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Cell Reports Nov 2023Platelets are anucleate blood cells that contain mitochondria and regulate blood clotting in response to injury. Mitochondria contain their own gene expression machinery...
Platelets are anucleate blood cells that contain mitochondria and regulate blood clotting in response to injury. Mitochondria contain their own gene expression machinery that relies on nuclear-encoded factors for the biogenesis of the oxidative phosphorylation system to produce energy required for thrombosis. The autonomy of the mitochondrial gene expression machinery from the nucleus is unclear, and platelets provide a valuable model to understand its importance in anucleate cells. Here, we conditionally delete Elac2, Ptcd1, or Mtif3 in platelets, which are essential for mitochondrial gene expression at the level of RNA processing, stability, or translation, respectively. Loss of ELAC2, PTCD1, or MTIF3 leads to increased megakaryocyte ploidy, elevated circulating levels of reticulated platelets, thrombocytopenia, and consequent extended bleeding time. Impaired mitochondrial gene expression reduces agonist-induced platelet activation. Transcriptomic and proteomic analyses show that mitochondrial gene expression is required for fibrinolysis, hemostasis, and blood coagulation in response to injury.
Topics: Humans; Genes, Mitochondrial; Proteomics; Hemostasis; Blood Coagulation; Blood Platelets; Megakaryocytes; Thrombosis; Gene Expression; Mitochondrial Proteins
PubMed: 37889747
DOI: 10.1016/j.celrep.2023.113312 -
Platelets Dec 2023When platelet concentrates (PCs) were first introduced in the 1960s as a blood component therapy, they were stored in the cold. As platelet transfusion became more... (Review)
Review
When platelet concentrates (PCs) were first introduced in the 1960s as a blood component therapy, they were stored in the cold. As platelet transfusion became more important for the treatment of chemotherapy-induced thrombocytopenia, research into ways to increase supply intensified. During the late 1960s/early 1970s, it was demonstrated through radioactive labeling of platelets that room temperature platelets (RTP) had superior post-transfusion recovery and survival compared with cold-stored platelets (CSP). This led to a universal switch to room temperature storage, despite CSP demonstrating superior hemostatic effectiveness upon being transfused. There has been a global resurgence in studies into CSP over the last two decades, with an increase in the use of PC to treat acute bleeding within hospital and pre-hospital care. CSP demonstrate many benefits over RTP, including longer shelf life, decreased bacterial risk and easier logistics for transport, making PC accessible in areas where they have not previously been, such as the battlefield. In addition, CSP are reported to have greater hemostatic function than RTP and are thus potentially better for the treatment of bleeding. This review describes the history of CSP, the functional and metabolic assays used to assess the platelet storage lesion in PC and the current research, benefits and limitations of CSP. We also discuss whether the application of new technology for studying mitochondrial and glycolytic function in PC could provide enhanced understanding of platelet metabolism during storage and thus contribute to the continued improvements in the manufacturing and storage of PC.
Topics: Humans; Blood Preservation; Blood Platelets; Cold Temperature; Platelet Transfusion; Hemorrhage; Energy Metabolism
PubMed: 36922733
DOI: 10.1080/09537104.2023.2188969 -
Nature Communications Nov 2023Circulating cell-free DNA (cfDNA) fragments are a biological analyte with extensive utility in diagnostic medicine. Understanding the source of cfDNA and mechanisms of...
Circulating cell-free DNA (cfDNA) fragments are a biological analyte with extensive utility in diagnostic medicine. Understanding the source of cfDNA and mechanisms of release is crucial for designing and interpreting cfDNA-based liquid biopsy assays. Using cell type-specific methylation markers as well as genome-wide methylation analysis, we determine that megakaryocytes, the precursors of anuclear platelets, are major contributors to cfDNA (~26%), while erythroblasts contribute 1-4% of cfDNA in healthy individuals. Surprisingly, we discover that platelets contain genomic DNA fragments originating in megakaryocytes, contrary to the general understanding that platelets lack genomic DNA. Megakaryocyte-derived cfDNA is increased in pathologies involving increased platelet production (Essential Thrombocythemia, Idiopathic Thrombocytopenic Purpura) and decreased upon reduced platelet production due to chemotherapy-induced bone marrow suppression. Similarly, erythroblast cfDNA is reflective of erythrocyte production and is elevated in patients with thalassemia. Megakaryocyte- and erythroblast-specific DNA methylation patterns can thus serve as biomarkers for pathologies involving increased or decreased thrombopoiesis and erythropoiesis, which can aid in determining the etiology of aberrant levels of erythrocytes and platelets.
Topics: Humans; Megakaryocytes; Thrombopoiesis; Erythropoiesis; Cell-Free Nucleic Acids; Blood Platelets; Erythroblasts; DNA
PubMed: 37985773
DOI: 10.1038/s41467-023-43310-2 -
Blood Reviews Jan 2024Immune thrombocytopenia (ITP) is a rare autoimmune condition, due to peripheral platelet destruction through antibody-dependent cellular phagocytosis,... (Review)
Review
Immune thrombocytopenia (ITP) is a rare autoimmune condition, due to peripheral platelet destruction through antibody-dependent cellular phagocytosis, complement-dependent cytotoxicity, cytotoxic T lymphocyte-mediated cytotoxicity, and megakaryopoiesis alteration. This condition may be idiopathic or triggered by drugs, vaccines, infections, cancers, autoimmune disorders and systemic diseases. Recent advances in our understanding of ITP immunobiology support the idea that other forms of thrombocytopenia, for instance, occurring after immunotherapy or cellular therapies, may share a common pathophysiology with possible therapeutic implications. If a decent pipeline of old and new agents is currently deployed for classical ITP, in other more complex immune-mediated thrombocytopenic disorders, clinical management is less harmonized and would deserve further prospective investigations. Here, we seek to provide a fresh overview of pathophysiology and current therapeutical algorithms for adult patients affected by this disorder with specific insights into poorly codified scenarios, including refractory ITP and post-immunotherapy/cellular therapy immune-mediated thrombocytopenia.
Topics: Adult; Humans; Purpura, Thrombocytopenic, Idiopathic; Thrombocytopenia; Immunotherapy; Blood Platelets
PubMed: 37980261
DOI: 10.1016/j.blre.2023.101141 -
Frontiers in Immunology 2023Immune responses are crucial to maintaining tissue homeostasis upon tissue injury. Upon various types of challenges, macrophages play a central role in regulating...
Immune responses are crucial to maintaining tissue homeostasis upon tissue injury. Upon various types of challenges, macrophages play a central role in regulating inflammation and tissue repair processes. While an immunomodulatory role of Wnt antagonist Dickkopf1 (DKK1) has been implicated, the role of Wnt antagonist DKK1 in regulating macrophage polarization in inflammation and the tissue repair process remains elusive. Here we found that DKK1 induces gene expression profiles to promote inflammation and tissue repair in macrophages. Importantly, DKK1 induced various genes, including inflammation and tissue repair, via JNK (c-jun N-terminal kinase) in macrophages. Furthermore, DKK1 potentiated IL-13-mediated macrophage polarization and activation. The co-inhibition of JNK and STAT6 markedly decreased gene expressions inflammation and fibrosis by DKK1 and IL-13. Interestingly, thrombocyte-specific deletion of DKK1 in mice reduced collagen deposition and decreased Arg1, CD206, HIF1α, and IL1β protein expressions in monocyte-derived alveolar macrophages in the acute sterile bleomycin (BLM)-induced lung injury model. These data suggested that thrombocytes communicate with macrophages via DKK1 to orchestrate inflammation and repair in this model. Taken together, our study demonstrates DKK1's role as an important regulatory ligand for macrophage polarization in the injury-induced inflammation and repair process in the lung.
Topics: Animals; Mice; Acute Lung Injury; Bleomycin; Blood Platelets; Inflammation; Interleukin-13; Macrophages
PubMed: 38162655
DOI: 10.3389/fimmu.2023.1247330 -
Arteriosclerosis, Thrombosis, and... Jun 2024
Review
Topics: Blood Platelets; Humans; Inflammation; Thrombosis; Animals; Platelet Activation; Inflammation Mediators; Signal Transduction
PubMed: 38776384
DOI: 10.1161/ATVBAHA.124.320149 -
Immunological platelet transfusion refractoriness: current insights from mechanisms to therapeutics.Platelets Dec 2024Although there have been tremendous improvements in the production and storage of platelets, platelet transfusion refractoriness (PTR) remains a serious clinical issue... (Review)
Review
Although there have been tremendous improvements in the production and storage of platelets, platelet transfusion refractoriness (PTR) remains a serious clinical issue that may lead to various severe adverse events. The burden of supplying platelets is worsened by rising market demand and limited donor pools of compatible platelets. Antibodies against platelet antigens are known to activate platelets through FcγR-dependent or complement-activated channels, thereby rapidly eliminating foreign platelets. Recently, other mechanisms of platelet clearance have been reported. The current treatment strategy for PTR is to select appropriate and compatible platelets; however, this necessitates a sizable donor pool and technical assistance for costly testing. Consolidation of these mechanisms should be of critical significance in providing insight to establish novel therapeutics to target immunological platelet refractoriness. Therefore, the purposes of this review were to explore the modulation of the immune system over the activation and elimination of allogeneic platelets and to summarize the development of alternative approaches for treating and avoiding alloimmunization to human leukocyte antigen or human platelet antigen in PTR.
Topics: Humans; Platelet Transfusion; Blood Platelets; Thrombocytopenia; Antigens, Human Platelet; HLA Antigens
PubMed: 38314765
DOI: 10.1080/09537104.2024.2306983 -
Journal of Neuroimmunology Sep 2023In this narrative review, we examine the association between gut dysbiosis, neuroinflammation, and stress-linked disorders, including depression, anxiety, and... (Review)
Review
In this narrative review, we examine the association between gut dysbiosis, neuroinflammation, and stress-linked disorders, including depression, anxiety, and post-traumatic stress disorder (PTSD), and investigate whether tryptophan (TRP) metabolism and platelets play a role in this association. The mechanisms underlying the aetiology of stress-linked disorders are complex and not yet completely understood. However, a potential link between chronic inflammation and these disorders may potentially be found in TRP metabolism and platelets. By critically analysing existing literature on platelets, the gut microbiome, and stress-linked disorders, we hope to elicit the role of platelets in mediating the effects on serotonin (5-HT) levels and neuroinflammation. We have included studies specifically investigating platelets and TRP metabolism in relation to inflammation, neuroinflammation and neuropsychiatric disorders. Alteration in microbial composition due to stress could contribute to increased intestinal permeability, facilitating the translocation of microbial products, and triggering the release of pro-inflammatory cytokines. This causes platelets to become hyperactive and secrete 5-HT into the plasma. Increased levels of pro-inflammatory cytokines may also lead to increased permeability of the blood-brain barrier (BBB), allowing inflammatory mediators entry into the brain, affecting the balance of TRP metabolism products, such as 5-HT, kynurenic acid (KYNA), and quinolinic acid (QUIN). These alterations may contribute to neuroinflammation and possible neurological damage. Furthermore, platelets can cross the compromised BBB and interact with astrocytes and neurons, leading to the secretion of 5-HT and pro-inflammatory factors, exacerbating inflammatory conditions in the brain. The mechanisms underlying neuroinflammation resulting from peripheral inflammation are still unclear, but the connection between the brain and gut through the bloodstream could be significant. Identifying peripheral biomarkers and mechanisms in the plasma that reflect neuroinflammation may be important. This review serves as a foundation for further research on the association between the gut microbiome, blood microbiome, and neuropsychiatric disorders. The integration of these findings with protein and metabolite markers in the blood may expand our understanding of the subject.
Topics: Humans; Tryptophan; Kynurenine; Neuroinflammatory Diseases; Serotonin; Blood Platelets; Dysbiosis; Inflammation; Cytokines
PubMed: 37523892
DOI: 10.1016/j.jneuroim.2023.578155 -
Medicine Aug 2023Gastric cancer (GC) is the remaining concern of cancer-associated health burden. Valuable predictive and prognostic indicators support the early diagnosis and improve...
Gastric cancer (GC) is the remaining concern of cancer-associated health burden. Valuable predictive and prognostic indicators support the early diagnosis and improve outcome. Immune escape and inflammation are important cancer hallmarks. The prognostic and diagnostic value of platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) was reported in some cancers. But these cheap and convenient indexes are far from clinical use. Thus, investigation the alteration of those index on GC is needed to impose the use of those indexes in clinic. The study recruited seventy-seven hospitalized patients newly diagnosed with GC and 90 healthy individuals. The clinical and preclinical data of participants were collected from Hospital Information Management system. This study were approved by the Ethical Committee, Vietnam Military Medical University. The data were analyzed on STATA version 14.0 and GraphPad Prism 8.0. The alteration of immunological system was reported by significantly higher white blood cell count, neutrophils, platelets, PLR, and NLR as well as decreased lymphocytes on GC, compared to healthy individuals. Those indexes were elevated on advanced stage GC, compared to early stage GC. Our receiver operating characteristic curve analysis showed the significant specificity and sensitivity of PLR (cutoff 135.0) and NLR (cutoff 2.0) on GC diagnosis with respective area under receiver operating characteristic curve of 84.74% and 85.17%, P < .0001. Besides, our results reported the tendency of increased PLR and NLR and short time from clinical signs to being diagnosed. PLR and NLR have significant specificity and sensitivity in diagnosis and prognosis of GC.
Topics: Humans; Blood Platelets; Neutrophils; Prognosis; Platelet Count; Stomach Neoplasms; Lymphocytes; Retrospective Studies
PubMed: 37543797
DOI: 10.1097/MD.0000000000034357 -
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