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Pharmacology & Therapeutics Jan 2019For many millions of patients at secondary risk of coronary thrombosis pharmaceutical protection is supplied by dual anti-platelet therapy. Despite substantial... (Review)
Review
For many millions of patients at secondary risk of coronary thrombosis pharmaceutical protection is supplied by dual anti-platelet therapy. Despite substantial therapeutic developments over the last decade recurrent thrombotic events occur, highlighting the need for further optimisation of therapies. Importantly, but often ignored, anti-platelet drugs interact with cyclic nucleotide systems in platelets and these are the same systems that mediate key endogenous pathways of platelet regulation, notably those dependent upon the vascular endothelium. The aim of this review is to highlight interactions between the anti-platelet drugs, aspirin and P2Y receptor antagonists and endogenous pathways of platelet regulation at the level of cyclic nucleotides. These considerations are key to concepts such as anti-platelet drug resistance and individualized anti-platelet therapy which cannot be understood by study of platelets in isolation from the circulatory environment. We also explore novel and emerging therapies that focus on preserving haemostasis and how the concepts outlined in this review could be exploited therapeutically to improve anti-thrombotic efficacy whilst reducing bleeding risk.
Topics: Animals; Aspirin; Blood Platelets; Endothelium, Vascular; Humans; Nucleotides, Cyclic; Platelet Aggregation Inhibitors; Purinergic P2Y Receptor Antagonists
PubMed: 30081048
DOI: 10.1016/j.pharmthera.2018.08.004 -
Cell Adhesion & Migration Sep 2016The primary physiological function of blood platelets is to seal vascular lesions after injury and form hemostatic thrombi in order to prevent blood loss. This task... (Review)
Review
The primary physiological function of blood platelets is to seal vascular lesions after injury and form hemostatic thrombi in order to prevent blood loss. This task relies on the formation of strong cellular-extracellular matrix interactions in the subendothelial lesions. The cytoskeleton of a platelet is key to all of its functions: its ability to spread, adhere and contract. Despite the medical significance of platelets, there is still no high-resolution structural information of their cytoskeleton. Here, we discuss and present 3-dimensional (3D) structural analysis of intact platelets by using cryo-electron tomography (cryo-ET) and atomic force microscopy (AFM). Cryo-ET provides in situ structural analysis and AFM gives stiffness maps of the platelets. In the future, combining high-resolution structural and mechanical techniques will bring new understanding of how structural changes modulate platelet stiffness during activation and adhesion.
Topics: Animals; Biomechanical Phenomena; Blood Platelets; Humans; Integrins; Models, Biological; Tomography
PubMed: 27104281
DOI: 10.1080/19336918.2016.1173803 -
Current Opinion in Hematology Sep 2014Several decades of work by many investigators have elucidated the major signaling pathways responsible for platelet activation. Still to be fully understood is how these... (Review)
Review
PURPOSE OF REVIEW
Several decades of work by many investigators have elucidated the major signaling pathways responsible for platelet activation. Still to be fully understood is how these pathways are integrated into a single network and how changing conditions within a growing thrombus affect that network. In this review we will consider some of the recent studies that address these issues and describe a model that provides insights into platelet activation as it occurs in vivo.
RECENT FINDINGS
Genetic and pharmacologic studies performed in vivo have demonstrated that platelet activation during hemostasis and thrombosis is heterogeneous. Those studies indicate that distinct platelet activation pathways are not merely redundant, but are coordinated in time and space to achieve an optimal response. This coordination is achieved at least in part by the evolving distribution of platelet agonists and changes in solute transport within a hemostatic plug.
SUMMARY
Studies examining the coordination of platelet signaling in time and space continue to increase our understanding of hemostasis and thrombosis. In addition to helping to decipher platelet biology, the results have implications for the understanding of new and existing antiplatelet agents and their potential risks.
Topics: Animals; Blood Platelets; Cell Shape; Humans; Platelet Activation; Signal Transduction; Vascular System Injuries
PubMed: 25023471
DOI: 10.1097/MOH.0000000000000070 -
Platelets 2015Although platelets are traditionally recognized for their central role in hemostasis, many lines of research clearly demonstrate these rather ubiquitous blood components... (Review)
Review
Although platelets are traditionally recognized for their central role in hemostasis, many lines of research clearly demonstrate these rather ubiquitous blood components are potent immune modulators and effectors. Platelets have been shown to directly recognize, sequester and kill pathogens, to activated and recruit leukocytes to sites of infection and inflammation, and to modulate leukocyte behavior, enhancing their ability to phagocytose and kill pathogens and inducing unique effector functions, such as the production of Neutrophil Extracellular Traps (NETs). This multifaceted response to infection and inflammation is due, in part, to the huge array of soluble mediators and cell surface molecules expressed by platelets. From their earliest origins as primordial hemocytes in invertebrates to their current form as megakaryocyte-derived cytoplasts, platelets have evolved to be one of the key regulators of host intravascular immunity and inflammation. In this review, we present the diverse roles platelets play in immunity and inflammation associated with autoimmune diseases and infection. Additionally, we highlight recent advances in our understanding of platelet behavior made possible through the use of advanced imaging techniques that allow us to visualize platelets and their interactions, in real-time, within the intact blood vessels of a living host.
Topics: Blood Platelets; Humans; Infections; Inflammation
PubMed: 25806786
DOI: 10.3109/09537104.2015.1010441 -
International Journal of Molecular... May 2021Hsia and collaborators [...].
Hsia and collaborators [...].
Topics: Animals; Biomedical Research; Blood Platelets; Disease; Health; Humans; Platelet Aggregation Inhibitors; Platelet Count; Regenerative Medicine
PubMed: 34067024
DOI: 10.3390/ijms22094968 -
Biochimica Et Biophysica Acta. Reviews... Sep 2022The interaction between circulating tumor cells and platelets is a key factor in cancer metastasis. These interactions, driven by a variety of receptors, support... (Review)
Review
The interaction between circulating tumor cells and platelets is a key factor in cancer metastasis. These interactions, driven by a variety of receptors, support circulating tumor cells by protecting them from immune detection, cushioning them from shear stress, and promoting their arrest at the endothelium. Additionally, platelets have been shown to accumulate in the primary tumors, promoting tumor growth and angiogenesis by releasing growth factors. Furthermore, tumor cells can interact with platelets by inducing aggregation, which further protects cancer cells. However, the platelet cancer cell interplay also offers new approaches to develop targeted therapies. The accumulation of platelets in tumors has successfully been leveraged to deliver chemotherapeutics and imaging agents. Likewise, these platelet-based interactions have been utilized to target cancer cells in circulation. Although these current systems have limitations including drug loading and storage, leveraging platelet-cancer cell interactions to effectively target circulating tumor cells and tumors shows great promise for future cancer treatments.
Topics: Blood Platelets; Cell Communication; Humans; Neoplastic Cells, Circulating; Neovascularization, Pathologic
PubMed: 35926688
DOI: 10.1016/j.bbcan.2022.188770 -
Methods in Molecular Biology (Clifton,... 2017Light transmittance aggregometry is the historical reference method for platelet function testing and continues to be used extensively. Whole blood impedance...
Light transmittance aggregometry is the historical reference method for platelet function testing and continues to be used extensively. Whole blood impedance lumiaggregometry represents an updated methodology that provides for simplified specimen management, an assay milieu that replicates in vivo platelet activation conditions, improved reproducibility, and near-patient testing. While the impedance-based whole blood aggregometer with luminescence channel is becoming the standard for platelet function testing using this methodology, at least three near-patient whole blood instruments are available, each employing its unique technology. We provide descriptions of whole blood lumiaggregometry and three near-patient systems. We include the principle of operation, materials, and stepwise example protocols and speculate on the importance of concordance among the platforms.
Topics: Blood Platelet Disorders; Blood Platelets; Electric Impedance; Humans; Indicators and Reagents; Luminescent Measurements; Platelet Aggregation; Platelet Function Tests; Quality Control
PubMed: 28804840
DOI: 10.1007/978-1-4939-7196-1_26 -
International Journal of Laboratory... Aug 2020So-called "reticulated" or "immature platelets," which are newly released into the circulation, are more reactive than mature platelets, contain more RNA, and can be... (Review)
Review
So-called "reticulated" or "immature platelets," which are newly released into the circulation, are more reactive than mature platelets, contain more RNA, and can be counted using flow cytometry after staining with thiazole orange or using some fully automated hematology analyzers, albeit with numerical disagreement. This review provides an overview of the state of the art of available technology for measuring immature or reticulated platelets (RP) with preanalytical (time stability, biological variation), analytical (methods, imprecision), and postanalytical (reference range) limitations. We also analyzed the clinical conditions in which immature/RP can be considered a diagnostic or prognostic tool (ie, differential diagnosis of thrombocytopenia, recovery after bone marrow or stem cell transplantation, risk assessment in cardiovascular diseases, response to antiplatelet drugs). They might also be of clinical utility in other settings but with lower evidence. The lack of a specific reference method and universal control material, as well as dependency of results on the measurement technique used, calls for different reference intervals and compromises comparison between clinical studies carried out using different analytical methods. To obviate lack of agreement between methods, more specific RNA dyes are necessary and the impact of the platelet size on the fluorescence signal defined. In the harmonization age, also in nomenclature field, a new definition instead of "reticulated" or "immature" platelets would be useful, and "young platelets" might be a more appropriate definition taking into account both the age and the functionality of this platelet fraction.
Topics: Benzothiazoles; Blood Platelets; Flow Cytometry; Humans; Platelet Function Tests; Quinolines; Thrombocytopenia
PubMed: 32157813
DOI: 10.1111/ijlh.13177 -
Platelets Jul 2017Platelets, responsible for clot formation and blood vessel repair, are produced by megakaryocytes in the bone marrow. Platelets are critical for hemostasis and wound... (Review)
Review
Platelets, responsible for clot formation and blood vessel repair, are produced by megakaryocytes in the bone marrow. Platelets are critical for hemostasis and wound healing, and are often provided following surgery, chemotherapy, and major trauma. Despite their importance, platelets today are derived exclusively from human volunteer donors. They have a shelf life of just five days, making platelet shortages common during long weekends, civic holidays, bad weather, and during major emergencies when platelets are needed most. Megakaryocytes in the bone marrow generate platelets by extruding long cytoplasmic extensions called proplatelets through gaps/fenestrations in blood vessels. Proplatelets serve as assembly lines for platelet production by sequentially releasing platelets and large discoid-shaped platelet intermediates called preplatelets into the circulation. Recent advances in platelet bioreactor development have aimed to mimic the key physiological characteristics of bone marrow, including extracellular matrix composition/stiffness, blood vessel architecture comprising tissue-specific microvascular endothelium, and shear stress. Nevertheless, how complex interactions within three-dimensional (3D) microenvironments regulate thrombopoiesis remains poorly understood, and the technical challenges associated with designing and manufacturing biomimetic microfluidic devices are often under-appreciated and under-reported. We have previously reviewed the major cell culture, platelet quality assessment, and regulatory roadblocks that must be overcome to make human platelet production possible for clinical use [1]. This review builds on our previous manuscript by: (1) detailing the historical evolution of platelet bioreactor design to recapitulate native platelet production ex vivo, and (2) identifying the associated challenges that still need to be addressed to further scale and validate these devices for commercial application. While platelets are among the first cells whose ex vivo production is spearheading major engineering advancements in microfluidic design, the resulting discoveries will undoubtedly extend to the production of other human tissues. This work is critical to identify the physiological characteristics of relevant 3D tissue-specific microenvironments that drive cell differentiation and elaborate upon how these are disrupted in disease. This is a burgeoning field whose future will define not only the ex vivo production of platelets and development of targeted therapies for thrombocytopenia, but the promise of regenerative medicine for the next century.
Topics: Animals; Bioreactors; Blood Platelets; Cell Culture Techniques; Humans; Megakaryocytes
PubMed: 28112988
DOI: 10.1080/09537104.2016.1265922 -
International Journal of Molecular... Oct 2020Platelets are highly abundant cell fragments of the peripheral blood that originate from megakaryocytes. Beside their well-known role in wound healing and hemostasis,... (Review)
Review
Platelets are highly abundant cell fragments of the peripheral blood that originate from megakaryocytes. Beside their well-known role in wound healing and hemostasis, they are emerging mediators of the immune response and implicated in a variety of pathophysiological conditions including cancer. Despite their anucleate nature, they harbor a diverse set of RNAs, which are subject to an active sorting mechanism from megakaryocytes into proplatelets and affect platelet biogenesis and function. However, sorting mechanisms are poorly understood, but RNA-binding proteins (RBPs) have been suggested to play a crucial role. Moreover, RBPs may regulate RNA translation and decay following platelet activation. In concert with other regulators, including microRNAs, long non-coding and circular RNAs, RBPs control multiple steps of the platelet life cycle. In this review, we will highlight the different RNA species within platelets and their impact on megakaryopoiesis, platelet biogenesis and platelet function. Additionally, we will focus on the currently known concepts of post-transcriptional control mechanisms important for RNA fate within platelets with a special emphasis on RBPs.
Topics: Animals; Blood Platelets; Humans; RNA Processing, Post-Transcriptional; RNA, Untranslated; RNA-Binding Proteins; Thrombopoiesis
PubMed: 33076269
DOI: 10.3390/ijms21207614