Overview of Aspirin and Platelet Biology

Aspirin (ASA) has historically been one of the most important drugs in cardiology and long cornerstone antiplatelet therapy. Although its role acute coronary syndrome remains undisputed, emerging data suggest that reappraisal efficacy long-term ASA some primary secondary prevention may be warranted. The aim this review is to place these new results context previous evidence on aspirin by appraising current body use for cardiovascular diseases. This overview first summarizes history discovery aspirin, as well pharmacology concept resistance. We subsequently recapitulate starting from classical studies order serve an introductory background examination recent clinical trials will performed rest articles Supplement. benefit incontrovertible, challenge universal need prevention, or lifelong treatment all adults with stable disease who are at highest risk ASA-induced bleeding. quickly changing times provides a clinician about drug care. According Ebers papyrus, salicylates extracted willow cortex can traced ancient Egyptians. papyrus considered comprehensive medical ever recovered it dates back 1534 BC. It covers more than 700 herbal remedies, but plant species mentioned tjeret salix, known today willows, which used general-purpose tonic anti-inflammatory and/or pain reliever nonspecific aches pains.1Jeffreys D. Aspirin: Remarkable Story Wonder Drug. Bloomsbury, New York, NY2004Google Scholar Hippocrates referred salicylic tea reduce fevers around 400 application “modern” medicine was recorded 1758 when Reverend Edward Stone administered ground-up dried bark English tree patients “agues” (malaria) noticed clear improvement symptoms.2Fuster V Sweeny J. A Historical contemporary therapeutic overview.Circulation. 2011; 123: 768-778Crossref PubMed Scopus (156) Google In 1828, Joseph Buchner Munich University refined into yellow crystals labeled salicin2Fuster (after Latin willow). side effects (e.g., gastric irritation) limited usefulness, salicin tested time “clinical trial” 1876; John Maclagan, Dundee Royal Infirmary, published Lancet administration rheumatism resulted remission fever joint inflammation.3Maclagan TJ. salicin.LAncet. 4: 342-343Abstract (63) 1863, Bayer company created obtain chemical dyes 1890, Carl Duisberg pharmaceutical group within Bayer, led chemist Arthur Eichengrun. 1894, young named Felix Hoffman joined group. 1897, Hoffmann started working find less irritating substitute acid; generally accepted he pursued idea because his father suffering taking sodium salicylate rheumatism. On August 10, 1897 (according laboratory notebooks), managed acetylate phenol refluxing acid acetic anhydride obtained acetylsalicylic purest form.1Jeffreys Acetylsalicylic found very effective reducing pain, inflammation, fever, produced no unpleasant effects. 1899, compound registered under “Aspirin” name: “A-” “acetylation”, “-spir-” “spirsaure” (Spirea umaria meadowplant, also obtained, German namesake acid), “-in” typical name ending. Currently widely medications globally, estimated 44,000 tons (50-120 billion pills) consumed each year, WHO's List Essential Medicines.4https://www.who.int/medicines/publications/essentialmedicines/en/. In: Accessed 11/3/2020.Google commonly available immediate-release enteric-coated formulations.5Patrono C Garcia Rodriguez LA Landolfi R Baigent Low-dose atherothrombosis.N Engl J Med. 2005; 353: 2373-2383Crossref (982) Scholar, 6Capodanno D Ingala S Calderone Angiolillo DJ. disease: latest evidence.Expert Rev Cardiovasc Ther. 2019; 17: 633-643Crossref (15) After oral intake, rapidly completely absorbed acidic conditions stomach upper small intestine through passive diffusion mechanism, typically quick (15 20 min) concentration peak, though pH presence food limit absorption rate.6Capodanno form gastrointestinal mucosa, lower bioavailability slower peak (3 4 h) increased intestine.7Patrono C. Role disease.Nat Cardiol. 16: 675-686Crossref (51) Around 60% 80% blood bound albumin. volume distribution 0.1 0.2 L/kg. Acidosis increases penetration tissues.5Patrono 7Patrono Given much doses metabolized (de-activated) liver, acts targets portal circulation, where platelets exposed higher level compared systemic circulation. half-life only 15 min, irreversibly inhibits cyclooxygenase (COX), so pharmacodynamic persist lifespan platelet (7 10 days). Therefore, production way overcome effect,8Capodanno beyond diabetes mellitus.Circulation. 2016; 134: 1579-1594Crossref (69) inhibitory marrow megakaryocytes have proposed.6Capodanno Salicylates excreted mainly kidneys salicyluric (75%). Renal excretion extremely sensitive changes urinary pH; 10-fold increase renal clearance occurs urine 5 8, hence alkalinization improve elimination overdose.7Patrono blocking (COX) activity prostaglandin H synthases 1 2, -1 -2, respectively. effect achieved acetylating serine residue (serine 529 COX-1 516 COX-2) substrate pocket COX, prevents arachidonic reaching COX catalytic site enzyme.2Fuster 5Patrono ScholarThis causes upstream block prostanoid biosynthesis and, ultimately, inhibition thromboxane A2 (TXA2) prostacyclin (PGI2) generation. Mature express produce TXA2 response variety stimuli. Vascular endothelial cells, both COX-2, represent main PGI2 selectively activity, whereas inhibit COX-2.7Patrono As result interaction, blunted lifetime (approximately days) must generated de novo re-establish COX1 activity. mechanism action specifically discovered Vane, shared Nobel Prize Medicine 1982 Sune Bengström Bengt Samuelsson (for their work prostaglandins TXA2). These molecules underlie two opposed biological pathway related activation aggregation. other side, anti-atherogenic vascular thrombo-resistance, exerts crucial protecting mucosa PGI2. Prostaglandins key epithelial mucus production, microvascular mucosal perfusion, wound healing tract. Inhibition latter, addition physical disruption protective phospholipid barrier thereby allowing direct injury, explains why bleeding perforation promoting lesions worsening existing factor analgesic doses).5Patrono Because low-dose measurable COX-2- PGI2-mediated functions, does not pressure, impair function, interfere antihypertensive diuretics angiotensin converting enzyme (ACE) inhibitors. Use proton pump inhibitors reduces Importantly, single low dose (75-100 mg) exceeds minimum required addresses interindividual variability response.8Capodanno additional mechanism(s) discovered. described proliferation smooth muscle cells,9Redondo Santos-Gallego CG Ganado P M Rico L Del Rio et al.Acetylsalicylic cell involving transforming growth factor-beta.Circulation. 2003; 107: 626-629Crossref (49) thus mitigating earlier phases atherogenesis. mediated via TGF-β antiproliferative actions abrogated antibodies against TGF-β.9Redondo findings confirmed itself release (such pioglitazone) proliferation.10Redondo Tejerina T. TGF-beta1: novel target pharmacology.Cytokine Growth Factor Rev. 2007; 18: 279-286Crossref (36) 11Redondo Ruiz E Padilla Pioglitazone induces apoptosis peroxisome proliferator-activated receptor-gamma, factor-beta1, Smad2-dependent mechanism.Diabetes. 54: 811-817Crossref Concomitant reversible nonsteroidal [NSAIDs] such ibuprofen naproxen) exert competitive irreversible acetylation ASA12Catella-Lawson F Reilly MP Kapoor SC Cucchiara AJ DeMarco Tournier B al.Cyclooxygenase aspirin.N 2001; 345: 1809-1817Crossref (1264) decrease aspirin. Furthermore, non-selective NSAIDS thrombotic events coadministered ASA.13Schjerning Olsen AM Gislason GH McGettigan Fosbøl Køber Torp-Pedersen Association NSAID receiving antithrombotic therapy after myocardial infarction.JAMA. 2015; 313: 805-814Crossref (100) interaction selective COX-2 (‘coxibs’), nonetheless complications.14Santos-Gallego Badimon Is price relief?: free lunch.J Am Coll 2020; 76: 530-532Crossref (1) resistance quite rare phenomenon defined failure fully inactivate COX-1.12Catella-Lawson 15Grosser T Fries LAwson JA Grant GR FitzGerald GA. Drug pseudoresistance: unintended consequence enteric coating aspirin.Circulation. 2013; 127: 377-385Crossref (141) Both pharmacological pharmacokinetic mechanisms involved responsiveness agents, include bioavailability, medication noncompliance, drug–drug interactions, cytochrome P450 genetic polymorphisms. stated before, tests do measure probably reason ambiguity topic.15Grosser egregious example16Santilli Rocca De Cristofaro Lattanzio Pietrangelo Davi G al.Platelet reflected consistently function assays: implications "resistance".J 2009; 53: 667-677Crossref (218) shows (as serum TXB2 levels) uniformly persistently suppressed (99%) healthy subjects; however, 11-dehydro-TXB2, acid-induced aggregation, VerifyNow® show stable, incomplete (65%, 80%, 35%), sensitive, functional assays leads misclassification "responder" "resistant" phenotypes. When COX-1-specific used, rarely observed almost always due interactions naproxen, ibuprofen), impaired formulation,5Patrono 8Capodanno termed “pseudoresistance”. Another causing pseudoresistance turnover, mechanisms. First, ASA, given minutes, present circulation moment. accelerated thrombopoiesis characterizes diabetic allow newly entering sufficiently potential strategy would administer twice daily,17Capodanno Patel Dharmashankar K Ferreiro JL Ueno dosing regimens type 2 mellitus artery disease.Circ Interv. 180-187Crossref (169) approach remain uncertain. Second, immature reticulated comprise youngest component circulating pool, contain cytosolic mRNA translationally active, thrombogenic platelets.18Guthikonda Lev EI DeLao Bergeron AL Dong JF al.Reticulated uninhibited aspirin.J Thromb Haemost. 5: 490-496Crossref (206) Even if able already platelet, new, fresh, unhibited active acetylated. “aspirin resistance” mature platelets,18Guthikonda elevated counts, associated adverse outcomes.19Ibrahim Schutt RC Hannawi Barker CM Kleiman NS. outcomes.J 2014; 64: 2122-2129Crossref (85) Platelets anucleated 2–5 μm disk-shaped cellular components, mean 6–10 femtoliters 6 orders magnitude eukaryotic cell).20Santos-Gallego Bayon JJ. Thrombi different pathologies: diagnosis treatment.Curr Treat Options 2010; 12: 274-291Crossref (34) circulate plasma play hemostasis maintenance, thrombosis formation, innate immunity, inflammation responses.21Davi Patrono Platelet 357: 2482-2494Crossref (1598) bone 7-10 days before they removed spleen. basic sequence aggregation three steps: initiation, extension, stabilization20Santos-Gallego 21Davi 22Santos-Gallego Picatoste Pathophysiology syndrome.Curr Atheroscler Rep. 401Crossref (189) 23Rivera Lozano ML Navarro-Nunez Vicente receptors signaling dynamics thrombus formation.Haematologica. 94: 700-711Crossref (250) (see Figure):1)Initiation stage: collagen-mediated formation subendothelial collagen becomes Platelets, glycoproteins (GP), interact collagen-deposited von Willebrand (vWF), change shape, adhere injury. attachment secretion adenosine diphosphate (ADP), serotonin, TXA2, leading recruitment activation. extant rheological largely influence adhesive interactions. At shear rate veins larger arteries), adhesion vessel wall primarily involves binding fibrilar collagen, fibronectin, laminin, while stress microvasculature stenotic tethering damaged subendothelium depends vWF. Type-I type-III collagens supporting vasculature. soluble vWF bind prevent normal immobilized onto (mainly I, III, VI) highly reactive toward flowing platelets.The GP Ib/IX/V complex major receptor mediating vWF, dysfunction Bernard Soulier (a congenital disorder). Two demonstrated surface directly VI immunoglobulin superfamily member integrin α2β1 (also Ia/IIa).2)Extension phase: Amplification characterized second wave further enhanced platelet-mediated thrombin, ADP, TXA2. marks extension phase, arriving initial monolayer.ADP stored δ-granules, secreted upon activation, binds classes purinergic receptors: P2Y1 P2Y12. P2Y12 amplify sustain ADP-mediated initiated P2Y1. Indeed, thienopyridine (ticlopidine, clopidogrel, prasugrel).Thromboxane labile synthesized activated sequential synthase enzymes. vasoconstrictor potent agonist conformational change. Once synthesized, diffuses across membrane activates recruited platelets. Overproduction implicated pathogenesis disease, including infarction unstable angina. discussed above, antiaggregant blockade synthesis inhibition. However, pathological high unclear, showing either vitro disturbed laminar flow parallel-plate perfusion chamber device,24Barstad RM Orvim U Hamers MJ Tjønnfjord GE Brosstad FR Sakariassen KS. Reduced flow.Circulation. 1996; 75: 827-832Google vivo high-degree stenosis dog animal model.25Maalej N Folts JD. Increased overcomes stenosed arteries.Circulation. 93: 1201-1205Crossref (79) ScholarThe (TP) mediates TP antagonists were investigated past agents development halted.Thrombin activator even concentrations, seems efficiently coupled PLCβ Thrombin-induced responses partially protease (PAR), namely PAR-1 PAR-4 humans (PAR-3 mice). PAR4 vorapaxar) developed antithrombotics, developments halted.3)Stabilization Following protein receptor-effector continue aggregate forming bridges between glycoproteins, fibrinogen, fibrin, glycoproteins. stabilization phase includes subsequent plug allows consolidation dispersal forces blood.The relevant during outside-in integrins, particularly αIIbβ3 (GPIIb/IIIa), fibrinogen. triggers essential stabilization, cytoskeletal reorganization, large aggregates, procoagulant surface, clot retraction helps narrow gaps local agonists. GPIIb/IIIa undergoing percutaneous interventions burden. Depending forms, platelet-rich (white clots, arteries) rich fibrin erythrocytes (red veins).20Santos-Gallego damage activate platelets, inflammation; instance, infections community-acquired pneumonia induce rates pneumonia.26Santos-Gallego sum evils: infarction: missing link?.J 1926-1928Crossref (32) Acute syndromes (ACS) caused superimposed over plaque rupture.20Santos-Gallego Based action, agent, become ACS.2Fuster Scopu