Antiplatelet Effects Research Articles

Effect of different cooking methods on S-Alk(en)yl-L-cysteine sulfoxides profile and antiplatelet activity of onion

• Onions are predominant with organosulfur and phenolic compounds endowed with promising functional effects. • Different cooking methods effects on organosulfur composition and bioactivities of onions. • Cooking methods altered the organosulfur content and antiplatelet activity of onions. • Stir-frying cooking was found effective to retain the high amount organosulfur compounds in onion. • Onion extracts showed significant inhibition on collagen-induced antiplatelet activity. Onions are a significant source of organosulfur compounds with promising biological effects. However, the effects of different cooking methods on organosulfur composition and biological properties in onions remain unclear. Therefore, the objective of this study was to determine the composition of organosulfur compounds and the antiplatelet effect of six different onion varieties processed using different cooking methods (boiling, stir-frying, and steaming).The organosulfur compounds were quantified by measuring the S-Alk(en)ey-L-cysteine sulfoxides (ACSOs) contents utilizing and high-pressure liquid chromatography (HPLC). Results showed no significant differences in ACSOs contents among onion varieties. However, ‘Guigum' (GG) and ‘Turbo’ (TB) varieties showed the highest amount of ACSOs at 100.6 and 98.0 mg/100 g fresh weight (FW), respectively. Total ACSOs contents in the other four varieties were 62.7∼72.4 mg/100g FW, showing similar contents. Stir-fried (without the addition of water) onions retained the highest content of total ACSO, followed by steamed treated onions. However, with the boiling method, sulfur compounds were eluted and lost in the cooking water, resulted in a 46.8% loss of ACSOs. Onion extracts showed significant inhibition of the collagen-induced aggregation of rat blood platelets. The highest effect of platelet aggregation was observed in stir-fried onion extracts, whereas the lowest was in boiled extracts. Results demonstrated that stir-frying is an effective cooking method to retain the highest amount of health-beneficial organosulfur compounds in onion.

Adenosine 2A Receptor Activation Amplifies Ibrutinib Antiplatelet Effect; Implications in Chronic Lymphocytic Leukemia.

Chronic lymphocytic leukemia patients have an increased bleeding risk with the introduction of Bruton tyrosine kinase (BTK) inhibitors. BTK is a signaling effector downstream of the platelet GPVI receptor. Innate platelet dysfunction in CLL patients and the contribution of the leukemia microenvironment to the anti-platelet effect of BTK inhibitors are still not well defined. Herein, we investigated platelet function in stable, untreated CLL patients in comparison to age-matched healthy subjects as control. Secondly, we proposed a novel mechanism of platelet dysfunction via the adenosinergic pathway during BTK inhibitor therapy. Our data indicate that the nucleotidase that produces adenosine, CD73, was expressed on one-third of B-cells in CLL patients. Inhibition of CD73 improved platelet response to ADP in the blood of CLL patients ex vivo. Using healthy platelets, we show that adenosine 2A (A2A) receptor activation amplifies the anti-platelet effect of ibrutinib (10 nM). Ibrutinib plus an A2A agonist-but not ibrutinib as a single agent-significantly inhibited collagen (10 µg/mL)-induced platelet aggregation. Mechanistically, A2A activation attenuated collagen-mediated inhibition of p-VASP and synergized with ibrutinib to inhibit the phosphorylation of AKT, ERK and SYK kinases. This manuscript highlights the potential role of adenosine generated by the microenvironment in ibrutinib-associated bleeding in CLL patients.

Pharmacological interventions for preventing venous thromboembolism in people undergoing bariatric surgery.

Pharmacological interventions for preventing venous thromboembolism in people undergoing bariatric surgery.

Antiplatelet efficacy of ticagrelor versus clopidogrel in Mediterranean patients with diabetes mellitus and chronic coronary syndromes: A crossover pharmacodynamic investigation.

Patients with diabetes mellitus (DM) have augmented platelet reactivity and diminished responsiveness to clopidogrel. Ticagrelor, a more potent P2Y12 inhibitor, is clinically superior to clopidogrel in acute coronary syndromes, although its role in chronic coronary syndromes (CCS) is still the subject of debate. The aim of this investigation was to compare the pharmacodynamic effectiveness of ticagrelor and clopidogrel in Mediterranean DM patients with CCS. In this prospective, randomized, crossover study, patients (n = 20) were randomized (1:1) to receive, on top of aspirin therapy, either ticagrelor 180 mg loading dose (LD)/90 mg maintenance dose (MD) b.i.d. or clopidogrel 600 mg LD/75 mg MD o.d. for 1 week in a crossover fashion with a 2-4 week washout period between regimens. Platelet function measurements were performed at 4 timepoints in each period (baseline, 2 h and 24 h after LD, and 1 week), including light transmission aggregometry (LTA, primary endpoint), VASP assay, Multiplate and VerifyNow P2Y12. The ticagrelor LD achieved greater platelet inhibitory effect than clopidogrel LD, assessed with LTA (20 μM ADP as agonist), at 2 h (34.9 ± 3.9% vs. 63.6 ± 3.9%; p < 0.001) and 24 h (39.4 ± 3.5% vs. 52.3 ± 3.8%; p = 0.014). After 1 week of therapy, platelet reactivity was again significantly inferior with ticagrelor compared to clopidogrel (30.7 ± 3.0% vs. 54.3 ± 3.0%; p < 0.001). The results were consistent with the other platelet function assays employed. In Mediterranean patients with DM and CCS, ticagrelor provides a more potent antiplatelet effect than clopidogrel after the LD and during the maintenance phase of therapy. [ClinicalTrials.gov], identifier [NCT02457130].

Shielding the Vulnerable: A Multicentre Australian Rollout of Evusheld to Patients with Chronic Lymphocytic Leukaemia (CLL-SHIELD)

Background Patients with CLL are vulnerable to COVID-19 infection and complications due to underlying immunosuppression and B-cell depleting/targeted therapy (Chatzikonstantinou, Leukemia 2021). Furthermore, CLL patients have reduced seroconversion to all available COVID-19 vaccines, despite multiple dosing (Langerbeins, Blood 2022). Tixagevimab and Cilgavimab (Evusheld) was approved for pre-exposure COVID-19 prophylaxis based on the global PROVENT study in patients at risk of inadequate vaccine response, including 383 (7.4%) with cancer, but with no specific CLL data reported (Levin NEJM 2022). Patients with CLL may derive particular benefit from passive immunization, but also may be uniquely exposed to side-effects including compound cardiac signals for both Evusheld and BTKi, and injection site bleeding from BTKi anti-platelet effects. On 17 June 2022, Evusheld became publicly available to all CLL patients in Victoria, regardless of treatment status. Herein we describe the rapid rollout of Evusheld at 2 major Melbourne centers, including the establishment of a CLL cohort (CLL-SHIELD) for prospective follow-up of toxicity and efficacy. Methods: Evusheld was offered to all patients with CLL at the Peter MacCallum Cancer Center (PMCC) and Alfred Health (AH) from 20 June 2022. The rollout occurred via email or direct clinician contact (phone or in-person) at PMCC, and via hard copy mail, e-mail or direct contact at AH. Patients consenting to Evusheld were offered enrollment onto CLL-SHIELD, with planned review of patient-reported adverse events and incidence of interim COVID-19 infections via a standard questionnaire at 3, 6, and 12 months post administration. Data are de-identified at site and aggregated for analysis, with planned sensitivity analyses for treatment-center effect. Both centers have adapted a general policy of withholding any BTKi therapy for 5 days prior to and 2 days post administration to mitigate potential injection-site bleeding risk. Results: A total of 475 patients with CLL were contacted from PMCC (n=367) and AH (n=108) in the first 5 weeks of rollout. Patient-clinician discussion took place directly in person or by phone for 251 (53%) of patients, whereas 183 were contacted only by e-mail, and 41 by hard copy mail. The proportions of patients consenting to Evusheld by initial contact methods were 77.6% (n=195) for direct contact, 29.5% (n=54) for e-mail, and 12.2% (n=5) for hard copy mail (p<0.00001). Twenty-six patients who did not respond to e-mail/mail were contacted directly by their clinicians for in-person discussions; all 26 subsequently consented to Evusheld. In total, the proportion of patients who declined Evusheld following in-person consultation was 8.3% (n=23), with a further 9.7% (n=27) currently remaining undecided. The rate of Evusheld decline for patients contacted by e-mail or mail cannot be determined as only one patient replied with a clear negative response. At data cut-off, 182 of 280 (65%) consenting patients have received or have a booking to receive Evusheld. Rollout of Evusheld is ongoing at both centers and all consenting patients will be offered enrolment onto CLL-SHIELD for prospective monitoring of efficacy and toxicity. Clinical results from the 3-month post Evusheld data-cut, including rates of adverse events and COVID-19 infection, will be presented at the meeting. Conclusion: Rapid implementation of an Evusheld program is feasible in a large CLL population. Patient uptake of Evusheld was significantly higher following direct patient-clinician contact, likely due to improved opportunities for informed discussions, although this approach places short-term strain on healthcare resources. Evusheld has high acceptance rate among CLL patients, with <10% declining pre-exposure prophylaxis following in-person consultation.

Antiplatelet Effects of Inhibiting Coagulation Factor XI in a Diet-Induced Obesity Model of Early Atherosclerosis

Background: Atherosclerosis-associated cardiovascular disease (CVD) remains the leading cause of non-communicable death worldwide. In the setting of atherosclerosis, platelets facilitate monocyte trafficking and drive inflammatory pathways. Previous studies have shown that coagulation factor (F) XI can interact directly with multiple pathways that are complicit in CVD, including platelet activation. Therefore, the objective of this study was to investigate the effects of pharmacologically inhibiting FXI on systemic platelet function in a diet-induced obesity model of early atherosclerosis. Methods: Five rhesus macaques on a high-fat diet for ≥2 years with detectable carotid intimal thickening were administered a FXI function-blocking antibody, h1A6 (2 mg/kg). Blood was collected at baseline, one, and seven days after treatment. Flow cytometry studies were performed to asses platelet function in lean rhesus macaques on a standard chow diet, as well as obese rhesus macaques a high fat diet before and after treatment with h1A6. Platelet reactivity and platelet-leukocyte aggregate (PLA) formation in response to platelet hemostatic agents against GPVI (collagen-related peptide, CRP-XL) and PAR-1 (thrombin analog, TRAP-6) were measured by P-selectin expression. The coagulability of platelets in response to CRP-XL or TRAP-6 was measured by phosphatidylserine (PS) exposure. Results: Obese NHPs demonstrated increased P-selectin expression and phosphatidylserine exposure in response to GPVI and PAR-1 agonists relative to lean NHPs. This suggests that diet-induced obesity may increase platelet sensitivity, PLA formation, and platelet coagulability. Administration of a FXI function-blocking antibody resulted in prolonged clotting times, decreased GPVI- and PAR-1 mediated platelet sensitivity, and reduced PLA formation compared to basal levels. Phosphatidyl serine exposure was not affected by FXI inhibition. Conclusions: Pharmacological inhibition of FXI reversed the elevated platelet sensitivity and PLA formation observed in the diet-induced obesity model. Taken together, this suggests that coagulation FXI may modulate the exacerbated platelet function that is associated with atherosclerosis.

The Antiplatelet Effect of 4-Methylcatechol in a Real Population Sample and Determination of the Mechanism of Action.

A polyphenol-rich diet has beneficial effects on cardiovascular health. However, dietary polyphenols generally have low bioavailability and reach low plasma concentrations. Small phenolic metabolites of these compounds formed by human microbiota are much more easily absorbable and could be responsible for this effect. One of these metabolites, 4-methylcatechol (4-MC), was suggested to be a potent anti-platelet compound. The effect of 4-MC was tested ex vivo in a group of 53 generally healthy donors using impedance blood aggregometry. The mechanism of action of this compound was also investigated by employing various aggregation inducers/inhibitors and a combination of aggregometry and enzyme linked immunosorbent assay (ELISA) methods. 4-MC was confirmed to be more potent than acetylsalicylic acid on both arachidonic acid and collagen-triggered platelet aggregation. Its clinically relevant effect was found even at a concentration of 10 μM. Mechanistic studies showed that 4-MC is able to block platelet aggregation caused by the stimulation of different pathways (receptors for the von Willebrand factor and platelet-activating factor, glycoprotein IIb/IIIa, protein kinase C, intracellular calcium elevation). The major mechanism was defined as interference with cyclooxygenase-thromboxane synthase coupling. This study confirmed the strong antiplatelet potential of 4-MC in a group of healthy donors and defined its mechanism of action.

Abstract 13051: Comparative Antiplatelet Effects of Chlorthalidone and Hydrochlorothiazide

Introduction: The ACC/AHA hypertension guidelines recommended chlorthalidone (CTD) over hydrochlorothiazide (HCTZ) due to its longer half-life and proven reduction in major adverse cardiovascular events. The mechanism of the potential benefit of CTD compared to HCTZ has not been established. Unlike other thiazide diuretics, studies suggest that CTD may affect platelet aggregation, gene transcription, angiogenesis, and vascular permeability. We aimed to compare the antiplatelet effects of CTD versus HCTZ. Methods: We conducted a prospective, double-blind, randomized, three-way crossover study comparing the antiplatelet effects of CTD, HCTZ, and aspirin (ASA) in healthy volunteers ≥ 19 years of age. ASA was included in the study as a known control for inhibition of platelet aggregation. Whole blood aggregometry was used to assess the impact of treatments on platelet activation and aggregation. Results: Of the 40 subjects, 34 (85%) completed the 3-way crossover comparison. Six subjects were excluded due to non-compliance and adverse effects. Compared to ASA, both CTD and HCTZ had no antiplatelet effects (Table 1). There was no statistically significant difference between CTD and HCTZ in terms of platelet function. Conclusions: Although recent studies showed increased cardiovascular benefit with CTD compared to HCTZ, CTD and HCTZ do not have antiplatelet effects. Larger studies are needed to confirm our findings.

Abstract 10842: Progression of COVID-19 Severity Among SARS-CoV-2 Positive Patients Prescribed Selective Serotonin Reuptake Inhibitors

Introduction: The clinical spectrum of COVID-19 can range from asymptomatic to severe, with severe resulting in part from an intense inflammatory response. Selective serotonin reuptake inhibitor (SSRI) is the most commonly prescribed class of antidepressants and has anti-inflammatory and anti-platelet effects. Recent studies reported greater survival and lesser COVID severity in patients taking SSRIs, specifically fluoxetine/fluvoxamine. Recently, application was made to the FDA for emergency use of fluvoxamine to prevent severe COVID-19, but it was denied based on insufficient data. Methods: Patients (n=33,088) testing positive for SARS-CoV-2 between March 14, 2020-December 31, 2021 as outpatients were studied. Patients were matched 3:1 by SSRI prescription at the time of a positive test by propensity score (±0.001). Patients were evaluated for COVID-19 hospitalization within 14-days and death within 3-months of positive SARS-CoV-2 test. Results: A total of 8,272 SSRI patients were well-matched to 24,816 no SSRI patients (Table 1). Hospitalization and death were significantly greater in the SSRI group compared to the no SSRI group (Table 1). A total of 2,067 (25.0%) of SSRI patients were taking fluoxetine or fluvoxamine. While attenuated, no SSRI remained associated with a lower 14-day COVID-19 hospitalization risk when compared to fluoxetine or fluvoxamine use, but not with 3-month death (Table 2). Conclusion: This study did not find a lower risk of progression of COVID-19 severity with the use of any SSRI or fluoxetine/fluvoxamine alone. Results from this study support the FDA’s decision to not recommend their use at an early stage of a COVID-19 infection.

The protective effect of rivaroxaban with or without aspirin on inflammation, oxidative stress, and platelet reactivity in isoproterenol-induced cardiac injury in rats.

Coronary artery diseases are principal sources of mortality and disability in global human population. Progressively, rivaroxaban is being evaluated for the prevention of atherosclerotic thrombi, particularly with anti-platelet agents. Hence, the current report aimed to investigate the cardioprotective effect of rivaroxaban on isoproterenol (ISO)-induced cardiac injury model in rats and the possible synergistic effect when combined with aspirin. Male Wistar rats were randomly assigned into five different groups. Cardiac injury was induced by subcutaneous injection of ISO (85mg/kg) for 2 consecutive days. Rat tail bleeding time was performed prior to sacrifice. Cardiac enzymes, platelet activity, inflammatory, and oxidative stress biomarkers levels were measured using enzyme-linked immunoassay (ELISA). Pre-administration of rivaroxaban alone and on combination with aspirin prevented ISO-induced increase in cardiac thiobarbituric acid reactive substances (TBARS), interleukin 6 (IL-6), and thromboxane B2 (TXB2) levels. Moreover, a significant prolongation of bleeding time was demonstrated among aspirin, rivaroxaban, and aspirin plus rivaroxaban treated groups. On the other hand, the combination treatment of aspirin plus rivaroxaban showed no marked difference in these biomarkers and bleeding time relative to either drug administered separately. However, a prominent decrease of cardiac 6-keto prostaglandin F1α (6-Keto-PGF1α) level was displayed in the combination treatment when compared with ISO and rivaroxaban-treated groups, whereas no significant improvement was seen in cardiac glycoprotein V (GPV) levels except in aspirin-treated group. The study results demonstrated that rivaroxaban decreases cardiac oxidative stress, inflammation, and platelets reactivity. However, the addition of rivaroxaban to aspirin did not seem to show synergistic antioxidant, anti-inflammatory, or antiplatelet effect.

Coenzyme Q10 Attenuates Human Platelet Aggregation Induced by SARS-CoV-2 Spike Protein via Reducing Oxidative Stress In Vitro.

Platelet hyperreactivity and oxidative stress are the important causes of thrombotic disorders in patients with COVID-19. Oxidative stress, induced by the excessive generation of reactive oxygen species (ROS), could increase platelet function and the risk of thrombus formation. Coenzyme Q10 (CoQ10), exhibits strong antioxidative activity and anti-platelet effect. However, the effects and mechanisms of CoQ10 on attenuating platelet aggregation induced by spike protein have never been studied. This study aims to investigate whether the SARS-CoV-2 spike protein potentiates human platelet function via ROS signaling and the protective effect of CoQ10 in vitro. Using a series of platelet function assays, we found that spike protein potentiated platelet aggregation and oxidative stress, such as ROS level, mitochondrial membrane potential depolarization, and lipid damage level (MDA and 8-iso-PGF2α) in vitro. Furthermore, CoQ10 attenuated platelet aggregation induced by spike protein. As an anti-platelet mechanism, we showed that CoQ10 significantly decreased the excess production of ROS induced by spike protein. Our findings show that the protective effect of CoQ10 on spike protein-potentiated platelet aggregation is probably associated with its strong antioxidative ability.

Bioactive food components and their inhibitory actions in multiple platelet pathways.

In addition to hemostasis and thrombosis, blood platelets are involved in various processes such as inflammation, infection, immunobiology, cancer metastasis, wound repair and angiogenesis. Platelets' hemostatic and non-hemostatic functions are mediated by the expression of various membrane receptors and the release of proteins, ions and other mediators. Therefore, specific activities of platelets responsible for the non-hemostatic disease are to be inhibited while leaving the platelet's hemostatic function unaffected. Platelets' anti-aggregatory property has been used as a primary criterion for antiplatelet drugs/bioactives; however, their non-hemostatic activities are not well known. This review describes the hemostatic and non-hemostatic function of human blood platelets and the modulatory effects of bioactive food components. PRACTICAL APPLICATIONS: In this review, we have discussed the antiplatelet effects of several food components. These bioactive compounds inhibit both hemostatic and non-hemostatic pathways involving blood platelet. Platelets have emerged as critical biological factors of normal and pathologic vascular healing and other diseases such as cancers and inflammatory and immune disorders. The challenge for therapeutic intervention in these disorders will be to find drugs and bioactive compounds that preferentially block specific sites implicated in emerging roles of platelets' complicated contribution to inflammation, tumour growth, or other disorders while leaving at least some of their hemostatic function intact.

Antiplatelet Effects of Clopidogrel Vs Aspirin in Virologically Controlled HIV: A Randomized Controlled Trial

Patients with HIV exhibit platelet activation and increased risk of cardiovascular disease, the prevention of which is not fully known. Fifty-five HIV-positive patients were randomized to clopidogrel, aspirin, or no-treatment for 14days, and the platelet phenotype and ability to induce endothelial inflammation assessed. Clopidogrel as opposed to aspirin and no-treatment reduced platelet activation (P-selectin and PAC-1 expression). Compared with baseline, platelet-induced proinflammatory transcript expression of cultured endothelial cells were reduced in those assigned to clopidogrel, with no change in the aspirin and no-treatment arms. In HIV, clinical trials of clopidogrel to prevent cardiovascular disease are warranted. (Antiplatelet Therapy in HIV; NCT02559414).

Aspirin, Risk of Colorectal Cancer, & Genetic Risk-Letter.

We read with interest the study by Bakshi and colleagues in which they explored the association between genetic susceptibility to colorectal cancer and aspirin, using a 95-variant colorectal cancer polygenic risk score (PRS) in the participants of ASPREE (ASPirin in Reducing Events in the Elderly) trial (1). The ASPREE trial was a prospective double-blinded, placebo-controlled randomized trial in which 12,609 individuals of European descent ages ≥70 years were enrolled. They concluded that the 95-SNP PRS continues to identify individuals at higher risk of colorectal cancer, including individuals with no family history of colorectal cancer. Recently, Chen and colleagues, using data collected from a large population-based case–control study on colorectal cancer in Germany, analyzed PRS based on 140 colorectal cancer–related risk loci to quantify the genetic risk, reported that regular use of NSAIDs, including aspirin, was associated with significantly reduced colorectal cancer risk regardless of individual genetic profile (2). However, randomization of aspirin treatment in the ASPREE trial was not associated with a reduced incidence of colorectal cancer (P = 0.7).Also, a pooled analysis of two large U.S. cohort studies was published, the Nurses’ Health Study and Health Professionals Follow-up Study, with a total of 94,540 participants ages ≥70 years old (3). The analysis showed that initiating aspirin at an older age was not associated with a lower risk of colorectal cancer. In contrast, those who used aspirin before age 70 years and continued into their 70s or later had a reduced risk of colorectal cancer. A possible explanation is that a beneficial effect of aspirin for colorectal cancer requires at least 5 to 10 years of use (3).Over the last decades, aspirin has been an extensively prescribed drug with antiplatelet and anti-inflammatory effects (4). The mechanism of aspirin's possible anticancer effect is under investigation, but it is believed that it is through inhibiting catalytic enzymes COX-1 and COX-2 involved in prostaglandin synthesis. Therefore, in subjects taking aspirin, gut microbiome composition will shift toward a lower proportion of proinflammatory, colorectal cancer–predisposing bacteria (e.g., Fusobacteria) and a higher proportion of anti-inflammatory, colorectal cancer–protective bacteria (e.g., butyrate-producing bacteria; ref. 5).The recent study by Bakshi and colleagues and other recent high impacted trials on the effect of aspirin on cardiovascular disease and colorectal cancer risks have high translational values into the daily practice. However, there is a need for future preclinical and clinical trials on the impact of aspirin on gut microbiota and their metabolic and immunoregulatory potential.See the Response, p. 703No disclosures were reported.

Bentracimab demonstrates reversal of antiplatelet effects of ticagrelor: impact of hematocrit and generic versions of ticagrelor in vitro

Abstract Recent clinical studies demonstrated bentracimab provides immediate and sustained reversal of ticagrelor's antiplatelet effects in patients undergoing surgical procedures or with bleeding. Ticagrelor reversal was assessed by VerifyNow PRUTest (VN) and other platelet function testing assays in Phase I-III studies. As decreases in hematocrit (hct) may impact the VN result, it remains to be demonstrated whether this assay can detect platelet function restoration by bentracimab in bleeding patients with low hct. Additionally, bentracimab utility against generic ticagrelors is unknown. The purpose of this study was to determine the impact of decreased hct and generic forms of ticagrelor on platelet function and subsequent reversal by bentracimab, as measured by light transmission aggregometry (LTA) and VN. The hct level in blood samples collected from healthy volunteers (n=10) was sequentially lowered to 32, 30, 25, 22.5, 20 or 15% by addition of autologous platelet-rich plasma to whole blood with matching platelet counts. Prepared samples were treated with nothing, vehicle, or ticagrelor (3.0 μg/mL) followed by treatment with bentracimab (1.2 mg/mL). In a separate study, blood collected from healthy volunteers (n=10) was treated with nothing, vehicle, ticagrelor or generic ticagrelors (3.0 and 5.6 μg/mL; mean and peak plasma levels in the Phase 1 trial) prior to addition of bentracimab (0, 0.6, 1.2, 1.8 and 2.4 mg/mL; below the reported minimum to peak plasma level) to demonstrate a dose response. Reversal was assessed by either ADP-mediated LTA or VN or both assays. Results show a decrease in hct to &amp;lt;30% significantly increased the PRU in untreated samples (p&amp;lt;0.05). Ticagrelor treatment significantly decreased the PRU in all hct groups (p&amp;lt;0.0001). When normalized to each donor's baseline PRU values, bentracimab reversed the ticagrelor effects within 10-min, restoring the PRU value to 54–73% for all hct groups. PRU values were further restored to 85–93% of baseline PRU after 1-hr treatment. The PRU inhibition for both 10-min and 1-hr treatments were not significantly different across the hct groups, except for the 10-min treatment in the 15% hct group vs. unadjusted hct group (p&amp;lt;0.05), suggesting equivalent reversal by bentracimab across the hct range. In the second study, treatment with generic ticagrelor demonstrated significant platelet inhibition and was comparable to standard ticagrelor. Bentracimab (&amp;gt;0.6 mg/mL) immediately restored platelet function after ticagrelor treatment to 80–100% of baseline using the VN test. LTA data demonstrated similar results to VN, but as expected, reversal was less robust with 5.6 μg/mL ticagrelor + 0.6 mg/mL bentracimab combination (mean 55% of baseline values). Collectively, these data suggest the VN test can effectively measure the antiplatelet effects of ticagrelor and subsequent reversal, even at low hct, and bentracimab is also capable of reversing the antiplatelet effects of generic forms of ticagrelor. Funding Acknowledgement Type of funding sources: Private company. Main funding source(s): PhaseBio Pharmaceuticals, Inc

Prognostic implication of platelet reactivity according to disease entity after drug eluting stent implantation: results from the PTRG-DES consortium

Abstract Background Relationship between the level of antiplatelet effect and clinical event appears weak in East Asian patients. In addition prognostic implication of platelet reactivity may differ according to index presentation of disease entity (AMI vs. non-AMI). Methods PTRG-PFT consortium was established to determine the linkage of platelet function with long-term clinical outcome during DAPT (aspirin+clopidogrel) in DES-treated East Asian patients (n=11,714). Platelet reactivity was measured using the VerifyNow P2Y12 assay and its level was divided according to quartile distribution (≤168, 169–220, 221–271, ≥272 P2Y12 reaction unit [PRU]). Primary endpoints were incidences of major adverse cardiac and cerebrovascular events (MACCE) post-PCI. Results Impact of platelet reactivity on MACCE occurrence appeared proportionally increased irrespective of type of disease entity, but their relationship was relatively stronger in the AMI vs. non-AMI group (Figure 1A and B). The cutoff of high-risk platelet reactivity was lower in the AMI group compared with the non-AMI group (225 vs. 245 PRU), and the cutoff of low-risk platelet reactivity (immunity zone) was similar between the groups (175 vs. 170 PRU). In the AMI patients (28.5%), 3rd and 4th quartiles significantly increased MACCE rate (HRadjusted 2.19 and 2.24) (Figure 1C and D). However, 4th quartile only was significantly associated with increased risk of MACCE among the non-AMI patients (71.5%) (HRadjusted 2.19). Conclusion Close associations between platelet reactivity and MACCE occurrence were observed irrespective of type of disease entity. In addition, the targeted antiplatelet level to prevent platelet-centric events appeared similar between the AMI and non-AMI patients. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Korean Society of Intervention Cardiology

S1563 ACE Inhibitor Use Is Associated With Angioectasias on Video Capsule Endoscopy (VCE) in Patients With Iron Deficiency Anemia

Introduction: Small bowel bleeding poses a clinical challenge in patients with vascular lesions. Bleeding recurrence after endoscopic therapy is high and medical therapies have limited efficacy. In those with left ventricular assist devices (LVADs), the use of angiotensin converting enzyme inhibitors (ACEi) has been associated with a reduced rate of gastrointestinal bleeding. Conversely, the antiplatelet effects of ACEi have been described thought due to their effects in decreasing platelet aggregation. Our aim was to determine whether ACEi or angiotensin receptor blocker (ARB) therapy had an impact on the rate of positive VCE small bowel findings in those with iron deficiency anemia (IDA). Methods: Data was collected from consecutive inpatient and outpatient VCE examinations performed between January 1, 2009 to March 1, 2018 at a single U.S. tertiary medical center performed for IDA. VCE studies were excluded in those with incomplete small bowel examinations (9) or technical failure (1). Patient demographics, laboratory values, medication use and endoscopic findings were recorded. VCE findings were based on the P0-P2 grading system. The primary outcome of interest was a positive (P2) VCE. Data were analyzed using Wilcoxon rank-sum test for continuous variables and Fischer’s exact test for dichotomous variables. Bivariate logistic regression was performed to identify independent factors predictive of positive VCE. Results: Eighty-two VCE were included in the final analysis. Median age was 67.6 (IQR: 57.1-75.5) years and 38 (46.3%) patients were male. Thirty-seven (45.1%) VCE examinations were positive with the most common finding of angiectasia in 21 (55.3%). Risk factors for positive VCE are listed in Table 1. In univariate analysis, ACEi therapy associated with both positive VCE (P=0.014) and the presence of angiectasia (P=0.021), whereas ARB therapy did not associate with positive VCE. ACEi findings remained significant in bivariate analysis after controlling for cardiac and pulmonary comorbidities. Conclusion: In this single center study the presence of ACEi use was associated with small bowel and/or stomach angiectasias on VCE in univariate analysis and when controlled for cardiac and pulmonary risk factors. Further studies are required to determine the mechanistic impact of ACEi on gastrointestinal bleeding risk such as the reduction in von Willebrand factor or factors that affect platelet aggregation. Table 1. - Univariate predictors of positive video capsule endoscopy in iron deficiency anemia Negative VCE (n = 45) Positive VCE (n =37) P-value Age, years, mean (SD) 63.6 (15.8) 68.6 (9.3) 0.303 Male sex, n (%) 21 (46.7) 17 (46) 1 White race, n (%) 22 (48.9) 20 (54.1) 0.223 Active smoking, n (%) 6 (14) 11 (29.7) 0.105 Outpatient location, n (%) 31 (68.9) 21 (56.8) 0.357 Chronic kidney disease, n (%) 10 (22.2) 13 (35.1) 0.224 Chronic liver disease, n (%) 3 (6.7) 4 (10.8) 0.696 Congestive heart failure, n (%) 10 (22.2) 13 (35.1) 0.224 Diabetes mellitus, n (%) 15 (33.3) 15 (40.5) 0.645 Cardiac valvular disease, n (%) 7 (15.6) 6 (16.2) 1 Coronary artery disease, n (%) 14 (31.1) 14 (37.8) 0.641 Cardiac arrhythmia, n (%) 10 (22.2) 18 (48.7) 0.019 Chronic lung disease, n (%) 10 (22.2) 13 (35.1) 0.224 Left ventricular assist device, n (%) 2 (4.4) 2 (5.4) 1 Blood transfusion in the preceding 4 weeks, n (%) 17 (37.8) 16 (43.2) 0.656 Aspirin, n (%) 20 (44.4) 14 (37.8) 0.654 Thienopyridine, n (%) 3 (6.7) 2 (5.4) 1 Coumadin, n (%) 1 (2.2) 5 (13.5) 0.086 SSRI/SNRI, n (%) 7 (15.6) 9 (24.3) 0.404 ACEi 7 (15.6) 15 (40.5) 0.014 ARB 9 (20) 7 (18.9) 1 Hemoglobin, g/dL1 9.9 (1.7) 9.2 (2.3) 0.216 Platelets, 109/L1 225.4 (67.5) 208.6 (84.9) 0.202 BUN, mg/dL1 21.9 (13.1) 26.7 (22) 0.869 Creatinine, mg/dL1 1.3 (0.5) 1.9 (1.5) 0.197 Ferritin, ng/mL,1 128 (259) 39.6 (28.7) 0.966 Percent saturation, %1 14.8 (15.1) 13.7 (15.4) 0.76

Personalized allocation of acetylsalicylic acid therapy for secondary prevention of coronary artery disease.

BackgroundA single-daily dose of 75 mg of acetylsalicylic acid inhibits 100% of thromboxane-B2 synthesis within 30–60 min. Thromboxane-B2 synthesis then recovers slowly as new platelets are released from the bone marrow. Normally, only 10% of the platelets are replaced daily by new platelets entering circulation. Hence, 24 h after a dose of acetylsalicylic acid, thromboxane-B2 synthesis is still suppressed by more than 90%. Hence, there is an adequate anti-platelet effect even after 24 h of acetylsalicylic acid intake. However, some patients treated with once-daily acetylsalicylic acid may have an incomplete 24-h suppression of thromboxane-B2 synthesis due to increased platelet turnover. The response could be improved in such patients by twice-daily acetylsalicylic acid administration. This study aimed to identify such a group of patients who would benefit from a twice-daily dose of acetylsalicylic acid.Materials and methodsSerum thromboxane-B2 levels were measured in 79 patients with coronary artery disease receiving 75 mg of acetylsalicylic acid for secondary prophylaxis. Serum levels of thromboxane-B2 were measured after 4 and 24 h of acetylsalicylic acid intake. Patients were then classified into three groups: steady suppression group (serum thromboxane B2 is adequately suppressed at 4 and 24 h), i.e., adequate response to acetylsalicylic acid; fast recovery group (more than 10% rise in serum thromboxane-B2 levels at 24-h when compared to at 4-h) and non-responders (serum thromboxane-B2 levels of >3,100 pg/ml after 4 h of acetylsalicylic acid intake). Patients in the fast recovery group were given twice-daily acetylsalicylic acid and thromboxane-B2 levels were re-measured.ResultsA total of 20 patients (24.3%) had steady suppression of thromboxane-B2 and 11 patients (13.9%) belonged to the fast recovery group, i.e., thromboxane-B2 levels were adequately suppressed at 4 h but had recovered by more than 10% at 24 h; which was adequately suppressed by twice-daily acetylsalicylic acid (p 0.004). A total of 48 patients (60.8%) were non-responders.ConclusionTwice-daily acetylsalicylic acid may be beneficial if serum thromboxane-B2 levels at 4 h are <3,100 and >3,100 pg/ml at 24 h. If thromboxane-B2 levels at 4 and 24 h is <3100 pg/ml but if there is a >10% rise in serum thromboxane B2 at 24 h as compared to that at 4 h, then twice-daily acetylsalicylic acid should be considered. However, if thromboxane-B2 at 4 and 24 h is >3,100 pg/ml consider switching over to a P2Y12 inhibitor.

A Comprehensive Literature Review on Cardioprotective Effects of Bioactive Compounds Present in Fruits of Aristotelia chilensis Stuntz (Maqui).

Some fruits and vegetables, rich in bioactive compounds such as polyphenols, flavonoids, and anthocyanins, may inhibit platelet activation pathways and therefore reduce the risk of suffering from CVD when consumed regularly. Aristotelia chilensis Stuntz (Maqui) is a shrub or tree native to Chile with outstanding antioxidant activity, associated with its high content in anthocyanins, polyphenols, and flavonoids. Previous studies reveal different pharmacological properties for this berry, but its cardioprotective potential has been little studied. Despite having an abundant composition, and being rich in bioactive products with an antiplatelet role, there are few studies linking this berry with antiplatelet activity. This review summarizes and discusses relevant information on the cardioprotective potential of Maqui, based on its composition of bioactive compounds, mainly as a nutraceutical antiplatelet agent. Articles published between 2000 and 2022 in the following bibliographic databases were selected: PubMed, ScienceDirect, and Google Scholar. Our search revealed that Maqui is a promising cardiovascular target since extracts from this berry have direct effects on the reduction in cardiovascular risk factors (glucose index, obesity, diabetes, among others). Although studies on antiplatelet activity in this fruit are recent, its rich chemical composition clearly shows that the presence of chemical compounds (anthocyanins, flavonoids, phenolic acids, among others) with high antiplatelet potential can provide this berry with antiplatelet properties. These bioactive compounds have antiplatelet effects with multiple targets in the platelet, particularly, they have been related to the inhibition of thromboxane, thrombin, ADP, and GPVI receptors, or through the pathways by which these receptors stimulate platelet aggregation. Detailed studies are needed to clarify this gap in the literature, as well as to specifically evaluate the mechanism of action of Maqui extracts, due to the presence of phenolic compounds.

Effect of Chronic Antiplatelet and Anticoagulant Medication in Neck Hematoma and Perioperative Outcomes after Carotid Endarterectomy

A retrospective analysis of neck hematoma, stroke, and mortality after symptomatic and asymptomatic carotid endarterectomy (CEA) was conducted, to determine the most appropriate perioperative medication for these patients. Thirty-day outcomes of moderate and severe neck bleeding were also investigated. Patients undergoing CEA in a Vascular Surgery department were analyzed (2015-2019). Preprocedure antithrombotic medication (from the 5 days prior to surgery) was identified. End point predictors were identified by univariate and multivariable analyses and adjusted for confounders. A total of 304 CEA were included. Almost half of the included patients (49.67%) were under low-dose aspirin, 17.55% other single antiplatelet agent, 12.59% dual antiplatelet therapy, 8.61% anticoagulation, and 10.92% no antithrombotic therapy. There was a 8.22% rate of important hematoma, including 4.93% severe (requiring surgical exploration) hematomas and a 30-day all-stroke incidence of 2.94% in symptomatic and 1.79% asymptomatic patients (P=0.51). When compared to aspirin, severe hematoma was more prevalent with single clopidogrel or triflusal (relative risk [RR] 4.25, P=0.11), dual antiplatelet group (RR 11.84, P=0.002), and anticoagulation (RR 8.604, P=0.02). Dual antiaggregation and anticoagulation did not confer postoperative stroke protection compared to single aspirin in either symptomatic or asymptomatic patients. Nonsignificant higher intrahospital mortality was noted in no medication, dual antiplatelet, and anticoagulation groups in contrast to aspirin. Severe neck bleeding was associated with increased congestive heart failure (9.26-fold, P=0.03) and longer hospital stay (11.20±24.69days vs. 3.18±4.79 with no bleeding, P<0.001), with a tendency for higher hospital readmission at 30 days (4.66-fold, P=0.13). Mortality and stroke rates were similar. Double antiaggregation and anticoagulation did not confer better perioperative outcomes after elective CEA in our study. These regimens were associated with an increased risk of neck hematoma, especially severe bleeding, with similar rates of neurologic events in both symptomatic and asymptomatic patients and no mortality benefit. Monotherapy with aspirin appears to be the safest perioperative antithrombotic regimen for elective CEA.