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JACC. Cardiovascular Interventions May 2024
Topics: Humans; Aspirin; Drug Administration Schedule; Hemorrhage; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Risk Assessment; Risk Factors; Treatment Outcome
PubMed: 38811106
DOI: 10.1016/j.jcin.2024.04.020 -
Life Sciences Aug 2024Dysregulated platelet aggregation is a fatal condition in many bacterial- and virus-induced diseases. However, classical antithrombotics cannot completely prevent...
AIMS
Dysregulated platelet aggregation is a fatal condition in many bacterial- and virus-induced diseases. However, classical antithrombotics cannot completely prevent immunothrombosis, due to the unaddressed mechanisms towards inflammation. Thus, targeting platelet hyperactivation together with inflammation might provide new treatment options in diseases, characterized by immunothrombosis, such as COVID-19 and sepsis. The aim of this study was to investigate the antiaggregatory effect and mode of action of 1.8-cineole, a monoterpene derived from the essential oil of eucalyptus leaves, known for its anti-inflammatory proprieties.
MAIN METHODS
Platelet activity was monitored by measuring the expression and release of platelet activation markers, i.e., P-selectin, CD63 and CCL5, as well as platelet aggregation, upon treatment with 1.8-cineole and stimulation with several classical stimuli and bacteria. A kinase activity assay was used to elucidate the mode of action, followed by a detailed analysis of the involvement of the adenylyl-cyclase (AC)-cyclic adenosine monophosphate (cAMP)-protein kinase A (PKA) pathway by Western blot and ELISA.
KEY FINDINGS
1.8-cineole prevented the expression and release of platelet activation markers, as well as platelet aggregation, upon induction of aggregation with classical stimuli and immunological agonists. Mechanistically, 1.8- cineole influences the activation of the AC-cAMP-PKA pathway, leading to higher cAMP levels and vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Finally, blocking the adenosine A receptor reversed the antithrombotic effect of 1.8-cineole.
SIGNIFICANCE
Given the recognized anti-inflammatory attributes of 1.8-cineole, coupled with our findings, 1.8-cineole might emerge as a promising candidate for treating conditions marked by platelet activation and abnormal inflammation.
Topics: Eucalyptol; Receptor, Adenosine A2A; Platelet Activation; Platelet Aggregation; Humans; Cyclic AMP; Blood Platelets; Signal Transduction; P-Selectin; Cyclic AMP-Dependent Protein Kinases; Platelet Aggregation Inhibitors; Anti-Inflammatory Agents; COVID-19
PubMed: 38810792
DOI: 10.1016/j.lfs.2024.122746 -
Journal of the American Heart... Jun 2024Ticagrelor is a platelet P2Y receptor inhibitor approved for use in patients with acute coronary syndromes, coronary artery disease, and low-moderate risk acute ischemic... (Review)
Review
Ticagrelor is a platelet P2Y receptor inhibitor approved for use in patients with acute coronary syndromes, coronary artery disease, and low-moderate risk acute ischemic stroke or high-risk transient ischemic attack. Clinical trials have evaluated the efficacy and safety of ticagrelor on ischemic and bleeding outcomes for different indications and with varying treatment approaches. As a result, there is a large body of clinical evidence demonstrating different degrees of net clinical benefit compared with other platelet inhibitor drugs based on indication, patient characteristics, clinical presentation, treatment duration, and other factors. We provide a review of the major trials of ticagrelor in the context of other randomized trials of clopidogrel and prasugrel to organize the volume of available information, elevate corroborating and conflicting data, and identify potential gaps as areas for further exploration of optimal antiplatelet treatment.
Topics: Humans; Ticagrelor; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists; Acute Coronary Syndrome; Randomized Controlled Trials as Topic; Treatment Outcome; Coronary Artery Disease; Hemorrhage
PubMed: 38804216
DOI: 10.1161/JAHA.123.031606 -
Journal of the American Heart... Jun 2024ADP and ATP are importantly involved in vascular and thrombotic homeostasis, via multiple receptor pathways. Blockade of ADP P2Y receptors inhibits platelet aggregation... (Randomized Controlled Trial)
Randomized Controlled Trial
Safety, Tolerability, and Pharmacodynamics of AZD3366 (Optimized Human CD39L3 Apyrase) Alone and in Combination With Ticagrelor and Acetylsalicylic Acid: A Phase 1, Randomized, Placebo-Controlled Study.
BACKGROUND
ADP and ATP are importantly involved in vascular and thrombotic homeostasis, via multiple receptor pathways. Blockade of ADP P2Y receptors inhibits platelet aggregation and represents an effective cardiovascular disease prevention strategy. AZD3366 (APT102), a long-acting recombinant form of an optimized CD39L3 human apyrase, has effectively reduced ATP, ADP, and platelet aggregation and provided tissue protection in preclinical models, features that could be very beneficial in treating patients with cardiovascular disease.
METHODS AND RESULTS
We conducted this phase 1, first-in-human study of single ascending doses of intravenous AZD3366 or placebo, including doses added to dual antiplatelet therapy with ticagrelor and acetylsalicylic acid. The primary objective was safety and tolerability; secondary and exploratory objectives included pharmacokinetics, pharmacodynamics (measured as inhibition of platelet aggregation), adenosine diphosphatase (ADPase) activity, and ATP/ADP metabolism. In total, 104 participants were randomized. AZD3366 was generally well tolerated, with no major safety concerns observed. ADPase activity increased in a dose-dependent manner with a strong correlation to AZD3366 exposure. Inhibition of ADP-stimulated platelet aggregation was immediate, substantial, and durable. In addition, there was a prompt decrease in systemic ATP concentration and an increase in adenosine monophosphate concentrations, whereas ADP concentration appeared generally unaltered. At higher doses, there was a prolongation of capillary bleeding time without detectable changes in the ex vivo thromboelastometric parameters.
CONCLUSIONS
AZD3366 was well tolerated in healthy participants and demonstrated substantial and durable inhibition of platelet aggregation after single dosing. Higher doses prolonged capillary bleeding time without detectable changes in ex vivo thromboelastometric parameters.
REGISTRATION
URL: https://www.clinicaltrials.gov; Unique Identifier: NCT04588727.
Topics: Humans; Male; Ticagrelor; Female; Apyrase; Platelet Aggregation; Aspirin; Platelet Aggregation Inhibitors; Middle Aged; Adult; Double-Blind Method; Dual Anti-Platelet Therapy; Drug Therapy, Combination; Young Adult; Adenosine Diphosphate; Blood Platelets; Dose-Response Relationship, Drug; Treatment Outcome; Recombinant Proteins; Purinergic P2Y Receptor Antagonists
PubMed: 38804212
DOI: 10.1161/JAHA.123.033985 -
BioRxiv : the Preprint Server For... May 2024Thrombosis is a major cause of myocardial infarction and ischemic stroke. The sodium/potassium ATPase (NKA), comprising α and β subunits, is crucial in maintaining...
BACKGROUND
Thrombosis is a major cause of myocardial infarction and ischemic stroke. The sodium/potassium ATPase (NKA), comprising α and β subunits, is crucial in maintaining intracellular sodium and potassium gradients. However, the role of NKA in platelet function and thrombosis remains unclear.
METHODS
We utilized wild-type (WT, α) and NKA α1 heterozygous (α) mice, aged 8 to 16 weeks, of both sexes. An intravital microscopy-based, FeCl-induced carotid artery injury thrombosis model was employed for in vivo thrombosis assessment. Platelet transfusion assays were used to evaluate platelet NKA α1 function on thrombosis. Human platelets isolated from healthy donors and heart failure patients treated with/without digoxin were used for platelet function and signaling assay. Complementary molecular approaches were used for mechanistic studies.
RESULTS
NKA α1 haplodeficiency significantly reduced its expression on platelets without affecting sodium homeostasis. It significantly inhibited 7.5% FeCl-induced thrombosis in male but not female mice without disturbing hemostasis. Transfusion of α, but not α, platelets to thrombocytopenic WT mice substantially prolonged thrombosis. Treating WT mice with low-dose ouabain or marinobufagenin, both binding NKA α1 and inhibiting its ion-transporting function, markedly inhibited thrombosis in vivo. NKA α1 formed complexes with leucine-glycine-leucine (LGL)-containing platelet receptors, including P2Y12, PAR4, and thromboxane A2 receptor. This binding was significantly attenuated by LGL>SFT mutation or LGL peptide. Haplodeficiency of NKA α1 in mice or ouabain treatment of human platelets notably inhibited ADP-induced platelet aggregation. While not affecting 10% FeCl-induced thrombosis, NKA α1 haplodeficiency significantly prolonged thrombosis time in mice treated with an ineffective dose of clopidogrel.
CONCLUSION
NKA α1 plays an essential role in enhancing platelet activation through binding to LGL-containing platelet GPCRs. NKA α1 haplodeficiency or inhibition with low-dose ouabain and marinobufagenin significantly inhibited thrombosis and sensitized clopidogrel's anti-thrombotic effect. Targeting NKA α1 emerges as a promising antiplatelet and antithrombotic therapeutic strategy.
PubMed: 38798556
DOI: 10.1101/2024.05.13.593923 -
BioRxiv : the Preprint Server For... May 2024Patients with pathogenic variants in (inherited platelet disorder (IPD)-18) have normal platelet counts but show impaired platelet aggregation due to diminished...
Patients with pathogenic variants in (inherited platelet disorder (IPD)-18) have normal platelet counts but show impaired platelet aggregation due to diminished activation of αIIbβ3 integrin. This defect results in moderate to severe bleeding episodes, especially following surgical procedures, which require patients to be transfused with platelets and/or pro-hemostatic agents. We recently demonstrated that the hemostatic efficacy of transfused platelets is limited by dysfunctional endogenous platelets in a mouse model of IPD-18 ( mice), as dysfunctional platelets were recruited to the forming hemostatic plug but did not participate in clot contraction. Consequently, higher amounts of transfused platelets were required to outcompete these dysfunctional cells and to reverse bleeding. We here studied the usefulness of thromboelastography with platelet mapping (TEG-PM), a method to evaluate platelet-dependent clot contraction, for monitoring of the hemostatic potential in mice transfused with various amounts of wild-type (WT) platelets. whole blood samples did not contract in TEG-PM, consistent with a critical role of this protein in αIIbβ3 activation. Addition of WT platelets improved TEG parameters (K time, α-angle, MA) in a ratio dependent manner, consistent with our recent in vivo studies showing impaired hemostasis at a 5:1, but not at a 2:1 ratio of mutant to WT platelets. Interestingly, K and α values were identified as better predictors of transfusion efficacy than MA, the most platelet-dependent TEG parameter. In conclusion, this proof-of-concept study supports the use of TEG-PM to monitor platelet transfusion ratios and hemostatic potential in IPD-18 and potentially other platelet disorders.
PubMed: 38798516
DOI: 10.1101/2024.05.09.593198 -
BioRxiv : the Preprint Server For... May 2024Platelets are highly reactive fragments of megakaryocytes that play a fundamental role in thrombosis and hemostasis. Predictably, all conventional anti-platelet...
Platelets are highly reactive fragments of megakaryocytes that play a fundamental role in thrombosis and hemostasis. Predictably, all conventional anti-platelet therapies elicit bleeding, raising the question whether the thrombotic activity of platelets can be targeted separately. In this study, we describe a novel approach of inhibiting platelet activation through the use of bispecific single-chain variable fragments (bi-scFvs), termed cis-acting platelet receptor inhibitors (CAPRIs) that harness the immunoreceptor tyrosine-based inhibition motif (ITIM)-containing co-inhibitory receptor G6b-B (G6B) to suppress immunoreceptor tyrosine-based (ITAM)-containing receptor-mediated platelet activation. CAPRI-mediated hetero-clustering of G6B with either the ITAM-containing GPVI-FcR γ-chain complex or FcγRIIA (CD32A) inhibited collagen- or immune complex-induced platelet aggregation. G6B-GPVI CAPRIs strongly and specifically inhibited thrombus formation on collagen under arterial shear, whereas G6B-CD32A CAPRI strongly and specifically inhibited thrombus formation to heparin-induced thrombocytopenia, vaccine-induced thrombotic thrombocytopenia and antiphospholipid syndrome complexes on Von Willebrand Factor-coated surfaces and photochemical-injured endothelial cells under arterial shear. Our findings provide proof-of-concept that CAPRIs are highly effective at inhibiting ITAM receptor-mediated platelet activation, laying the foundation for a novel family of anti-thrombotic therapeutics with potentially improved efficacy and fewer bleeding outcomes compared with current anti-platelet therapies. .
PubMed: 38798354
DOI: 10.1101/2024.05.10.593500 -
Scientific Reports May 2024Spontaneous intracerebral hemorrhage (SICH) remains a devastating form of stroke. Prior use of antiplatelets or warfarin before SICH is associated with poor outcomes,...
Spontaneous intracerebral hemorrhage (SICH) remains a devastating form of stroke. Prior use of antiplatelets or warfarin before SICH is associated with poor outcomes, but the effects of direct oral anticoagulants (DOACs) remain unclear. This study aimed to clarify trends in prior antithrombotic use and to assess the associations between prior use of antithrombotics and in-hospital mortality using a multicenter prospective registry in Japan. In total, 1085 patients were analyzed. Prior antithrombotic medication included antiplatelets in 14.2%, oral anticoagulants in 8.1%, and both in 1.8%. Prior warfarin use was significantly associated with in-hospital mortality (odds ratio [OR] 5.50, 95% confidence interval [CI] 1.30-23.26, P < 0.05) compared to no prior antithrombotic use. No such association was evident between prior DOAC use and no prior antithrombotic use (OR 1.34, 95% CI 0.44-4.05, P = 0.606). Concomitant use of antiplatelets and warfarin further increased the in-hospital mortality rate (37.5%) compared to warfarin alone (17.2%), but no such association was found for antiplatelets plus DOACs (8.3%) compared to DOACs alone (11.9%). Prior use of warfarin remains an independent risk factor for in-hospital mortality after SICH in the era of DOACs. Further strategies are warranted to reduce SICH among patients receiving oral anticoagulants and to prevent serious outcomes.
Topics: Humans; Hospital Mortality; Aged; Female; Male; Registries; Cerebral Hemorrhage; Warfarin; Japan; Aged, 80 and over; Anticoagulants; Fibrinolytic Agents; Middle Aged; Risk Factors; Platelet Aggregation Inhibitors; Prospective Studies
PubMed: 38796624
DOI: 10.1038/s41598-024-62717-5 -
Pharmaceuticals (Basel, Switzerland) May 2024Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely utilized pharmaceuticals worldwide. Besides their recognized anti-inflammatory effects, these... (Review)
Review
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most widely utilized pharmaceuticals worldwide. Besides their recognized anti-inflammatory effects, these drugs exhibit various other pleiotropic effects in several cells, including platelets. Within this article, the multifaceted properties of NSAIDs on platelet functions, activation and viability, as well as their interaction(s) with established antiplatelet medications, by hindering several platelet agonists' pathways and receptors, are thoroughly reviewed. The efficacy and safety of NSAIDs as adjunctive therapies for conditions involving inflammation and platelet activation are also discussed. Emphasis is given to the antiplatelet potential of commonly administered NSAIDs medications, such as ibuprofen, diclofenac, naproxen and ketoprofen, alongside non-opioid analgesic and antipyretic medications like paracetamol. This article delves into their mechanisms of action against different pathways of platelet activation, aggregation and overall platelet functions, highlighting additional health-promoting properties of these anti-inflammatory and analgesic agents, without neglecting the induced by these drugs' side-effects on platelets' functionality and thrombocytopenia. Environmental issues emerging from the ever-increased subscription of these drugs are also discussed, along with the need for novel water treatment methodologies for their appropriate elimination from water and wastewater samples. Despite being efficiently eliminated during wastewater treatment processes on occasion, NSAIDs remain prevalent and are found at significant concentrations in water bodies that receive effluents from wastewater treatment plants (WWTPs), since there is no one-size-fits-all solution for removing all contaminants from wastewater, depending on the specific characteristics of the wastewater. Several novel methods have been studied, with adsorption being proposed as a cost-effective and environmentally friendly method for wastewater purification from such drugs. This article also presents limitations and future prospects regarding the observed antiplatelet effects of NSAIDs, as well as the potential of novel derivatives of these compounds, with benefits in other important platelet functions.
PubMed: 38794197
DOI: 10.3390/ph17050627 -
Pharmaceuticals (Basel, Switzerland) Apr 2024Polypharmacy is a global healthcare concern, especially among the elderly, leading to drug interactions and adverse reactions, which are significant causes of death in...
Polypharmacy is a global healthcare concern, especially among the elderly, leading to drug interactions and adverse reactions, which are significant causes of death in developed nations. However, the integration of pharmacogenetics can help mitigate these risks. In this study, the data from 483 patients, primarily elderly and polymedicated, were analyzed using Eugenomic's personalized prescription software, g-Nomic. The most prescribed drug classes included antihypertensives, platelet aggregation inhibitors, cholesterol-lowering drugs, and gastroprotective medications. Drug-lifestyle interactions primarily involved inhibitions but also included inductions. Interactions were analyzed considering gender. Significant genetic variants identified in the study encompassed , and . To prevent adverse reactions and enhance medication effectiveness, it is strongly recommended to consider pharmacogenetics testing. This approach shows great promise in optimizing medication regimens and ultimately improving patient outcomes.
PubMed: 38794134
DOI: 10.3390/ph17050565