Target For Antithrombotic Drugs Research Articles

Molecular Docking of Ferulic Acid Derivatives on P2Y12 Receptor and their ADMET Prediction

P2Y12 is a platelet receptor that is involved in ADP signal transduction and is an attractive target for antithrombotic drugs. The side effects of antithrombotic drugs are not pleasant for the patient, so research into the development of new antithrombotic agents is still necessary. Evaluation of absorption, distribution, metabolism, elimination, and the toxicity profile of candidate drugs is an important step in drug development. The aim of this study was to predict the potency of ferulic acid (FA) and its derivatives (FA1-24) as antiplatelet drugs by a docking study on the P2Y12 receptor (PDB ID: 4PXZ) and their ADMET performance. The docking study was performed using Molegro Virtual Docker, version 5.5. ADMET prediction of FA was conducted using the pkCSM online tool. The results of the in silico study showed that FA-19 had the lowest MolDock score (MDS), which means that this compound is predicted to have the greatest activity. FA-19 is also predicted to be practically non-toxic. It is expected that FA-19 will have good intestinal absorption and is similarly distributed in the intestine and in the blood plasma. Its penetration in the blood-brain barrier is moderate but does not inhibit the CYP2D6 and CYP3A4 enzymes.

A function-blocking PAR4 antibody is markedly antithrombotic in the face of a hyperreactive PAR4 variant

AbstractThrombin activates human platelets via 2 protease-activated receptors (PARs), PAR1 and PAR4, both of which are antithrombotic drug targets: a PAR1 inhibitor is approved for clinical use, and a PAR4 inhibitor is in trial. However, a common sequence variant in human PAR4 (rs773902, encoding Thr120 in place of Ala120) renders the receptor more sensitive to agonists and less sensitive to antagonists. Here, we develop the first human monoclonal function-blocking antibody to human PAR4 and show it provides equivalent efficacy against the Ala120 and Thr120 PAR4 variants. This candidate was generated from a panel of anti-PAR4 antibodies, was found to bind PAR4 with affinity (KD ≈ 0.4 nM) and selectivity (no detectable binding to any of PAR1, PAR2, or PAR3), and is capable of near-complete inhibition of thrombin cleavage of either the Ala120 or Thr120 PAR4 variant. Platelets from individuals expressing the Thr120 PAR4 variant exhibit increased thrombin-induced aggregation and phosphatidylserine exposure vs those with the Ala120 PAR4 variant, yet the PAR4 antibody inhibited these responses equivalently (50% inhibitory concentration, 4.3 vs 3.2 µg/mL against Ala120 and Thr120, respectively). Further, the antibody significantly impairs platelet procoagulant activity in an ex vivo thrombosis assay, with equivalent inhibition of fibrin formation and overall thrombus size in blood from individuals expressing the Ala120 or Thr120 PAR4 variant. These findings reveal antibody-mediated inhibition of PAR4 cleavage and activation provides robust antithrombotic activity independent of the rs773902 PAR4 sequence variant and provides rationale for such an approach for antithrombotic therapy targeting this receptor.

Mechanisms of Hirudo in promoting blood circulation and removing stasis based on network pharmacology

The study aims to analyze the mechanisms of Hirudo in promoting blood circulation and removing blood stasis based on network pharmacology. A database of chemical components of Hirudo was established through literature retrieval. The targets were predicted by using the reverse pharmacophore matching method and screened according to the antithrombotic and anticoagulant drug targets approved by FDA in the DrugBank database. Then, the targets were analyzed by KEGG pathway analysis, the protein interactions were analyzed by using BioGrid database, and the active constituents-target-pathway network model of Hirudo was established to study the mechanisms of Hirudo in promoting blood circulation and removing blood stasis. This study collected 49 chemical components of Hirudo, including amino acid, polypeptide, fatty acid ester, alkaloid, glycosides, and steroid. Totally 376 targets were predicted, and 5 critical targets related to the effects of Hirudo in promoting blood circulation and removing blood stasis were screened, including fibrinogen gamma chain, plasminogen, prothrombin, Urokinase-type plasminogen activator and coagulation factor X. The potential regulatory pathways included complement and coagulation cascades, platelet activation, VEGF signaling pathway, focal adhesion. This study reflects the multi-component, multi-target and multi-pathway features of Hirudo, and provides a scientific basis for elucidating the mechanisms of action of Hirudo in promoting blood circulation and removing blood stasis, as well as a reference for the study of mechanisms of traditional Chinese medicine.

Poly-P as Modulator of Hemostasis, Thrombosis, and Inflammation

Polyphosphate (polyP), consisting of linear polymers of inorganic phosphates, is ubiquitous in biology. PolyP metabolism has been most extensively explored in microbes, but until very recently, roles for polyP in mammalian cells have been poorly understood. In 2004, polyP was shown to be a major component of dense granules in human platelets, and to be secreted upon platelet activation.1 In 2006, we demonstrated that polyP is a potent modulator of the blood clotting system.2 Subsequent work from our lab and others has shown that polyP accelerates blood clotting and slows fibrinolysis, in a manner that is highly dependent on polymer length.3 Long-chain polyP (present in infectious microorganisms) potently triggers the contact pathway and may participate in innate immunity/host responses to pathogens. PolyP of the size secreted by platelets (60 to 100 phosphates long) accelerates factor V activation, abrogates the anticoagulant activity of tissue factor pathway inhibitor, enhances fibrin clot structure, and greatly accelerates factor XI activation by thrombin. PolyP also enhances the proinflammatory activity of histones and inhibits complement. PolyP is a potential antithrombotic drug target, with a novel mechanism of action and possibly fewer bleeding side-effects compared to conventional anticoagulant drugs.4 1. Ruiz FA, Lea CR, Oldfield E, Docampo R. Human platelet dense granules contain polyphosphate and are similar to acidocalcisomes of bacteria and unicellular eukaryotes. J Biol Chem . 2004;279(43):44250-44257. 2. Smith SA, Mutch NJ, Baskar D, Rohloff P, Docampo R, Morrissey JH. Polyphosphate modulates blood coagulation and fibrinolysis. Proc Natl Acad Sci U S A . 2006;103(4):903-908. 3. Morrissey JH, Smith SA. Polyphosphate as modulator of hemostasis, thrombosis, and inflammation. J Thromb Haemost . 2015;13 Suppl 1:S92-97. 4. Travers RJ, Shenoi RA, Kalathottukaren MT, Kizhakkedathu JN, Morrissey JH. Nontoxic polyphosphate inhibitors reduce thrombosis while sparing hemostasis. Blood . 2014;124(22):3183-3190. Disclosures Morrissey: Novo Nordisk: Consultancy, Honoraria, Research Funding; rEVO Biologics: Consultancy, Honoraria; Paul, Weiss, Rifkind, Wharton & Garrison LLP: Consultancy; Cayuga Pharmaceuticals: Consultancy; PrevThro Pharmaceuticals: Equity Ownership; Kerafast, Inc.: Research Funding.

In silico Approach for Anti-Thrombosis Drug Discovery: P2Y1R Structure-Based TCMs Screening.

Cardiovascular diseases (CVDs), including thrombosis, which is induced by platelet aggregation, are the leading cause of mortality worldwide. The P2Y1 receptor (P2Y1R) facilitates platelet aggregation and is thus an important potential anti-thrombotic drug target. The P2Y1R protein structure contains a binding site for receptor antagonist MRS2500 within its seven-transmembrane bundle, which also provides suitable pockets for numerous other ligands to act as nucleotide antagonists of P2Y1R. The Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) comprises 499 Chinese Pharmacopoeia-registered herbs and the structure information for 29,384 ingredients. In silico docking of these compounds into the P2Y1R protein structure within the MRS2500 pocket can identify potential antithrombotic drugs from natural medicinal plants. Docking studies were performed and scored to evaluate ligand-binding affinities. In this study, a total of 8987 compounds from Traditional Chinese Medicine (TCM) were filtered by Lipinski's rule of five, and their ideal oral-intake properties were evaluated. Of these, 1656 compounds distributed in 443 herbs docked into the P2Y1R-MRS2500 structure in 16,317 poses. A total of 38 compounds were ranked with a DockScore above 70, and these may have significant potential for development into anti-thrombosis drugs. These computational results suggested that licorice (Glycyrrhiza uralensis Fisch), cimicifugae (Cimicifuga foetida L.), and ganoderma (Ganoderma lucidum Karst) and their chemical constituents, which have not previously been widely used for anti-thrombosis, may have unexpected effects on platelet aggregation. Moreover, two types of triterpene scaffolds summarized from 10 compounds were distributed in these three herbs and also docked into P2Y1R. These scaffold structures may be utilized for the development of drugs to inhibit platelet aggregation.

N-(3-hydroxymethyl-β-carboline-1-yl-ethyl- 2-yl)-l-Phe: development toward a nanoscaled antitumor drug capable of treating complicated thrombosis and inflammation.

It is well documented that the surfaces of cancer cells, activated platelets and inflammatory cells are rich in P-selectin. N-(3-hydroxymethyl-β-carboline-1-yl-ethyl-2-yl)-l-Phe (HMCEF) is a P-selectin inhibitor capable of simultaneously inhibiting thrombosis and inflammation. Based on the knowledge that P-selectin is a common target for antithrombotic, anti-inflammatory and antitumor drugs, the aim of this study article was to estimate the possibility of HMCEF as a nanoscaled antitumor drug. Images of transmission electron micro scopy, scanning electron microscopy and atomic force microscopy proved that HMCEF forms nanoparticles with a diameter of <120 nm that promote delivery in blood circulation. In vitro HMCEF intercalates into calf thymus DNA, cuts off DNA pBR22 and inhibits the proliferation of cancer cells. In vivo HMCEF dose dependently (0.2, 2 and 200 nmol/kg per day) slows tumor growth in treated S180 mice, and has a minimal effective dose of 2 nmol/kg per day. At 200 nmol/kg per day, HMCEF does not affect the liver and the kidney of the treated S180 mice, and at 20,000 nmol/kg HMCEF does not affect the liver and the kidney of the treated healthy ICR mice. HMCEF is a promising antitumor drug, which is characterized by its high safety and efficacy in the prevention of the complications of thrombosis and inflammation in patients.

Platelet Shape Changes and Cytoskeleton Dynamics as Novel Therapeutic Targets for Anti-Thrombotic Drugs.

Platelets play an essential role in hemostasis through aggregation and adhesion to vascular injury sites but their unnecessary activation can often lead to thrombotic diseases. Upon exposure to physical or biochemical stimuli, remarkable platelet shape changes precede aggregation or adhesion. Platelets shape changes facilitate the formation and adhesion of platelet aggregates, but are readily reversible in contrast to the irrevocable characteristics of aggregation and adhesion. In this dynamic phenomenon, complex molecular signaling pathways and a host of diverse cytoskeleton proteins are involved. Platelet shape change is easily primed by diverse pro-thrombotic xenobiotics and stimuli, and its inhibition can modulate thrombosis, which can ultimately contribute to the development or prevention of thrombotic diseases. In this review, we discussed the current knowledge on the mechanisms of platelet shape change and also pathological implications and therapeutic opportunities for regulating the related cytoskeleton dynamics.

Inhibition of protease‐activated receptor 4 impairs platelet procoagulant activity during thrombus formation in human blood

Essentials The platelet thrombin receptor, PAR4, is an emerging anti-thrombotic drug target. We examined the anti-platelet & anti-thrombotic effects of PAR4 inhibition in human blood. PAR4 inhibition impaired platelet procoagulant activity in isolated cells and during thrombosis. Our study shows PAR4 is required for platelet procoagulant function & thrombosis in human blood. Background Thrombin-induced platelet activation is important for arterial thrombosis. Thrombin activates human platelets predominantly via protease-activated receptor (PAR)1 and PAR4. PAR1 has higher affinity for thrombin, and the first PAR1 antagonist, vorapaxar, was recently approved for use as an antiplatelet agent. However, vorapaxar is contraindicated in a significant number of patients, owing to adverse bleeding events. Consequently, there is renewed interest in the role of platelet PAR4 in the setting of thrombus formation. Objectives To determine the specific antiplatelet effects of inhibiting PAR4 function during thrombus formation in human whole blood. Methods and Results We developed a rabbit polyclonal antibody against the thrombin cleavage site of PAR4, and showed it to be a highly specific inhibitor of PAR4-mediated platelet function. This function-blocking anti-PAR4 antibody was used to probe for PAR4-dependent platelet functions in human isolated platelets in the absence and presence of concomitant PAR1 inhibition. The anti-PAR4 antibody alone was sufficient to abolish the sustained elevation of cytosolic calcium level and consequent phosphatidylserine exposure induced by thrombin, but did not significantly inhibit integrin αII b β3 activation, α-granule secretion, or aggregation. In accord with these in vitro experiments on isolated platelets, selective inhibition of PAR4, but not of PAR1, impaired thrombin activity (fluorescence resonance energy transfer-based thrombin sensor) and fibrin formation (anti-fibrin antibody) in an ex vivo whole blood flow thrombosis assay. Conclusions These findings demonstrate that PAR4 is required for platelet procoagulant function during thrombus formation in human blood, and suggest PAR4 inhibition as a potential target for the prevention of arterial thrombosis.

Platelet–vessel wall interactions and drug effects

Abstract Platelet–vessel wall interaction is necessary for hemostasis and vascular repair, but also plays a fundamental role in the early and late development of atherosclerosis and atherothrombotic vascular events. A plethora of adhesion molecules, biological mediators and receptors are engaged in the regulation of platelet function in hemostasis and thrombosis. Currently available antiplatelet drugs act on targets that are critical for both, physiological hemostasis and pathological intravascular thrombosis. Consequently, their major disadvantage is bleeding complications, especially when different antiplatelet drugs are combined or applied together with anticoagulants, such as in antithrombotic therapy of acute coronary syndromes. Aspirin, clopidogrel and GPIIb/IIIa antagonists are commonly used inhibitors of platelet aggregation or secretion. In addition, they modify platelet interactions with the vessel wall, which may contribute to or modulate their antithrombotic action. Some commonly used drugs without primary antiplatelet effects, such as heparins or statins, also appear to modify platelet interaction with the vessel wall. Present research on antithrombotic drug targets aims to identify new pharmacological concepts which more specifically address the pathophysiological mechanisms leading to intravascular thrombosis, thus intending to reduce interference with hemostasis. This review article summarizes the biological and pathological mechanisms involved in thrombogenic platelet–vessel wall interaction, describes the current knowledge on the clinically available drugs in this field and gives an outlook on emerging concepts and innovative pharmacological compounds, which may improve efficacy and safety of antiplatelet therapy in the future.

The Molecular Mechanism of P2Y1 Receptor Activation

AbstractHuman purinergic G protein‐coupled receptor P2Y1 (P2Y1R) is activated by adenosine 5′‐diphosphate (ADP) to induce platelet activation and thereby serves as an important antithrombotic drug target. Crystal structures of P2Y1R revealed that one ligand (MRS2500) binds to the extracellular vestibule of this GPCR, whereas another (BPTU) occupies the surface between transmembrane (TM) helices TM2 and TM3. We introduced a total of 20 μs all‐atom long‐timescale molecular dynamic (MD) simulations to inquire why two molecules in completely different locations both serve as antagonists while ADP activates the receptor. Our results indicate that BPTU acts as an antagonist by stabilizing extracellular helix bundles leading to an increase of the lipid order, whereas MRS2500 blocks signaling by occupying the ligand binding site. Both antagonists stabilize an ionic lock within the receptor. However, binding of ADP breaks this ionic lock, forming a continuous water channel that leads to P2Y1R activation.

The Molecular Mechanism of P2Y1 Receptor Activation.

Human purinergic G protein‐coupled receptor P2Y1 (P2Y1R) is activated by adenosine 5′‐diphosphate (ADP) to induce platelet activation and thereby serves as an important antithrombotic drug target. Crystal structures of P2Y1R revealed that one ligand (MRS2500) binds to the extracellular vestibule of this GPCR, whereas another (BPTU) occupies the surface between transmembrane (TM) helices TM2 and TM3. We introduced a total of 20 μs all‐atom long‐timescale molecular dynamic (MD) simulations to inquire why two molecules in completely different locations both serve as antagonists while ADP activates the receptor. Our results indicate that BPTU acts as an antagonist by stabilizing extracellular helix bundles leading to an increase of the lipid order, whereas MRS2500 blocks signaling by occupying the ligand binding site. Both antagonists stabilize an ionic lock within the receptor. However, binding of ADP breaks this ionic lock, forming a continuous water channel that leads to P2Y1R activation.

A Novel Prioritization Method in Identifying Recurrent Venous Thromboembolism-Related Genes.

Identifying the genes involved in venous thromboembolism (VTE) recurrence is important not only for understanding the pathogenesis but also for discovering the therapeutic targets. We proposed a novel prioritization method called Function-Interaction-Pearson (FIP) by creating gene-disease similarity scores to prioritize candidate genes underling VTE. The scores were calculated by integrating and optimizing three types of resources including gene expression, gene ontology and protein-protein interaction. As a result, 124 out of top 200 prioritized candidate genes had been confirmed in literature, among which there were 34 antithrombotic drug targets. Compared with two well-known gene prioritization tools Endeavour and ToppNet, FIP was shown to have better performance. The approach provides a valuable alternative for drug targets discovery and disease therapy.

Reversing Antisense Oligonucleotide Activity with a Sense Oligonucleotide Antidote: Proof of Concept Targeting Prothrombin.

The tissue half-life of second-generation antisense oligonucleotide drugs (ASOs) is generally longer than traditional small molecule therapeutics. Thus, a strategy to reverse the activity of antisense drugs is warranted in certain settings. In this study, we describe a strategy employing the administration of a complementary sense oligonucleotide antidote (SOA). As a model system we have chosen to target the coagulation factor and antithrombotic drug target, prothrombin, to assess the feasibility of this approach. ASO targeting mouse prothrombin specifically suppressed >90% hepatic prothrombin mRNA levels and circulating prothrombin protein in mice. These effects were dose- and time-dependent, and as expected produced predictable increases in anticoagulation activity [prothrombin time/activated partial thromboplastin time (PT/aPTT)]. Treatment with prothrombin SOAs resulted in a dose-dependent reversal of ASO activity, as measured by a return in prothrombin mRNA levels and thrombin activity, and normalization of aPTT and PT. The antithrombotic activity of prothrombin ASOs was demonstrated in a FeCl3-induced thrombosis mouse model, and as predicted for this target, the doses required for antithrombotic activity were also associated with increased bleeding. Treatment with SOA was able to prevent prothrombin ASO-induced bleeding in a dose-dependent manner. These studies demonstrate for the first time the utility of SOAs to selectively and specifically reverse the intracellular effects of an antisense therapy.

Two disparate ligand-binding sites in the human P2Y1 receptor.

In response to adenosine 5'-diphosphate, the P2Y1 receptor (P2Y1R) facilitates platelet aggregation, and thus serves as an important antithrombotic drug target. Here we report the crystal structures of the human P2Y1R in complex with a nucleotide antagonist MRS2500 at 2.7 Å resolution, and with a non-nucleotide antagonist BPTU at 2.2 Å resolution. The structures reveal two distinct ligand-binding sites, providing atomic details of P2Y1R's unique ligand-binding modes. MRS2500 recognizes a binding site within the seven transmembrane bundle of P2Y1R, which is different in shape and location from the nucleotide binding site in the previously determined structure of P2Y12R, representative of another P2YR subfamily. BPTU binds to an allosteric pocket on the external receptor interface with the lipid bilayer, making it the first structurally characterized selective G-protein-coupled receptor (GPCR) ligand located entirely outside of the helical bundle. These high-resolution insights into P2Y1R should enable discovery of new orthosteric and allosteric antithrombotic drugs with reduced adverse effects.

Platelets and Arterial Thrombosis: Evolving Role of Platelet Gpvi as an Antithrombotic Drug Target

Acute coronary syndrome is one of the leading causes of mortality and morbidity worldwide. Although the recent advancements in existing anti-platelet therapeutics have significantly reduced the burden of cardiovascular deaths but owing to their global impact on primary haemostasis, their clinical benefits are often limited by bleeding risk. Recent developments in the understanding of platelet biology have placed platelet-collagen interaction at the critical position in the sequence of events during arterial thrombosis. Thus there is considerable interest in developing novel therapeutic strategies against platelet collagen receptor glycoprotein VI (GPVI) because not only its selective blockade or deficiency holds promise for the reduced risk of bleeding complications as evidenced in mice and humans, but also the exclusive expression of GPVI on platelets and megakaryocytes offers to prevent the adverse off-target effects of antithrombotic drugs. The present review summarizes recent developments in understanding of platelet functions during arterial thrombosis and structural and functional attributes of platelet GPVI to identify it as a novel antithrombotic drug target. Moreover, it also emphasises on the development of GPVI antagonists using various experimental approaches as well as their prospective use in cardiovascular disorders.

The P2Y receptors and thrombosis

Blood platelets play a key role in arterial thrombosis which is one of the leading causes of mortality in western countries. They may also be involved in the pathogenesis of deep vein thrombosis. Adenosine 5′‐diphosphate (ADP) is one of the most important mediators of platelet activation. Two G protein‐coupled ADP receptors, P2Y1 and P2Y12, selectively contribute to platelet aggregation and formation of a thrombus. Playing a central role in platelet activation and in growth and stabilization of a thrombus, the P2Y12 receptor is an established target of antithrombotic drugs like the thienopyridines clopidogrel or prasugrel, or direct reversible antagonists such as ticagrelor or cangrelor. Each of these drugs has proven efficacy in large clinical trials. At a preclinical stage, studies in P2Y1 deficient mice and using selective P2Y1 antagonists in experimental models of thrombosis and inflammation have shown that this receptor is also an attractive target for new antithrombotic compounds. WIREs Membr Transp Signal 2013. doi: 10.1002/wmts.97Conflict of interest: The authors have declared no conflicts of interest for this article.For further resources related to this article, please visit the WIREs website.

Circulation : Clinical Summaries

<i>Circulation</i> : Clinical Summaries

2-Aminothiazole based P2Y1 antagonists as novel antiplatelet agents

ADP receptors, P2Y1 and P2Y12 have been recognized as potential targets for antithrombotic drugs. A series of P2Y1 antagonists that contain 2-aminothiazoles as urea surrogates were discovered. Extensive SAR of the thiazole ring is described. The most potent compound 7j showed good P2Y1 binding (Ki=12nM), moderate antagonism of platelet aggregation (PA IC50=5.2μM) and acceptable PK in rats.

At the center of the circle: purinergic signaling in the autocrine loops of pancreatic islets

AbstractThe endocrine pancreas is essential for monitoring and regulating the metabolic status of the body by sensing changes in glucose and free fatty acids and respond by secreting hormones such as insulin and glucagon. Although pancreatic islets only make up a small percentage of the pancreas mass, its malfunction causes severe disease. Despite insulin treatment, and the development of novel antidiabetic drugs, diabetes is still one of the most costly and invaliding diseases, leaving an open arena for drug target discovery within the endocrine pancreas. Purinergic receptors are a class of receptors, which has already been utilized as a successful antithrombotic drug target used in secondary prevention after myocardial infarction. The versatility and broad expression of these receptors make them interesting for pharmacological manipulation in treatment of disease. Purinergic receptors include four G‐protein coupled adenosine receptors (A1, A2A, A2B, and A3), eight G‐protein coupled nucleotide (ATP, ADP, UTP, UDP, UDP‐glucose) gated receptors (P2Y1, P2Y2, P2Y4, P2Y6, P2Y11, P2Y12, P2Y13, and P2Y14), and finally seven ATP‐gated ion channels (P2X1‐7). Ectonucleotidases degrade nucleotides to their di‐ and mono derivatives, which in turn can stimulate their favored P2 receptor. Adenosine monophosphate (AMP) is finally hydrolyzed to adenosine, which in turn can act on adenosine receptors. Each P2Y receptor couples to different G‐proteins leading to different intracellular pathways downstream of stimulation. WIREs Membr Transp Signal 2013, 2:107–119. doi: 10.1002/wmts.82For further resources related to this article, please visit the WIREs website.The authors have declared no conflicts of interest for this article.

Glycoprotéines, maladies héréditaires des plaquettes, rôle des plaquettes dans la réparation tissulaire

Recognition that platelets have a glycocalyx rich in membrane glycoproteins prompted the discovery in France that inherited bleeding syndromes due to defects of platelet adhesion and aggregation were caused by deficiencies in major receptors at the platelet surface. Identification of the alpha IIb beta3 integrin prompted the development of powerful anti-thrombotic drugs that have gained worldwide use. Since these discoveries, the genetic causes of many other defects of platelet function and production have been elucidated, with the identification of an ADP receptor, P2 Y12, another widespread target for anti-thrombotic drugs. Discovery of the molecular basis of a rare disease of storage of biologically active proteins in platelet alpha-granules has been accompanied by the recognition of the roles of platelets in inflammation, the innate immune system and tissue repair, opening new avenues for therapeutic advances.