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Critical Reviews in Biochemistry and... Dec 2023Dogma had been firmly entrenched in the minds of the scientific community that the anucleate mammalian platelet was incapable of protein biosynthesis since their... (Review)
Review
Dogma had been firmly entrenched in the minds of the scientific community that the anucleate mammalian platelet was incapable of protein biosynthesis since their identification in the late 1880s. These beliefs were not challenged until the 1960s when several reports demonstrated that platelets possessed the capacity to biosynthesize proteins. Even then, many still dismissed the synthesis as trivial and unimportant for at least another two decades. Research in the field expanded after the 1980s and numerous reports have since been published that now clearly demonstrate the potential significance of platelet protein synthesis under normal, pathological, and activating conditions. It is now clear that the platelet proteome is not a static entity but can be altered slowly or rapidly in response to external signals to support physiological requirements to maintain hemostasis and other biological processes. All the necessary biological components to support protein synthesis have been identified in platelets along with post-transcriptional processing of mRNAs, regulators of translation, and post-translational modifications such as glycosylation. The last comprehensive review of the subject appeared in 2009 and much work has been conducted since that time. The current review of the field will briefly incorporate the information covered in earlier reviews and then bring the reader up to date with more recent findings.
Topics: Animals; Blood Platelets; Hemostasis; Protein Processing, Post-Translational; Proteome; Glycosylation; Mammals
PubMed: 37347996
DOI: 10.1080/10409238.2023.2224532 -
Cellular and Molecular Gastroenterology... 2024Alcohol-associated liver disease (ALD) is a major contributor to liver-related mortality globally. An increasing body of evidence underscores the pivotal role of... (Review)
Review
Alcohol-associated liver disease (ALD) is a major contributor to liver-related mortality globally. An increasing body of evidence underscores the pivotal role of platelets throughout the spectrum of liver injury and recovery, offering unique insights into liver homeostasis and pathobiology. Alcoholic-associated steatohepatitis is characterized by the infiltration of hepatic neutrophils. Recent studies have highlighted the extensive distance neutrophils travel through sinusoids to reach the liver injury site, relying on a platelet-paved endothelium for efficient crawling. The adherence of platelets to neutrophils is crucial for accurate migration from circulation to the inflammatory site. A gradual decline in platelet levels leads to diminished neutrophil recruitment. Platelets exhibit the ability to activate neutrophils. Platelet activation is heightened upon the release of platelet granule contents, which synergistically activate neutrophils through their respective receptors. The sequence culminates in the formation of platelet-neutrophil complexes and the release of neutrophil extracellular traps intensifies liver damage, fosters inflammatory immune responses, and triggers hepatotoxic processes. Neutrophil infiltration is a hallmark of alcohol-associated steatohepatitis, and the roles of neutrophils in ALD pathogenesis have been studied extensively, however, the involvement of platelets in ALD has received little attention. The current review consolidates recent findings on the intricate and diverse roles of platelets and neutrophils in liver pathophysiology and in ALD. Potential therapeutic strategies are highlighted, focusing on targeting platelet-neutrophil interactions and activation in ALD. The anticipation is that innovative methods for manipulating platelet and neutrophil functions will open promising avenues for future ALD therapy.
Topics: Humans; Neutrophils; Blood Platelets; Liver Diseases, Alcoholic; Animals; Neutrophil Infiltration; Liver; Cell Communication; Platelet Activation
PubMed: 38461963
DOI: 10.1016/j.jcmgh.2024.03.001 -
Transfusion Oct 2023Mitochondria play a critical role in the production of cell energy and the regulation of cell death. Therefore, mitochondria orchestrate numerous cell effector...
BACKGROUND
Mitochondria play a critical role in the production of cell energy and the regulation of cell death. Therefore, mitochondria orchestrate numerous cell effector functions, including fine-tuning the immune system. While mitochondria are mainly found intracellularly, they can escape the confine of the cell during the process of extracellular vesicle release. Platelets patrol blood vessels to ensure vasculature integrity and to support the immune system. In blood, platelets are the primary source of circulating mitochondria. Activated platelets produce extracellular vesicles, including a subset of mitochondria-containing vesicles.
STUDY DESIGN AND METHODS
We characterized mitochondrial functions in platelet-derived extracellular vesicles, and examined whether they could impact the bioenergetics of cellular immune recipients using an extracellular flux analyzer to measure real-time bioenergetics.
RESULTS
We validated that extracellular vesicles derived from activated platelets contain the necessary mitochondrial machinery to respirate and generate energy. Moreover, neutrophils and monocytes efficiently captured platelet-derived extracellular vesicles, enhancing their mitochondrial fitness. This process required functional mitochondria from donor platelets, as it was abolished by the inactivation of extracellular mitochondria using mitochondrial poison.
DISCUSSION
Together, the data suggest that extracellular mitochondria produced by platelets may support other metabolic functions through transcellular bioenergetics.
Topics: Humans; Blood Platelets; Mitochondria; Energy Metabolism; Extracellular Vesicles; Exercise
PubMed: 37642274
DOI: 10.1111/trf.17524 -
Biochemical and Biophysical Research... Jan 2024Celastrol is an active pentacyclic triterpenoid extracted from Tripterygium wilfordii and has anti-inflammatory and anti-tumor properties. Whether Celastrol modulates...
INTRODUCTION
Celastrol is an active pentacyclic triterpenoid extracted from Tripterygium wilfordii and has anti-inflammatory and anti-tumor properties. Whether Celastrol modulates platelet function remains unknown. Our study investigated its role in platelet function and thrombosis.
METHODS
Human platelets were isolated and incubated with Celastrol (0, 1, 3 and 5 μM) at 37 °C for 1 h to measure platelet aggregation, granules release, spreading, thrombin-induced clot retraction and intracellular calcium mobilization. Additionally, Celastrol (2 mg/kg) was intraperitoneally administrated into mice to evaluate hemostasis and thrombosis in vivo.
RESULTS
Celastrol treatment significantly decreased platelet aggregation and secretion of dense or alpha granules induced by collagen-related peptide (CRP) or thrombin in a dose-dependent manner. Additionally, Celastrol-treated platelets showed a dramatically reduced spreading activity and decreased clot retraction. Moreover, Celastrol administration prolonged tail bleeding time and inhibited formation of arterial/venous thrombosis. Furthermore, Celastrol significantly reduced calcium mobilization.
CONCLUSION
Celastrol inhibits platelet function and venous/arterial thrombosis, implying that it might be utilized for treating thrombotic diseases.
Topics: Humans; Animals; Mice; Platelet Activation; Calcium; Thrombin; Hemostasis; Platelet Aggregation; Blood Platelets; Pentacyclic Triterpenes; Thrombosis
PubMed: 38091842
DOI: 10.1016/j.bbrc.2023.149366 -
International Journal of Hematology Jun 2024The role of platelets in coronavirus disease (COVID-19) severity requires further exploration. To determine whether the platelet index is useful in predicting COVID-19...
The role of platelets in coronavirus disease (COVID-19) severity requires further exploration. To determine whether the platelet index is useful in predicting COVID-19 severity, we compared the platelet index in patients with higher and lower oxygen requirements (≥ 4 L/min vs. < 4 L/min) and patients without COVID-19. We also analyzed the time course of the platelet index in each group. A total of 285 patients with COVID-19 and 36 without COVID-19 who were hospitalized at Fussa Hospital were analyzed. After matching for oxygen requirement at admission, multivariate analysis was performed. Platelets (≤ 16.6 × 10/μL) and platelet-large cell ratio (P-LCR) (≥ 27.8%) were significant factors influencing severity. Based on these factors, we created the Fussa platelet score, and the group with a Fussa platelet score ≥ 2 was significantly more likely to reach the 4 L/min oxygen requirement (event-free survival: Fussa platelet score ≥ 2 versus < 2, P < 0.00000001). Analysis of platelet index by time period showed a significant increase from 6-10 days after onset. The Fussa platelet score can be measured quickly, easily, and inexpensively in a clinic and may be useful in determining need for transfer to a critical care hospital.
Topics: Humans; COVID-19; Male; Female; Severity of Illness Index; Middle Aged; Platelet Count; Aged; Blood Platelets; SARS-CoV-2; Retrospective Studies; Adult; Aged, 80 and over; Prognosis
PubMed: 38520659
DOI: 10.1007/s12185-024-03737-9 -
Jak2 V617F clonal hematopoiesis promotes arterial thrombosis via platelet activation and cross talk.Blood Apr 2024JAK2 V617F (JAK2VF) clonal hematopoiesis (CH) has been associated with atherothrombotic cardiovascular disease (CVD). We assessed the impact of Jak2VF CH on arterial... (Meta-Analysis)
Meta-Analysis
JAK2 V617F (JAK2VF) clonal hematopoiesis (CH) has been associated with atherothrombotic cardiovascular disease (CVD). We assessed the impact of Jak2VF CH on arterial thrombosis and explored the underlying mechanisms. A meta-analysis of 3 large cohort studies confirmed the association of JAK2VF with CVD and with platelet counts and adjusted mean platelet volume (MPV). In mice, 20% or 1.5% Jak2VF CH accelerated arterial thrombosis and increased platelet activation. Megakaryocytes in Jak2VF CH showed elevated proplatelet formation and release, increasing prothrombogenic reticulated platelet counts. Gp1ba-Cre-mediated expression of Jak2VF in platelets (VFGp1ba) increased platelet counts to a similar level as in 20% Jak2VF CH mice while having no effect on leukocyte counts. Like Jak2VF CH mice, VFGp1ba mice showed enhanced platelet activation and accelerated arterial thrombosis. In Jak2VF CH, both Jak2VF and wild-type (WT) platelets showed increased activation, suggesting cross talk between mutant and WT platelets. Jak2VF platelets showed twofold to threefold upregulation of COX-1 and COX-2, particularly in young platelets, with elevated cPLA2 activation and thromboxane A2 production. Compared with controls, conditioned media from activated Jak2VF platelets induced greater activation of WT platelets that was reversed by a thromboxane receptor antagonist. Low-dose aspirin ameliorated carotid artery thrombosis in VFGp1ba and Jak2VF CH mice but not in WT control mice. This study shows accelerated arterial thrombosis and platelet activation in Jak2VF CH with a major role of increased reticulated Jak2VF platelets, which mediate thromboxane cross talk with WT platelets and suggests a potential beneficial effect of aspirin in JAK2VF CH.
Topics: Animals; Humans; Mice; Aspirin; Blood Platelets; Clonal Hematopoiesis; Mice, Knockout; Platelet Activation; Thrombosis
PubMed: 38142422
DOI: 10.1182/blood.2023022260 -
Journal of Translational Medicine Aug 2023Cyclooxygenase (COX)-2 is a rate-limiting enzyme in the biosynthesis of prostanoids, which is mostly inducible by inflammatory cytokines. The participation of COX-2 in...
BACKGROUND
Cyclooxygenase (COX)-2 is a rate-limiting enzyme in the biosynthesis of prostanoids, which is mostly inducible by inflammatory cytokines. The participation of COX-2 in the maturation of megakaryocytes has been reported but barely studied in primary immune thrombocytopenia (ITP).
METHODS
The expressions of COX-2 and Caspase-1, Caspase-3 and Caspase-3 p17 subunit in platelets from ITP patients and healthy controls (HC), and the expressions of COX-2 and CD41 in bone marrow (BM) of ITP patients were measured and analyzed for correlations. The effects of COX-2 inhibitor on megakaryopoiesis and thrombopoiesis were assessed by in vitro culture of Meg01 cells and murine BM-derived megakaryocytes and in vivo experiments of passive ITP mice.
RESULTS
The expression of COX-2 was decreased and Caspase-1 and Caspase-3 p17 were increased in platelets from ITP patients compared to HC. In platelets from ITP patients, the COX-2 expression was positively correlated with platelet count and negatively correlated to the expression of Caspase-1. In ITP patients BM, the expression of CD41 was positively correlated with the expression of COX-2. COX-2 inhibitor inhibited the count of megakaryocytes and impaired the maturation and platelet production in Meg01 cells and bone marrow-derived megakaryocytes. COX-2 inhibitor aggravated thrombocytopenia and damaged megakaryopoiesis in ITP murine model.
CONCLUSION
COX-2 plays a vital role in the physiologic and pathologic conditions of ITP by intervening the survival of platelets and impairing the megakaryopoiesis and thrombopoiesis of megakaryocytes.
Topics: Animals; Mice; Blood Platelets; Caspase 3; Cyclooxygenase 2; Cyclooxygenase 2 Inhibitors; Megakaryocytes; Purpura, Thrombocytopenic, Idiopathic; Thrombopoiesis
PubMed: 37573325
DOI: 10.1186/s12967-023-04389-9 -
Microvascular Research Jan 2024Thrombosis can lead to significant mortality and morbidity. Both platelets and vascular endothelial cells play significant roles in thrombosis. Platelets' response to...
Thrombosis can lead to significant mortality and morbidity. Both platelets and vascular endothelial cells play significant roles in thrombosis. Platelets' response to blood flow-induced shear stress can vary greatly depending on shear stress magnitude, pattern and shear exposure time. Endothelial cells are also sensitive to the biomechanical environment. Endothelial cell activation and dysfunction can occur under low oscillatory shear stress and low tensile strain. Platelet and endothelial cell interaction can also be affected by mechanical conditions. The goal of this study was to investigate how blood flow-induced shear stress, vascular wall tensile strain, platelet-endothelial cell stress history, and platelet-endothelial cell interaction affect platelet thrombogenicity. Platelets and human coronary artery endothelial cells were pretreated with physiological and pathological shear stress and/or tensile strain separately. The pretreated cells were then put together and exposed to pulsatile shear stress and cyclic tensile strain simultaneously in a shearing-stretching device. Following treatment, platelet thrombin generation rate, platelet and endothelial cell activation, and platelet adhesion to endothelial cells was measured. The results demonstrated that shear stress pretreatment of endothelial cells and platelets caused a significant increase in platelet thrombin generation rate, cell surface phosphatidylserine expression, and adhesion to endothelial cells. Shear stress pretreatment of platelets and endothelial cells attenuated endothelial cell ICAM-1 expression under stenosis conditions, as well as vWF expression under recirculation conditions. These results indicate that platelets are sensitized by prior shearing, while in comparison, the interaction with shear stress-pretreated platelets may reduce endothelial cell sensitivity to pathological shear stress and tensile strain.
Topics: Humans; Endothelial Cells; Thrombin; Blood Platelets; Platelet Adhesiveness; Thrombosis; Stress, Mechanical; Platelet Activation
PubMed: 37793562
DOI: 10.1016/j.mvr.2023.104613 -
Cell Death and Differentiation Aug 2023Necroptosis is a form of programmed cell death executed by receptor-interacting serine/threonine protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like...
Necroptosis is a form of programmed cell death executed by receptor-interacting serine/threonine protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like (MLKL). Platelets are circulating cells that play central roles in haemostasis and pathological thrombosis. In this study we demonstrate seminal contribution of MLKL in transformation of agonist-stimulated platelets to active haemostatic units progressing eventually to necrotic death on a temporal scale, thus attributing a yet unrecognized fundamental role to MLKL in platelet biology. Physiological agonists like thrombin instigated phosphorylation and subsequent oligomerization of MLKL in platelets in a RIPK3-independent but phosphoinositide 3-kinase (PI3K)/AKT-dependent manner. Inhibition of MLKL significantly curbed agonist-induced haemostatic responses in platelets that included platelet aggregation, integrin activation, granule secretion, procoagulant surface generation, rise in intracellular calcium, shedding of extracellular vesicles, platelet-leukocyte interactions and thrombus formation under arterial shear. MLKL inhibition, too, prompted impairment in mitochondrial oxidative phosphorylation and aerobic glycolysis in stimulated platelets, accompanied with disruption in mitochondrial transmembrane potential, augmented proton leak and drop in both mitochondrial calcium as well as ROS. These findings underscore the key role of MLKL in sustaining OXPHOS and aerobic glycolysis that underlie energy-intensive platelet activation responses. Prolonged exposure to thrombin provoked oligomerization and translocation of MLKL to plasma membranes forming focal clusters that led to progressive membrane permeabilization and decline in platelet viability, which was prevented by inhibitors of PI3K/MLKL. In summary, MLKL plays vital role in transitioning of stimulated platelets from relatively quiescent cells to functionally/metabolically active prothrombotic units and their ensuing progression to necroptotic death.
Topics: Protein Kinases; Blood Platelets; Necroptosis; Calcium; Phosphatidylinositol 3-Kinases; Thrombin; Cell Death; Receptor-Interacting Protein Serine-Threonine Kinases
PubMed: 37301927
DOI: 10.1038/s41418-023-01181-6 -
Thrombosis and Haemostasis Sep 2023Extracellular vesicles (EVs), shed in response to cell activation, stress, or injury, are increased in the blood of patients with cardiovascular disease. EVs are...
BACKGROUND
Extracellular vesicles (EVs), shed in response to cell activation, stress, or injury, are increased in the blood of patients with cardiovascular disease. EVs are characterized by expressing parental-cell antigens, allowing the determination of their cellular origin. Platelet-derived EVs (pEVs) are the most abundant in blood. Although not universally given, EVs generally express phosphatidylserine (PS) in their membrane.
OBJECTIVES
To investigate pEVs in chronic and acute conditions, such as chronic heart failure (CHF) and first-onset acute coronary syndrome (ACS), in patients treated as per guidelines.
METHODS
EVs in CHF patients ( = 119), ACS patients ( = 58), their respective controls (non-CHF [ = 21] and non-ACS [ = 24], respectively), and a reference control group ( = 31) were characterized and quantified by flow cytometry, using monoclonal antibodies against platelet antigens, and annexin V (AV) to determine PS exposure.
RESULTS
CHF patients had higher EVs-PS numbers, while ACS had predominantly EVs-PS. In contrast to ACS, CHF patients had significantly reduced numbers of pEVs carrying PECAM and α-integrin epitopes (CD31/AV, CD41a/AV, and CD31/CD41a/AV), while no differences were observed in P-selectin-rich pEVs (CD62P/AV) compared with controls. Additionally, background etiology of CHF (ischemic vs. nonischemic) or ACS type (ST-elevation myocardial infarction [STEMI] vs. non-STEMI [NSTEMI]) did not affect pEV levels.
CONCLUSION
PS exposure in EV and pEV-release differ between CHF and ACS patients, with tentatively different functional capacities beyond coagulation to inflammation and cross-talk with other cell types.
Topics: Humans; Extracellular Vesicles; Blood Platelets; Acute Coronary Syndrome; Antibodies, Monoclonal; Inflammation
PubMed: 37075787
DOI: 10.1055/s-0043-57017