However, there are also proteins shed from platelets whose role in platelet biology, either before or after shedding, is not entirely clear. Surgical Screen: Patients administered anti-platelet therapies are at risk of increased bleeding during operations. Blood 2017; 130 (6): 713721. During the last decade, the additional use of platelet function tests to evaluate the effect of antiplatelet therapy has also emerged in an attempt to identify patients with an increased risk of arterial thrombosis. In recent years, the assessment of platelet (dys)function has become increasingly necessary in a variety of clinical settings: 1) for the identification of patients with bleeding disorders; 2) for monitoring the response to antiplatelet treatment; 3) in the evaluation of perioperative hemostasis; and 4) in transfusion medicine. A comparison of platelet function tests and thromboxane metabolites to evaluate aspirin response in healthy individuals and patients with coronary artery disease. We report here for the first time, an alteration of platelet function attributable to this drug. wrote the paper. Although not yet clinically available, a recently described microfluidic method resolves these problems by including a chemically fixed endothelial cell lining that retains its ability to modulate hemostasis under continuous pathophysiological shear rates, even after a few days of storage.27 The platelet function analyzer (PFA)-100 method includes shear but is not recommended because it is less specific for aspirins effect.26 An additional major limitation of all methods for monitoring the antiplatelet effects of aspirin is that the results of different methods correlate poorly with each other and with the gold standard serum TXB2 method.28,29, The generally accepted aspirin dose is 75, 81, or 100 mg, depending on the available commercial formulations of the drug in different countries.17 Because 75 mg daily is at least twice as high as the lowest dose necessary and sufficient to fully inhibit platelet COX-1 activity, there are no significant differences in the antiplatelet effects of doses ranging between 75 and 100 mg.17 Randomized comparisons of higher vs lower aspirin doses in patients with ACS30 and cerebrovascular disease31,32 showed no evidence of superiority of higher vs lower doses of aspirin.17 Although aspirin 325 mg can be used as a loading dose in the setting of ACS or acute ischemic stroke, prescribing aspirin 325 mg daily for long-term treatment does not produce any additional benefit, while exposing the patient to unnecessary possible side effects: gastrointestinal damage, bleeding complications, and possibly negative interactions with ticagrelor.4,17 Nevertheless, the 2014 American Heart Association/American College of Cardiology non-ST elevation acute coronary syndromes guidelines still allow an aspirin maintenance dose range of 81 to 325 mg per day, with some degree of preference given to 81 mg daily.33 Although aspirin is usually administered daily, there is evidence that twice-daily dosing may be beneficial in patients with diabetes mellitus, obesity, essential thrombocythemia, myeloproliferative neoplasms, and coronary artery bypass surgery, possibly because of increased platelet turnover.17,34-37, Aspirin resistance is a widely used term in the medical literature38 and there are reports of associations between lack of response to aspirin-dependent tests and major adverse cardiovascular effects.39 However, if resistance is defined in pharmacological terms as the failure of aspirin intake to fully inactivate its target, platelet COX-1, as evidenced by lack of inhibition of thromboxane B2 generation, then aspirin resistance is either a very rare phenomenon40-42 or does not exist.17 Based on this pharmacologic definition, a study of 400 healthy volunteers failed to identify a single case of aspirin resistance.40 Pseudo-resistance, reflecting delayed and reduced drug absorption and therefore impairment of the pharmacodynamic effect, may complicate enteric-coated, but not immediate-release, aspirin administration.17,40,43,44 Patient nonadherence and/or drug-drug interactions between aspirin and another nonsteroidal anti-inflammatory drug (NSAID, eg, ibuprofen,45 naproxen46-48) is probably responsible for many literature reports of aspirin resistance. In fact, there is now ample evidence that there is spatial, as well as temporal, heterogeneity within a growing hemostatic plug and that the attachment of new platelets is transient unless a sufficient degree of activation of that particular platelet is achieved.79 Historically, the challenge has been to explain how fast-moving platelets can linger long enough to become activated and form stable attachments to the growing mass. Light transmission aggregometry has been the gold standard for over 60 years, with inherent challenges of working with live dynamic cells in specialized . Modified with permission from Michelson AD. The history of platelet function testing began in 1901, when a French physician, M.G. Alan D. Michelson, Deepak L. Bhatt; How I use laboratory monitoring of antiplatelet therapy. However, mucocutaneous bleeding can arise from more than just platelet defects, because it reflects the integrity of the vasculature and the presence of critical plasma proteins, as well as quantitative and qualitative platelet defects. Platelet function tests may be far less expensive than a series of magnetic resonance imaging scans, but they are neither inexpensive nor undemanding of technician time. DO NOT SEND THROUGH PNEUMATIC TUBE SYSTEM. Platelet functional defects in women with unexplained menorrhagia, Platelet cyclooxygenase inhibition by low-dose aspirin is not reflected consistently by platelet function assays: implications for aspirin resistance., Platelet reactivity after clopidogrel treatment assessed with point-of-care analysis and early drug-eluting stent thrombosis, Comparison of platelet function tests in predicting clinical outcome in patients undergoing coronary stent implantation, VerifyNow and VASP phosphorylation assays give similar results for patients receiving clopidogrel, but they do not always correlate with platelet aggregation, Multidisciplinary approach to the challenge of hemostasis, 2010 by the American Society of Hematology, Copyright 2023 by American Society of Hematology, Emerging Ideas About Platelets and Platelet Function, Evaluating Platelet Function In Vitro and In Vivo. Investigating people with mucocutaneous bleeding suggestive of primary hemostatic defects: a low likelihood of a definitive diagnosis? The first goal of platelet function testing in the clinical laboratory is, therefore, to document that an intrinsic function defect may exist and exclude VWF deficiency. In the arterial circulation, higher flow rates limit fibrin formation by washing out soluble clotting factors. 180 - 376 PRU. Collagen fibrils within the vessel wall become exposed to the circulation when the endothelial cell monolayer is breached, forming a complex with von Willebrand factor (VWF). Appropriate platelet activation limits the extent of blood loss following vascular injury and promotes subsequent wound healing without causing vascular occlusion. CABG, coronary artery bypass graft; CEA, carotid endarterectomy; KGD, Lys-Gly-Asp; PAD, peripheral artery disease; PDE, phosphodiesterase; RGD, Arg-Gly-Asp; TIA, transient ischemic attack. Frequent questions to hematologists about aspirin and clopidogrel, the 2 most commonly used antiplatelet therapies, are: Could the patient be aspirin resistant or clopidogrel resistant? In addition, several randomized trials have failed to demonstrate improvement in clinical outcomes when using platelet function tests in clinical decision-making. Thank you for submitting a comment on this article. Antiplatelet therapy: what have we learned from the ANTARCTIC trial? The present study aims to investigate the performance of two different point-of-care . Full 2.7mL tube preferred, full 1.8mL tube is acceptable. PFA is an integrative test that provides a global indicator of platelet function. 1-year cardiovascular death, MI, stroke, stent thrombosis, urgent revascularization, and BARC-defined bleeding (types 2, 3, or 5): 28% vs 28%; HR 1.0. The net result is a hemostatic plug comprised of activated platelets embedded within a cross-linked fibrin mesh, a structure stable enough to withstand the shear forces generated by flowing blood in arterial circulation. Platelet function testing in the clinical setting is usually performed in a specialized laboratory where sufficient numbers of patients can be studied on an annual basis to ensure reproducibility and correct interpretation of the results. As is frequently done in the context of deep venous thrombosis, it is worth considering how many members of a large group of patients with clinical histories suggestive of a platelet function defect will prove to have something that is well understood by present technology. You are asked by cardiology to do a hematology consult on a 65-year-old man with a history of acute myocardial infarction. Circulating platelets must be able to sustain repeated contact with the normal vessel wall without premature activation, recognize the unique features of a damaged wall, cease forward motion upon recognition of damage, adhere despite the forces produced by continued blood flow, and cohere to each other, forming a stable plug of the correct size that can remain in place until it is no longer needed. Please check for further notifications by email. Platelet function tests are mainly used in the diagnostic work-up of platelet disorders. Although a number of small studies have suggested possible benefit from guided therapy in these clinical settings and in children, it is prudent to consider that highly favorable results were reported from early small randomized controlled trials73 in patients with coronary artery disease before much larger, more definitive randomized controlled trials failed to confirm any benefit from this approach.74-76 There is a possible role for platelet function testing (1) to document patient adherence to antiplatelet therapy or to confirm suspected nonadherence in patients with ischemic events42,49 and (2) to determine the timing of cardiac surgery following withdrawal of a P2Y12 inhibitor to provide reassurance to the surgeon and allow earlier operation in patients with urgent indications but in whom the surgeon may otherwise feel obligated to wait the requisite number of days listed in the drug labeling or guidelines.80-82 Although research studies are still ongoing, there is no current clinical role for routine platelet function or genetic testing for antiplatelet resistance. Molecular targets of antiplatelet agents. ATP indicated adenosine triphosphate; PAR-1, protease-activated receptor-1; TRAP, thrombin receptor activation peptide (an agonist for platelet PAR-1); VASP, vasodilator-stimulated protein. However, as the central role of platelets implicated in the etiology of arterial thrombotic diseases such as myocardial infarction and stroke became widely known, platelet function tests are now being promoted to monitor the efficacy of antiplatelet drugs and also . Search for other works by this author on: RGS proteins have a signalling complex: interactions between RGS proteins and GPCRs, effectors, and auxiliary proteins, Activation of platelet function through G protein-coupled receptors, The final steps of integrin activation: the end game, Congenital disorders associated with platelet dysfunctions, Cell biology. Screening tests of platelet function: update on their appropriate uses for diagnostic testing, Congenital platelet disorders: overview of their mechanisms, diagnostic evaluation and treatment, Changes in the platelet membrane glycoprotein IIb.IIIa complex during platelet activation, Genetic testing in the diagnostic evaluation of inherited platelet disorders, Genotype-phenotype relationship for six common polymorphisms in genes affecting platelet function from 286 healthy subjects and 160 patients with mucocutaneous bleeding of unknown cause, Genetic polymorphisms of the platelet receptors P2Y(12), P2Y(1) and GP IIIa and response to aspirin and clopidogrel. Lumi-aggregometry in this case typically shows a secretion defect that can be overcome by raising the agonist concentration and a specific defect in platelet responses to exogenous arachidonate that can be bypassed by substituting a TxA2 analog, such as U46619. Cangrelor was found to reduce periprocedural ischemic events significantly, with no significant excess in the number of blood transfusions per patient compared with a strategy of clopidogrel loading in the catheterization laboratory after the coronary anatomy is delineated. This article reviews platelet function, molecular targets of antiplatelet agents, and clinical indications for antiplatelet therapy before focusing on a frequent question to hematologists about the 2 most commonly used antiplatelet therapies: Could the patient be aspirin resistant or clopidogrel resistant? The results have clinical, as well as therapeutic, implications. The literature does not support antiplatelet therapy for asymptomatic, incidentally discovered peripheral artery disease. Several trials are ongoing to determine if high-risk patients, such as those with diabetes mellitus, truly benefit from aspirin therapy in the contemporary era. In a study of clopidogrel-treated patients after PCI, CYP2C19*2 carriers identified at the bedside were treated with prasugrel, which reduced their on-treatment platelet reactivity.87 In a small mechanistic study, among patients with stable cardiovascular disease in the Escalating Clopidogrel by Involving a Genetic Strategy-Thrombolysis In Myocardial Infarction 56 trial, tripling the maintenance dose of clopidogrel to 225 mg daily in CYP2C19*2 heterozygotes achieved levels of platelet reactivity similar to that seen with the standard 75-mg dose in noncarriers; in contrast, for CYP2C19*2 homozygotes, doses as high as 300 mg daily did not result in comparable degrees of platelet inhibition.88 However a genome-wide association study found that the CYP2C19*2 polymorphism accounted for only 12% of the variation in platelet aggregation following clopidogrel administration,55 and clopidogrel pharmacokinetics and pharmacodynamics still vary widely in patients lacking the CYP2C19*2 polymorphism.51 Therefore, attempts to use the CYP2C19*2 polymorphism as a guide to modifying clopidogrel therapy in patients would not be expected to be of clinical benefit in most clopidogrel-treated patients with high on-treatment platelet reactivity. 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