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Thrombosis Research Jun 2024Dysregulated host response to infection causes life-threatening organ dysfunction. Excessive inflammation and abnormal blood coagulation can lead to disseminated...
INTRODUCTION
Dysregulated host response to infection causes life-threatening organ dysfunction. Excessive inflammation and abnormal blood coagulation can lead to disseminated intravascular coagulation (DIC) and multiple-organ failure in the late sepsis stages. Platelet function impairment in sepsis contributes to bleeding, secondary infection, and tissue injury. Platelet transfusion is considered in patients with sepsis with DIC and bleeding; however, its benefits are limited and of low quality. Fibrinogen plays a crucial role in platelet function, and establishing a fibrin network binds to activated integrin αIIbβ3 and promotes outside-in signaling that amplifies platelet functions. However, the role of fibrinogen in sepsis-induced platelet dysfunction remains unclear.
MATERIALS AND METHODS
We evaluated the effects of fibrinogen on platelet hyporeactivity during septic shock in adult male Wistar rats using lipopolysaccharide (LPS) injection and cecal ligation and puncture (CLP) surgery. Changes in the hemodynamic, biochemical, and coagulation parameters were examined. Platelet activation and aggregation were measured using whole-blood assay, 96-well plate-based aggregometry, and light-transmission aggregometry. Additionally, platelet adhesion, spreading, and fibrin clot retraction were evaluated.
RESULTS
Rats with LPS- and CLP-induced sepsis displayed considerable decreases in plasma fibrinogen levels and platelet aggregation, adhesion, spreading, and clot retraction. The aggregation of platelets obtained from rats with sepsis was markedly augmented by fibrinogen supplementation. Additionally, fibrinogen administration improved platelet adhesion, spreading, and clot retraction in rats with sepsis.
CONCLUSIONS
Fibrinogen supplementation could serve as a potential therapeutic intervention for alleviating platelet hyporeactivity in patients with sepsis and bleeding.
PubMed: 38945093
DOI: 10.1016/j.thromres.2024.109072 -
Journal of Pharmaceutical and... Jun 2024Oxylipins are important low abundant signaling molecules in living organisms. In platelets they play a primary role in platelet activation and aggregation in the course...
Non-enantioselective, enantioselective, and two-dimensional liquid chromatography coupled with tandem mass spectrometry for the study of stereochemical disposition of oxylipins in cGMP-regulated hemin-treated platelets.
Oxylipins are important low abundant signaling molecules in living organisms. In platelets they play a primary role in platelet activation and aggregation in the course of thrombotic events. In vivo, they are enzymatically synthesized by cyclooxygenases, lipoxygenases, or cytochrome P450 isoenzmes, resulting in diverse polyunsaturated fatty acid (FA) metabolites including hydroxy-, epoxy-, oxo-FAs, and endoperoxides with pro-thrombotic or anti-thrombotic effects. In a recent study, it was reported that hemin induces platelet death which was accompanied by enhanced reactive oxygen species (ROS) production (measured by flow cytometry) and lipid peroxidation (as determined by proxy using flow cytometry with BODIPY-C11 as sensor). Lipidomic studies further indicated significant changes of the platelet lipidome upon ex vivo hemin treatment, amongst others oxylipins were increased. The effect could be (at least partly) reversed by riociguat/diethylamine NONOate diethylammonium salt (DEA/NO) which modulates the soluble guanylate cyclase(sGC)-cGMP-cGMP-dependent protein kinase I(cGKI) signaling axis. In the original work, oxylipins were measured by a non-enantioselective UHPLC-tandem-MS assay which may not give the full picture whether oxylipin elevation is due to ROS or by enzymatic processes. We present here the study of the stereochemical disposition of hemin-induced platelet lipidome alterations using Chiralpak IA-U column with amylose tris(3,5-dimethylphenylcarbamate) chiral selector immobilized on 1.6 µm silica particles. It was found that the major platelet oxylipins 12-HETE, 12-HEPE and 14-HDoHE (from 12-LOX) and 12-HHT (from COX-1) were present in S-configuration indicating their enzymatic formation. On the other hand, both R and S enantiomers of 9- and 13-HODE, 11- and 15-HETE were detected, possibly due to enzyme promiscuity rather than non-specific oxidation (by ROS or autoxidation), as confirmed by multi-loop based two-dimensional LC-MS using selective comprehensive mode with achiral RPLC in the 1st dimension and chiral LC in the 2nd using a multiple heart-cutting interface. For 12-HETrE, a peak at the retention time of the R-enantiomer was ruled out as isobaric interference by 2D-LC-MS. In particular, arachidonic acid derivates 12(S)-HHT, 11(R)-HETE and 15(S)-HETE were found to be sensitive to hemin and cGMP modulation.
PubMed: 38943819
DOI: 10.1016/j.jpba.2024.116328 -
Medicine Jun 2024This retrospective study aims to explore the sex disparity in dual antiplatelet therapy (DAPT) noncompliance among left main stem percutaneous coronary intervention... (Observational Study)
Observational Study
This retrospective study aims to explore the sex disparity in dual antiplatelet therapy (DAPT) noncompliance among left main stem percutaneous coronary intervention (PCI) patients with drug-eluting stent (DES) and identify predictors associated with non-adherence. Data were collected from the medical records of 1585 patients, including 1104 males and 481 females, who underwent left main stem PCI with DES. Baseline characteristics, angiographic features, and DAPT compliance rates at 1 month and 12 months were analyzed. Univariate logistic regression was used to identify predictors of DAPT noncompliance. The overall DAPT noncompliance rate at 1 month was 8.5%, increasing to 15.5% at 12 months. Females exhibited slightly higher noncompliance rates than males at both 1 month (15.6% vs 14.5%) and 12 months (28.1% vs 19.0%), although the difference was not statistically significant. Smoking status showed a modest impact on non-adherence, with current smokers exhibiting a lower noncompliance rate (14.9% at 1 month). Prior coronary artery disease history was associated with increased noncompliance at 12 months (18.9%). Angiographic characteristics, including lesion location and Syntax score, had no consistent association with DAPT noncompliance. This study highlights sex disparity in DAPT noncompliance among patients undergoing left main stem PCI with DES. Comorbidities, socioeconomic status, smoking status, and prior coronary artery disease history were identified as predictors of non-adherence.
Topics: Humans; Male; Female; Percutaneous Coronary Intervention; Retrospective Studies; Middle Aged; Drug-Eluting Stents; Sex Factors; Aged; Medication Adherence; Platelet Aggregation Inhibitors; Coronary Artery Disease; Dual Anti-Platelet Therapy; Risk Factors; Coronary Angiography
PubMed: 38941403
DOI: 10.1097/MD.0000000000038724 -
Open Veterinary Journal May 2024Pseudothrombocytopenia is a commonly obtained false negative result when analyzing feline platelet (PLT) count by an automated machine. It is related to ethylenediamine...
BACKGROUND
Pseudothrombocytopenia is a commonly obtained false negative result when analyzing feline platelet (PLT) count by an automated machine. It is related to ethylenediamine tetra-acetic acid (EDTA), a widely utilized anticoagulant in blood collection tubes, resulting in EDTA-dependent pseudothrombocytopenia (EDTA-PTCP).
AIM
To investigate whether treated with kanamycin enhanced the quantity of PLT aggregations in feline blood specimens collected using EDTA-PTCP.
METHODS
Thirty-one blood samples were obtained using EDTA tubes. The complete blood count was analyzed using an automated Mindray BC-5000Vet. Both Manual cell counts and thin blood smears were performed to estimate the amount of red blood cell, white blood cell, and PLTs as well as to evaluate the severity scores of PLT clumping, respectively. Comparisons were made between those pre-treated and those treated with kanamycin in the EDTA tube.
RESULTS
There were significantly different mean PLT counts in the samples before and after they were treated with kanamycin, both on automated (156.6 ± 76.4 . 260.3 ± 115.5; < 0.001) and manual (168.5 ± 92.1 . 262.8 ± 119.6; < 0.001) readings, with a 95% confidence interval of 0.19 (0.022-0.365).
CONCLUSION
This study suggests that in clinical laboratory practice, kanamycin should be added to feline blood specimens with EDTA-PTCP.
Topics: Animals; Cats; Edetic Acid; Kanamycin; Thrombocytopenia; Cat Diseases; Anticoagulants; Platelet Count; Blood Specimen Collection; Female; Male; Platelet Aggregation
PubMed: 38938430
DOI: 10.5455/OVJ.2024.v14.i5.15 -
Journal of Cardiothoracic Surgery Jun 2024Thoracic endovascular aortic repair (TEVAR) is a minimally invasive technique used to treat type B aortic dissections. Left subclavian artery (LSA) reconstruction is...
BACKGROUND
Thoracic endovascular aortic repair (TEVAR) is a minimally invasive technique used to treat type B aortic dissections. Left subclavian artery (LSA) reconstruction is required when treating patients with involvement of LSA. The best antiplatelet therapy after LSA reconstruction is presently uncertain.
METHODS
This study retrospectively analyzed 245 type B aortic dissection patients who underwent left subclavian artery revascularization during TEVAR. Out of 245 patients, 159 (64.9%) were in the single antiplatelet therapy (SAPT) group, receiving only aspirin, and 86 (35.1%) were in the dual antiplatelet therapy (DAPT) group, receiving aspirin combined with clopidogrel. During the 6-month follow-up, primary endpoints included hemorrhagic events (general bleeding and hemorrhagic strokes), while secondary endpoints comprised ischemic events (left upper limb ischemia, ischemic stroke, and thrombotic events), as well as death and leakage events. Both univariate and multivariate Cox regression analyses were performed on hemorrhagic and ischemic events, with the Kaplan-Meier method used to generate the survival curve.
RESULTS
During the six-month follow-up, the incidence of hemorrhagic events in the DAPT group was higher (8.2% vs. 30.2%, P < 0.001). No significant differences were observed in ischemic events, death, or leakage events among the different antiplatelet treatment schemes. Multivariate Cox regression analysis showed that DAPT (HR: 2.22, 95% CI: 1.07-4.60, P = 0.032) and previous chronic conditions (HR:3.88, 95% CI: 1.24-12.14, P = 0.020) significantly affected the occurrence of hemorrhagic events. Chronic conditions in this study encompassed depression, vitiligo, and cholecystolithiasis. Carotid subclavian bypass (CSB) group (HR:0.29, 95% CI: 0.12-0.68, P = 0.004) and single-branched stent graft (SBSG) group (HR:0.26, 95% CI: 0.13-0.50, P < 0.001) had a lower rate of ischemic events than fenestration TEVAR (F-TEVAR). Survival analysis over 6 months revealed a lower risk of bleeding associated with SAPT during hemorrhagic events (P = 0.043).
CONCLUSIONS
In type B aortic dissection patients undergoing LSA blood flow reconstruction after synchronous TEVAR, the bleeding risk significantly decreases with the SAPT regimen, and there is no apparent ischemic compensation within 6 months. Patients with previous chronic conditions have a higher risk of bleeding. The CSB group and SBSG group have less ischemic risk compared to F-TEVAR group.
Topics: Humans; Male; Female; Retrospective Studies; Platelet Aggregation Inhibitors; Subclavian Artery; Middle Aged; Aortic Dissection; Endovascular Procedures; Aortic Aneurysm, Thoracic; Aged; Clopidogrel; Aspirin; Aorta, Thoracic; Treatment Outcome; Blood Vessel Prosthesis Implantation; Postoperative Complications; Endovascular Aneurysm Repair
PubMed: 38937841
DOI: 10.1186/s13019-024-02932-3 -
Scientific Reports Jun 2024The association of postpartum cardiac reverse remodeling (RR) with urinary proteome, particularly in pregnant women with cardiovascular (CV) risk factors who show...
The association of postpartum cardiac reverse remodeling (RR) with urinary proteome, particularly in pregnant women with cardiovascular (CV) risk factors who show long-term increased risk of cardiovascular disease and mortality is unknown. We aim to profile the urinary proteome in pregnant women with/without CV risk factors to identify proteins associated with postpartum RR. Our study included a prospective cohort of 32 healthy and 27 obese and/or hypertensive and/or diabetic pregnant women who underwent transthoracic echocardiography, pulse-wave-velocity, and urine collection at the 3rd trimester and 6 months postpartum. Shotgun HPLC-MS/MS profiled proteins. Generalized linear mixed-effects models were used to identify associations between urinary proteins and left ventricle mass (LVM), a surrogate of RR. An increase in arterial stiffness was documented from 3rd trimester to 6 months after delivery, being significantly elevated in women with CV risk factors. In addition, the presence of at least one CV risk factor was associated with worse LVM RR. We identified 6 and 11 proteins associated with high and low LVM regression, respectively. These proteins were functionally linked with insulin-like growth factor (IGF) transport and uptake regulation by IGF binding-proteins, platelet activation, signaling and aggregation and the immune system's activity. The concentration of IGF-1 in urine samples was associated with low LVM regression after delivery. Urinary proteome showed a predicting potential for identifying pregnant women with incomplete postpartum RR.
Topics: Humans; Female; Pregnancy; Adult; Proteome; Postpartum Period; Ventricular Remodeling; Prospective Studies; Biomarkers; Vascular Stiffness; Echocardiography; Risk Factors
PubMed: 38937573
DOI: 10.1038/s41598-024-65612-1 -
Pharmaceuticals (Basel, Switzerland) May 2024Selective COX-1 inhibitors are preferential therapeutic targets for platelet aggregation and clotting responses. In this study, we examined the selective...
Selective COX-1 inhibitors are preferential therapeutic targets for platelet aggregation and clotting responses. In this study, we examined the selective COX-1-inhibitory activities of four newly synthesized compounds, -, along with their abilities to inhibit platelet aggregation against ADP and collagen. The target compounds - were synthesized using the conventional method, sonication, and microwave-assisted methods. Microanalytical and spectral data were utilized to elucidate the structures of the new compounds -. Additionally, a spectral NMR experiment [NOESY] was conducted to emphasize the configuration around the double bond of the imine group C=N. The obtained results revealed no observed correlation between any of the neighboring protons, suggesting that the configuration at the C=N double bond is . Biological results revealed that all the screened compounds - might serve as selective COX-1 inhibitors. They showed IC values ranging from 0.71 μM to 4.82 μM against COX-1 and IC values ranging from 9.26 μM to 15.24 μM against COX-2. Their COX-1 selectivity indices ranged between 2.87 and 18.69. These compounds show promise as promising anti-platelet aggregation agents. They effectively prevented platelet aggregation induced by ADP with IC values ranging from 0.11 μM to 0.37 μM, surpassing the standard aspirin with an IC value of 0.49 μM. Additionally, they inhibited the platelet aggregation induced by collagen with IC values ranging from 0.12 μM to 1.03 μM, demonstrating superior efficacy compared to aspirin, which has an IC value of 0.51 μM. In silico molecular modeling was performed for all the target compounds within the active sites of COX-1 and COX-2 to rationalize their selective inhibitory activities towards COX-1. It was found that the binding interactions of the designed compounds within the COX-1 active site had remained unaffected by the presence of celecoxib. Molecular modeling and DFT calculations using the B3LYP/6-31+G (d,p) level were performed to study the stability of -forms with respect to -forms for the investigated compounds. A strong correlation was observed between the experimental observations and the quantum chemical descriptors.
PubMed: 38931377
DOI: 10.3390/ph17060710 -
International Journal of Molecular... Jun 2024Integrin αβ mediates platelet aggregation by binding the Arginyl-Glycyl-Aspartic acid (RGD) sequence of fibrinogen. RGD binding occurs at a site topographically...
Integrin αβ mediates platelet aggregation by binding the Arginyl-Glycyl-Aspartic acid (RGD) sequence of fibrinogen. RGD binding occurs at a site topographically proximal to the α and β subunits, promoting the conformational activation of the receptor from bent to extended states. While several experimental approaches have characterized RGD binding to αβ integrin, applying computational methods has been significantly more challenging due to limited sampling and the need for a priori information regarding the interactions between the RGD peptide and integrin. In this study, we employed all-atom simulations using funnel metadynamics (FM) to evaluate the interactions of an RGD peptide with the α and β subunits of integrin. FM incorporates an external history-dependent potential on selected degrees of freedom while applying a funnel-shaped restraint potential to limit RGD exploration of the unbound state. Furthermore, it does not require a priori information about the interactions, enhancing the sampling at a low computational cost. Our FM simulations reveal significant molecular changes in the β subunit of integrin upon RGD binding and provide a free-energy landscape with a low-energy binding mode surrounded by higher-energy prebinding states. The strong agreement between previous experimental and computational data and our results highlights the reliability of FM as a method for studying dynamic interactions of complex systems such as integrin.
Topics: Oligopeptides; Platelet Glycoprotein GPIIb-IIIa Complex; Protein Binding; Humans; Molecular Dynamics Simulation; Blood Platelets; Binding Sites; Integrin beta3
PubMed: 38928286
DOI: 10.3390/ijms25126580 -
International Journal of Molecular... Jun 2024Platelets have a fundamental role in mediating hemostasis and thrombosis. However, more recently, a new idea is making headway, highlighting the importance of platelets... (Review)
Review
Platelets have a fundamental role in mediating hemostasis and thrombosis. However, more recently, a new idea is making headway, highlighting the importance of platelets as significant actors in modulating immune and inflammatory responses. In particular, platelets have an important role in the development of vascular amyloid-b-peptide(ab) deposits, known to play a relevant role in Alzheimer's disease (AD) through accumulation and deposition within the frontal cortex and hippocampus in the brain. The involvement of platelets in the pathogenesis of AD opens up the highly attractive possibility of applying antiplatelet therapy for the treatment and/or prevention of AD, but conclusive results are scarce. Even less is known about the potential role of platelets in mild cognitive impairment (MCI). The aim to this brief review is to summarize current knowledge on this topic and to introduce the new perspectives on the possible role of platelet activation as therapeutic target both in AD and MCI.
Topics: Humans; Blood Platelets; Alzheimer Disease; Platelet Activation; Neurodegenerative Diseases; Cognitive Dysfunction; Animals; Amyloid beta-Peptides; Platelet Aggregation Inhibitors
PubMed: 38927999
DOI: 10.3390/ijms25126292 -
Biomolecules Jun 2024The crucial role of platelets in hemostasis and their broad implications under various physiological conditions underscore the importance of accurate platelet-function... (Review)
Review
The crucial role of platelets in hemostasis and their broad implications under various physiological conditions underscore the importance of accurate platelet-function testing. Platelets are key to clotting blood and healing wounds. Therefore, accurate diagnosis and management of platelet disorders are vital for patient care. This review outlines the significant advancements in platelet-function testing technologies, focusing on their working principles and the shift from traditional diagnostic methods to more innovative approaches. These improvements have deepened our understanding of platelet-related disorders and ushered in personalized treatment options. Despite challenges such as interpretation of complex data and the costs of new technologies, the potential for artificial-intelligence integration and the creation of wearable monitoring devices offers exciting future possibilities. This review underscores how these technological advances have enhanced the landscape of precision medicine and provided better diagnostic and treatment options for platelet-function disorders.
Topics: Humans; Blood Platelets; Blood Platelet Disorders; Platelet Function Tests; Precision Medicine; Hemostasis
PubMed: 38927117
DOI: 10.3390/biom14060714