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Thrombosis Research Jun 2023Thrombocytopenia is a common haematological problem worldwide. Currently, there are no relatively safe and effective agents for the treatment of thrombocytopenia. To...
Thrombocytopenia is a common haematological problem worldwide. Currently, there are no relatively safe and effective agents for the treatment of thrombocytopenia. To address this challenge, we propose a computational method that enables the discovery of novel drug candidates with haematopoietic activities. Based on different types of molecular representations, three deep learning (DL) algorithms, namely recurrent neural networks (RNNs), deep neural networks (DNNs), and hybrid neural networks (RNNs+DNNs), were used to develop classification models to distinguish between active and inactive compounds. The evaluation results illustrated that the hybrid DL model exhibited the best prediction performance, with an accuracy of 97.8 % and Matthews correlation coefficient of 0.958 on the test dataset. Subsequently, we performed drug discovery screening based on the hybrid DL model and identified a compound from the FDA-approved drug library that was structurally divergent from conventional drugs and showed a potential therapeutic action against thrombocytopenia. The novel drug candidate wedelolactone significantly promoted megakaryocyte differentiation in vitro and increased platelet levels and megakaryocyte differentiation in irradiated mice with no systemic toxicity. Overall, our work demonstrates how artificial intelligence can be used to discover novel drugs against thrombocytopenia.
Topics: Animals; Mice; Artificial Intelligence; Thrombopoiesis; Neural Networks, Computer; Algorithms; Thrombocytopenia
PubMed: 37119555
DOI: 10.1016/j.thromres.2023.04.011 -
The Journal of the Association of... Jan 2023In diabetic patients, platelets are known to be hyper-reactive with sub threshold stimuli leading to accelerated thrombopoiesis because of their rapid consumption in...
INTRODUCTION
In diabetic patients, platelets are known to be hyper-reactive with sub threshold stimuli leading to accelerated thrombopoiesis because of their rapid consumption in thrombus formation. HbA1C provides reliable measure of chronic glycemica and correlates with the risk of long term diabetes complications, so that it is currently considered the test of choice for monitoring and management of diabetes mellitus.
MATERIALS
85 consecutive patients on the basis of case selection criteria, presenting to the outpatient and inpatient department of General Medicine were included in the study The purpose of the study and procedures involved were explained to all the patients included in the study in their own language and thereafter an informed consent was taken. Detailed history and clinical examination was done.
RESULT
Statistically positive correlation between MPV and HbA1C levels in diabetic patients with micro-and macrovascular complications, such that for every 1 unit increase in HbA1C (%), the MPV (fl) increases by 0.20 units. Conversely, for every 1 unit increase in MPV (fl), the HbA1C (%) increases by 0.83 units. No statistically significant correlation between MPV and HbA1C in controlled diabetic group.
CONCLUSION
A statistically significant positive correlation was observed between MPV and HbA1C in whole population of study subjects as well as in uncontrolled diabetic group.
Topics: Humans; Diabetes Mellitus, Type 2; Mean Platelet Volume; Glycated Hemoglobin; Blood Platelets; Diabetes Complications
PubMed: 37116020
DOI: No ID Found -
Journal of Thrombosis and Haemostasis :... Sep 2023Germline mutations in the ETV6 transcription factor gene are responsible for familial thrombocytopenia and leukemia predisposition syndrome. Although previous studies...
BACKGROUND
Germline mutations in the ETV6 transcription factor gene are responsible for familial thrombocytopenia and leukemia predisposition syndrome. Although previous studies have shown that ETV6 plays an important role in megakaryocyte (MK) maturation and platelet formation, the mechanisms by which ETV6 dysfunction promotes thrombocytopenia remain unclear.
OBJECTIVES
To decipher the transcriptional mechanisms and gene regulatory network linking ETV6 germline mutations and thrombocytopenia.
METHODS
Presuming that ETV6 mutations result in selective effects at a particular cell stage, we applied single-cell RNA sequencing to understand gene expression changes during megakaryopoiesis in peripheral CD34 cells from healthy controls and patients with ETV6-related thrombocytopenia.
RESULTS
Analysis of gene expression and regulon activity revealed distinct clusters partitioned into 7 major cell stages: hematopoietic stem/progenitor cells, common-myeloid progenitors (CMPs), MK-primed CMPs, granulocyte-monocyte progenitors, MK-erythroid progenitors (MEPs), progenitor MKs/mature MKs, and platelet-like particles. We observed a differentiation trajectory in which MEPs developed directly from hematopoietic stem/progenitor cells and bypassed the CMP stage. ETV6 deficiency led to the development of aberrant cells as early as the MEP stage, which intensified at the progenitor MK/mature MK stage, with a highly deregulated core "ribosome biogenesis" pathway. Indeed, increased translation levels have been documented in patient CD34-derived MKs with overexpression of ribosomal protein S6 and phosphorylated ribosomal protein S6 in both CD34-derived MKs and platelets. Treatment of patient MKs with the ribosomal biogenesis inhibitor CX-5461 resulted in an increase in platelet-like particles.
CONCLUSION
These findings provide novel insight into both megakaryopoiesis and the link among ETV6, translation, and platelet production.
Topics: Humans; Cell Differentiation; Megakaryocytes; Ribosomal Protein S6; Single-Cell Analysis; Thrombocytopenia; Thrombopoiesis; Antigens, CD34; ETS Translocation Variant 6 Protein
PubMed: 37085035
DOI: 10.1016/j.jtha.2023.04.007 -
Nature Communications Apr 2023Megakaryocytes (MK) generate platelets. Recently, we and others, have reported MK also regulate hematopoietic stem cells (HSC). Here we show high ploidy large...
Megakaryocytes (MK) generate platelets. Recently, we and others, have reported MK also regulate hematopoietic stem cells (HSC). Here we show high ploidy large cytoplasmic megakaryocytes (LCM) are critical negative regulators of HSC and critical for platelet formation. Using a mouse knockout model (Pf4-Srsf3) with normal MK numbers, but essentially devoid of LCM, we demonstrate a pronounced increase in BM HSC concurrent with endogenous mobilization and extramedullary hematopoiesis. Severe thrombocytopenia is observed in animals with diminished LCM, although there is no change in MK ploidy distribution, uncoupling endoreduplication and platelet production. When HSC isolated from a microenvironment essentially devoid of LCM reconstitute hematopoiesis in lethally irradiated mice, the absence of LCM increases HSC in BM, blood and spleen, and the recapitulation of thrombocytopenia. In contrast, following a competitive transplant using minimal numbers of WT HSC together with HSC from a microenvironment with diminished LCM, sufficient WT HSC-generated LCM regulates a normal HSC pool and prevents thrombocytopenia. Importantly, LCM are conserved in humans.
Topics: Humans; Animals; Megakaryocytes; Hematopoietic Stem Cells; Blood Platelets; Thrombopoiesis; Hematopoiesis; Thrombocytopenia; Disease Models, Animal; Ploidies; Serine-Arginine Splicing Factors
PubMed: 37055407
DOI: 10.1038/s41467-023-37780-7 -
Nature Communications Apr 2023Thrombocytopenia is a major complication in a subset of patients with multiple myeloma (MM). However, little is known about its development and significance during MM....
Thrombocytopenia is a major complication in a subset of patients with multiple myeloma (MM). However, little is known about its development and significance during MM. Here, we show thrombocytopenia is linked to poor prognosis in MM. In addition, we identify serine, which is released from MM cells into the bone marrow microenvironment, as a key metabolic factor that suppresses megakaryopoiesis and thrombopoiesis. The impact of excessive serine on thrombocytopenia is mainly mediated through the suppression of megakaryocyte (MK) differentiation. Extrinsic serine is transported into MKs through SLC38A1 and downregulates SVIL via SAM-mediated tri-methylation of H3K9, ultimately leading to the impairment of megakaryopoiesis. Inhibition of serine utilization or treatment with TPO enhances megakaryopoiesis and thrombopoiesis and suppresses MM progression. Together, we identify serine as a key metabolic regulator of thrombocytopenia, unveil molecular mechanisms governing MM progression, and provide potential therapeutic strategies for treating MM patients by targeting thrombocytopenia.
Topics: Humans; Bone Marrow; Thrombopoiesis; Multiple Myeloma; Thrombocytopenia; Bone Marrow Cells; Megakaryocytes; Blood Platelets; Tumor Microenvironment
PubMed: 37055385
DOI: 10.1038/s41467-023-37699-z -
Blood Advances Aug 2023Erythrocytes undergo a well-defined switch from fetal to postnatal circulation, which is mainly reflected by the stage-specific expression of hemoglobin chains....
Erythrocytes undergo a well-defined switch from fetal to postnatal circulation, which is mainly reflected by the stage-specific expression of hemoglobin chains. Perinatal alterations in thrombopoiesis are poorly understood. We assessed the ontogenesis of platelet phenotype and function from early prematurity to adulthood. We recruited 64 subjects comprising 7 extremely preterm (27-31 weeks gestational age), 25 moderately preterm (32-36 weeks), 10 term neonates, 8 infants (<2 years), 5 children (2-13 years), and 9 adults (>13 years). Blood was withdrawn at up to 3 different time points in neonates (t1: 0-2, t2: 3-7, and t3: 8-14 days after birth). We found that the expression levels of the major surface receptors for fibrinogen, collagen, vWF, fibronectin, and laminin were reduced but correlated with decreased platelet size, indicating a normal surface density. Although CD62P and CD63 surface exposure upon stimulation with TRAP-6, ADP, or U46619 was unaltered or only slightly reduced in neonates, GPIIb/IIIa inside-out and outside-in activation was blunted but showed a continuous increase until adulthood, correlating with the expression of the GPIIb/IIIa regulating tetraspanin CD151. Platelet subpopulation analysis using automated clustering revealed that neonates presented with a CD63+/PAC-1- pattern, followed by a continuous increase in CD63+/PAC-1+ platelets until adulthood. Our findings revealed that the number of platelet-monocyte and platelet-neutrophil aggregates, but not platelet-lymphocyte aggregates, is increased in neonates and that neonatal aggregate formation depends in part on CD62P activation. Our PLatelets In Neonatal Infants Study (PLINIUS) provides several lines of evidence that the platelet phenotype and function evolve continuously from neonates to adulthood.
Topics: Humans; Pregnancy; Female; Infant, Newborn; Blood Platelets; Platelet Activation; Platelet Glycoprotein GPIIb-IIIa Complex; Infant, Premature; 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid
PubMed: 37042931
DOI: 10.1182/bloodadvances.2023009824 -
Biological Research Mar 2023Splenectomy may lead to severe postoperative complications, including sepsis and cancers. A possible solution to this problem is heterotopic autotransplantation of the...
BACKGROUND
Splenectomy may lead to severe postoperative complications, including sepsis and cancers. A possible solution to this problem is heterotopic autotransplantation of the spleen. Splenic autografts rapidly restore the regular splenic microanatomy in model animals. However, the functional competence of such regenerated autografts in terms of lympho- and hematopoietic capacity remains uncertain. Therefore, this study aimed to monitor the dynamics of B and T lymphocyte populations, the monocyte-macrophage system, and megakaryocytopoiesis in murine splenic autografts.
METHODS
The model of subcutaneous splenic engraftment was implemented in C57Bl male mice. Cell sources of functional recovery were studied using heterotopic transplantations from B10-GFP donors to C57Bl recipients. The cellular composition dynamics were studied by immunohistochemistry and flow cytometry. Expression of regulatory genes at mRNA and protein levels was assessed by real-time PCR and Western blot, respectively.
RESULTS
Characteristic splenic architecture is restored within 30 days post-transplantation, consistent with other studies. The monocyte-macrophage system, megakaryocytes, and B lymphocytes show the highest rates, whereas the functional recovery of T cells takes longer. Cross-strain splenic engraftments using B10-GFP donors indicate the recipient-derived cell sources of the recovery. Transplantations of scaffolds populated with splenic stromal cells or without them afforded no restoration of the characteristic splenic architecture.
CONCLUSIONS
Allogeneic subcutaneous transplantation of splenic fragments in a mouse model leads to their structural recovery within 30 days, with full reconstitution of the monocyte-macrophage, megakaryocyte and B lymphocyte populations. The circulating hematopoietic cells provide the likely source for the cell composition recovery.
Topics: Male; Mice; Animals; Spleen; Transplantation, Autologous; Splenectomy; T-Lymphocytes; Disease Models, Animal
PubMed: 36991509
DOI: 10.1186/s40659-023-00427-4 -
International Journal of Molecular... Mar 2023Protein glycosylation, including sialylation, involves complex and frequent post-translational modifications, which play a critical role in different biological... (Review)
Review
Protein glycosylation, including sialylation, involves complex and frequent post-translational modifications, which play a critical role in different biological processes. The conjugation of carbohydrate residues to specific molecules and receptors is critical for normal hematopoiesis, as it favors the proliferation and clearance of hematopoietic precursors. Through this mechanism, the circulating platelet count is controlled by the appropriate platelet production by megakaryocytes, and the kinetics of platelet clearance. Platelets have a half-life in blood ranging from 8 to 11 days, after which they lose the final sialic acid and are recognized by receptors in the liver and eliminated from the bloodstream. This favors the transduction of thrombopoietin, which induces megakaryopoiesis to produce new platelets. More than two hundred enzymes are responsible for proper glycosylation and sialylation. In recent years, novel disorders of glycosylation caused by molecular variants in multiple genes have been described. The phenotype of the patients with genetic alterations in and is consistent with syndromic manifestations, severe inherited thrombocytopenia, and hemorrhagic complications.
Topics: Humans; Glycosylation; Thrombocytopenia; Blood Platelets; Megakaryocytes; Thrombopoiesis; Thrombopoietin; Nucleotide Transport Proteins
PubMed: 36982178
DOI: 10.3390/ijms24065109 -
Journal of Equine Veterinary Science Jul 2023The interpretation of the blood count is essential to help the equine clinician in the diagnosis, prognosis, patient management, and control of equine diseases.... (Review)
Review
The interpretation of the blood count is essential to help the equine clinician in the diagnosis, prognosis, patient management, and control of equine diseases. Hematologic alterations often reflect the condition of the individual or an overall response to a pathological situation. A thorough clinical examination of the patient is essential to correctly interpret the hematological results. The most common abnormalities in the erythrogram are mainly anemia and polycythemia. The frequent causes of anemia in horses are acute and chronic blood loss, hemolytic anemia, and anemia caused by chronic disease. Evaluation of leukogram, including a total white cell count, a differential cell count, absolute numbers of specific leukocytes can help identify abnormalities that may suggest specific diseases such as a viral or bacterial infection, inflammatory disorders or even a neoplastic process. The platelet count is most often used to monitor or diagnose conditions that cause too much bleeding related with thrombocytopenia; it can be due to multiple mechanisms such as reduction of thrombopoiesis (myeloptisis, myelofibrosis, myeloproliferative disease, and idiopathic medullary aplasias or due to the effect of mielosuppresive drugs), increased peripheral destruction of platelets (immune mediated thrombocytopenia), consumption (dissemined intravascular coagulation) sequestration of the spleen and loss of platelets by idiopathic origin.
Topics: Horses; Animals; Blood Platelets; Thrombocytopenia; Platelet Count; Anemia; Horse Diseases
PubMed: 36958411
DOI: 10.1016/j.jevs.2023.104292 -
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