-4 (synd4) is a heparan sulfate proteoglycan, involved in repair following tissue damage, through modulating neovascularization and inflammation. In acute myocardial infarction its myocardial expression is up-regulated in a time-dependent manner, and in synd4-deficient mice severe cardiac dysfunction and abnormal remodeling are observed following induction of myocardial infarction. Here we explored the therapeutic potential of sustained synd4 over-expression in the context of myocardial infarction. Adenovirus containing the synd4 gene (Ad-synd4), or corresponding control adenovirus (Ad-null), was administered intramyocardially in rats immediately after induction of myocardial infarction. Cardiac function was ascertained by echocardiography, hemodynamic assessment and brain natriuretic peptide level 28 days post-intervention. Hearts were excised for molecular and histological analyses at predetermined time points. We observed reduced mortality and improved cardiac function post-myocardial infarction in the Ad-synd4 as compared to the Ad-null group, with associated attenuation of cardiac remodeling, less myocyte loss and reduced fibrosis. Additionally, the Ad-synd4 group exhibited endothelial cell activation and increased angiogenesis and arteriogenesis in the myocardium. The Ad-synd4 group also showed evidence of reduced myocardial inflammation as compared with the Ad-null group, with reduced inflammatory cell (CD45+) and myofibroblast (α-SMA+) infiltration as well as suppressed collagen III deposition and iNOS expression. Our results suggest that sustained synd4 over-expression in the myocardium is of therapeutic benefit following experimental myocardial infarction, through inducing neovascularization, suppressing tissue inflammation and fibrosis, with resultant improvements in cardiac function and remodeling.

Role of platelet function testing in acute coronary syndromes: a meta-analysis.

OBJECTIVE: This meta-analysis aimed to evaluate whether using platelet function testing (PFT) in acute coronary syndromes (ACS) to personalise antiplatelet therapy including a P2Y12 antagonist offers any clinical benefits to indicate incorporation into routine practice. METHODS: A search was conducted on five databases for randomised controlled trials (RCTs) conducted between 1 January 2000 and 17 July 2022, which included an ADP-specific platelet function assays and P2Y12 antagonists as part of dual antiplatelet therapy (DAPT) and have reported the efficacy and/or safety outcomes. The reported event frequencies were used to calculate the risk ratios (RRs) with a 95% CI. The χ2 heterogeneity statistical test and sensitivity analysis were used for heterogeneity assessment. RESULTS: Five RCTs with 7691 patients were included in the analysis. No significant risk reduction was seen in major adverse cardiovascular events (RR=0.95, p=0.42), individual cardiac events (cardiovascular death: RR=0.76, p=0.26; myocardial infarction: RR=0.96, p=0.74; stent thrombosis: RR=0.92, p=0.83; stroke: RR=0.91, p=0.72; target vessel revascularisation: RR=1.06, p=0.47) and overall clinical outcome (RR=0.90, p=0.22). There was also no difference in the rate of bleeding between PFT-guided and standard therapies (major bleeding: RR=0.97, p=0.78, minor bleeding: RR=0.89, p=0.19 and any bleeding: RR=1.04, p=0.33). CONCLUSION: Compared with standard DAPT with P2Y12 antagonists, using PFT to adjust antiplatelet therapy does not improve clinical outcomes. Therefore, the positions of key guidelines on routine testing in ACS should remain unchanged. In addition, the study highlights the need for well-designed and powered RCTs and standardised testing methodologies to provide reliable findings and definitive conclusions.

Activation of endothelial nitric oxide synthase is dependent on its interaction with globular actin in human umbilical vein endothelial cells.

Endothelial nitric oxide synthase (eNOS) has been reported to associate with globular actin, and this association increases eNOS activity. Adenosine, histamine, salbutamol and thrombin cause activation of eNOS through widely different mechanisms. Whether these eNOS agonists can regulate eNOS activity through affecting its association with actin is unknown. As previously reported, we confirmed in cultured human umbilical vein endothelial cells (HUVEC) that histamine and thrombin increased intracellular Ca(2+) whereas adenosine and salbutamol did not, and that these four agonists caused different effects on actin filament structure. Nevertheless, despite their divergent effects on intracellular Ca(2+) and on actin filament structure, we found by immunoprecipitation that adenosine, histamine, salbutamol and thrombin all caused an increase in association between eNOS and globular actin. This increase of association was inhibited by pre-treatment with phalloidin, an actin filament stabilizer. All of these agonists also increased phosphorylation of eNOS on serine residue 1177, eNOS activity, and cyclic guanosine-3', 5'-monophosphate, and these increases were all attenuated by phalloidin. Agonist-induced phosphorylation of eNOS on serine 1177 was attenuated by Akt inhibition, whereas association of eNOS with actin was not. We also found, in HEK-293 cells transfected with the eNOS mutants eNOS-S1177A or eNOS-S1177D, that the association between eNOS and globular actin was decreased as compared to cells transfected with wild-type eNOS. We conclude that association of globular actin with eNOS plays an essential and necessary role in agonist-induced eNOS activation, through enabling its phosphorylation by Akt at serine residue 1177.

S-nitrosophytochelatins: investigation of the bioactivity of an oligopeptide nitric oxide delivery system.

This study investigates the in vitro bioactivity of S-nitrosophytochelatins (SNOPCs), oligopeptide analogues of S-nitrosoglutathione (GSNO), and their mechanisms of nitric oxide (NO) delivery. SNOPCs were more potent than GSNO in inhibiting platelet aggregation and stimulating vasorelaxation. Their potency was related to the number of S-nitrosated moieties per mole compound. Transnitrosation reactions with cell membrane surface components were shown to be the primary mode of NO delivery to intracellular targets for SNOPCs, while delivery via γ-glutamyl transpeptidase was unique to GSNO. Due to rapid NO release, larger SNOPCs elicited a more transitory effect compared to smaller compounds. The duration of effect was influenced by compound molecular weight, NO release kinetics, ability to undergo transnitrosation, and incubation time with tissues. In summary, a new oligopeptide NO delivery system based on SNOPCs was shown to be biologically active and can be used to investigate the mechanisms of NO delivery to intracellular targets.

Current concepts of platelet activation: possibilities for therapeutic modulation of heterotypic vs. homotypic aggregation.

Thrombogenic and inflammatory activity are two distinct aspects of platelet biology, which are sustained by the ability of activated platelets to interact with each other (homotypic aggregation) and to adhere to circulating leucocytes (heterotypic aggregation). These two events are regulated by distinct biomolecular mechanisms that are selectively activated in different pathophysiological settings. They can occur simultaneously, for example, as part of a pro-thrombotic/pro-inflammatory response induced by vascular damage, or independently, as in certain clinical conditions in which abnormal heterotypic aggregation has been observed in the absence of intravascular thrombosis. Current antiplatelet drugs have been developed to target specific molecular signalling pathways mainly implicated in thrombus formation, and their ever increasing clinical use has resulted in clear benefits in the treatment and prevention of arterial thrombotic events. However, the efficacy of currently available antiplatelet drugs remains suboptimal, most likely because their therapeutic action is limited to only few of the signalling pathways involved in platelet homotypic aggregation. In this context, modulation of heterotypic aggregation, which is believed to contribute importantly to acute thrombotic events, as well to the pathophysiology of atherosclerosis itself, may offer benefits over and above the classical antiplatelet approach. This review will focus on the distinct biomolecular pathways that, following platelet activation, underlie homotypic and heterotypic aggregation, aiming potentially to identify novel therapeutic targets.