CYP2C19 Genetic Testing for Oral P2Y12 Inhibitor Therapy: A Scientific Statement From the American Heart Association.

There is significant variability in the efficacy and safety of oral P2Y12 inhibitors, which are used to prevent ischemic outcomes in common diseases such as coronary and peripheral arterial disease and stroke. Clopidogrel, a prodrug, is the most used oral P2Y12 inhibitor and is activated primarily after being metabolized by a highly polymorphic hepatic cytochrome CYP2C219 enzyme. Loss-of-function genetic variants in CYP2C219 are common, can result in decreased active metabolite levels and increased on-treatment platelet aggregation, and are associated with increased ischemic events on clopidogrel therapy. Such patients can be identified by CYP2C19 genetic testing and can be treated with alternative therapy. Conversely, universal use of potent oral P2Y12 inhibitors such as ticagrelor or prasugrel, which are not dependent on CYP2C19 for activation, has been recommended but can result in increased bleeding. Recent clinical trials and meta-analyses have demonstrated that a precision medicine approach in which loss-of-function carriers are prescribed ticagrelor or prasugrel and noncarriers are prescribed clopidogrel results in reducing ischemic events without increasing bleeding risk. The evidence to date supports CYP2C19 genetic testing before oral P2Y12 inhibitors are prescribed in patients with acute coronary syndromes or percutaneous coronary intervention. Clinical implementation of such genetic testing will depend on among multiple factors: rapid availability of results or adoption of the concept of performing preemptive genetic testing, provision of easy-to-understand results with therapeutic recommendations, and seamless integration in the electronic health record.

Dual antithrombotic treatment in chronic coronary syndrome: European Society of Cardiology criteria vs. CHADS-P2A2RC score.

AIMS: According to the 2019 European Society of Cardiology (ESC) guidelines on chronic coronary syndromes (CCS), adding a P2Y12 inhibitor or rivaroxaban to aspirin should be considered in high-risk patients. We estimated the proportion of patients eligible for treatment with the ESC criteria and examined if a recently validated risk score (CHADS-P2A2RC) could improve risk prediction. METHODS AND RESULTS: We included 61 338 CCS patients undergoing first-time coronary angiography in Western Denmark (2003-16) and classified them according to the ESC criteria and the CHADS-P2A2RC score. The ESC criteria identified 33.9% as high risk, 53.3% as moderate risk, and 12.8% as low risk. The CHADS-P2A2RC score identified 24.9% as high risk (≥4 points), 48.1% as moderate risk (2-3 points), and 27.0% as low risk (≤1 points). Major adverse cardiovascular events per 100 person-years were 4.8 [95% confidence interval (CI) 4.6-5.0] in patients considered high risk with both schemes, 2.1 (95% CI 2.0-2.2) in patients considered high risk with the ESC but low-to-moderate risk with the CHADS-P2A2RC criteria, 3.8 (95% CI 3.6-4.1) in patients considered low-to-moderate risk with the ESC but high risk with the CHADS-P2A2RC criteria, and 1.5 (95% CI 1.5-1.6) in patients considered low-to-moderate risk with both schemes. The CHADS-P2A2RC score enabled correct downward risk reclassification of 5161 patients (8%) without events, yielding an improved specificity of 9.7%, a loss of sensitivity of 4.4%, and an overall net reclassification index of 0.053. CONCLUSION: Based on the 2019 ESC guidelines, dual antithrombotic treatment should be considered in one-third of CCS patients. The CHADS-P2A2RC score improved risk classification and may particularly identify low-risk patients with limited benefit from treatment.

PERIPHERAL NERVE BLOCKS IN PATIENTS ON ANTITHROMBOTIC DRUGS - A RESCUE OR AN UNNECESSARY RISK?

Bleeding complications after peripheral nerve blocks (PNBs) in patients treated with an antiplatelet agent and/or an anticoagulant drug are rare, with estimated incidence of 0.67% (0.51-0.83%). However, they can result in significant patient morbidity and may require follow-up investigations and interventions. The evidence for bleeding risks and complications after PNB is very low or nonexistent, therefore, recommendations and guidelines are based on retrospective analyses, case reports, expert opinions and expert panel consensus. In the manuscript, an expert panel consensus on classification of PNBs according to the potential risk of serious bleeding complications is presented. The risks of bleeding depend on the location (vicinity of the vessels and critical structures at risk from the mass effect of a hematoma), block depth (which influences needle visibility), associated comorbidities and anticoagulation status, body habitus, site compressibility, whether the bleeding or hematoma are easy or not to assess and how easy or not an intervention may be applied to prevent or treat bleeding. Also, technical factors are considered: type and size of the used needle, technical difficulties, multiple attempts, needle passes and bloody tap, use of catheters and type of nerve location technique (USG versus blind techniques) and operator experience. In all patients on antithrombotic drugs, benefits vs. risks should be weighted. A bleeding risk should be minimized with the optimization of patient's coagulation: appropriate antithrombotic drug timing before PNB, dose of antithrombotic drug, indication for the drug and risk factors that may influence drug pharmacokinetics (bodyweight, age, renal and hepatic function). Superficial PNBs may be performed in the presence of antithrombotic drug. For deep PNBs, a recommendations for neuraxial procedures should be considered.

Effects of morphine on P2Y12 platelet inhibitors in patients with acute myocardial infarction: A meta-analysis.

OBJECTIVE: To explore the effects of morphine on P2Y12 platelet inhibitors in patients with acute myocardial infarction (AMI). METHODS: PubMed, Embase, Cochrane Library, and Web of Science were used to retrieve literature through 11th May 2019. Standardized weighted mean difference (SMD) and relative risk (RR) with 95% confidence intervals (CI), P-value, and I2 value were used to assess the strength of the association in this meta-analysis. Outcomes included platelet reactivity, high residual platelet reactivity (HRPR), ticagrelor maximum concentration (Cmax), ticagrelor area under curve (AUC), death rate, reinfarction rate, stroke, stent thrombosis, thrombolysis in myocardial infarction (TIMI) hemorrhage, dyspnea, emesis, contrast-induced nephropathy, and pulmonary edema. RESULTS: A total of 13 articles were included in this study, containing 5688 patients (morphine group: n = 2014, control group: n = 3674). Results illustrated that the morphine group had a higher platelet reactivity (SMD: 0.834, 95%CI: 0.483-1.186, P < 0.001) and HRPR rate (RR: 1.994, 95%CI: 1.536-2.588, P < 0.001) than the control group, while the Cmax of ticagrelor (WMD: -481.838, 95%CI: -841.242-122.434, P = 0.009) was lower than that of the control group. The death rate of the morphine group was lower than that in the control group (RR: 0.561, 95%CI: 0.337-0.933, P = 0.026). The morphine group had a higher emesis rate than the control group (RR: 4.486, 95%CI: 2.263-8.891, P < 0.001). CONCLUSION: Morphine effectively suppresses the inhibition effect of P2Y12 platelet inhibitors in patients with AMI.

Point-of-Care Platelet Function Monitoring: Implications for Patients With Platelet Inhibitors in Cardiac Surgery.

Although most physicians are comfortable managing the limited anticoagulant effect of aspirin, the recent administration of potent P2Y12 receptor inhibitors in patients undergoing cardiac surgery remains a dilemma. Guidelines recommend discontinuation of potent P2Y12 inhibitors 5- to- 7 days before surgery to reduce the risk of postoperative hemorrhage. Such a strategy might not be feasible before urgent surgery, due to ongoing myocardial ischemia or in patients at high risk for thromboembolic events. Recently, different point-of-care devices to assess functional platelet quality have become available for clinical use. The aim of this narrative review was to evaluate the implications and potential benefits of platelet function monitoring in guiding perioperative management and therapeutic options in patients treated with antiplatelets, including aspirin or P2Y12 receptor inhibitors, undergoing cardiac surgery. No objective superiority of one point-of-care device over another was found in a large meta-analysis. Their accuracy and reliability are generally limited in the perioperative period. In particular, preoperative platelet function testing has been used to assess platelet contribution to bleeding after cardiac surgery. However, predictive values for postoperative hemorrhage and transfusion requirements are low, and there is a significant variability between and within these tests. Further, platelet function monitoring has been used to optimize the preoperative waiting period after cessation of dual antiplatelet therapy before urgent cardiac surgery. Furthermore, studies assessing their value in therapeutic decisions in bleeding patients after cardiac surgery are scarce. A general and liberal use of perioperative platelet function testing is not yet recommended.

The effect of anti-thrombotics on the postoperative bleeding rate in patients undergoing craniotomy for brain tumor.

OBJECTIVE: The peak prevalence of many brain tumors is in elderly patients. These patients are often treated with platelet inhibitors (PIs) or anticoagulants (ACs), creating a challenge for neurosurgeons concerning the perioperative management. The aim of this study is to analyze the effect of PI/AC treatment on the postoperative bleeding rates in patients undergoing craniotomy due to a brain tumor. METHODS: Retrospective analysis of 415 consecutive patients undergoing craniotomy/craniectomy due to a brain tumor. Ninety-nine patients with PI/AC treatment (PI/AC group consisting of 64 PI, 29 AC, and six multiple) and 316 patients without PI/AC (control group) were primarily compared for hemorrhage rate. Secondary outcome measures were clinical outcome and mortality. The association between short preoperative discontinuation (≤5 days), early postoperative resumption time (≤5 days), as well as short total discontinuation time (≤5 days) of PI/AC and postoperative bleeding rates was analyzed. RESULTS: Postoperative bleeding rates were comparable between the groups (12.2% and 13.5% in the PI/AC and control group, respectively; p=.74). The majority of bleeds were asymptomatic (85.2%). No significant difference in the postoperative mortality rate was observed (1.0% and 1.6% in the PI/AC and the control group, respectively; p=.67). Shorter discontinuation time of PI/AC was not significantly associated with higher postoperative bleeding rates (preoperative: 12.1% vs. 12.3%; p=.94, postoperative: 11.1% vs. 12.5%, respectively; p=.87, total: 16.7% vs. 12%, respectively; p=.73). CONCLUSIONS: Patients treated with PI/AC undergoing craniotomy for the resection of brain tumor do not seem to have increased rates of postoperative bleeding or mortality. We did not find a significant correlation between short discontinuation time of PI/AC in the perioperative period and postoperative bleeding.

Cardiopulmonary bypass and dual antiplatelet therapy: a strategy to minimise transfusions and blood loss.

BACKGROUND: Patients with preoperative dual antiplatelet therapy prior to coronary artery bypass surgery are at risk of bleeding and blood component transfusion. We hypothesise that an optimised cardiopulmonary bypass strategy reduces postoperative blood loss and transfusions. METHODS: In total, 60 patients admitted for coronary artery bypass grafting with ticagrelor and aspirin medication withdrawn <96 hours before surgery were prospectively randomised into two equal sized groups. Cardiopulmonary bypass combined a closed Cortiva® heparin-coated circuit with low systemic heparinisation (activated clotting time < 250 seconds) and intraoperative cell salvage in the study group, whereas the control group used a Balance® coated open circuit, full systemic heparinisation (activated clotting time > 480 seconds) and conventional cardiotomy suction. This perfusion strategy was evaluated by the chest drain volume after 24 hours, perioperative haemoglobin and platelet loss accompanied by global coagulation assessments. RESULTS: Patients in the study group demonstrated significantly better outcomes signified by lower blood loss 554 ± 224 versus 1,100 ± 989 mL (p < 0.001), reduced packed red cell transfusion 7% versus 53% (p < 0.001), reduced haemoglobin -28 ± 15 versus -40 ± 14 g/L (p = 0.004) and platelet loss -35 ± 36 versus -82 ± 67 × 109/L (p = 0.001). Indices of rotational thromboelastometry indicated shorter clotting times within the internal and external pathways. Adenosine diphosphate activated platelet function was within normal range based on Multiplate® aggregometry, while ROTEM® platelet analyses indicated inhibited function both preoperatively and post-bypass. Platelet inhibition by aspirin was verified throughout the perioperative period. Platelet function showed no intergroup differences. CONCLUSION: A stringent perfusion strategy reduced blood loss and transfusions in dual antiplatelet therapy patients requiring urgent surgery.

Diagnostic and therapeutic approach in adult patients with traumatic brain injury receiving oral anticoagulant therapy: an Austrian interdisciplinary consensus statement.

There is a high degree of uncertainty regarding optimum care of patients with potential or known intake of oral anticoagulants and traumatic brain injury (TBI). Anticoagulation therapy aggravates the risk of intracerebral hemorrhage but, on the other hand, patients take anticoagulants because of an underlying prothrombotic risk, and this could be increased following trauma. Treatment decisions must be taken with due consideration of both these risks. An interdisciplinary group of Austrian experts was convened to develop recommendations for best clinical practice. The aim was to provide pragmatic, clear, and easy-to-follow clinical guidance for coagulation management in adult patients with TBI and potential or known intake of platelet inhibitors, vitamin K antagonists, or non-vitamin K antagonist oral anticoagulants. Diagnosis, coagulation testing, and reversal of anticoagulation were considered as key steps upon presentation. Post-trauma management (prophylaxis for thromboembolism and resumption of long-term anticoagulation therapy) was also explored. The lack of robust evidence on which to base treatment recommendations highlights the need for randomized controlled trials in this setting.

Influence of selected antithrombotic treatment on thromboelastometric results.

Rotatory thromboelastometry (ROTEM®) is used for diagnosing and monitoring bleeding patients. Some of these patients receive antithrombotic treatment, thus having an increased risk of bleeding. Only sparse knowledge exists about whether the ROTEM® analysis is influenced by antithrombotic treatment. The objective of the present study was to examine if the ROTEM® results are affected in patients receiving antithrombotic treatment. This prospective observational study included patients receiving either vitamin K-antagonists (VKA), aspirin (ASA) or ASA combined with an adenosine diphosphate (ADP) receptor antagonist (ASA + ADP). ROTEM® analyses were performed using the standard assays EXTEM®, INTEM® and FIBTEM®. Furthermore, haemoglobin, platelet count, International Normalized Ratio (INR), activated partial thromboplastin time, fibrinogen (functional), creatinine, estimated glomerular filtration rate, and C-reactive protein were determined. The study included 231 patients receiving antithrombotic treatment and compared the results to ROTEM® previously collected data from 73 healthy subjects. The VKA (n = 73) patients had a consistently prolonged EXTEM clot initiation (p < .0001), which was significantly correlated to the INR (Spearman's r = 0.53, p < .0001). Additionally, the VKA patients had significantly reduced clot propagation [reduced maximum velocity, maximum velocity (MaxVel) and increased time to maximum velocity (MaxVelt)]. ASA (n = 80) and ASA + ADP patients (n = 78) revealed a prolonged clot initiation. ASA patients had decreased clot propagation (increased MaxVelt), whereas ASA + ADP patients had an inconsistent change in clot propagation (increased MaxVel and MaxVelt). In conclusion, VKA treatment was revealed by the ROTEM® analysis. On the contrary, ASA and ASA + ADP treatment were not consistently revealed by the analysis.

The management of anticoagulation in patients undergoing therapeutic plasma exchange: A concise review.

We surveyed multiple apheresis centers represented by the authors for their clinical approach to the management of anticoagulation issues during therapeutic plasma exchange (TPE). We present the results of their practices and a review of the pertinent literature. As plasma is removed during TPE, replacement with all or partial non-plasma-containing fluids (eg, 5% albumin) may lead to significant changes in hemostasis. These changes are amplified in patients who are receiving anticoagulation. We discuss various anticoagulants as well as the monitoring and adjustment of anticoagulation before, during, and after TPE. No single guideline can be applied, but rather, patients must be monitored individually, taking into account their often complex clinical conditions and medication profiles.

Editor's Choice - The National Norwegian Carotid Study: Time from Symptom Onset to Surgery is too Long, Resulting in Additional Neurological Events.

OBJECTIVE/BACKGROUND: The objective was to observe for 1 year all patients in Norway operated on for symptomatic carotid stenosis with respect to (i) the time from the index event to surgery and neurological events during this time; (ii) the level in the healthcare system causing delay of surgical treatment; and (iii) the possible relationship between peri-operative use of platelet inhibitors and neurological events while awaiting surgery. METHODS: This was a prospective national multicentre study of a consecutive series of symptomatic patients. Patients were eligible for inclusion when referred for surgery. An index event was defined as the neurological event prompting contact with the healthcare system. All 15 departments in Norway performing carotid endarterectomy (CEA) participated. RESULTS: Three hundred and seventy one patients were eligible for inclusion between 1 April 2014 and 31 March 2015, and 368 patients (99.2%) were included. Fifty-four percent of the patients contacted their general practitioner on the day of the index event. Primary healthcare referred 84.2% of the patients to hospital on the same day as examined. In hospital median time from admission to referral for vascular surgery was 3 days. Median time between referral to the operating unit and actual CEA was 5 days. Overall, 61.7% of the patients were operated on within 2 weeks of the index event. Twelve patients (3.3%) suffered a new neurological event while awaiting surgery. The percentage of patients on dual antiplatelet therapy was lower (25.0%) in this group than among the other patients (62.6%) (p = .008). The combined 30 day mortality and stroke rate was 3.8%. CONCLUSION: This national study with almost complete inclusion and follow-up shows that the delays occur mainly at patient level and in hospital. The delay is associated with new neurological events. Dual antiplatelet therapy is associated with reduced risk of having a new neurological event before surgery.

Therapeutic implications of protein disulfide isomerase inhibition in thrombotic disease.

The study of thrombus formation has increasingly applied in vivo tools such as genetically modified mice and intravital microscopy to the evaluation of molecular and cellular mechanisms of thrombosis. Among several unexpected findings of this approach was the discovery that protein disulfide isomerase serves an essential role in thrombus formation at sites of vascular injury. The observation that the commonly ingested quercetin flavonoid, quercetin-3-rutinoside, inhibits protein disulfide isomerase and blocks thrombus formation in preclinical studies has set the stage for clinical trials using protein disulfide isomerase antagonists as antithrombotics. Although the mechanisms by which protein disulfide isomerase facilitates platelet activation and fibrin formation have yet to be elucidated, protein disulfide isomerase antagonists are currently being developed as antithrombotics. This review will consider what is known about the role of protein disulfide isomerase in platelet accumulation and fibrin generation with a focus on pharmacological strategies for blocking protein disulfide isomerase activity in the context of thrombus formation. Potential indications and clinical trial design for testing the efficacy of protein disulfide isomerase inhibition to reduce the incidence of thrombosis will be considered.

Ticagrelor protects the heart against reperfusion injury and improves remodeling after myocardial infarction.

OBJECTIVE: In addition to P2Y12 receptor antagonism, ticagrelor inhibits adenosine cell uptake. Prior data show that 7-day pretreatment with ticagrelor limits infarct size. We explored the acute effects of ticagrelor and clopidogrel on infarct size and potential long-term effects on heart function. APPROACH AND RESULTS: Rats underwent 30-minute ischemia per 24-hour reperfusion. (1) Ticagrelor (10 or 30 mg/kg) or clopidogrel (12.5 mg/kg) was given via intraperitoneal injection 5 minutes before reperfusion. (2) Rats received ticagrelor acute (intraperitoneal; 30 mg/kg), chronic (oral; 300 mg/kg per day) for 4 weeks starting 1 day after reperfusion or the combination (acute+chronic). Another group received clopidogrel (intraperitoneal [12.5 mg/kg]+oral [62.5 mg/kg per day]) for 4 weeks. (1) Ticagrelor dose-dependently reduced infarct size, 10 mg/kg (31.5%±1.8%; P<0.001) and 30 mg/kg (21.4%±2.6%; P<0.001) versus control (45.3±1.7%), whereas clopidogrel had no effect (42.4%±2.6%). Ticagrelor, but not clopidogrel, increased myocardial adenosine levels, increased phosphorylation of Akt, endothelial NO synthase, and extracellular-signal-regulated kinase 1/2 4 hours after reperfusion and decreased apoptosis. (2) After 4 weeks, left ventricular ejection fraction was reduced in the vehicle-treated group (44.8%±3.5%) versus sham (77.6%±0.9%). All ticagrelor treatments improved left ventricular ejection fraction, acute (69.5%±1.6%), chronic (69.2%±1.0%), and acute+chronic (76.3%±1.2%), whereas clopidogrel had no effect (37.4%±3.7%). Ticagrelor, but not clopidogrel, attenuated fibrosis and decreased collagen-III mRNA levels 4 weeks after ischemia/reperfusion. Ticagrelor, but not clopidogrel, attenuated the increase in proinflammatory tumor necrosis factor-α, interleukin-1ß, and interleukin-18, and increased anti-inflammatory 15-epi-lipoxin-A4 levels. CONCLUSIONS: Ticagrelor, but not clopidogrel, administered just before reperfusion protects against reperfusion injury. This acute treatment or chronic ticagrelor for 4 weeks or their combination improved heart function, whereas clopidogrel, despite achieving a similar degree of platelet inhibition, had no effect.

Characterization of a novel function-blocking antibody targeted against the platelet P2Y1 receptor.

OBJECTIVE: Platelet hyperactivity is associated with vascular disease and contributes to the genesis of thrombotic disorders. ADP plays an important role in platelet activation and activates platelets through 2 G-protein-coupled receptors, the Gq-coupled P2Y1 receptor (P2Y1R), and the Gi-coupled P2Y12 receptor. Although the involvement of the P2Y1R in thrombogenesis is well established, there are no antagonists that are currently available for clinical use. APPROACH AND RESULTS: Our goal is to determine whether a novel antibody targeting the ligand-binding domain, ie, second extracellular loop (EL2) of the P2Y1R (EL2Ab) could inhibit platelet function and protect against thrombogenesis. Our results revealed that the EL2Ab does indeed inhibit ADP-induced platelet aggregation, in a dose-dependent manner. Furthermore, EL2Ab was found to inhibit integrin GPIIb-IIIa activation, dense and α granule secretion, and phosphatidylserine exposure. These inhibitory effects translated into protection against thrombus formation, as evident by a prolonged time for occlusion in a FeCl3-induced thrombosis model, but this was accompanied by a prolonged tail bleeding time. We also observed a dose-dependent displacement of the radiolabeled P2Y1R antagonist [(3)H]MRS2500 from its ligand-binding site by EL2Ab. CONCLUSIONS: Collectively, our findings demonstrate that EL2Ab binds to and exhibits P2Y1R-dependent function-blocking activity in the context of platelets. These results add further evidence for a role of the P2Y1R in thrombosis and validate the concept that targeting it is a relevant alternative or complement to current antiplatelet strategies.

Mortality among head trauma patients taking preinjury antithrombotic agents: a retrospective cohort analysis from a Level 1 trauma centre.

BACKGROUND: Bleeding represents the most well-known and the most feared complications caused by the use of antithrombotic agents. There is, however, limited documentation whether pre-injury use of antithrombotic agents affects outcome after head trauma. The aim of this study was to define the relationship between the use of preinjury antithrombotic agents and mortality among elderly people sustaining blunt head trauma. METHODS: A retrospective cohort analysis was performed on the hospital based trauma registry at Oslo University Hospital. Patients aged 55 years or older sustaining blunt head trauma between 2004 and 2006 were included. Multivariable logistic regression analyses were used to identify independent predictors of 30-day mortality. Separate analyses were performed for warfarin use and platelet inhibitor use. RESULTS: Of the 418 patients admitted with a diagnosis of head trauma, 137 (32.8 %) used pre-injury antithrombotic agents (53 warfarin, 80 platelet inhibitors, and 4 both). Seventy patients died (16.7 %); 15 (28.3 %) of the warfarin users, 12 (15.0 %) of the platelet inhibitor users, and two (50 %) with combined use of warfarin and platelet inhibitors, compared to 41 (14.6 %) of the non-users. There was a significant interaction effect between warfarin use and the Triage Revised Trauma Score collected upon the patients' arrival at the hospital. After adjusting for potential confounders, warfarin use was associated with increased 30-day mortality among patients with normal physiology (adjusted OR 8,3; 95 % CI, 2.0 to 34.8) on admission, but not among patients with physiological derangement on admission. Use of platelet inhibitors was not associated with increased mortality. CONCLUSIONS: The use of warfarin before trauma was associated with increased 30-day mortality among a subset of patients. Use of platelet inhibitors before trauma was not associated with increased mortality. These results indicate that patients on preinjury warfarin may need closer monitoring and follow up after trauma despite normal physiology on admission to the emergency department.

Targeting glycoprotein VI and the immunoreceptor tyrosine-based activation motif signaling pathway.

Coronary artery thrombosis and ischemic stroke are often initiated by the disruption of an atherosclerotic plaque and consequent intravascular platelet activation. Thus, antiplatelet drugs are central in the treatment and prevention of the initial, and subsequent, vascular events. However, novel pharmacological targets for platelet inhibition remain an important goal of cardiovascular research because of the negative effect of existing antiplatelet drugs on primary hemostasis. One promising target is the platelet collagen receptor glycoprotein VI. Blockade or antibody-mediated depletion of this receptor in circulating platelets is beneficial in experimental models of thrombosis and thrombo-inflammatory diseases, such as stroke, without impairing hemostasis. In this review, we summarize the importance of glycoprotein VI and (hem)immunoreceptor tyrosine-based activation motif signaling in hemostasis, thrombosis, and thrombo-inflammatory processes and discuss the targeting strategies currently under development for inhibiting glycoprotein VI and its signaling.

Platelets mediate oxidized low-density lipoprotein-induced monocyte extravasation and foam cell formation.

OBJECTIVE: A growing body of evidence indicates that platelets contribute to the onset and progression of atherosclerosis by modulating immune responses. We aimed to elucidate the effects of oxidized low-density lipoprotein (OxLDL) on platelet-monocyte interactions and the consequences of these interactions on platelet phagocytosis, chemokine release, monocyte extravasation, and foam cell formation. APPROACH AND RESULTS: Confocal microscopy and flow cytometric analysis revealed that in vitro and in vivo stimulation with OxLDL resulted in rapid formation of platelet-monocyte aggregates, with a preference for CD16+ monocyte subsets. This platelet-monocyte interaction facilitated OxLDL uptake by monocytes, in a process that involved platelet CD36-OxLDL interaction, release of chemokines, such as CXC motif ligand 4, direct platelet-monocyte interaction, and phagocytosis of platelets. Inhibition of cyclooxygenase with acetylsalicylic acid and antagonists of ADP receptors, P2Y1 and P2Y12, partly abrogated OxLDL-induced platelet-monocyte aggregates and platelet-mediated lipid uptake in monocytes. Platelets also enhanced OxLDL-induced monocyte transmigration across an endothelial monolayer via direct interaction with monocytes in a transwell assay. Importantly, in LDLR(-/-) mice, platelet depletion resulted in a significant decrease of peritoneal macrophage recruitment and foam cell formation in a thioglycollate-elicited peritonitis model. In platelet-depleted wild-type mice, transfusion of ex vivo OxLDL-stimulated platelets induced monocyte extravasation to a higher extent when compared with resting platelets. CONCLUSIONS: Our results on OxLDL-mediated platelet-monocyte aggregate formation, which promoted phenotypic changes in monocytes, monocyte extravasation and enhanced foam cell formation in vitro and in vivo, provide a novel mechanism for how platelets potentiate key steps of atherosclerotic plaque development and plaque destabilization.

Net clinical benefit of extended dual pathway inhibition according to baseline risk in patients with chronic coronary syndrome: a COMPASS substudy.

AIMS: Guidelines recommend extended dual pathway inhibition (DPI) with aspirin and rivaroxaban in patients with chronic coronary syndrome (CCS) at high ischaemic risk. The CHADS-P2A2RC score improves risk prediction and enables antithrombotic treatment allocation in these patients. This study evaluated the net clinical benefit of DPI treatment according to baseline risk as classified by the CHADS-P2A2RC score in patients with CCS included in the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial. METHODS AND RESULTS: COMPASS patients with CCS (n = 14 670), randomized to aspirin alone or DPI, were stratified according to cardiovascular risk using the CHADS-P2A2RC score. Endpoints were major adverse cardiovascular events (MACE), all-cause death, fatal/critical organ bleeding, and composite adverse events (MACE and bleeding). Net clinical benefit was the 30-month risk difference of MACE and bleeding. Thirty-month incidences of MACE [7.9% vs. 3.9%, hazard ratio (HR) 2.01, 95% confidence interval (CI) 1.83-2.18] and fatal/critical organ bleeding (1.2% vs. 0.8%, HR 1.49, 95% CI 1.06-1.92) were higher in high-risk (CHADS-P2A2RC ≥ 4) than in low/moderate-risk (CHADS-P2A2RC < 4) patients. DPI reduced MACE (low/moderate risk: HR 0.62, 95% CI 0.47-0.82; high risk: HR 0.82, 95% CI 0.68-0.99, P for interaction 0.09) and all-cause death (low/moderate risk: HR 0.65, 95% CI 0.46-0.91; high risk: HR 0.81, 95% CI 0.65-1.00, P for interaction 0.29), without substantially increasing fatal/critical organ bleeding (low/moderate risk: HR 1.35, 95% CI 0.72-2.53; high risk: HR 1.18, 95% CI 0.73-1.90, P for interaction 0.73). DPI provided net clinical benefit of similar magnitude in low/moderate-risk (-1.81%, 95% CI -3.00 to -0.62) and high-risk (-1.96%, 95% CI -3.60 to -0.33) CCS patients. CONCLUSION: As classified by the CHADS-P2A2RC score, low/moderate- and high-risk patients with CCS derived similar net clinical benefit and reduction in all-cause death from DPI treatment.

Antiplatelet strategies: past, present, and future.

Antiplatelet therapy plays a critical role in the prevention and treatment of major cardiovascular diseases triggered by thrombosis. Since the 1900s, significant progress in reducing morbidity and death caused by cardiovascular diseases has been made. However, despite the development and approval of drugs that specifically target the platelet, including inhibitors for cycloxygenase-1, P2Y12 receptor, integrin αIIbß3, phosphodiesterases, and protease-activated receptor 1, the risk of recurrent thrombotic events remains high, and the increased risk of bleeding is a major concern. Scientific advances in our understanding of the role of platelets in haemostasis and thrombosis have revealed novel targets, such as protease-activated receptor 4 (PAR4), glycoprotein Ib (GPIb)-V-IX complex, glycoprotein VI, and 12-lipoxygenase. The antithrombotic effects and safety of the pharmacologic inhibition of these targets are currently under investigation in clinical studies. This review provides an overview of drugs in early development to target the platelet and those in current use in clinical practice. Furthermore, it describes the emerging drug targets being developed and studied to reduce platelet activity and outlines potential novel therapeutic targets in the platelet.

Performance of DAPT Score and ESC Criteria for Predicting Clinical Outcomes in Chinese Patients with Acute Coronary Syndrome.

Purpose: The values of European Society of Cardiology (ESC) criteria and dual antiplatelet therapy (DAPT) score in the stratification of ischemic risk were assessed in this study. Methods: A total of 489 patients with acute coronary syndrome who received DAPT at discharge between June 2020 and August 2020 were enrolled. The primary endpoint was the occurrence of major adverse cardiovascular events (MACE), which included recurrent ACS or unplanned revascularization, all-cause death, or ischemic stroke during a 27-month follow-up period. Results: Patients with ESC-defined high-risk showed a significantly higher risk of MACE (HR 2.75, 95% CI 1.78-4.25), all-cause death (HR 2.49, 95% CI 1.14-5.43), and recurrent ACS or unplanned revascularization (HR 2.80, 95% CI 1.57-4.99) than those with ESC-defined low/medium-risk during follow-up. The results of landmark analysis showed that patients in the high-risk group had a significantly higher risk of MACE (HR 2.80,95 CI% 1.57-4.97), recurrent ACS or unplanned revascularization (HR 3.19,95 CI% 1.47-6.93) within one year, and a higher risk of MACE (HR 2.69,95 CI% 1.38-5.23) after one year. There was no significant difference in the incidence of MACE between patients with a DAPT score ≥2 and a DAPT score <2. The C-indices of ESC criteria and DAPT score for prediction of MACE were 0.63 (95% CI 0.57-0.70) and 0.54 (95% CI 0.48-0.61), respectively. The predictive value of ESC criteria for MACE was better than the DAPT score according to the DeLong test (z-statistic=2.30, P=0.020). Conclusion: Patients with ESC-defined high-risk had a higher risk of MACE compared to those with ESC-defined low/medium-risk. The discriminant ability of the ESC criteria was better than the DAPT score for MACE. The ESC criteria demonstrated moderate discriminatory capacity of MACE in ACS patients treated with DAPT.