Antiplatelet Effects Research Articles

Cilostazol Alleviates Delayed Cerebral Ischemia After Subarachnoid Hemorrhage by Attenuating Microcirculatory Dysfunction.

Cilostazol, a phosphodiesterase 3 (PDE3) inhibitor that exerts antiplatelet effects, has therapeutic potential for delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). However, its mechanism of action remains unclear. We hypothesized that cilostazol alleviates DCI by improving cerebral microcirculatory dysfunction, which is a component of early brain injury. To test this hypothesis, we analyzed the intracerebral circulation time (iCCT) in 256 patients with aSAH from two randomized controlled trials (74 received cilostazol, 54 received pitavastatin, and 128 were controls). A minority of patients (n = 72, 28%) developed severe angiographic vasospasm (aVS) and DCI (n = 42, 16%) and had poor outcomes (n = 35, 14%). We measured iCCT as the time to peak in the ultraearly phase (baseline) and the subacute phase or at DCI onset (follow-up). The cilostazol group had shorter follow-up iCCT and larger iCCT differences than the other groups, indicating improved microcirculatory function, particularly in patients with DCI and poor outcomes. Multivariate analysis revealed that cilostazol treatment is a significant predictor of favorable outcomes, whereas DCI occurrence, a decrease in iCCT differences, and high clinical severity (Hunt & Hess grades 3-4) were associated with poor outcomes. Diminished microcirculatory dysfunction may alleviate DCI and improve outcomes among patients with aSAH following cilostazol treatment. Further research is warranted to confirm these findings and explore the dose-dependent effects of cilostazol on the microcirculatory function.

Use of common cardiovascular disease drugs and risk of dementia: A case-control study in Swedish national register data.

Cardiovascular drug use may help prevent dementia; however, current evidence is mixed. Using a case-control design, we investigated the association between duration and combination of multiple cardiovascular drug classes and incident dementia. From the Swedish national registers, we included 88,065 incident dementia cases aged ≥70 at diagnosis between 2011 and 2016 and 880,650 age- and sex-matched controls. Cardiovascular drug use was ascertained from the Prescribed Drug Register. Long-term users (≥ 5years) of antihypertensives, diuretics, lipid-lowering drugs (LLDs), and oral anticoagulants (OACs) had statistically significantly fewer dementia diagnoses (odds ratio [OR] 0.75-0.91) than non-users. Antiplatelets use was associated with more dementia diagnoses (OR 1.13-1.25). Use of antihypertensives in combination with diuretics, LLDs, and OACs for ≥5 years was associated with fewer dementia diagnoses (OR 0.66-0.84). Preventing dementia via cardiovascular drug pathways may be possible. It is however important to consider the potential long-term negative cognitive effect of antiplatelets. Use ≥5 years of common cardiovascular drugs was associated with lower dementia risk. Common cardiovascular drug combination use was associated with lower dementia risk. Anti-platelet use of any duration was associated with higher dementia risk.

Impact of antiplatelets, anticoagulants and cyclic nucleotide stimulators on neutrophil extracellular traps (NETs) and inflammatory markers during COVID-19.

While the association between coronavirus disease-19 (COVID-19) and neutrophils extracellular traps (NETs) is recognized, uncertainties remain regarding its precise onset, timing of resolution and target therapy. To assess changes in inflammatory and NET markers during the first week of COVID-19 hospitalization, and the association with disease severity. "In vitro" experiments investigated the effect of antiplatelets, anticoagulants, and cyclic nucleotide stimulators on NETs release. Prospective cohort study, changes in interleukin (IL)-6, IL-8, IL-17, TNF-α, RANTES, PF4, and citrullinated-H3 (citH3) levels within each outcome group was evaluated using ANOVA. Differences between moderately ill, critically ill, and non-survivors were determined using Kruskal-Wallis and logistic regression. Healthy neutrophils were stimulated with phorbol-12-myristate-13-acetate (PMA) or COVID-19 sera and treated with unfractionated heparin (UFH), low molecular weight heparin (LMWH), aspirin (ASA), ticagrelor, cinaciguat, sildenafil, and milrinone. The proportion of NETosis was assessed using IncuCyte Cell Imager. Of the 125 patients, 40.8% had moderate COVID-19, 40.8% had critical COVID-19 but recovered, and 18.4% died. From admission to hospitalization day 8, IL-6 levels decreased in moderately and critically ill, but not in non-survivors, while citH3 levels increased in critically ill and non-survivors. IL-6, IL-8, and TNF-α levels were associated with critical and fatal COVID-19. The release of NETs by neutrophils stimulated with PMA or COVID-19 sera was decreased in the presence of ASA, UFH, LMWH and cyclic nucleotide stimulators in a dose-dependent manner. In the first week of hospitalization, NET markers rose later than inflammatory markers in severe COVID-19 cases. Cyclic nucleotide stimulators, ASA and heparin may emerge as treatment approaches as they may modulate NETosis.

Abstract 4129709: Aspirin-Nanoparticle for Dual Therapies: Targeted Anti-Inflammatory and Prolonged Anti-Platelet Effects for Atherosclerosis

Background: The current unmet needs for aspirin usage in atherosclerosis lie in its short half-life and narrow indication for anti-platelet effects. Daily aspirin intake is mandatory, and the anti-inflammatory effects of aspirin for atherosclerosis have not successfully translated to clinical practice. Nanoparticles remain in circulation for 2-3 days, with a large portion being cleared by splenic monocytes, which are known to inherently target inflamed sites. Hypothesis: By altering the pharmacokinetics of aspirin through loading into nanoparticles, aspirin-nanoparticles can exert prolonged anti-platelet effects and target atherosclerosis sites via monocyte carriers for anti-inflammatory effects, resulting in dual therapies. Methods: Splenic monocytes were loaded with aspirin-liposomes and co-cultured with endothelial cells or platelets to examine the interactions between them using high-resolution time-series microscopy. Prolonged anti-platelet effects and targeted anti-inflammatory effects of aspirin were validated in intact mice and hindlimb ischemia models, respectively. Furthermore, the dual therapies of aspirin-liposomes were validated in an atherosclerotic mouse model created by partial carotid ligation and a western diet in apoE gene knock-out mice. Results: When splenic monocytes were loaded with aspirin-liposomes, they emitted extracellular vesicles (EVs) loaded with aspirin towards endothelial cells or platelets. As inflamed cells upregulate caveolin expression, they uptake an increased amount of transferred EVs compared to non-inflamed cells. Additionally, aspirin-liposomes showed prolonged circulation time and increased splenic accumulation compared to aspirin itself, resulting in prolonged anti-platelet effects (>7 days) and targeted anti-inflammatory effects at inflamed sites. Compared to the daily oral aspirin group in the atherosclerosis model, the weekly intravenous aspirin-liposome group showed superior therapeutic effects, including attenuated systemic and local inflammation and patent lumen in atherosclerotic sites. Conclusion: Aspirin-nanoparticles can exert prolonged anti-platelet effects combined with targeted anti-inflammatory effects, resulting in superior therapeutic effects on atherosclerosis.

Risk factors for major bleeding among patients with chronic kidney disease treated with acetylsalicylic acid.

Individuals with chronic kidney disease (CKD) are at increased risk for thrombotic events and bleeding. Acetylsalicylic acid (ASA), an effective antiplatelet agent, is one of the most frequently used medications for both primary and secondary prevention of cardiovascular disease (CVD). However, it can also contribute to bleeding events due to its inherent antiplatelet effect. The objective of this study was to determine the characteristics of CKD patients at increased risk for bleeding under ASA therapy. This retrospective analysis included patients with non-dialysis dependent CKD who were treated with ASA for primary prevention of CVD for at least 3 consecutive months and did not receive anti-coagulants or anti-platelets. Data were collected from electronic medical records from January 2014 to December 2018. CKD diagnosis was based on an estimated glomerular filtration rate of <60 ml/min/1.73 m2. CKD patients who experienced major bleeding events during ASA therapy (bleeding group) vs. all others (control group) were compared. Additional outcomes included first documented non-fatal cardiovascular event and all-cause mortality. Of the 900 adult CKD patients included in this analysis, 82 (9.1%) had a major bleeding event during 31.6±25.9 months of follow-up. The most common bleeding site was gastrointestinal (52 cases, 63.4% of major bleeding events). Patients who had a major bleeding event were older (76.5±10 vs. 74±10.3 years, P=0.038). On multivariate analysis, age was the most important predictor of major bleeding event (odds ratio 1.029, 95% confidence interval 1.004-1.056). Given its controversial efficacy in primary prevention of CVD in CKD patients, characterizing those at increased risk for bleeding under ASA therapy is important in the era of tailored medicine. Age, CKD stage and cardiovascular risk are key factors to consider regarding the safety and effectiveness of ASA for CKD patients.

Antioxidant and antiplatelet effect of nanodispersions with conjugate of glutathione and lipoic acid

To increase the therapeutic effectiveness of antioxidants (lipoic acid and glutathione) and improve their transport to target cells, various methods of modifying its substances are used. In this work, the synthesis of an amide derivative of lipoic acid and glutathione (GSH–LA) is performed, and GSH–LA nanodispersions based on Pluronic F68 are obtained. The most pronounced antioxidant and antiplatelet effects are exhibited by nanoparticles containing GSH–LA at the maximum tested concentration.

Long-term FXa inhibition attenuates thromboinflammation after acute myocardial infarction and stroke by platelet proteome alteration

BackgroundImmediate activated factor (F)X (FXa) inhibition exerts direct antiplatelet effects in the context of arterial thrombosis but little is known about the impact of long-term therapy on platelet function in ischemic cardiovascular diseases. ObjectivesTherefore, we analyzed platelet-derived effects of long-term FXa inhibition in the setting of acute myocardial infarction (AMI) and stroke. MethodsWe evaluated the effect of acute versus chronic FXa inhibition on thromboinflammation following AMI and stroke in mice in vivo. Mechanistically, we identified changes in platelet gene expression and proteome under chronic FXa nonvitamin K antagonist oral anticoagulant treatment and characterized its functional consequence on platelet physiology. In a prospectively recruited cohort of patients with AMI, we determined cardiovascular magnetic resonance based cardiac endpoints under FXa nonvitamin K antagonist oral anticoagulant effects on clinical endpoints in a cohort of patients with AMI. ResultsChronic but not acute FXa inhibition reduced cerebral and myocardial infarct size and improved cardiac function 24 hours after AMI in mice. Mechanistically, we identified an attenuated thromboinflammatory response with reduced neutrophil extracellular trap formation in mice and patient samples. Proteome and RNA expression analysis of FXa inhibitor treated patients revealed a reduction of key regulators within the membrane trafficking and secretion machinery hampering platelet α and dense granule release. Subsequent, thromboinflammatory neutrophil extracellular trap density in thrombi isolated from stroke and myocardial infarction patients was reduced. Patients with AMI treated with FXa inhibitors showed decreased infarct size after myocardial infarction compared to patients without anticoagulation treatment. ConclusionLong-term FXa inhibition induces antithromboinflammatory proteome signatures in platelets, improving infarct size after myocardial infarction and stroke.

Functional Foods in Preventing Human Blood Platelet Hyperactivity-Mediated Diseases-An Updated Review.

A systematic search of the PUBMED database from 2000 to 2023 was conducted using the selected keywords: "functional foods", "polyphenols", "fatty acids", "herbs", fruits and vegetables", "cardioprotective agents", "plant", "platelet aggregation", "platelet activation", "clinical and non-clinical trial", "randomized", and "controlled". Potent natural antiplatelet factors have been described, including omega-3 fatty acids, polyphenols, and other phytochemicals. Antiplatelet bioactive compounds in food that can prevent platelet hyperactivity and thus may prevent several platelet-mediated diseases, including cardiovascular disease. This narrative review describes the work during 2000-2023 in developing functional foods from natural sources with antiplatelet effects.

Metabolomics revealed pharmacodynamic effects of aspirin and indobufen in patients after percutaneous transluminal angioplasty surgery.

Aspirin and indobufen are commonly used therapeutic drugs for the prevention of vascular restenosis (VR) after percutaneous transluminal angioplasty surgery. They both exhibited antiplatelet effects but molecular mechanisms underlying metabolic changes induced by them remain unclear. In this study, we collected plasma samples from patients on aspirin medication (n = 5), patients on indobufen medication, patients with no medication after PTA, and healthy controls (CKs) (n = 5). Our investigation aimed to reveal the metabolic processes in patients during vascular restenosis and its amelioration through drug therapy using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Our data showed significant alterations in amino acid and choline metabolism in patients without medication after PTA. Aspirin and indobufen were able to regulate these metabolic pathways to alleviate VR symptoms. We identified several characteristic amino acids, including pro-leu, L-citrulline, his-glu, and L-glutamate, as important biomarkers for VR assessment in patients without medication after PTA. A total of 17 and 4 metabolites involved in arginine and phenylalanine metabolism were specifically induced by aspirin and indobufen, respectively. Their expression levels were significantly regulated by aspirin or indobufen, nearly reaching normal levels. Taken together, our identification of metabolites involved in metabolic changes affected by aspirin and indobufen medication enhances the understanding of VR pathology after PTA. This may help identify early diagnostic biomarkers and therapeutic targets.

Phase I results of both IV and oral administration for CG-0255: a novel fast-acting antiplatelet drug with a new activation pathway

Abstract Clopidogrel is an extremely widely used antiplatelet drug, but with serious shortcomings. It is a prodrug that depends critically on liver CYP oxidation enzyme CYP2C19 for activation to its active metabolite H4. However, large fractions of world population carry loss of function CYP2C19 alleles, ranging from a low ~21% in Latino to a strikingly high ~59% in east Asian population. Known as clopidogrel resistance, US FDA added a black box warning to clopidogrel label. Despite this issue, routine CYP2C19 screening for clopidogrel patients is not performed, putting many patients at risk. Clopidogrel is also slow to take effect and not amenable for IV formulation, limiting its clinical use in emergency. To overcome these issues, we have invented a novel antiplatelet drug CG-0255, which is the world’s first thioester prodrug with a new activation pathway. CG-0255 has been designed to require only abundantly present and widely distributed carboxylesterases for metabolizing to its active metabolite, which is identical to clopidogrel active metabolite H4 generated through CYP metabolism. Thus, CG-0255 completely bypasses the CYP metabolism and overcomes clopidogrel resistance. In addition, CG-0255 has a much faster onset of action and high solubility in water and has been formulated for both IV and oral administration. Here we report the results of an open label phase I study of CG-0255 oral tablets to assess safety, tolerability, pharmacodynamics (PK), and pharmacokinetics (PD: inhibition of platelet aggregation, IPA) in healthy volunteers. It was a single dose escalation study, 4 cohorts with 6 participants each given CG-0255 oral tablets at doses ranging from 2 to 10 mg. Clopidogrel was the positive control and given at 300 mg. Blood samples for PK/PD analysis were collected pre-dosing and at various time points post dosing. VerifyNow was used for IPA measurement. CG-0255 is generally safe and well tolerated. PK analysis shows fast and consistent conversion of CG-0255 to active metabolite H4. PD results indicate that CG-0255 IPA is dose-dependent, easily matching or surpassing that of clopidogrel 300 mg for all doses. At the highest 10 mg dose, CG-0255 IPA reaches over 90% in less than 30 minutes, well above that of clopidogrel. In addition, CG-0255 IPA shows minimum individual variations, and the antiplatelet effect is long lasting due to its irreversible binding to the P2Y12 receptor. These results are consistent with our earlier reported Phase I results for CG-0255 IV injection. In conclusion, CG-0255 is a novel, fast-acting and long-lasting antiplatelet drug. It shares identical metabolite H4 with clopidogrel but relies only on carboxylesterases for activation, overcoming the resistance and other issues associated CYP-based oxidation metabolism. As the only antiplatelet drug available for both IV and oral administrations, CG-0255 fills unmet medical needs and will greatly benefit patients and medical community.

Ticagrelor or prasugrel versus clopidogrel in patients with coronary heart disease

Abstract Introduction Antiplatelet therapy is pivotal in the management of coronary heart disease (CHD), especially after percutaneous coronary intervention (PCI). Clopidogrel has long been the cornerstone of dual antiplatelet therapy. However, newer agents like prasugrel and ticagrelor boast of faster onset of action and greater platelet inhibition, which may translate to improved outcomes. Purpose Our hypothesis is that prasugrel or ticagrelor are superior to clopidogrel in reducing cardiovascular mortality in chronic CHD patients. Methods We conducted a retrospective cohort study using the TriNetX network database, including patients with chronic CHD on dual antiplatelet therapy. A total of 1,420,165 patients on clopidogrel and 197,783 on prasugrel or ticagrelor were identified. We assessed the primary composite endpoint of cardiovascular mortality over a 5-year follow-up period, using event-free survival as our main outcome measure. Results The 5-year follow-up data revealed a significant difference in event-free survival between the groups. Patients on prasugrel or ticagrelor had a markedly higher event-free survival rate of 83.156% compared to 73.209% for those on clopidogrel. The Log Rank test showed a confidence interval of 1.544 to 1.592 with a highly significant p-value of &amp;lt;0.0001. Discussion The data suggest a clear benefit of prasugrel or ticagrelor over clopidogrel for event-free survival in CHD patients. This could be attributed to the more potent antiplatelet effects of these drugs, leading to reduced thrombotic events. Given the substantial sample size and robustness of the data, the findings advocate for a paradigm shift in the choice of more potent antiplatelet agents in clinical practice. Conclusion Our analysis supports the hypothesis that prasugrel or ticagrelor are associated with significantly lower cardiovascular mortality compared to clopidogrel in patients with chronic coronary heart disease.5-year Kaplan-Meier curves for mortality

PERSPECTIVES FOR THE USE OF PLANT RAW MATERIALS OF THE CLOVER MEADOW (TRIFOLIUM PRATENSE L.) IN PHARMACY

Background. The creation and registration of original medicines based on plant raw materials are becoming promising areas in pharmaceutical practice. Clover meadow (Trifolium pratense L.) has been used in folk medicine for a long time, due to the content of many biologically active substances with Therapeutic properties. It grows over large areas; extracts are easy to obtain from plant raw materials and have a certain economic attractiveness. In this regard, compounds extracted from meadow clover can be considered as potential precursors for the development of new promising pharmaceuticals. Aim. Carrying out a narrative review on the Perspectives of the use of biologically active substances extracted from the plant raw materials of meadow clover in pharmaceutical practice. Material and methods. The scientific publications of the PubMed biomedical research database are analyzed. Results. Meadow clover (Trifolium pratense L.) is a widespread perennial herbaceous plant belonging to the pharmacopoeia group. Extracts obtained from plant raw materials have a wide range of biological activity. The largest proportion of them are isoflavones, flavonoids, saponins, clovamides and phenolic acids. Isoflavones have a phytoestrogenic effect, and in this regard, they are successfully used in the treatment of diseases of the reproductive system. In addition, their anti-inflammatory, reparative properties have been proven; they can be used for the prevention and recovery of metabolic disorders. Flavonoids, saponins, clovamides and phenolic acids have antioxidant and antiplatelet effects. Conclusion. Among biologically active substances extracted from meadow clover, the greatest use in pharmacological practice was noted for isoflavones. At the same time, there are a few other potentially effective compounds with known medicinal properties. Their further study is required in order to create new original medicines

The effect of concurrent clopidogrel and omeprazole administration on clopidogrel metabolism and platelet function in healthy cats.

Some studies in humans show that the concurrent use of clopidogrel and omeprazole decreases plasma clopidogrel active metabolite (CAM) concentrations and clopidogrel antiplatelet effects. Whether this drug interaction occurs in cats is unknown. We hypothesized that administration of clopidogrel with omeprazole would decrease plasma CAM concentrations and decrease clopidogrel antiplatelet effects in healthy cats. Ten domestic cats. In this 2-sequence, 2-period, 2-treatment randomized crossover study, healthy cats were randomly assigned to receive clopidogrel only (18.75 mg PO q24h) or clopidogrel with omeprazole (1 mg/kg PO q12h) for 10 days, followed by a 2-week washout period, and then the opposite treatment for another 10 days. Blood was collected by jugular venipuncture on days 0, 5, and 10. Plasma CAM concentrations were measured using high-performance liquid chromatography-tandem mass spectrometry. Platelet function was evaluated using Plateletworks, Multiplate Analyzer, and Platelet Function Analyzer-100 (PFA-100). Multiplate Analyzer and PFA-100 detected no difference in platelet function between days or treatment groups. Plateletworks detected a significant difference (P < .001) in platelet function from day 0 to 5 and day 0 to 10 in both treatment groups but no difference between treatment groups. Plasma CAM concentrations were significantly lower on day 10 (P < .02) in cats receiving both medications versus clopidogrel only. Concurrent omeprazole and clopidogrel administration was associated with altered pharmacokinetics on day 10, but no difference in pharmacodynamics between the 2 treatment groups. The short-term use of clopidogrel and omeprazole does not seem to alter platelet function significantly.

Effects of selective serotonin reuptake inhibitors on platelet functions: a literature review.

Many epidemiological studies have evidenced an increased bleeding risk associated with selective serotonin reuptake inhibitors (SSRIs), yet the underlying mechanisms remain unclear. This review summarizes data on SSRIs' effects on platelet functions assessed with assays used in clinical practice and highlights the areas that deserve further investigation. Conflicting results of SSRI effects on platelet aggregation were observed irrespectively of the agonist used, the antidepressant drug or the study type. Alike, discrepant results were reported with flow-cytometry-based assays assessing either platelet surface glycoprotein levels, integrin activation, agonist-induced secretion of intraplatelet granule content or membrane anionic phospholipid exposure. Other tests may have detected a platelet function defect in SSRIs samples, however, results were largely inconsistent. Critical literature examination unveils very low certainty of evidence on potential SSRI effect on platelet functions. Findings are often inconsistent even when similar methods are used, most likely because of differences in study design, included patients (age, comorbid conditions), SSRIs' type and dose, uncontrolled confounding factors, and statistical analysis power. Further studies are needed to disentangle any intrinsic antiplatelet effect of SSRIs and the multiple confounding factors, mainly the depression control itself and the degree of platelet SERT inhibition.

Unbiased high-throughput screening of drug-repurposing libraries identifies small-molecule inhibitors of clot retraction

AbstractPlatelet clot retraction, the ultimate phase of platelet thrombus formation, is critical for clot stabilization. It requires functional αIIbβ3 receptors, fibrin, and the integrated actions of the actin-myosin contractile and cytoskeletal systems. Disturbances in clot retraction have been associated with both bleeding and thrombosis. We recently demonstrated that platelets treated with the αIIbβ3 antagonist peptide RGDW, which eliminates fibrinogen-mediated platelet aggregation, are still able to retract clots. We have exploited this observation to develop an unbiased, functional high-throughput assay to identify small-molecule inhibitors of fibrin-mediated clot retraction adapted for a 384-well plate format. We tested 9710 compounds from drug-repurposing libraries (DRLs). These libraries contain compounds that are either US Food and Drug Administration approved or have undergone preclinical/clinical development. We identified 27 compounds from the Library of Pharmacologically Active Compounds library as inhibitors of clot retraction, of which 14 are known inhibitors of platelet function. From the DRLs, we identified 135 compounds (1.6% hit rate). After extensive curation, these compounds were categorized based on the activity of their reported target. Multiple kinase and phosphodiesterase inhibitors with known antiplatelet effects were identified, along with multiple deubiquitination and receptor inhibitors, as well as compounds that have not previously been reported to have antiplatelet activity. Studies of 1 of the deubiquitination inhibitors (degrasyn) suggest that its effects are downstream of thrombin-induced platelet-fibrinogen interactions and thus may permit the separation of platelet thrombin-induced aggregation-mediated events from clot retraction. Additional studies of the identified compounds may lead to novel mechanisms of inhibiting thrombosis.

Pharmacological effects of small molecule BCR-ABL tyrosine kinase inhibitors on platelet function.

Tyrosine kinase inhibitors (TKIs) targeting the BCR-ABL fusion protein, such as imatinib (Gleevec), have revolutionized targeted cancer therapies. However, drug resistance and side effects, particularly those affecting hemostasis, continue to pose significant challenges for TKI therapies. As tyrosine kinases serve pivotal roles in platelet hemostatic function, we investigated the potential impact of both established and emerging ABL TKIs on human platelet activities ex vivo Our study included standard-of-care agents (e.g., imatinib and nilotinib), and second-generation ABL inhibitors including ponatinib and bosutinib designed to mitigate drug resistance. Additionally, we explored the effects of allosteric inhibitors targeting the myristoyl pocket of ABL (e.g., asciminib and GNF-2), and novel agents in preclinical development, including ELVN-919, which uniquely exhibits high specificity for the ABL kinase active site. Our findings reveal that while ABL inhibitors such as ponatinib and bosutinib impede platelet activity, highly specific new-generation ABL inhibitors, including first-in-class therapeutics, do not impact platelet function ex vivo Overall, these new insights around the effects of ABL TKIs on platelet function could inform the development of targeted therapies with reduced hematologic toxicities. Significance Statement This study examines the effects of clinically relevant small molecule BCR-ABL tyrosine kinase inhibitors (TKIs) on platelet activity. This analysis includes first-time assessments of agents such as asciminib and ELVN-919 on human platelet function ex vivo, alongside established therapies (e.g., imatinib, ponatinib) with well-characterized effects on platelet function, to discern potential anti-platelet and other effects of BCR-ABL TKIs and inform clinical safety.

8539 Curcumin a Double Edged Sword: A Case of Curcumin Induced Pituitary Macroadenoma Apoplexy

Abstract Disclosure: P. Balozian: None. D. Alfakara: None. M. Linz: None. &amp;lt;Curcumin, the active component of turmeric, exerts numerous beneficial anti-inflammatory, antiplatelet, and anticoagulant effects. Recent literature has shown however that curcumin inhibits proliferation and induces apoptosis of pituitary cells. Despite these findings, there are limited clinical cases reporting an association between curcumin and pituitary adenoma apoplexy.We report the case of a 39-year old G9P6A3 female with Hashimoto’s disease and class II obesity who presented with a constant bifrontal excruciating headache, blurry vision, photophobia, and nausea. She also had fatigue and amenorrhea for two years. Her exam showed normal vitals, decreased visual acuity, diplopia, and bitemporal hemianopsia. Data showed a serum prolactin of 69 ug/L , plasma IGF-1 of 133 ng/ml (Z score -0.4), TSH of 2.58 with a free T4 of 0.47 ng/dl [0.61-1.12 ng/dL], a random cortisol of 12.7 mcg/dl despite her stress and pain, ACTH of 27 pg/ml, DHEA-S of 46 mcg/dl, an LH of 0.5 IU/L, and an FSH of 4mIU/ml with an estradiol of 25 pg/ml. MRI of the pituitary revealed a 1.8 cm macroadenoma with a mass effect on the overlying optic chiasm and a T1 intrinsic hyperintense signal indicative of a hemorrhagic component. She was given IV dexamethasone for 24 hours then underwent transsphenoidal resection of the hemorrhagic tumor that resulted in rapid resolution of headaches and visual symptoms. She was not given any glucocorticoids during or after surgery. Labs immediately after surgery revealed a prolactin of &amp;lt;1ug/L and a cortisol of 26.7 mcg/dl. Pathology showed corticotroph tumor with hemosiderin deposition with a 4.2% Ki67 and negative ACTH immunostaining. On medication review, patient had been taking large doses of curcumin. In the absence of other recent precipitating factors, it was highly likely that she had curcumin-triggered apoplexy of a pituitary macroadenoma. Most recent bloodwork, about 20 months from presentation, revealed a serum prolactin of 5.0 ug/L, IGF-1 of 123ng/mL (Z score -0.6), TSH of 0.97 mIU/L with a free T4 of 0.85 ng/dL, a random cortisol of 5.3 ug/dL, ACTH of 18.2 pg/mL, DHEA-S of 94 ug/dL, LH of 2.5 IU/L, FSH of 4.3 IU/L, and an estradiol of 45 pg/mL. Regular menstrual cycles had resumed. Headaches, nausea, and vision abnormalities completely resolved.The case illustrates the need to identify any herbal remedies and supplements a patient is taking, particularly turmeric, as supplements may contribute to increased bleeding tendency of an already existing adenoma. The case also emphasizes the potential rapid recovery of pituitary function after surgical resection of an apoplectic pituitary tumor.&amp;gt; Presentation: 6/3/2024

The first in-human study to evaluate the antiplatelet properties of the clopidogrel conjugate DT-678 in acute coronary syndrome patients and healthy volunteers.

DT-678 is a novel antiplatelet prodrug, capable of releasing the antiplatelet active metabolite of clopidogrel (AM) upon exposure to glutathione. In this study, we investigated factors responsible for clopidogrel high on-treatment platelet reactivity (HTPR) in acute coronary syndrome (ACS) patients and evaluated the capacity of DT-678 to overcome HTPR. A total of 300 consecutive ACS patients naive to P2Y12 receptor inhibitors were recruited and genotyped for CYP2C19 alleles. Blood samples were drawn before and after administration of 600-mg clopidogrel. Platelet reactivity index (PRI) and plasma AM concentrations were determined and grouped according to their CYP2C19 genotypes. DT-678 was applied ex vivo to whole blood samples to examine its inhibitory effects. To further examine the antiplatelet effectiveness of DT-678 in vivo, 20 healthy human subjects were recruited in a Phase I clinical trial, and each received a single dose of either 3-mg DT-678 or 75-mg clopidogrel. The pharmacokinetics and pharmacodynamics in different CYP2C19 genotype groups were compared. Statistical analyses revealed that CYP2C19 genotype, body mass index, hyperuricaemia, and baseline PRI were significantly associated with a higher risk of clopidogrel HTPR in ACS patients. The addition of DT-678 ex vivo decreased baseline PRI regardless of CYP2C19 genotypes, overcoming clopidogrel HTPR. This observation was further confirmed in healthy volunteers receiving 3mg of DT-678. These results suggest that DT-678 effectively overcomes clopidogrel HTPR resulting from genetic and/or clinical factors in Chinese ACS patients, demonstrating its potential to improve antiplatelet therapy.

Aspirin's Antiplatelet Effects Promote Arteriovenous Fistula Maturation in Hemodialysis Patients: A Systematic Review

Background: Arteriovenous fistula (AVF) is the preferred vascular access for hemodialysis, offering superior long-term patency and lower infection rates compared to other options. However, AVF maturation remains a significant challenge. This systematic review aims to evaluate the efficacy of aspirin in promoting AVF maturation and preventing failure in hemodialysis patients. Methods: A comprehensive search of electronic databases, including ScienceDirect, SpringerLink, PubMed, Cochrane, and ProQuest, was conducted from 2014 to 2024. Studies investigating the impact of aspirin on AVF maturation and failure were included. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were followed. Results: Five studies met the inclusion criteria, encompassing a total of 982 participants. Four studies indicated that aspirin significantly enhanced AVF maturation by increasing flow volume and promoting the development of a robust fistula. However, one study found that aspirin did not significantly reduce the risk of thrombosis or AVF failure. Conclusion: Aspirin appears to be a promising adjunct therapy for promoting AVF maturation in hemodialysis patients. Its antiplatelet effects, primarily through cyclooxygenase inhibition and reduced platelet activation, contribute to improved flow volume and fistula maturation. While the evidence for aspirin's role in preventing AVF failure is mixed, its potential benefits in enhancing maturation warrant further investigation.

Anti-platelet Effects of Artemisinin through Regulation of Cyclic Nucleotide on Collagen-induced human Platelets

Anti-platelet Effects of Artemisinin through Regulation of Cyclic Nucleotide on Collagen-induced human Platelets