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Nature Communications Jul 2023Platelets, small hemostatic blood cells, are derived from megakaryocytes. Both bone marrow and lung are principal sites of thrombopoiesis although underlying mechanisms...
Platelets, small hemostatic blood cells, are derived from megakaryocytes. Both bone marrow and lung are principal sites of thrombopoiesis although underlying mechanisms remain unclear. Outside the body, however, our ability to generate large number of functional platelets is poor. Here we show that perfusion of megakaryocytes ex vivo through the mouse lung vasculature generates substantial platelet numbers, up to 3000 per megakaryocyte. Despite their large size, megakaryocytes are able repeatedly to passage through the lung vasculature, leading to enucleation and subsequent platelet generation intravascularly. Using ex vivo lung and an in vitro microfluidic chamber we determine how oxygenation, ventilation, healthy pulmonary endothelium and the microvascular structure support thrombopoiesis. We also show a critical role for the actin regulator Tropomyosin 4 in the final steps of platelet formation in lung vasculature. This work reveals the mechanisms of thrombopoiesis in lung vasculature and informs approaches to large-scale generation of platelets.
Topics: Mice; Animals; Blood Platelets; Microfluidics; Megakaryocytes; Thrombopoiesis; Lung
PubMed: 37419900
DOI: 10.1038/s41467-023-39598-9 -
Hamostaseologie Feb 2024
Topics: Humans; Sodium Citrate; Blood Platelets
PubMed: 38417800
DOI: 10.1055/s-0044-1782595 -
Platelets Dec 2023Platelets play a critical role in immune response. Coronavirus disease 2019 (COVID-19) patients with a severe course often show pathological coagulation parameters...
Platelets play a critical role in immune response. Coronavirus disease 2019 (COVID-19) patients with a severe course often show pathological coagulation parameters including thrombocytopenia, and at the same time the proportion of immature platelets increases. In this study, the platelet count and the immature platelet fraction (IPF) of hospitalized patients with different oxygenation requirements was investigated daily over a course of 40 days. In addition, the platelet function of COVID-19 patients was analyzed. It was found that the number of platelets in patients with the most severe course (intubation and extracorporeal membrane oxygenation (ECMO)) was significantly lower (111.5 ∙ 10 /mL) than in the other groups (mild (no intubation, no ECMO): 203.5 ∙ 10 /mL, < .0001, moderate (intubation, no ECMO): 208.0 ∙ 10 /mL, < .0001). IPF tended to be elevated (10.9%). Platelet function was reduced. Differentiation by outcome revealed that the deceased patients had a highly significant lower platelet count and higher IPF (97.3 ∙ 10 /mL, < .0001, 12.2%, = .0003).
Topics: Humans; COVID-19; Blood Platelets; Thrombocytopenia; Platelet Count; Blood Coagulation
PubMed: 36883692
DOI: 10.1080/09537104.2023.2184183 -
International Journal of Biological... 2023Abnormal megakaryocyte maturation and platelet production lead to platelet-related diseases and impact the dynamic balance between hemostasis and bleeding. Cellular...
Abnormal megakaryocyte maturation and platelet production lead to platelet-related diseases and impact the dynamic balance between hemostasis and bleeding. Cellular repressor of E1A-stimulated gene 1 (CREG1) is a glycoprotein that promotes tissue differentiation. However, its role in megakaryocytes remains unclear. In this study, we found that CREG1 protein is expressed in platelets and megakaryocytes and was decreased in the platelets of patients with thrombocytopenia. A cytosine arabinoside-induced thrombocytopenia mouse model was established, and the mRNA and protein expression levels of CREG1 were found to be reduced in megakaryocytes. We established megakaryocyte/platelet conditional knockout () and transgenic mice (tg-). Compared to mice, mice exhibited thrombocytopenia, which was mainly caused by inefficient bone marrow (BM) thrombocytopoiesis, but not by apoptosis of circulating platelets. Cultured -megakaryocytes exhibited impairment of the actin cytoskeleton, with less filamentous actin, significantly fewer proplatelets, and lower ploidy. CREG1 directly interacts with MEK1/2 and promotes MEK1/2 phosphorylation. Thus, our study uncovered the role of CREG1 in the regulation of megakaryocyte maturation and thrombopoiesis, and it provides a possible theoretical basis for the prevention and treatment of thrombocytopenia.
Topics: Animals; Mice; Blood Platelets; Bone Marrow; Megakaryocytes; Mice, Transgenic; Thrombocytopenia; Thrombopoiesis; Humans
PubMed: 37496998
DOI: 10.7150/ijbs.78660 -
European Heart Journal Jan 2024The leading cause of heart disease in developed countries is coronary atherosclerosis, which is not simply a result of ageing but a chronic inflammatory process that can... (Review)
Review
The leading cause of heart disease in developed countries is coronary atherosclerosis, which is not simply a result of ageing but a chronic inflammatory process that can lead to acute clinical events upon atherosclerotic plaque rupture or erosion and arterial thrombus formation. The composition and location of atherosclerotic plaques determine the phenotype of the lesion and whether it is more likely to rupture or to erode. Although plaque rupture and erosion both initiate platelet activation on the exposed vascular surface, the contribution of platelets to thrombus formation differs between the two phenotypes. In this review, plaque phenotype is discussed in relation to thrombus composition, and an overview of important mediators (haemodynamics, matrix components, and soluble factors) in plaque-induced platelet activation is given. As thrombus formation on disrupted plaques does not necessarily result in complete vessel occlusion, plaque healing can occur. Therefore, the latest findings on plaque healing and the potential role of platelets in this process are summarized. Finally, the clinical need for more effective antithrombotic agents is highlighted.
Topics: Humans; Plaque, Atherosclerotic; Coronary Artery Disease; Blood Platelets; Rupture, Spontaneous; Thrombosis; Biology
PubMed: 37940193
DOI: 10.1093/eurheartj/ehad720 -
Medicine Dec 2023Immune and inflammatory responses play an important role in tumorigenesis and metastasis. Inflammation is an important component of the tumor microenvironment, and the... (Review)
Review
Immune and inflammatory responses play an important role in tumorigenesis and metastasis. Inflammation is an important component of the tumor microenvironment, and the changes in inflammatory cells may affect the occurrence and development of tumors. Complete blood count at the time of diagnosis and treatment can reflect the inflammatory status within the tumor. Studies have shown that the number of certain inflammatory cells in peripheral blood and their ratios are important prognostic factors for many malignancies, including neutrophil, lymphocyte, monocyte, and platelet counts, as well as neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, systemic immune-inflammation index, systemic inflammation response index and pan-immune-inflammation-value. The value of peripheral blood inflammation indexes in predicting the efficacy and prognosis of breast cancer neoadjuvant therapy is worth recognizing. This review details the application of peripheral blood inflammation indexes in the evaluation of efficacy and prediction of prognosis in neoadjuvant therapy for breast cancer, aiming to provide a more comprehensive reference for the comprehensive diagnosis and treatment of breast cancer.
Topics: Humans; Female; Lymphocytes; Blood Cell Count; Prognosis; Neutrophils; Blood Platelets; Inflammation; Breast Neoplasms; Retrospective Studies; Tumor Microenvironment
PubMed: 38050296
DOI: 10.1097/MD.0000000000036315 -
Platelets Dec 2023Extracellular vesicles (EVs) contain the characteristics of their cell of origin and mediate cell-to-cell communication. Platelet-derived extracellular vesicles (PEVs)... (Review)
Review
Extracellular vesicles (EVs) contain the characteristics of their cell of origin and mediate cell-to-cell communication. Platelet-derived extracellular vesicles (PEVs) not only have procoagulant activity but also contain platelet-derived inflammatory factors (CD40L and mtDNA) that mediate inflammatory responses. Studies have shown that platelets are activated during storage to produce large amounts of PEVs, which may have implications for platelet transfusion therapy. Compared to platelets, PEVs have a longer storage time and greater procoagulant activity, making them an ideal alternative to platelets. This review describes the reasons and mechanisms by which PEVs may have a role in blood transfusion therapy.
Topics: Humans; Blood Platelets; Platelet Transfusion; Extracellular Vesicles; Blood Transfusion
PubMed: 37578045
DOI: 10.1080/09537104.2023.2242708 -
Journal of Thrombosis and Haemostasis :... Nov 2023Glucocorticoids are widely known for their immunomodulatory action. Their synthetic analogs are used to treat several autoimmune diseases, including immune...
BACKGROUND
Glucocorticoids are widely known for their immunomodulatory action. Their synthetic analogs are used to treat several autoimmune diseases, including immune thrombocytopenia. However, their efficacy and mechanisms of action in immune thrombocytopenia are not fully understood.
OBJECTIVES
To investigate the mechanism of glucocorticoid actions on platelet production.
METHODS
The actions of glucocorticoids on platelet production were studied combining in vivo, ex vivo and in vitro approaches.
RESULTS
Dexamethasone reduced bleeding in mice and rapidly increased circulating young platelet counts. In vitro glucocorticoid treatment stimulated proplatelet formation by megakaryocytes and platelet-like particle release. This effect was blocked by glucocorticoid receptor antagonist RU486, indicating a glucocorticoid receptor-dependent mechanism. Genome-wide analysis revealed that dexamethasone regulates the expression of >1000 genes related to numerous cellular functions, including predominant cytoplasm and cytoskeleton reorganization. Dexamethasone and other glucocorticoids induced the expression of Gda (the gene encoding guanine deaminase), which has been reported to have a role in dendrite development. Inhibition of guanine deaminase enzymatic activity blocked dexamethasone stimulation of proplatelet formation, implicating a critical role for this enzyme in glucocorticoid-mediated platelet production.
CONCLUSION
Our findings identify glucocorticoids as new regulators of thrombopoiesis.
Topics: Mice; Animals; Megakaryocytes; Thrombopoiesis; Glucocorticoids; Purpura, Thrombocytopenic, Idiopathic; Receptors, Glucocorticoid; Guanine Deaminase; Transcriptome; Blood Platelets; Thrombocytopenia; Dexamethasone
PubMed: 37336437
DOI: 10.1016/j.jtha.2023.06.012 -
Cell Reports Methods Jul 2023A characteristic clinical complication in cancer patients is the frequent incidence of thrombotic events. Numerous studies have shown hyperactive/activated platelets to...
A characteristic clinical complication in cancer patients is the frequent incidence of thrombotic events. Numerous studies have shown hyperactive/activated platelets to be a critical earlier trigger for cancer-associated thrombus formation. However, there currently is no viable approach to monitor specific changes in tumor-associated platelet activity. Here, we describe a chromatograph-like microfluidic device that is highly sensitive to the activity status of peripheral circulating platelets in both tumor-bearing mice and clinical cancer patients. Our results show a strongly positive correlation between platelet activation status and tumor progression. Six-month follow-up data from advanced cancer patients reveal positive links between platelet activity level and thrombus occurrence rate, with a high predictive capacity of thrombotic events (AUC = 0.842). Our findings suggest that circulating platelet activity status determined by this microfluidic device exhibits sensitive, predictive potential for thrombotic events in cancer patients for directing well-timed antithrombosis treatment.
Topics: Mice; Animals; Blood Platelets; Platelet Activation; Thrombosis; Neoplasms
PubMed: 37533637
DOI: 10.1016/j.crmeth.2023.100513 -
Hamostaseologie Apr 2024
Review
Topics: Humans; Blood Platelets; Inflammation; Animals
PubMed: 38688266
DOI: 10.1055/a-2280-1098