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Therapeutic Advances in Hematology 2023Platelets, derived from a certain subpopulation of megakaryocytes, are closely related to hemostasis, coagulation, metastasis, inflammation, and cancer progression.... (Review)
Review
Platelets, derived from a certain subpopulation of megakaryocytes, are closely related to hemostasis, coagulation, metastasis, inflammation, and cancer progression. Thrombopoiesis is a dynamic process regulated by various signaling pathways in which thrombopoietin (THPO)-MPL is dominant. Thrombopoiesis-stimulating agents could promote platelet production, showing therapeutic effects in different kinds of thrombocytopenia. Some thrombopoiesis-stimulating agents are currently used in clinical practices to treat thrombocytopenia. The others are not in clinical investigations to deal with thrombocytopenia but have potential in thrombopoiesis. Their potential values in thrombocytopenia treatment should be highly regarded. Novel drug screening models and drug repurposing research have found many new agents and yielded promising outcomes in preclinical or clinical studies. This review will briefly introduce thrombopoiesis-stimulating agents currently or potentially valuable in thrombocytopenia treatment and summarize the possible mechanisms and therapeutic effects, which may enrich the pharmacological armamentarium for the medical treatment of thrombocytopenia.
PubMed: 36865986
DOI: 10.1177/20406207231152746 -
Blood Jan 2023
Topics: Humans; Glycosylation; Thrombopoiesis; Mutation; Thrombocytopenia
PubMed: 36701170
DOI: 10.1182/blood.2022019021 -
Journal of Thrombosis and Haemostasis :... Feb 2023Platelet shedding from mature megakaryocytes (MKs) in thrombopoiesis is the critical step for elevating circulating platelets fast and efficiently, however, the...
BACKGROUND
Platelet shedding from mature megakaryocytes (MKs) in thrombopoiesis is the critical step for elevating circulating platelets fast and efficiently, however, the underlying mechanism is still not well-illustrated, and the therapeutic targets and candidates are even less.
OBJECTIVES
In order to investigate the mechanisms for platelet shedding after vasopressin treatment and find new therapeutic targets for thrombocytopenia.
METHODS
Platelet production was evaluated both in vivo and in vitro after arginine vasopressin (AVP) administration. The underlying biological mechanism of AVP-triggered thrombopoiesis were then investigated by a series of molecular and bioinformatics techniques.
RESULTS
it is observed that proplatelet formation and platelet shedding in the final stages of thrombopoiesis promoted by AVP, an endogenous hormone, can quickly increases peripheral platelets. This rapid elevation is thus able to speed up platelet recovery after radiation as expected. The mechanism analysis reveal that proplatelet formation and platelet release from mature MKs facilitated by AVP is mainly mediated by Akt-regulated mitochondrial metabolism. In particular, phosphorylated Akt regulates mitochondrial metabolism through driving the association of hexokinase-2 with mitochondrial voltage dependent anion channel-1 in AVP-mediated thrombopoiesis. Further studies suggest that this interaction is stabilized by IκBα, the expression of which is controlled by insulin-regulated membrane aminopeptidase.
CONCLUSION
these data demonstrate that phosphorylated Akt-mediated mitochondrial metabolism regulates platelet shedding from MKs in response to AVP, which will provide new therapeutic targets and further drug discovery clues for thrombocytopenia treatment.
Topics: Humans; Proto-Oncogene Proteins c-akt; Blood Platelets; Megakaryocytes; Thrombopoiesis; Thrombocytopenia; Vasopressins
PubMed: 36700501
DOI: 10.1016/j.jtha.2022.11.018 -
Journal of Thrombosis and Haemostasis :... Feb 2023Inherited platelet disorders (IPDs) are a heterogeneous group of rare diseases that are caused by the defects in early megakaryopoiesis, proplatelet formation, and/or...
BACKGROUND
Inherited platelet disorders (IPDs) are a heterogeneous group of rare diseases that are caused by the defects in early megakaryopoiesis, proplatelet formation, and/or mature platelet function. Although genomic sequencing is increasingly used to identify genetic variants underlying IPD, this technique does not disclose resulting molecular changes that impact platelet function. Proteins are the functional units that shape platelet function; however, insights into how variants that cause IPDs impact platelet proteomes are limited.
OBJECTIVES
The objective of this study was to profile the platelet proteomics signatures of IPDs.
METHODS
We performed unbiased label-free quantitative mass spectrometry (MS)-based proteome profiling on platelets of 34 patients with IPDs with variants in 13 ISTH TIER1 genes that affect different stages of platelet development.
RESULTS
In line with the phenotypical heterogeneity between IPDs, proteomes were diverse between IPDs. We observed extensive proteomic alterations in patients with a GFI1B variant and for genetic variants in genes encoding proteins that impact cytoskeletal processes (MYH9, TUBB1, and WAS). Using the diversity between IPDs, we clustered protein dynamics, revealing disrupted protein-protein complexes. This analysis furthermore grouped proteins with similar cellular function and location, classifying mitochondrial protein constituents and identifying both known and putative novel alpha granule associated proteins.
CONCLUSIONS
With this study, we demonstrate a MS-based proteomics perspective to IPDs. By integrating the effects of IPDs that impact different aspects of platelet function, we dissected the biological contexts of protein alterations to gain further insights into the biology of platelet (dys)function.
Topics: Humans; Proteomics; Proteome; Blood Platelet Disorders; Blood Platelets; Thrombopoiesis
PubMed: 36700500
DOI: 10.1016/j.jtha.2022.11.021 -
Frontiers in Immunology 2022Platelets, generated from precursor megakaryocytes (MKs), are central mediators of hemostasis and thrombosis. The process of thrombopoiesis is extremely complex,... (Review)
Review
Platelets, generated from precursor megakaryocytes (MKs), are central mediators of hemostasis and thrombosis. The process of thrombopoiesis is extremely complex, regulated by multiple factors, and related to many cellular events including apoptosis. However, the role of apoptosis in thrombopoiesis has been controversial for many years. Some researchers believe that apoptosis is an ally of thrombopoiesis and platelets production is apoptosis-dependent, while others have suggested that apoptosis is dispensable for thrombopoiesis, and is even inhibited during this process. In this review, we will focus on this conflict, discuss the relationship between megakaryocytopoiesis, thrombopoiesis and apoptosis. In addition, we also consider why such a vast number of studies draw opposite conclusions of the role of apoptosis in thrombopoiesis, and try to figure out the truth behind the mystery. This review provides more comprehensive insights into the relationship between megakaryocytopoiesis, thrombopoiesis, and apoptosis and finds some clues for the possible pathological mechanisms of platelet disorders caused by abnormal apoptosis.
Topics: Megakaryocytes; Thrombopoiesis; Blood Platelets; Hemostasis; Apoptosis; Fenbendazole
PubMed: 36685543
DOI: 10.3389/fimmu.2022.1025945 -
International Journal of Molecular... Jan 2023Platelets are the second most abundant blood component after red blood cells and can participate in a variety of physiological and pathological functions. Beyond its... (Review)
Review
Platelets are the second most abundant blood component after red blood cells and can participate in a variety of physiological and pathological functions. Beyond its traditional role in hemostasis and thrombosis, it also plays an indispensable role in inflammatory diseases. However, thrombocytopenia is a common hematologic problem in the clinic, and it presents a proportional relationship with the fatality of many diseases. Therefore, the prevention and treatment of thrombocytopenia is of great importance. The expression of Toll-like receptors (TLRs) is one of the most relevant characteristics of thrombopoiesis and the platelet inflammatory function. We know that the TLR family is found on the surface or inside almost all cells, where they perform many immune functions. Of those, TLR2 and TLR4 are the main stress-inducing members and play an integral role in inflammatory diseases and platelet production and function. Therefore, the aim of this review is to present and discuss the relationship between platelets, inflammation and the TLR family and extend recent research on the influence of the TLR2 and TLR4 pathways and the regulation of platelet production and function. Reviewing the interaction between TLRs and platelets in inflammation may be a research direction or program for the treatment of thrombocytopenia-related and inflammatory-related diseases.
Topics: Humans; Thrombopoiesis; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptors; Thrombocytopenia; Inflammation
PubMed: 36674552
DOI: 10.3390/ijms24021010 -
The Malaysian Journal of Pathology Dec 2022Thrombocytopenia is a common complication in dengue that sometimes necessitates platelet transfusion. Immature platelet fraction (IPF) measures immature platelets that...
INTRODUCTION
Thrombocytopenia is a common complication in dengue that sometimes necessitates platelet transfusion. Immature platelet fraction (IPF) measures immature platelets that indirectly reflect thrombopoiesis and is helpful in predicting platelet recovery.
OBJECTIVES
This study aimed to evaluate the role of IPF% and identify its cut-off value in predicting platelet recovery in dengue patients with thrombocytopenia.
MATERIALS AND METHODS
Serial platelet count and IPF results were obtained from fifty-four confirmed dengue patients with platelet count <50x109 /L. Median peak IPF% and number of patients with platelet recovery were determined. Receiver operating characteristic (ROC) curve is generated to identify the IPF% cut-off value to predict platelet recovery.
RESULTS
Median peak IPF% among dengue patients was 12.15% with 83.3% of them achieving platelet recovery after reaching the peak IPF%. There was a significant difference between median IPF% on day one of admission with peak IPF% among dengue patients. ROC curve analysis showed IFP% of 10.55% can be used to predict platelet recovery with a sensitivity of 69% and a specificity of 67%.
CONCLUSION
IPF% is a reliable and useful parameter in predicting platelet recovery in dengue patients. This would assist the clinician in managing dengue patients especially those with severe thrombocytopenia without giving unnecessary platelet transfusion.
Topics: Humans; Blood Platelets; Thrombocytopenia; Platelet Count; Platelet Transfusion; Dengue
PubMed: 36591717
DOI: No ID Found -
International Journal of Molecular... Dec 2022Thrombocytopenia has long been considered an important complication of chemotherapy and radiotherapy, which severely limits the effectiveness of cancer treatment and the...
BACKGROUND
Thrombocytopenia has long been considered an important complication of chemotherapy and radiotherapy, which severely limits the effectiveness of cancer treatment and the overall survival of patients. However, clinical treatment options are extremely limited so far. Ruxolitinib is a potential candidate.
METHODS
The impact of ruxolitinib on the differentiation and maturation of K562 and Meg-01 cells megakaryocytes (MKs) was examined by flow cytometry, Giemsa and Phalloidin staining. A mouse model of radiation-injured thrombocytopenia (RIT) was employed to evaluate the action of ruxolitinib on thrombocytopoiesis. Network pharmacology, molecular docking, drug affinity responsive target stability assay (DARTS), RNA sequencing, protein blotting and immunofluorescence analysis were applied to explore the targets and mechanisms of action of ruxolitinib.
RESULTS
Ruxolitinib can stimulate MK differentiation and maturation in a dose-dependent manner and accelerates recovery of MKs and thrombocytopoiesis in RIT mice. Biological targeting analysis showed that ruxolitinib binds directly to Toll Like Receptor 2 (TLR2) to activate Rac1/cdc42/JNK, and this action was shown to be blocked by C29, a specific inhibitor of TLR2.
CONCLUSIONS
Ruxolitinib was first identified to facilitate MK differentiation and thrombocytopoiesis, which may alleviate RIT. The potential mechanism of ruxolitinib was to promote MK differentiation via activating the Rac1/cdc42/JNK pathway through binding to TLR2.
Topics: Animals; Mice; MAP Kinase Signaling System; Thrombopoiesis; Toll-Like Receptor 2; Molecular Docking Simulation; cdc42 GTP-Binding Protein; Thrombocytopenia; rac1 GTP-Binding Protein
PubMed: 36555781
DOI: 10.3390/ijms232416137 -
Platelets Dec 2023Noncoding RNAs (ncRNAs) are a group of RNA molecules that cannot encode proteins, and a better understanding of the complex interaction networks coordinated by ncRNAs... (Review)
Review
Noncoding RNAs (ncRNAs) are a group of RNA molecules that cannot encode proteins, and a better understanding of the complex interaction networks coordinated by ncRNAs will provide a theoretical basis for the development of therapeutics targeting the regulatory effects of ncRNAs. Platelets are produced upon the differentiation of hematopoietic stem cells into megakaryocytes, 10 per day, and are renewed every 8-9 days. The process of thrombopoiesis is affected by multiple factors, in which ncRNAs also exert a significant regulatory role. This article reviewed the regulatory roles of ncRNAs, mainly microRNAs (miRNAs), circRNAs (circular RNAs), and long non-coding RNAs (lncRNAs), in thrombopoiesis in recent years as well as their roles in primary immune thrombocytopenia (ITP).
Topics: Humans; Thrombopoiesis; Blood Platelets; Megakaryocytes; MicroRNAs; RNA, Untranslated
PubMed: 36550091
DOI: 10.1080/09537104.2022.2157382 -
Haematologica Apr 2023Cardiovascular (CV) disease prevention with low-dose aspirin can be less effective in patients with a faster recovery of platelet (PLT) cyclooxygenase (COX)-1 activity...
Cardiovascular (CV) disease prevention with low-dose aspirin can be less effective in patients with a faster recovery of platelet (PLT) cyclooxygenase (COX)-1 activity during the 24-hour dosing interval. We previously showed that incomplete suppression of TXA2 over 24 hours can be rescued by a twice daily aspirin regimen. Here we show that reduced PLT glycoprotein (GP)Ibα shedding characterizes patients with accelerated COX-1 recovery and may contribute to higher thrombopoietin (TPO) production and higher rates of newly formed PLT, escaping aspirin inhibition over 24 hours. Two hundred aspirin-treated patients with high CV risk (100 with type 2 diabetes mellitus) were stratified according to the kinetics of PLT COX-1 activity recovery during the 10- to 24-hour dosing interval. Whole proteome analysis showed that PLT from patients with accelerated COX-1 recovery were enriched in proteins involved in cell survival, inhibition of apoptosis and cellular protrusion formation. In agreement, we documented increased plasma TPO, megakaryocyte maturation and proplatelet formation, and conversely increased PLT galactose and reduced caspase 3, phosphatidylserine exposure and ADAM17 activation, translating into diminished GPIbα cleavage and glycocalicin (GC) release. Treatment of HepG2 cells with recombinant GC led to a dose-dependent reduction of TPO mRNA in the liver, suggesting that reduced GPIbα ectodomain shedding may unleash thrombopoiesis. A cluster of clinical markers, including younger age, non-alcoholic fatty liver disease, visceral obesity and higher TPO/GC ratio, predicted with significant accuracy the likelihood of faster COX-1 recovery and suboptimal aspirin response. Circulating TPO/GC ratio, reflecting a dysregulation of PLT lifespan and production, may provide a simple tool to identify patients amenable to more frequent aspirin daily dosing.
Topics: Humans; Aspirin; Thrombopoiesis; Diabetes Mellitus, Type 2; Blood Platelets; Thrombocytopenia; Platelet Membrane Glycoproteins
PubMed: 36546455
DOI: 10.3324/haematol.2022.281006