Platelet function testing and clinical outcomes in peripheral arterial disease: Systematic review and narrative synthesis.

OBJECTIVE: This systematic review aims to comprehensively assess the contemporary literature on platelet function testing (PFT) in individuals undergoing revascularization therapy for peripheral arterial disease (PAD). The goal is to identify whether PFT can aid in detecting antiplatelet resistance, predicting post-procedural thrombotic complications, and informing tailored treatment strategies. METHODS: Following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, a literature review was conducted using PubMed databases. Search terms included relevant medical subject headings (MeSH) terms. Eligible articles published in English between 1990 and 2023 were analyzed. Studies that examined PFT outcomes in patients with PAD after lower extremity revascularization were included. RESULTS: Ten studies met the inclusion criteria. Various PFT methods were used, including thromboelastography with platelet mapping, multiplate analyzer, Cytochrome P450 2C19 testing, VerifyNow, corrected whole blood aggregometry, platelet function analyzer-100, and light transmission aggregometry. PFT identified individuals who were resistant or non-sensitive to antiplatelet therapy, with such patients facing increased risks of graft/stent thrombosis, amputation, and reintervention. However, substantial heterogeneity in surgical procedures, drug regimens, and testing methods was observed among the studies. CONCLUSIONS: PFTs can play a crucial role in detecting resistance and non-sensitivity to antiplatelet drugs in patients with PAD post-revascularization. However, heterogeneity of data and methods underlines the need for standardized protocols and consensus-building among PFTs. Enhancing clinical utility and reliability could help optimize antiplatelet thromboprophylaxis, minimize thrombotic complications, and improve treatment strategies in vascular surgery. Further research is necessary to solidify the role of PFTs in guiding antiplatelet therapy post-revascularization in patients with PAD.

Platelet function testing: Update on determinant variables and permissive windows using a platelet-count-based device.

While there are various aspects of platelet biology that can be studied in the lab (i.e. adhesion, degranulation, integrin activation), the master test for platelet function is that which gives a measure of the platelet aggregation capacity upon stimulation with an agonist. Platelet function testing is necessary for the diagnosis of platelet disorders and the monitoring of patients receiving anti-platelet treatments. Furthermore, it becomes relevant in the quality control of platelet concentrates for transfusion purposes, especially considering the global concern about long term storage, other forms of storage (i.e. cryopreservation, lyophilization), and the impact of Pathogen Reduction Treatments (PRTs) on platelet performance upon transfusion. However, it has been acknowledged as technically difficult and demanding, since a fine platelet function test must be carried out under specific conditions. Still, there might be occasions that preclude the platelet function testing abiding to the gold standard requirements, thus, leaving us with the necessity to redefine which variables may condition or limit the analysis of platelet function testing. In the present manuscript, we test different variables (such as the anticoagulant used or the time elapsed since extraction) and the possibility to reconstitute blood prior to platelet function analysis. This study aims to provide windows of action at the diagnostics lab, especially when not all of the recommended procedures and conditions can be followed: for example, when a sample is sent from a long distance, when there is a limitation on blood extraction volume or when certain parameters (platelet count) preclude reliable test results.

Role of Cyp2c19 Genotype-Guided Antiplatelet Therapy After Percutaneous Coronary Intervention.

PURPOSE OF REVIEW: Identification of a reliable discriminatory test to accurately stratify patient responses to antiplatelet therapy following coronary revascularization has become increasingly desirable to optimize therapeutic efficacy and safety. RECENT FINDINGS: The expansion of platelet function testing to include genotype assessment has been an evolutionary journey, initially fraught with confounding results. However, more recent and rigorous data analysis suggests that genotype testing- guided, tailored antiplatelet therapy may hold promise in optimizing treatment of patients after coronary intervention. Current evidence increasingly supports the use of genotype guided CYP2C19 testing to better match the post coronary intervention patient with the most efficacious and least risky antiplatelet inhibitor. The risk stratification of poor, intermediate, and good metabolizers of these drugs with such testing promises to yield clinical dividends in terms of morbidity, mortality and cost control, in this growing patient population.

Analysis of Platelet Function Testing in Children Receiving Aspirin for Antiplatelet Effects.

Aspirin (ASA) remains the most common antiplatelet agent used in children. VerifyNow Aspirin Test® (VN) assesses platelet response to ASA, with therapeutic effect defined by the manufacturer as ≤ 549 aspirin reaction units (ARU). Single-center, observational, analysis of 195 children (< 18 years-old) who underwent first VN between 2015 and 2020. Primary outcome was proportion of patients with ASA biochemical resistance (> 549 ARU). Secondary outcomes included incidence of new clinical thrombotic and bleeding events during ≤ 6 months from VN in those who received ASA monotherapy (n = 113). Median age was 1.8 years. Common indications for ASA included cardiac anomalies or dysfunction (74.8%) and ischemic stroke (22.6%). Median ASA dose before VN was 4.6 mg/kg/day. Mean VN was 471 ARU. ASA biochemical resistance was detected in 14.4% (n = 28). Of 113 patients receiving ASA monotherapy, 14 (12.4%) had a thrombotic event and 2 (1.8%) had a bleeding event. Mean VN was significantly higher at initial testing in patients experiencing thrombotic event compared to those without thrombosis (516 vs 465 ARU, [95% CI: 9.8, 92.2], p = 0.02). Multivariable analysis identified initial VN ASA result ≥ 500 ARU at initial testing as the only significant independent risk factor for thrombosis (p < 0.01). VN testing identifies ASA biochemical resistance in 14.4% of children. VN ASA ≥ 500 ARU rather than ≥ 550 ARU at initial testing was independently associated with increased odds of thrombosis. Designated cut-off of 550 ARU for detecting platelet dysfunction by ASA may need reconsideration in children.

Current Strategies to Guide the Antiplatelet Therapy in Acute Coronary Syndromes.

The role of antiplatelet therapy in patients with acute coronary syndromes is a moving target with considerable novelty in the last few years. The pathophysiological basis of the treatment depends on platelet biology and physiology, and the interplay between these aspects and clinical practice must guide the physician in determining the best therapeutic options for patients with acute coronary syndromes. In the present narrative review, we discuss the latest novelties in the antiplatelet therapy of patients with acute coronary syndromes. We start with a description of platelet biology and the role of the main platelet signal pathways involved in platelet aggregation during an acute coronary syndrome. Then, we present the latest evidence on the evaluation of platelet function, focusing on the strengths and weaknesses of each platelet's function test. We continue our review by describing the role of aspirin and P2Y12 inhibitors in the treatment of acute coronary syndromes, critically appraising the available evidence from clinical trials, and providing current international guidelines and recommendations. Finally, we describe alternative therapeutic regimens to standard dual antiplatelet therapy, in particular for patients at high bleeding risk. The aim of our review is to give a comprehensive representation of current data on antiplatelet therapy in patients with acute coronary syndromes that could be useful both for clinicians and basic science researchers to be up-to-date on this complex topic.

Clopidogrel Hyperresponsiveness and Hemorrhagic Complications Using On-Label Clopidogrel Dosing after Pipeline Embolization.

Introduction: Clopidogrel hyperresponsiveness is a timely topic, with wide ranging reports of hemorrhagic complications, using various clopidogrel dosing strategies following neuroendovascular procedures. This study serves to investigate hemorrhagic complications using standard clopidogrel doses and timing of these complications in relation to the procedure. Materials and Methods: Retrospective cohort of consecutive adult patients undergoing flow diversion with Pipeline Embolization Device (PED) at an academic medical center, receiving on-label clopidogrel doses. Patients with clopidogrel hyperresponsiveness (VerifyNowTM P2Y12 reaction unit (PRU) ≤ 70) were compared to those who were normoresponsive. The primary outcome is the rate of hemorrhagic complications between groups. Results: Of 148 included patients, 54 (36.5%) were identified as clopidogrel hyperresponsive (PRU ≤ 70) and 94 (63.5%) as clopidogrel normoresponsive (PRU 71 - 194). There were no hemorrhagic complications observed in patients who were clopidogrel hyperresponsive, with 5 occurring in patients who were normoresponsive (P = 0.09). Three (60%) of the hemorrhages were intracranial with most occurring intra-procedure or within the first week of the procedure. Age > 60 years was the only candidate predictor for hemorrhagic complications (P = 0.004). Conclusion: Our findings are contradictory, with lower hemorrhagic complications in clopidogrel hyperresponders than prior literature, and most occurring intra-op or in the immediate acute post-op phase.

Clopidogrel resistance and its relevance: Current concepts.

Clopidogrel is the most widely used P2Y12 receptor inhibitor (P2Y12i) as a part of dual antiplatelet therapy along with aspirin. Clopidogrel is a pro-drug and is metabolized to its active metabolite by the hepatic enzyme cytochrome P4502C19 (CYP2C19). This active metabolite is responsible for the antiplatelet action of clopidogrel. Recent studies have demonstrated that single nucleotide polymorphisms in the CYP2C19 gene, including CYP2C19*2,*3,*4, and *5 alleles, result in reduced production of the active metabolite of clopidogrel, and hence reduced inhibition of platelet aggregation. This in turn enhances the incidence of stent thrombosis and recurrent cardiovascular (CV) events. We report a case of coronary stent thrombosis due to clopidogrel resistance proven by CYP2C19 genotyping. We then review the literature on clopidogrel resistance and its impact on CV outcomes. Subsequently, we discuss the methods of diagnosis of resistance, evidence from clinical trials for tailoring clopidogrel therapy, the role of potent P2Y12 inhibitors, the current guidelines, and future directions.

Does one size really fit all? The case for personalized antiplatelet therapy in interventional cardiology.

Cardiovascular disease is the leading cause of death worldwide. Dual antiplatelet therapy (DAPT), with aspirin plus a P2Y12 inhibitor, is currently recommended as a default for patients after acute coronary syndrome (ACS) and following percutaneous coronary intervention (PCI). However, controversies arise over the role of aspirin, the optimal duration of DAPT after drug-eluting stent (DES) implantation, the choice of P2Y12 inhibitor and the variability in individual responses to antiplatelet agents. Recent data indicate that monotherapy with a P2Y12 inhibitor may have adequate anti-ischemic effects with lower bleeding risk. Additionally, discrepancies in DAPT duration recommendations and the optimal P2Y12 inhibitor, provides more uncertainty. We ask the question "does one size really fits all?" or should a more personalized strategy should be implemented.

Diseases affecting the heart and blood circulation are the leading cause of death worldwide. Treatment with drugs that prevents platelets from clumping (called antiplatelets) like aspirin plus another drug group (called P2Y12 inhibitors) like clopidogrel, ticagrelor and prasugrel, is currently recommended as a default for patients after heart attack and/or in whom coronary stents are inserted. However, it is very well documented that the response of any individual to these drugs is highly variable, and that the patients who don't respond as well to them are at increased risk of having clot events in their coronary arteries. On the other hand, people who respond to the drugs very sensitively have a higher bleeding risk. Despite these observations, there is no attempt to test the response of individuals patients to their antiplatelet drugs in routine practice. This review article looks in detail and whether the currently used strategy of "One size fits all" should be changed, given that there may well now be the chance to perform routine testing on everyone, and personalize their treatment accordingly.

Advances and Perspectives in methods for identifying high platelet reactivity.

Antiplatelet therapy is the foundational treatment for the prevention and treatment of coronary and cerebrovascular ischemic events in patients with coronary heart disease, ischemic stroke, and transient ischemic attack (TIA). However, with more and more studies reporting an increased risk of thrombosis in some patients due to poor response to therapeutic agents, the selection of appropriate P2Y12 inhibitors has become a major challenge that needs to be addressed urgently. Currently, commonly used oral P2Y12 inhibitors include clopidogrel, ticagrelor, and prasugrel. Assessing patients' risk factors before the development of treatment regimens by effectively predicting the risk of high platelet reactivity with specific P2Y12 inhibitors in advance to avert the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) is the key point to the problem. Up to now, methods available for predicting platelet reactivity include genetic testing, platelet function testing, and risk scores. This review provides a summarization of the existent available identification methods and analyzes the advantages and drawbacks of different methods in specific clinical settings, intending to guide the rational clinical application of P2Y12 receptor inhibitors.

Variabilidad de la respuesta plaquetaria a la aspirina / Assessing platelet response to aspirin

Introducción y objetivos: A pesar de que el estudio Antiplatelet Trialists' Collaboration demostró una reducción del 25% de los eventos mayores con el uso de aspirina en enfermos de alto riesgo, un porcentaje de pacientes presentan eventos isquémicos recurrentes. Esto ha llevado a la descripción de la "resistencia a la aspirina" con una tasa muy variable, de 0.4% a 83%. Este estudio evaluó la variabiliad en la función plaquetaria basal, la prevalencia de la resistencia a la aspirina, y la efectividad y reproducibilidad de los estudios de función plaquetaria. Materiales y métodos: Se llevó a cabo un estudio aleatorizado y cruzado de mediciones repetidas, con sujetos saludables de entre 18 y 60 años. Luego de firmar el consentimiento informado, los pacientes fueron distribuidos en forma aleatorizada a recibir aspirina en dosis de 75 mg o 300 mg; fueron evaluados al inicio y luego de cuatro períodos de tres semanas mediante diferentes técnicas: Optical Platelet Aggregation (OPA), PFA-100™, VerifyNow™, y los niveles séricos y urinarios de tromboxano B2 (TXB2). Se obtuvo la aprobación del comité de ética local. El análisis estadístico fue realizado con el programa SPSS17. Resultados: El índice global de resistencia a la aspirina fue variable, entre 2.4% y 63.5% en función de la técnica utilizada. Se demostró una variabilidad interindividual e intraindividual significativa al inicio y con la administración de placebo en las diferentes técnicas. La sensibilidad de los ensayos varió entre 24% (OPA ADP10) y 87.8% (tromboxano sérico), y la especificidad varió entre 81% (PFA-100™) y 97.4% (tromboxano). La selección de "valores de corte" alternativos provocó tasas de prevalencia diferentes de resistencia bioquímica a la aspirina, con un mecanismo de compensación entre la sensibilidad y la especificidad. Conclusiones: La respuesta a la aspirina mostró una marcada variabilidad interensayo, interindividual y temporal. Se requieren varias evaluaciones con diferentes técnicas para diagnosticar en forma confiable la resistencia a la aspirina. La selección de valores discriminativos alternativos debería considerarse al evaluar formalmente esta entidad

Introduction: Despite the 25% reduction in major events with aspirin in high-risk patients reported by the Antiplatelet Trialists' Collaboration, a proportion of patients develop recurrent ischaemic events. This has led to the emergence of 'aspirin resistance' with rates between 0.4% and 83% reported. This study assessed variability in baseline platelet function, prevalence of aspirin resistance, and the performance and reproducibility of platelet function testing methods. Materials and Methods: A repeated-measures randomised crossover study was performed in healthy individuals aged 18-60 years. After informed consent, patients were randomised to aspirin dose (75 mg or 300 mg) and treatment sequence with testing at baseline and after each four 3-week treatment period via Optical Platelet Aggregation (OPA), PFA-100™, VerifyNow™, and serum and urinary thromboxane (TXB2) levels. Local ethical approval was granted. Statistical analysis was performed using SPSS17. Results: The overall rate of aspirin resistance varied from 2.4% to 63.5% depending on the assay used. Significant inter- and intra-individual variability existed at baseline and on placebo testing between assays. Assay sensitivities ranged from 24.0% (OPA ADP10) to 87.8% (serum TXB2), and specificities from 81.0% (PFA-100™) to 97.4% (serum TXB2). Selection of alternative "cut-off" values resulted in differing prevalence rates of biochemical aspirin resistance with a trade-off between sensitivity and specificity. Conclusions: Response to aspirin shows marked inter-assay, inter-individual and temporal variability. Testing on multiple occasions using several assays is necessary to reliably diagnose aspirin resistance. Selection of alternative assay "cut-off" values should be considered when formally assessing aspirin response