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Article ; Online: Ca

Bye, Alexander P / Gibbins, Jonathan M / Mahaut-Smith, Martyn P

2020 Volume 13, Issue 615

Abstract: Cells sense extracellular nucleotides through the P2Y class of purinergic G protein-coupled receptors (GPCRs), which stimulate integrin activation through signaling events, including intracellular ... ...

Abstract	Cells sense extracellular nucleotides through the P2Y class of purinergic G protein-coupled receptors (GPCRs), which stimulate integrin activation through signaling events, including intracellular Ca
MeSH term(s)	Actin Cytoskeleton/drug effects ; Actin Cytoskeleton/metabolism ; Adenosine Diphosphate/pharmacology ; Animals ; Calcium/metabolism ; Cells, Cultured ; Fibrinogen/metabolism ; Humans ; Male ; Megakaryocytes/cytology ; Megakaryocytes/drug effects ; Megakaryocytes/metabolism ; Microscopy, Confocal ; Platelet Glycoprotein GPIIb-IIIa Complex/metabolism ; Rats, Wistar ; Receptors, Purinergic/metabolism ; Signal Transduction/drug effects ; Signal Transduction/physiology
Chemical Substances	Platelet Glycoprotein GPIIb-IIIa Complex ; Receptors, Purinergic ; Adenosine Diphosphate (61D2G4IYVH) ; Fibrinogen (9001-32-5) ; Calcium (SY7Q814VUP)
Language	English
Publishing date	2020-01-21
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2417226-1
ISSN	1937-9145 ; 1945-0877
ISSN (online)	1937-9145
ISSN	1945-0877
DOI	10.1126/scisignal.aav7354
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Pirtobrutinib results in reversible platelet dysfunction compared to ibrutinib and acalabrutinib.

Bye, Alexander P / Kriek, Neline / Sage, Tanya / Rawlings, Suzannah J / Prodger, Catherine / Kesavan, Murali / Lees, Charlotte / Booth, Stephen / Cowen, Louise G / Shefferd, Kirsty / Desborough, Michael J / Gibbins, Jonathan M / Eyre, Toby A

Haematologica

2023 Volume 108, Issue 5, Page(s) 1429–1435

MeSH term(s)	Humans ; Pyrazines ; Benzamides ; Protein Kinase Inhibitors ; Leukemia, Lymphocytic, Chronic, B-Cell
Chemical Substances	acalabrutinib (I42748ELQW) ; ibrutinib (1X70OSD4VX) ; pirtobrutinib ; Pyrazines ; Benzamides ; Protein Kinase Inhibitors
Language	English
Publishing date	2023-05-01
Publishing country	Italy
Document type	Letter ; Research Support, Non-U.S. Gov't
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2022.281402
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Article ; Online: 1,8-Cineole Affects Agonists-Induced Platelet Activation, Thrombus Formation and Haemostasis.

Alatawi, Kahdr A / Ravishankar, Divyashree / Patra, Pabitra H / Bye, Alexander P / Stainer, Alexander R / Patel, Ketan / Widera, Darius / Vaiyapuri, Sakthivel

Cells

2021 Volume 10, Issue 10

Abstract: 1,8-cineole, a monoterpenoid is a major component of eucalyptus oil and has been proven to possess numerous beneficial effects in humans. Notably, 1,8-cineole is the primary active ingredient of a clinically approved drug, ... ...

Abstract	1,8-cineole, a monoterpenoid is a major component of eucalyptus oil and has been proven to possess numerous beneficial effects in humans. Notably, 1,8-cineole is the primary active ingredient of a clinically approved drug, Soledum
MeSH term(s)	Animals ; Blood Platelets/drug effects ; Cells, Cultured ; Eucalyptol/pharmacology ; Hemostasis/drug effects ; Humans ; Mice ; Platelet Activation/drug effects ; Platelet Aggregation/drug effects ; Thrombosis/drug therapy
Chemical Substances	Eucalyptol (RV6J6604TK)
Language	English
Publishing date	2021-10-01
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells10102616
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Screening and High-Throughput Platelet Assays.

Bye, Alexander P / Unsworth, Amanda J / Gibbins, Jonathan M

Methods in molecular biology (Clifton, N.J.)

2018 Volume 1812, Page(s) 81–94

Abstract: High-throughput assays are important biological research tools but are rarely utilized for platelet research. However, screening compounds for efficacy against a physiologically relevant cellular response in primary cells such as platelets can be an ... ...

Abstract	High-throughput assays are important biological research tools but are rarely utilized for platelet research. However, screening compounds for efficacy against a physiologically relevant cellular response in primary cells such as platelets can be an advantageous approach to compound screening and drug development. In this section we describe a panel of three high-throughput microtiter plate assays designed for platelets that can be used as the basis for compound screening, or be modified and used individually to increase throughput in platelet research laboratories. The platelet adhesion assay has the lowest requirement for platelet numbers and is therefore capable of the greatest throughput and so is suggested as the primary screen used to identify hits. A secondary screen against the "gold standard" of platelet function, aggregation, is used to confirm and further characterize hits. Finally, a Ca
MeSH term(s)	Blood Platelets/cytology ; Calcium Signaling ; Cell Aggregation ; Cytological Techniques/methods ; Humans ; Platelet Adhesiveness
Language	English
Publishing date	2018-08-31
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-8585-2_5
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Multiple myeloma and its treatment contribute to increased platelet reactivity.

Mitchell, Joanne L / Khan, Dalia / Rana, Rekha H / Kriek, Neline / Unsworth, Amanda J / Sage, Tanya / Bye, Alexander P / Laffan, Michael / Shapiro, Susan / Thakurta, Anjan / Grech, Henri / Ramasamy, Karthik / Gibbins, Jonathan M

Platelets

2023 Volume 34, Issue 1, Page(s) 2264940

Abstract: ... MM where increases in fibrinogen binding, P-selectin exposure, altered receptor expression, elevated ...

Abstract	Multiple myeloma (MM) and its precursor states, smoldering myeloma (SM) and monoclonal gammopathy of undetermined significance (MGUS) are associated with increased incidence of thrombosis, however the cause of this is unknown. Lenalidomide treatment of MM substantially improves patient survival, although significantly increases thrombotic risk by an unknown mechanism. This pilot study aimed to establish the impact of MM and its treatment with Lenalidomide on platelet function. We analyzed platelet function in MGUS, SM and MM compared to healthy controls. We report an increase in platelet reactivity in MGUS, SM, and MM where increases in fibrinogen binding, P-selectin exposure, altered receptor expression, elevated levels of aggregation and enhanced sensitivity to agonist stimulation were observed. We also demonstrate an increase in patient platelet reactivity post Lenalidomide treatment compared to pre-treatment. We show Lenalidomide treatment of platelets
MeSH term(s)	Humans ; Multiple Myeloma/drug therapy ; Multiple Myeloma/complications ; Lenalidomide/pharmacology ; Lenalidomide/therapeutic use ; Pilot Projects ; Thrombosis/complications ; Monoclonal Gammopathy of Undetermined Significance/complications
Chemical Substances	Lenalidomide (F0P408N6V4)
Language	English
Publishing date	2023-10-11
Publishing country	England
Document type	Journal Article
ZDB-ID	1034283-7
ISSN	1369-1635 ; 0953-7104
ISSN (online)	1369-1635
ISSN	0953-7104
DOI	10.1080/09537104.2023.2264940
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Article: Validation of Different Combination of Three Reversing Half-Hitches Alternating Posts (RHAPs) Effects on Arthroscopic Knot Integrity.

Chong, Alexander Cm / Prohaska, Daniel J / Bye, Brian P

Kansas journal of medicine

2017 Volume 10, Issue 2, Page(s) 35–39

Abstract: Introduction: With arthroscopic techniques being used, the importance of knot tying has been examined. Previous literature has examined the use of reversing half-hitches on alternating posts (RHAPs) on knot security. Separately, there has been research ... ...

Abstract	Introduction: With arthroscopic techniques being used, the importance of knot tying has been examined. Previous literature has examined the use of reversing half-hitches on alternating posts (RHAPs) on knot security. Separately, there has been research regarding different suture materials commonly used in the operating room. The specific aim of this study was to validate the effect of different stacked half-hitch configuration and different braided suture materials on arthroscopic knot integrity. Methods: Three different suture materials tied with five different RHAPs in arthroscopic knots were compared. A single load-to-failure test was performed and the mean ultimate clinical failure load was obtained. Results: Significant knot holding strength improvement was found when one half-hitch was reversed as compared to baseline knot. When two of the half-hitches were reversed, there was a greater improvement with all knots having a mean ultimate clinical failure load greater than 150 newtons (N). Comparison of the suture materials demonstrated a higher mean ultimate clinical failure load when Force Fiber Conclusions: A significant effect was observed in regards to both stacked half-hitch configuration and suture materials used on knot loop and knot security. Caution should be used with tying three RHAPs in arthroscopic surgery, particularly with a standard knot pusher and arthroscopic cannulas. The findings of this study indicated the importance of three RHAPs in performing arthroscopic knot tying and provided evidence regarding discrepancies of maximum clinical failure loads observed between orthopaedic surgeons, thereby leading to better surgical outcomes in the future.
Language	English
Publishing date	2017-05-15
Publishing country	United States
Document type	Journal Article
ISSN	1948-2035
ISSN	1948-2035
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: 1,8-Cineole Affects Agonists-Induced Platelet Activation, Thrombus Formation and Haemostasis

Kahdr A. Alatawi / Divyashree Ravishankar / Pabitra H. Patra / Alexander P. Bye / Alexander R. Stainer / Ketan Patel / Darius Widera / Sakthivel Vaiyapuri

Cells, Vol 10, Iss 2616, p

2021 Volume 2616

Abstract	1,8-cineole, a monoterpenoid is a major component of eucalyptus oil and has been proven to possess numerous beneficial effects in humans. Notably, 1,8-cineole is the primary active ingredient of a clinically approved drug, Soledum ® which is being mainly used for the maintenance of sinus and respiratory health. Due to its clinically valuable properties, 1,8-cineole has gained significant scientific interest over the recent years specifically to investigate its anti-inflammatory and antioxidant effects. However, the impact of 1,8-cineole on the modulation of platelet activation, thrombosis and haemostasis was not fully established. Therefore, in this study, we demonstrate the effects of 1,8-cineole on agonists-induced platelet activation, thrombus formation under arterial flow conditions and haemostasis in mice. 1,8-cineole largely inhibits platelet activation stimulated by glycoprotein VI (GPVI) agonists such as collagen and cross-linked collagen-related peptide (CRP-XL), while it displays minimal inhibitory effects on thrombin or ADP-induced platelet aggregation. It inhibited inside-out signalling to integrin αIIbβ3 and outside-in signalling triggered by the same integrin as well as granule secretion and intracellular calcium mobilisation in platelets. 1,8-cineole affected thrombus formation on collagen-coated surface under arterial flow conditions and displayed a minimal effect on haemostasis of mice at a lower concentration of 6.25 µM. Notably, 1,8-cineole was found to be non-toxic to platelets up to 50 µM concentration. The investigation on the molecular mechanisms through which 1,8-cineole inhibits platelet function suggests that this compound affects signalling mediated by various molecules such as AKT, Syk, LAT, and cAMP in platelets. Based on these results, we conclude that 1,8-cineole may act as a potential therapeutic agent to control unwarranted platelet reactivity under various pathophysiological settings.
Keywords	1,8-cineole ; platelets ; collagen ; haemostasis ; thrombosis ; platelet reactivity ; Biology (General) ; QH301-705.5
Subject code	630
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Immobilization of Nonactivated Unfixed Platelets for Real-Time Single-Cell Analysis.

Bye, Alexander P / Ilkan, Zeki / Unsworth, Amanda J / Jones, Chris I

Methods in molecular biology (Clifton, N.J.)

2018 Volume 1812, Page(s) 1–11

Abstract: Existing methods for measuring the response of individual platelets to stimulation are limited. They either measure each platelet at one discrete time-point (flow cytometry) or rely on adhesive ligands to immobilize platelets that concomitantly generate ... ...

Abstract	Existing methods for measuring the response of individual platelets to stimulation are limited. They either measure each platelet at one discrete time-point (flow cytometry) or rely on adhesive ligands to immobilize platelets that concomitantly generate activation signals (microscopy). Such methods of immobilization make it impossible to assess resting platelets, the changes that occur as platelets transition from resting to active states, or the signals generated by soluble agonists, such as ADP and thrombin, or by mechanical stimulus, independently from those generated by the adhesive ligand. Here we describe a microscopy method that allows the immobilization of platelets to a glass cover slip without triggering platelet activation. This method makes use of specific antibodies that bind platelet PECAM-1 without activating it. Platelets can therefore be immobilized to PECAM-1 antibody coated biochips without causing activation and perfused with agonists or inhibitors. Using this method, platelets can be stimulated by an array of soluble agonists at any concentration or combination, in the presence or absence of inhibitors or shear forces. This chapter describes in detail this PECAM-1 mediated immobilized platelet method and its use for measuring changes in Ca
MeSH term(s)	Blood Platelets/cytology ; Blood Platelets/metabolism ; Calcium Signaling ; Humans ; Platelet Activation ; Platelet Endothelial Cell Adhesion Molecule-1/metabolism ; Single-Cell Analysis/methods
Chemical Substances	Platelet Endothelial Cell Adhesion Molecule-1
Language	English
Publishing date	2018-08-28
Publishing country	United States
Document type	Journal Article
ISSN	1940-6029
ISSN (online)	1940-6029
DOI	10.1007/978-1-4939-8585-2_1
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Platelet factor XIII-A regulates platelet function and promotes clot retraction and stability.

Mitchell, Joanne L / Little, Gemma / Bye, Alexander P / Gaspar, Renato S / Unsworth, Amanda J / Kriek, Neline / Sage, Tanya / Stainer, Alexander / Sangowawa, Ibidayo / Morrow, Gael B / Bastos, Ricardo N / Shapiro, Susan / Desborough, Michael J R / Curry, Nicola / Gibbins, Jonathan M / Whyte, Claire S / Mutch, Nicola J / Jones, Christopher I

Research and practice in thrombosis and haemostasis

2023 Volume 7, Issue 5, Page(s) 100200

Abstract: ... In the absence of FXIII-A, platelets show reduced sensitivity to agonist stimulation, including decreased P ...

Abstract	Background: Factor XIII (FXIII) is an important proenzyme in the hemostatic system. The plasma-derived enzyme activated FXIII cross-links fibrin fibers within thrombi to increase their mechanical strength and cross-links fibrin to fibrinolytic inhibitors, specifically α Objectives: This study aims to identify the role of platelet FXIII-A in platelet function. Methods: We used normal healthy platelets with a cell permeable FXIII inhibitor and platelets from FXIII-deficient patients as a FXIII-free platelet model in a range of platelet function and clotting tests. Results: Our data demonstrate that platelet FXIII-A enhances fibrinogen binding to the platelet surface upon agonist stimulation and improves the binding of platelets to fibrinogen and aggregation under flow in a whole-blood thrombus formation assay. In the absence of FXIII-A, platelets show reduced sensitivity to agonist stimulation, including decreased P-selectin exposure and fibrinogen binding. We show that FXIII-A is involved in platelet spreading where a lack of FXIII-A reduces the ability of platelets to fully spread on fibrinogen and collagen. Our data demonstrate that platelet FXIII-A is important for clot retraction where clots formed in its absence retracted to a lesser extent. Conclusion: Overall, this study shows that platelet FXIII-A functions during thrombus formation by aiding platelet activation and thrombus retraction in addition to its antifibrinolytic roles.
Language	English
Publishing date	2023-06-07
Publishing country	United States
Document type	Journal Article
ISSN	2475-0379
ISSN (online)	2475-0379
DOI	10.1016/j.rpth.2023.100200
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Article ; Online: Identification of new drugs to counteract anti-spike IgG-induced hyperinflammation in severe COVID-19.

Geyer, Chiara E / Chen, Hung-Jen / Bye, Alexander P / Manz, Xue D / Guerra, Denise / Caniels, Tom G / Bijl, Tom Pl / Griffith, Guillermo R / Hoepel, Willianne / de Taeye, Steven W / Veth, Jennifer / Vlaar, Alexander Pj / Vidarsson, Gestur / Bogaard, Harm Jan / Aman, Jurjan / Gibbins, Jonathan M / van Gils, Marit J / de Winther, Menno Pj / den Dunnen, Jeroen

Life science alliance

2023 Volume 6, Issue 11

Abstract: Previously, we and others have shown that SARS-CoV-2 spike-specific IgG antibodies play a major role in disease severity in COVID-19 by triggering macrophage hyperactivation, disrupting endothelial barrier integrity, and inducing thrombus formation. This ...

Abstract	Previously, we and others have shown that SARS-CoV-2 spike-specific IgG antibodies play a major role in disease severity in COVID-19 by triggering macrophage hyperactivation, disrupting endothelial barrier integrity, and inducing thrombus formation. This hyperinflammation is dependent on high levels of anti-spike IgG with aberrant Fc tail glycosylation, leading to Fcγ receptor hyperactivation. For development of immune-regulatory therapeutics, drug specificity is crucial to counteract excessive inflammation whereas simultaneously minimizing the inhibition of antiviral immunity. We here developed an in vitro activation assay to screen for small molecule drugs that specifically counteract antibody-induced pathology. We identified that anti-spike-induced inflammation is specifically blocked by small molecule inhibitors against SYK and PI3K. We identified SYK inhibitor entospletinib as the most promising candidate drug, which also counteracted anti-spike-induced endothelial dysfunction and thrombus formation. Moreover, entospletinib blocked inflammation by different SARS-CoV-2 variants of concern. Combined, these data identify entospletinib as a promising treatment for severe COVID-19.
MeSH term(s)	Humans ; COVID-19 ; SARS-CoV-2 ; Antibodies, Viral ; Inflammation/drug therapy ; Immunoglobulin G/pharmacology
Chemical Substances	Antibodies, Viral ; Immunoglobulin G
Language	English
Publishing date	2023-09-12
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2575-1077
ISSN (online)	2575-1077
DOI	10.26508/lsa.202302106
Database	MEDical Literature Analysis and Retrieval System OnLINE

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