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Research (Washington, D.C.) 2024Platelet activation contributes to sepsis development, leading to microthrombosis and increased inflammation, which results in disseminated intravascular coagulation and...
Platelet activation contributes to sepsis development, leading to microthrombosis and increased inflammation, which results in disseminated intravascular coagulation and multiple organ dysfunction. Although Cathelicidin can alleviate sepsis, its role in sepsis regulation remains largely unexplored. In this study, we identified Cath-HG, a novel Cathelicidin from skin, and analyzed its structure using nuclear magnetic resonance spectroscopy. The modulatory effect of Cath-HG on the symptoms of mice with sepsis induced by cecal ligation and puncture was evaluated in vivo, and the platelet count, degree of organ damage, and microthrombosis were measured. The antiplatelet aggregation activity of Cath-HG was studied in vitro, and its target was verified. Finally, we further investigated whether Cath-HG could regulate thrombosis in vivo in a FeCl injury-induced carotid artery model. The results showed that Cath-HG exhibited an α-helical structure in sodium dodecyl sulfate solution and effectively reduced organ inflammation and damage, improving survival in septic mice. It alleviated sepsis-induced thrombocytopenia and microthrombosis. In vitro, Cath-HG specifically inhibited collagen-induced platelet aggregation and modulated glycoprotein VI (GPVI) signaling pathways. Dot blotting, enzyme-linked immunosorbent assay, and pull-down experiments confirmed GPVI as the target of Cath-HG. Molecular docking and amino acid residue truncations/mutations identified crucial sites of Cath-HG. These findings suggest that GPVI represents a promising therapeutic target for sepsis, and Cath-HG may serve as a potential treatment for sepsis-related thrombocytopenia and thrombotic events. Additionally, identifying Cath-HG as a GPVI inhibitor provides insights for developing novel antithrombotic therapies targeting platelet activation mediated by GPVI.
PubMed: 38840901
DOI: 10.34133/research.0381 -
Journal of Stroke May 2024Cancer can induce hypercoagulability, which may lead to stroke. This occurs when tumor cells activate platelets as part of their growth and metastasis. Tumor cells... (Review)
Review
Cancer can induce hypercoagulability, which may lead to stroke. This occurs when tumor cells activate platelets as part of their growth and metastasis. Tumor cells activate platelets by generating thrombin and expressing tissue factor, resulting in tumor cell-induced platelet aggregation. Histopathological studies of thrombi obtained during endovascular thrombectomy in patients with acute stroke and active cancer have shown a high proportion of platelets and thrombin. This underscores the crucial roles of platelets and thrombin in cancer-associated thrombosis. Cancer-associated stroke typically occurs in patients with active cancer and is characterized by distinctive features. These features include multiple infarctions across multiple vascular territories, markedly elevated blood D-dimer levels, and metastasis. The presence of cardiac vegetations on echocardiography is a robust indicator of cancer-associated stroke. Suspicion of cancer-associated stroke during endovascular thrombectomy arises when white thrombi are detected, particularly in patients with active cancer. Cancer-associated stroke is almost certain when histopathological examination of thrombi shows a very high platelet and a very low erythrocyte composition. Patients with cancer-associated stroke have high risks of mortality and recurrent stroke. However, limited data are available on the optimal treatment regimen for stroke prevention in these patients. Thrombosis mechanism in cancer is well understood, and distinct therapeutic targets involving thrombin and platelets have been identified. Therefore, direct thrombin inhibitors and/or antiplatelet agents may effectively prevent stroke recurrence. Additionally, this strategy has potential benefits in cancer treatment as accumulating evidence suggests that aspirin use reduces cancer progression, metastasis, and cancer-related mortality. However, clinical trials are necessary to assess the efficacy of this strategy involving the use of direct thrombin inhibitors and/or antiplatelet therapies.
PubMed: 38836266
DOI: 10.5853/jos.2023.03279 -
ACS Nano Jun 2024Amyloid-like fibrils are garnering keen interest in biotechnology as supramolecular nanofunctional units to be used as biomimetic platforms to control cell behavior....
Amyloid-like fibrils are garnering keen interest in biotechnology as supramolecular nanofunctional units to be used as biomimetic platforms to control cell behavior. Recent insights into fibril functionality have highlighted their importance in tissue structure, mechanical properties, and improved cell adhesion, emphasizing the need for scalable and high-kinetics fibril synthesis. In this study, we present the instantaneous and bulk formation of amyloid-like nanofibrils from human platelet lysate (PL) using the ionic liquid cholinium tosylate as a fibrillating agent. The instant fibrillation of PL proteins upon supramolecular protein-ionic liquid interactions was confirmed from the protein conformational transition toward cross-β-sheet-rich structures. These nanofibrils were utilized as building blocks for the formation of thin and flexible free-standing membranes via solvent casting to support cell self-aggregation. These PL-derived fibril membranes reveal a nanotopographically rough surface and high stability over 14 days under cell culture conditions. The culture of mesenchymal stem cells or tumor cells on the top of the membrane demonstrated that cells are able to adhere and self-organize in a three-dimensional (3D) spheroid-like microtissue while tightly folding the fibril membrane. Results suggest that nanofibril membrane incorporation in cell aggregates can improve cell viability and metabolic activity, recreating native tissues' organization. Altogether, these PL-derived nanofibril membranes are suitable bioactive platforms to generate 3D cell-guided microtissues, which can be explored as bottom-up strategies to faithfully emulate native tissues in a fully human microenvironment.
Topics: Humans; Blood Platelets; Nanofibers; Mesenchymal Stem Cells; Cell Aggregation; Cell Adhesion; Amyloid; Membranes, Artificial
PubMed: 38833572
DOI: 10.1021/acsnano.4c02790 -
Platelets Dec 2024Acquired disorders of platelet function are an underdiagnosed cause of bleeding tendency. A 14-year-old girl developed moderate mucocutaneous bleeding two weeks after a...
Acquired disorders of platelet function are an underdiagnosed cause of bleeding tendency. A 14-year-old girl developed moderate mucocutaneous bleeding two weeks after a infection successfully treated with clarithromycin. The patient was referred to us 7 months later for laboratory investigation of the persisting bleeding diathesis. The patient's personal and family histories were negative for bleeding disorders. Complete blood count, von Willebrand Factor levels and coagulation tests were normal; platelet aggregation, ATP secretion, δ-granules content and serum thromboxane B2 levels were defective. At follow-up visits, laboratory parameters and the bleeding diathesis progressively normalized within 2 years. The patient's condition is compatible with a diagnosis of acquired Storage Pool Deficiency (SPD), associated with defective thromboxane A2 production. To our knowledge, this is the first case of acquired, transient SPD with spontaneous remission. The pathogenic role of infection or clarithromycin is possible, albeit uncertain.
Topics: Humans; Female; Adolescent; Platelet Storage Pool Deficiency; Thromboxane A2; Blood Platelets; Hemorrhagic Disorders
PubMed: 38832819
DOI: 10.1080/09537104.2024.2358241 -
Archives of Razi Institute Dec 2023Snake venoms are rich in valuable substances that have medical potential in the diagnosis and treatment of hemostatic diseases. The present paper was aimed at the...
Snake venoms are rich in valuable substances that have medical potential in the diagnosis and treatment of hemostatic diseases. The present paper was aimed at the purification and functional characterization basis of a thrombin-like enzyme and its role in the functioning of the coagulation cascade and platelet aggregation pathway. A thrombin-like serine protease was purified from the Iranian venom (TLIECV), employing a one-step chromatographic procedure. This peptide was collected in high yield and purity by a single chromatographic step using RP-HPLC equipped with a C column. This peptide showed a 3000 Da molecular weight in gel-electrophoresis. Evidence in the SDS-PAGE gel has confirmed high recovery of fraction in optimal terms. Subsequently, this peptide was identified via its intact molecular mass and peptide mass fingerprint (PMF) using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF/MS). Multiple sequence alignments were performed by ClustalW, the Bioedit software. Molegro Data Modeller (MDM) 3.0 software was used to predict the putative tertiary structure of the peptide. The enzyme possessed fibrinogenolytic, procoagulant, and aggregation inducer properties. Moreover, the SDS-PAGE (12%) was applied to examine fibrinogenolytic function. The purified enzyme degraded the Aα chain of fibrinogen while the Bβ and γ chains were not digested. According to that, the deficient human plasma in factor X and normal human plasma were also coagulated by TLIECV, it takes part in the common and intrinsic routes of the coagulation cascade. These findings proved that TLIECV is a serine protease identical to procoagulant thrombin-like snake venom proteases; however, it specifically releases the Aα chain of bovine fibrinogen. Because of its function to make up for the deficiency of factor X and its platelet aggregation inducer property, TLIECV could be considered a molecular impact to reveal the hemostasis mechanisms.
Topics: Viperidae; Animals; Viper Venoms; Iran; Thrombin; Platelet Aggregation; Humans; Electrophoresis, Polyacrylamide Gel; Amino Acid Sequence; Echis; Venomous Snakes
PubMed: 38828174
DOI: 10.32592/ARI.2023.78.6.1822 -
Drug Design, Development and Therapy 2024Mechanistic studies showed that morphine may impair the antiplatelet effect of P2Y12 inhibitors. However, Several clinical studies with cardiovascular events as an...
PURPOSE
Mechanistic studies showed that morphine may impair the antiplatelet effect of P2Y12 inhibitors. However, Several clinical studies with cardiovascular events as an outcome are contradictory, and the broader impact of this drug interaction on additional organ systems remains uncertain. With multisource data, this study sought to determine the effects of morphine interaction with P2Y12 inhibitors on major adverse outcomes comprehensively, and identify the warning indicators.
PATIENTS AND METHODS
Interaction signals were sought in 187,919 safety reports from the FDA Adverse Event Reporting System (FAERS) database, utilizing reporting odds ratios (repOR). In a cohort of 5240 acute coronary syndrome patients, the analyses were validated, and the biological effects of warning indicators were further studied with Mendelian randomization and mediation analysis.
RESULTS
Potential risk of renal system adverse events in patients cotreated with morphine is significantly higher in FAERS (repOR 4.83, 95% CI 4.42-5.28, false discovery rate adjusted- =3.55*10). The analysis of in-house patient cohorts validated these results with an increased risk of acute kidney injury (adjusted OR: 1.65; 95% CI: 1.20 to 2.26), and we also found a risk of myocardial infarction in patients treated with morphine (adjusted OR: 1.55; 95% CI: 1.14 to 2.11). The Morphine group exhibited diminished Plateletcrit (PCT) levels post-surgery and lower PCT levels were associated with an increased risk of AKI.
CONCLUSION
The administration of morphine in patients treated with P2Y12 receptor inhibitors should be carefully evaluated. PCT may serve as a potential warning indicator for morphine-related renal injury.
Topics: Humans; Morphine; Purinergic P2Y Receptor Antagonists; Acute Coronary Syndrome; Male; Female; Middle Aged; Aged; Platelet Aggregation Inhibitors; Analgesics, Opioid
PubMed: 38828024
DOI: 10.2147/DDDT.S458299 -
International Journal of Cardiology Sep 2024The comparative efficacy and safety of adjusted- and standard-dose prasugrel in East Asian patients with acute myocardial infarction (AMI) undergoing percutaneous... (Comparative Study)
Comparative Study
BACKGROUND
The comparative efficacy and safety of adjusted- and standard-dose prasugrel in East Asian patients with acute myocardial infarction (AMI) undergoing percutaneous coronary intervention (PCI) remain unclear. This study aimed to comparatively assess the ischaemic and bleeding outcomes of adjusted-dose (maintenance dose: 3.75 mg) and standard-dose (maintenance dose: 10 mg) prasugrel in East Asian patients with AMI undergoing PCI.
METHODS
From a combined dataset sourced from nationwide AMI registries in Japan and South Korea (n = 17,118), patients treated with either adjusted- or standard-dose prasugrel were identified. Patients who did not undergo emergent PCI, those on oral anticoagulants, and those meeting the criteria of contraindication of prasugrel in South Korea (age ≥ 75 years, body weight < 60 kg, or history of stroke) were excluded. Major adverse cardiovascular events (MACE) and Thrombolysis in Myocardial Infarction (TIMI) major bleeding events were compared between the adjusted-dose (n = 1160) and standard-dose (n = 1086) prasugrel groups.
RESULTS
Within the propensity-matched cohort (n = 702 in each group), no significant difference was observed in the in-hospital MACE between the adjusted- and standard-dose prasugrel groups (1.85% vs. 2.71%, odds ratio [OR] 0.68, 95% confidence interval [CI] 0.33-1.38, p = 0.286). However, the incidence of in-hospital major bleeding was significantly lower in the adjusted-dose prasugrel group than in the standard-dose group (0.43% vs. 1.71%, OR 0.25, 95% CI 0.07-0.88, p = 0.031). The cumulative 12-month incidence of MACE was equivalent in both groups (4.70% vs. 4.70%, OR 1.00, 95% CI 0.61-1.64, p = 1.000).
CONCLUSIONS
Among East Asian patients with AMI undergoing PCI, those administered adjusted-dose prasugrel exhibited a lower risk of in-hospital bleeding events than those administered standard-dose prasugrel, while maintaining a comparable 1-year incidence of MACE.
Topics: Aged; Female; Humans; Male; Middle Aged; Cohort Studies; Dose-Response Relationship, Drug; East Asian People; Hemorrhage; Japan; Myocardial Infarction; Percutaneous Coronary Intervention; Platelet Aggregation Inhibitors; Prasugrel Hydrochloride; Registries; Republic of Korea; Treatment Outcome
PubMed: 38823533
DOI: 10.1016/j.ijcard.2024.132197 -
The Veterinary Quarterly Dec 2024Dogs that had splenectomy are predisposed to fatal thrombotic conditions, and thrombocytosis is a risk factor for post-splenectomy hypercoagulability. However, in...
Dogs that had splenectomy are predisposed to fatal thrombotic conditions, and thrombocytosis is a risk factor for post-splenectomy hypercoagulability. However, in veterinary medicine, there are no specific therapeutic approaches for managing this hypercoagulability. This study aimed to determine the preventive effect of clopidogrel on post-operative hypercoagulability during the first 2 weeks post-splenectomy in dogs with splenic masses. This study included 12 dogs that had splenectomy. Seven dogs received no treatment (group A), and five were treated with clopidogrel (group B). Clopidogrel was loaded at 10 mg/kg on day 2 and continued at 2 mg/kg until day 14. Blood samples were collected on the day of surgery and 2, 7, and 14 days after splenectomy in both groups. In group B, thromboelastography (TEG) was performed on the same days. In group A, there was significant elevation of platelet counts on days 7 ( = 0.007) and 14 ( = 0.001) compared to day 0. In group B, the platelet counts were significantly elevated on day 7 ( = 0.032) but no significant difference was found on day 14 compared to day 0. Platelet counts on day 14 were significantly higher in group A than in group B ( = 0.03). The lower platelet counts were correlated with alterations in TEG parameters, and no significant differences were found in the K and α-angle values at all postoperative assessment points compared to day 0. Our study suggests that clopidogrel may reduce post-operative thrombocytosis and hypercoagulability in dogs that undergo splenectomy for splenic masses.
Topics: Animals; Dogs; Splenectomy; Clopidogrel; Dog Diseases; Platelet Count; Female; Male; Thrombophilia; Platelet Aggregation Inhibitors; Thrombelastography; Postoperative Complications; Splenic Neoplasms; Splenic Diseases; Thrombocytosis
PubMed: 38823415
DOI: 10.1080/01652176.2024.2347926 -
Thrombosis Journal May 2024Von Willebrand factor (vWF) plays a crucial role in hemostasis, acting as a key factor for platelet adhesion/aggregation and as a transport protein for coagulation...
Impact of extracorporeal membrane oxygenation treatments on acquired von Willebrand syndrome in patients with out-of-hospital cardiac arrest: a retrospective observational study.
BACKGROUND
Von Willebrand factor (vWF) plays a crucial role in hemostasis, acting as a key factor for platelet adhesion/aggregation and as a transport protein for coagulation factor VIII. vWF is secreted as a giant multimer, and it undergoes shear stress-dependent cleavage by a specific metalloproteinase in plasma. Among vWF multimers, high-molecular-weight (large) multimers are essential for hemostasis. Acquired von Willebrand syndrome, linked to various conditions, is a hemostatic disorder due to reduced vWF activity. Extracorporeal membrane oxygenation (ECMO), utilized recently for out-of-hospital cardiac arrest patients, generates high shear stress inside the pump. This stress may induce a conformational change in vWF, enhancing cleavage by a specific metalloproteinase and thereby reducing vWF activity. However, no study has investigated the effects of ECMO on vWF-related factors in patients receiving or not receiving ECMO. This study aimed to elucidate the relationship between ECMO treatment and acquired von Willebrand syndrome-related factors in patients with out-of-hospital cardiac arrest.
METHODS
This study included patients with cardiogenic out-of-hospital cardiac arrest admitted to our hospital. The patients were categorized into two groups (ECMO and non-ECMO) based on the presence or absence of ECMO treatment. Plasma samples were collected from patients admitted to the emergency department (days 0-4). The vWF antigen (vWF: Ag), vWF ristocetin cofactor activity (vWF: RCo), and factor VIII activity were measured. Additionally, a large multimer of vWF was evaluated through vWF multimer analysis, utilizing western blotting to probe vWF under non-reducing conditions.
RESULTS
The ECMO and non-ECMO groups included 10 and 22 patients, respectively. The median ECMO treatment in the ECMO group was 64.6 h. No differences in vWF: Ag or factor VIII activity were observed between the two groups during the observation period. However, the ECMO group exhibited a decrease in large vWF multimers and vWF: RCo during ECMO. Strong correlations were observed between vWF: RCo and vWF: Ag in both groups, although the relationships were significantly different between the two groups.
CONCLUSIONS
ECMO treatment in patients with out-of-hospital cardiac arrest resulted in the loss of large vWF multimers and decreased vWF activity. Hence, decreased vWF activity should be considered as a cause of bleeding during ECMO management.
PubMed: 38822325
DOI: 10.1186/s12959-024-00617-4 -
Scientific Reports May 2024Aspirin is widely used for both primary and secondary prevention of panvascular diseases, such as stroke and coronary heart disease (CHD). The optimal balance between...
Aspirin is widely used for both primary and secondary prevention of panvascular diseases, such as stroke and coronary heart disease (CHD). The optimal balance between reducing panvascular disease events and the potential increase in bleeding risk remains unclear. This study aimed to develop a predictive model specifically designed to assess bleeding risk in individuals using aspirin. A total of 58,415 individuals treated with aspirin were included in this study. Detailed data regarding patient demographics, clinical characteristics, comorbidities, medical history, and laboratory test results were collected from the Affiliated Dongyang Hospital of Wenzhou Medical University. The patients were randomly divided into two groups at a ratio of 7:3. The larger group was used for model development, while the smaller group was used for internal validation. To develop the prediction model, we employed least absolute shrinkage and selection operator (LASSO) regression followed by multivariate logistic regression. The performance of the model was assessed through metrics such as the area under the receiver operating characteristic (ROC) curve (AUC), calibration curves, and decision curve analysis (DCA). The LASSO-derived model employed in this study incorporated six variables, namely, sex, operation, previous bleeding, hemoglobin, platelet count, and cerebral infarction. It demonstrated excellent performance at predicting bleeding risk among aspirin users, with a high AUC of 0.866 (95% CI 0.857-0.874) in the training dataset and 0.861 (95% CI 0.848-0.875) in the test dataset. At a cutoff value of 0.047, the model achieved moderate sensitivity (83.0%) and specificity (73.9%). The calibration curve analysis revealed that the nomogram closely approximated the ideal curve, indicating good calibration. The DCA curve demonstrated a favorable clinical net benefit associated with the nomogram model. Our developed LASSO-derived predictive model has potential as an alternative tool for predicting bleeding in clinical settings.
Topics: Humans; Aspirin; Male; Female; Hemorrhage; Middle Aged; Aged; ROC Curve; Risk Assessment; Risk Factors; Logistic Models; Platelet Aggregation Inhibitors
PubMed: 38822153
DOI: 10.1038/s41598-024-63437-6