Antiplatelet drugs block platelet activation by VITT patient serum.
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ABSTRACT:
SUBMITTER: Smith CW
PROVIDER: S-EPMC8697531 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The purpose of this study was to identify changes in platelet mRNA that result from exposure to antiplatelet therapy. A total of 84 healthy volunteers were recruited into a longitudinal study of various antiplatelet exposures with 58 completing all study visits. This was a 5 visit study where each visit was separated by ~ 4 weeks. At each Visit purified platelets using a CD45 negative selection protocol was performed in addition to platelet function testing using light transmittance aggregometry (ADP, EPI, and Collagen) and PFA100 (Col/EPI). After the baseline visit (V1), participants were randomized to receive 81mg/day or 325mg/day aspirin x 4 weeks followed by Visit 2. Participants then crossed over to the alternative dose of aspirin for 4 weeks followed by Visit 3. Between Visits 3 and 4 participants washed out their aspirin for 4 weeks. The final exposure was ticagrelor 90mg twice daily x 4 weeks until Visit 5.
2022-03-14 | GSE158765 | GEO
Project description: Not available
| S-EPMC9262283 | biostudies-literature
Project description:BACKGROUNDAntiplatelet medications are increasingly used in dogs. Remote analysis of platelet activity is challenging, limiting assessment of antiplatelet drug efficacy.HYPOTHESIS/OBJECTIVESTo evaluate a method used in humans for stimulation and remote analysis of canine platelet activity.ANIMALSForty-five dogs of various ages without a coagulopathy or thrombocytopenia. Six were receiving antiplatelet medication.METHODSProspective observational study. Platelets were stimulated with combinations of arachidonic acid (AA) and epinephrine (Epi) or adenosine diphosphate (ADP) and the thromboxane A2 -mimetic U46619 (U4). PAMFix was added to the blood samples to facilitate delayed analysis of platelet activity. Activity was assessed by flow cytometric measurement of surface P-selectin (CD62P) expression.RESULTSCanine platelets could be stimulated with both AA/Epi and ADP/U4. The levels of P-selectin were significantly greater than paired, unstimulated samples (P < 0.001). Inhibition of P-selectin expression occurred after this stimulation by adding antiplatelet drugs in vitro. The efficacy of antiplatelet drugs in samples from treated dogs was also measurable ex vivo using this method. Delayed analysis of platelet activity at time points up to 22 days demonstrated excellent correlation between respective mf values at each time point (r2 = 0.92, P < 0.0001).CONCLUSIONS AND CLINICAL IMPORTANCEThis study evaluated a new method to remotely assess canine platelet activity. It shows that PAMFix can be used for this purpose. This provides opportunities to interrogate the inhibitory action of antiplatelet drugs in clinical settings.
| S-EPMC5787215 | biostudies-literature
Project description:Cardiovascular diseases are the leading cause of death in the Western world. Several factors have led to the increase in vascular disorders, including the aging population, unhealthy lifestyles, increasing rates of diabetes and raised lipids, and further risk factors resulting in inflammation and calcification of the vascular endothelium. Activated platelets in damaged blood vessels can trigger arterial thrombus formation, leading to vascular occlusion with subsequent organ hypoperfusion and clinical manifestation of myocardial infarction, stroke, or peripheral artery disease. Platelet inhibitors such as aspirin and clopidogrel (Plavix(®) and generics) are prescribed as primary or secondary prevention to attenuate chronic platelet activation. However, a significant proportion of patients do not respond adequately to uniform antiplatelet treatment. These 'non-responders' have an increased risk for stent thrombosis, stroke, and other ischemic complications. Platelet function (PF) tests can identify these patients thus enabling physicians to offer personalized and alternative treatment strategies. Recent alternatives to clopidogrel include prasugrel (Efient(®)) and ticagrelor (Brilique(®)) - that are both more potent than clopidogrel but also more expensive and associated with a higher risk of bleeding complications. Given these drawbacks, PF testing might help clinicians to prescribe optimal antiplatelet agent to maximize patient safety and efficacy while minimizing costs. While randomized studies using different test systems have left clinicians puzzled about the medical value of tailored antiplatelet therapy, accumulated evidence from recent studies on tailored antiplatelet therapies and the association with improved outcomes have now resulted in a consensus expert opinion for the specific adoption of PF diagnostics into clinical practice.
| S-EPMC4975182 | biostudies-other
Project description:Platelet mRNA in response to antiplatelet therapy exposure
| PRJNA666442 | ENA
Project description:Vaccination is crucial in combatting the severe acute respiratory syndrome coronavirus 2 pandemic. The rare complication of thrombocytopenia and thrombotic complications at unusual sites after ChAdOx1 nCov-19 vaccination is caused by platelet-activating antibodies directed against platelet factor 4 (PF4). We present a widely applicable whole-blood standard flow cytometric assay to identify the pathogenic antibodies associated with vaccine-induced immune-mediated thrombotic thrombocytopenia (VITT) after ChAdOx1 nCov-19 vaccination. This assay will enable rapid diagnosis by many laboratories. This trial was registered at www.clinicaltrials.gov as #NCT04370119.
| S-EPMC8105122 | biostudies-literature
Project description:Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe adverse effect of ChAdOx1 nCoV-19 COVID-19 vaccine (Vaxzevria) and Janssen Ad26.COV2.S COVID-19 vaccine, and it is associated with unusual thrombosis. VITT is caused by anti-platelet factor 4 (PF4) antibodies activating platelets through their FcγRIIa receptors. Antibodies that activate platelets through FcγRIIa receptors have also been identified in patients with COVID-19. These findings raise concern that vaccination-induced antibodies against anti-SARS-CoV-2 spike protein cause thrombosis by cross-reacting with PF4. Immunogenic epitopes of PF4 and SARS-CoV-2 spike protein were compared using in silico prediction tools and 3D modeling. The SARS-CoV-2 spike protein and PF4 share at least 1 similar epitope. Reactivity of purified anti-PF4 antibodies from patients with VITT was tested against recombinant SARS-CoV-2 spike protein. However, none of the affinity-purified anti-PF4 antibodies from 14 patients with VITT cross-reacted with SARS-CoV-2 spike protein. Sera from 222 polymerase chain reaction-confirmed patients with COVID-19 from 5 European centers were tested by PF4-heparin enzyme-linked immunosorbent assays and PF4-dependent platelet activation assays. We found anti-PF4 antibodies in sera from 19 (8.6%) of 222 patients with COVID-19. However, only 4 showed weak to moderate platelet activation in the presence of PF4, and none of those patients developed thrombotic complications. Among 10 (4.5%) of 222 patients who had COVID-19 with thrombosis, none showed PF4-dependent platelet-activating antibodies. In conclusion, antibodies against PF4 induced by vaccination do not cross-react with the SARS-CoV-2 spike protein, indicating that the intended vaccine-induced immune response against SARS-CoV-2 spike protein is not the trigger of VITT. PF4-reactive antibodies found in patients with COVID-19 in this study were not associated with thrombotic complications.
| S-EPMC8294553 | biostudies-literature
Project description:BackgroundDuring long-term antiplatelet agents (APAs) administration, patients with thrombotic diseases take a fairly high risk of life-threatening bleeding, especially when in need of urgent surgery. Rapid functional reversal of APAs remains an issue yet to be efficiently resolved by far due to the lack of any specific reversal agent in the clinic, which greatly restricts the use of APAs.MethodsFlow cytometry analysis was first applied to assess the dose-dependent reversal activity of platelet-mimicking perfluorocarbon-based nanosponges (PLT-PFCs) toward ticagrelor. The tail bleeding time of mice treated with APAs followed by PLT-PFCs was recorded at different time points, along with corresponding pharmacokinetic analysis of ticagrelor and tirofiban. A hemorrhagic transformation model was established in experimental stroke mice with thrombolytic/antiplatelet therapy. Magnetic resonance imaging was subsequently applied to observe hemorrhage and thrombosis in vivo. Further evaluation of the spontaneous clot formation activity of PLT-PFCs was achieved by clot retraction assay in vitro.ResultsPLT-PFCs potently reversed the antiplatelet effect of APAs by competitively binding with APAs. PLT-PFCs showed high binding affinity comparable to fresh platelets in vitro with first-line APAs, ticagrelor and tirofiban, and efficiently reversed their function in both tail bleeding and postischemic-reperfusion models. Moreover, the deficiency of platelet intrinsic thrombotic activity diminished the risk of thrombogenesis.ConclusionsThis study demonstrated the safety and effectiveness of platelet-mimicking nanosponges in ameliorating the bleeding risk of different APAs, which offers a promising strategy for the management of bleeding complications induced by antiplatelet therapy.
| S-EPMC9891290 | biostudies-literature
Project description:Patients with CKD display a significantly higher risk of cardiovascular and thromboembolic complications, with around half of patients with advanced CKD ultimately dying of cardiovascular disease. Paradoxically, these patients also have a higher risk of hemorrhages, greatly complicating patient therapy. Platelets are central to hemostasis, and altered platelet function resulting in either platelet hyper- or hyporeactivity may contribute to thrombotic or hemorrhagic complications. Different molecular changes have been identified that may underlie altered platelet activity and hemostasis in CKD. In this study, we summarize the knowledge on CKD-induced aberrations in hemostasis, with a special focus on platelet abnormalities. We also discuss how prominent alterations in vascular integrity, coagulation, and red blood cell count in CKD may contribute to altered hemostasis in these patients who are high risk. Furthermore, with patients with CKD commonly receiving antiplatelet therapy to prevent secondary atherothrombotic complications, we discuss antiplatelet treatment strategies and their risk versus benefit in terms of thrombosis prevention, bleeding, and clinical outcome depending on CKD stage. This reveals a careful consideration of benefits versus risks of antiplatelet therapy in patients with CKD, balancing thrombotic versus bleeding risk. Nonetheless, despite antiplatelet therapy, patients with CKD remain at high cardiovascular risk. Thus, deep insights into altered platelet activity in CKD and underlying mechanisms are important for the optimization and development of current and novel antiplatelet treatment strategies, specifically tailored to these patients who are high risk. Ultimately, this review underlines the importance of a closer investigation of altered platelet function, hemostasis, and antiplatelet therapy in patients with CKD.
| S-EPMC8763166 | biostudies-literature
Project description:The paper reflects the results of molecular docking and mathematical DFT simulation for antiplatelet drugs and the target platelet receptor/ferment interaction in the limited area. The results of Raman spectra simulation are implemented and obtained from the interaction of the clopidogrel metabolite of the P2Y12 receptor. The interaction of aspirin with the COX-1 enzyme was also investigated. As a result, theoretical Raman spectra of the drug-receptor area were obtained. The theoretical data were compared with the experimental SERS results. The characteristic bands corresponding to metabolite/ferment and antiplatelet drug vibrations were clarified. The prospects of obtaining results for pathologies based on platelet conformations during cardiovascular diseases have been demonstrated.
| S-EPMC10792092 | biostudies-literature