Pub Date : 2024-12-01Epub Date: 2024-02-19DOI: 10.1080/09537104.2024.2315037
Longqiang Shu, Shanyi Lin, Shumin Zhou, Ting Yuan
Glycosylation is a ubiquitous cellular or microenvironment-specific post-translational modification that occurs on the surface of normal cells and tumor cells. Tumor cell-associated glycosylation is involved in hematogenous metastasis. A wide variety of tumors undergo aberrant glycosylation to interact with platelets. As platelets have many opportunities to engage circulating tumor cells, they represent an important avenue into understanding the role glycosylation plays in tumor metastasis. Platelet involvement in tumor metastasis is evidenced by observations that platelets protect tumor cells from damaging shear forces and immune system attack, aid metastasis through the endothelium at specific sites, and facilitate tumor survival and colonization. During platelet-tumor-cell interactions, many opportunities for glycan-ligand binding emerge. This review integrates the latest information about glycans, their ligands, and how they mediate platelet-tumor interactions. We also discuss adaptive changes that tumors undergo upon glycan-lectin binding and the impact glycans have on targeted therapeutic strategies for treating tumors in clinical settings.
{"title":"Glycan-Lectin interactions between platelets and tumor cells drive hematogenous metastasis.","authors":"Longqiang Shu, Shanyi Lin, Shumin Zhou, Ting Yuan","doi":"10.1080/09537104.2024.2315037","DOIUrl":"10.1080/09537104.2024.2315037","url":null,"abstract":"<p><p>Glycosylation is a ubiquitous cellular or microenvironment-specific post-translational modification that occurs on the surface of normal cells and tumor cells. Tumor cell-associated glycosylation is involved in hematogenous metastasis. A wide variety of tumors undergo aberrant glycosylation to interact with platelets. As platelets have many opportunities to engage circulating tumor cells, they represent an important avenue into understanding the role glycosylation plays in tumor metastasis. Platelet involvement in tumor metastasis is evidenced by observations that platelets protect tumor cells from damaging shear forces and immune system attack, aid metastasis through the endothelium at specific sites, and facilitate tumor survival and colonization. During platelet-tumor-cell interactions, many opportunities for glycan-ligand binding emerge. This review integrates the latest information about glycans, their ligands, and how they mediate platelet-tumor interactions. We also discuss adaptive changes that tumors undergo upon glycan-lectin binding and the impact glycans have on targeted therapeutic strategies for treating tumors in clinical settings.</p>","PeriodicalId":20268,"journal":{"name":"Platelets","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139900279","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The purpose of this study is to investigate the molecular interactions and potential therapeutic uses of Eltrombopag (EPAG), a small molecule that activates the cMPL receptor. EPAG has been found to be effective in increasing platelet levels and alleviating thrombocytopenia. We utilized computational techniques to predict and confirm the complex formed by the ligand (EPAG) and the Thrombopoietin receptor (TPO-R) cMPL, elucidating the role of RAS, JAK-2, STAT-3, and other essential elements for downstream signaling. Molecular dynamics (MD) simulations were employed to evaluate the stability of the ligand across specific proteins, showing favorable characteristics. For the first time, we examined the presence of TPO-R in human umbilical cord mesenchymal stem cells (hUCMSC) and human gingival mesenchymal stem cells (hGMSC) proliferation. Furthermore, treatment with EPAG demonstrated angiogenesis and vasculature formation of endothelial lineage derived from both MSCs. It also indicated the activation of critical factors such as RUNX-1, GFI-1b, VEGF-A, MYB, GOF-1, and FLI-1. Additional experiments confirmed that EPAG could be an ideal molecule for protecting against UVB radiation damage, as gene expression (JAK-2, ERK-2, MCL-1, NFkB, and STAT-3) and protein CD90/cMPL analysis showed TPO-R activation in both hUCMSC and hGMSC. Overall, EPAG exhibits significant potential in treating radiation damage and mitigating the side effects of radiotherapy, warranting further clinical exploration.
{"title":"Molecular insights on Eltrombopag: potential mitogen stimulants, angiogenesis, and therapeutic radioprotectant through TPO-R activation.","authors":"Rajasekaran Subbarayan, Dhasarathdev Srinivasan, Salman Shadula Osmania, Dinesh Murugan Girija, Shoeb Ikhlas, Nityanand Srivastav, Ranjith Balakrishnan, Rupendra Shrestha, Ankush Chauhan","doi":"10.1080/09537104.2024.2359028","DOIUrl":"https://doi.org/10.1080/09537104.2024.2359028","url":null,"abstract":"<p><p>The purpose of this study is to investigate the molecular interactions and potential therapeutic uses of Eltrombopag (EPAG), a small molecule that activates the cMPL receptor. EPAG has been found to be effective in increasing platelet levels and alleviating thrombocytopenia. We utilized computational techniques to predict and confirm the complex formed by the ligand (EPAG) and the Thrombopoietin receptor (TPO-R) cMPL, elucidating the role of RAS, JAK-2, STAT-3, and other essential elements for downstream signaling. Molecular dynamics (MD) simulations were employed to evaluate the stability of the ligand across specific proteins, showing favorable characteristics. For the first time, we examined the presence of TPO-R in human umbilical cord mesenchymal stem cells (hUCMSC) and human gingival mesenchymal stem cells (hGMSC) proliferation. Furthermore, treatment with EPAG demonstrated angiogenesis and vasculature formation of endothelial lineage derived from both MSCs. It also indicated the activation of critical factors such as RUNX-1, GFI-1b, VEGF-A, MYB, GOF-1, and FLI-1. Additional experiments confirmed that EPAG could be an ideal molecule for protecting against UVB radiation damage, as gene expression (JAK-2, ERK-2, MCL-1, NFkB, and STAT-3) and protein CD90/cMPL analysis showed TPO-R activation in both hUCMSC and hGMSC. Overall, EPAG exhibits significant potential in treating radiation damage and mitigating the side effects of radiotherapy, warranting further clinical exploration.</p>","PeriodicalId":20268,"journal":{"name":"Platelets","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141238033","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-07-23DOI: 10.1080/09537104.2024.2380374
Clifford Pierre, Kirsten W Alcorn, Dong Chen, Joanna Fesler, Daniel Landis, Zachary N Litvack, Barbara A Konkle, Livia Hegerova
Dense-granule deficiency (DGD) is an inherited platelet disorder due to the absence of dense granules essential for activation of platelets in the event of vascular injury. Decreased platelet dense granules can be detected by electron microscopy, while other tests of hemostasis, including platelet function analyzer (PFA®) closure times, may be normal. The present case report describes a patient with a lifelong history of mucocutaneous bleeding and excessive hemorrhage with resection of vestibular Schwannoma. After hemostasis was obtained the case was aborted and the neurosurgeon noted bleeding resembled as if patient was on an antiplatelet drug. Subsequent hematologic workup revealed a severe platelet function disorder. There is a paucity of literature on management of intracranial neurosurgery in patients with inherited platelet disorders. Patients undergoing major surgical procedures often receive tranexamic acid (TXA), desmopressin, and/or human-leukocyte antigen (HLA)-matched platelet transfusions. We review the clinical management of intracranial tumor surgery, as well as Cyberknife radiosurgery, in our patient with DGD. After diagnosis was known, thoughtful hemostatic planning with empiric platelet transfusions and TXA prevented recurrent bleeding.
{"title":"Neurosurgical bleeding in platelet storage pool disorder: a case report.","authors":"Clifford Pierre, Kirsten W Alcorn, Dong Chen, Joanna Fesler, Daniel Landis, Zachary N Litvack, Barbara A Konkle, Livia Hegerova","doi":"10.1080/09537104.2024.2380374","DOIUrl":"https://doi.org/10.1080/09537104.2024.2380374","url":null,"abstract":"<p><p>Dense-granule deficiency (DGD) is an inherited platelet disorder due to the absence of dense granules essential for activation of platelets in the event of vascular injury. Decreased platelet dense granules can be detected by electron microscopy, while other tests of hemostasis, including platelet function analyzer (PFA®) closure times, may be normal. The present case report describes a patient with a lifelong history of mucocutaneous bleeding and excessive hemorrhage with resection of vestibular Schwannoma. After hemostasis was obtained the case was aborted and the neurosurgeon noted bleeding resembled as if patient was on an antiplatelet drug. Subsequent hematologic workup revealed a severe platelet function disorder. There is a paucity of literature on management of intracranial neurosurgery in patients with inherited platelet disorders. Patients undergoing major surgical procedures often receive tranexamic acid (TXA), desmopressin, and/or human-leukocyte antigen (HLA)-matched platelet transfusions. We review the clinical management of intracranial tumor surgery, as well as Cyberknife radiosurgery, in our patient with DGD. After diagnosis was known, thoughtful hemostatic planning with empiric platelet transfusions and TXA prevented recurrent bleeding.</p>","PeriodicalId":20268,"journal":{"name":"Platelets","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748937","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-02-23DOI: 10.1080/09537104.2024.2316744
Eva Dohle, Lena Schmeinck, Kamelia Parkhoo, Robert Sader, Shahram Ghanaati
Blood concentrates like platelet rich fibrin (PRF) have been established as a potential autologous source of cells and growth factors with regenerative properties in the field of dentistry and regenerative medicine. To further analyze the effect of PRF on bone tissue regeneration, this study investigated the influence of liquid PRF matrices on human healthy primary osteoblasts (pOB) and co-cultures composed of pOB and human dermal vascular endothelial cells (HDMEC) as invitro model for bone tissue regeneration. Special attention was paid to the PRF mediated influence on osteoblastic differentiation and angiogenesis. Based on the low-speed centrifugation concept, cells were treated indirectly with PRF prepared with a low (44 g) and high relative centrifugal force (710 g) before the PRF mediated effect on osteoblast proliferation and differentiation was assessed via gene and protein expression analyses and immunofluorescence. The results revealed a PRF-mediated positive effect on osteogenic proliferation and differentiation accompanied by increased concentration of osteogenic growth factors and upregulated expression of osteogenic differentiation factors. Furthermore, it could be shown that PRF treatment resulted in an increased formation of angiogenic structures in a bone tissue mimic co-culture of endothelial cells and osteoblasts induced by the PRF mediated increased release of proangiogenic growth factors. The effects on osteogenic proliferation, differentiation and vascularization were more evident when low RCF PRF was applied to the cells. In conclusion, PRF possess proosteogenic, potentially osteoconductive as well as proangiogenic properties, making it a beneficial tool for bone tissue regeneration.
{"title":"Platelet rich fibrin as a bioactive matrix with proosteogenic and proangiogenic properties on human healthy primary cells in vitro.","authors":"Eva Dohle, Lena Schmeinck, Kamelia Parkhoo, Robert Sader, Shahram Ghanaati","doi":"10.1080/09537104.2024.2316744","DOIUrl":"10.1080/09537104.2024.2316744","url":null,"abstract":"<p><p>Blood concentrates like platelet rich fibrin (PRF) have been established as a potential autologous source of cells and growth factors with regenerative properties in the field of dentistry and regenerative medicine. To further analyze the effect of PRF on bone tissue regeneration, this study investigated the influence of liquid PRF matrices on human healthy primary osteoblasts (pOB) and co-cultures composed of pOB and human dermal vascular endothelial cells (HDMEC) as <i>in</i> <i>vitro</i> model for bone tissue regeneration. Special attention was paid to the PRF mediated influence on osteoblastic differentiation and angiogenesis. Based on the low-speed centrifugation concept, cells were treated indirectly with PRF prepared with a low (44 g) and high relative centrifugal force (710 g) before the PRF mediated effect on osteoblast proliferation and differentiation was assessed via gene and protein expression analyses and immunofluorescence. The results revealed a PRF-mediated positive effect on osteogenic proliferation and differentiation accompanied by increased concentration of osteogenic growth factors and upregulated expression of osteogenic differentiation factors. Furthermore, it could be shown that PRF treatment resulted in an increased formation of angiogenic structures in a bone tissue mimic co-culture of endothelial cells and osteoblasts induced by the PRF mediated increased release of proangiogenic growth factors. The effects on osteogenic proliferation, differentiation and vascularization were more evident when low RCF PRF was applied to the cells. In conclusion, PRF possess proosteogenic, potentially osteoconductive as well as proangiogenic properties, making it a beneficial tool for bone tissue regeneration.</p>","PeriodicalId":20268,"journal":{"name":"Platelets","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139932585","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-08-30DOI: 10.1080/09537104.2024.2388103
Jakub Trizuljak, Paulína Likavcová, Kateřina Staňo Kozubík, Zuzana Vrzalová, Jakub Hynšt, Tereza Deissová, Jiří Štika, Lenka Radová, Marie Prudková, Jana Vaculová, Ivona Blaháková, Petr Smejkal, Jan Kamelander, Šárka Pospíšilová, Michael Doubek
Inherited thrombocytopenias (ITs) encompass a group of rare disorders characterized by diminished platelet count. Recent advancements have unveiled various forms of IT, with inherited thrombocytopenia 2 (THC2) emerging as a prevalent subtype associated with germline variants in the critical 5' untranslated region of the ANKRD26 gene. This region is crucial in regulating the gene expression of ANKRD26, particularly in megakaryocytes. THC2 is an autosomal dominant disorder presenting as mild-to-moderate thrombocytopenia with minimal symptoms, with an increased risk of myeloproliferative malignancies. In our study of a family with suspected IT, three affected individuals harbored the c.-118C>T ANKRD26 variant, while four healthy members carried the c.-140C>G ANKRD26 variant. We performed a functional analysis by studying platelet-specific ANKRD26 gene expression levels using quantitative real-time polymerase-chain reaction. Functional analysis of the c.-118C>T variant showed a significant increase in ANKRD26 expression in affected individuals, supporting its pathogenicity. On the contrary, carriers of the c.-140C>G variant exhibited normal platelet counts and no significant elevation in the ANKRD26 expression, indicating the likely benign nature of this variant. Our findings provide evidence confirming the pathogenicity of the c.-118C>T ANKRD26 variant in THC2 and suggest the likely benign nature of the c.-140C>G variant.
{"title":"Impact of thrombocytopenia-associated c.-118C>T and c.-140C>G ANKRD26 5'UTR variants in three-generational pedigree.","authors":"Jakub Trizuljak, Paulína Likavcová, Kateřina Staňo Kozubík, Zuzana Vrzalová, Jakub Hynšt, Tereza Deissová, Jiří Štika, Lenka Radová, Marie Prudková, Jana Vaculová, Ivona Blaháková, Petr Smejkal, Jan Kamelander, Šárka Pospíšilová, Michael Doubek","doi":"10.1080/09537104.2024.2388103","DOIUrl":"10.1080/09537104.2024.2388103","url":null,"abstract":"<p><p>Inherited thrombocytopenias (ITs) encompass a group of rare disorders characterized by diminished platelet count. Recent advancements have unveiled various forms of IT, with inherited thrombocytopenia 2 (THC2) emerging as a prevalent subtype associated with germline variants in the critical 5' untranslated region of the <i>ANKRD26</i> gene. This region is crucial in regulating the gene expression of <i>ANKRD26</i>, particularly in megakaryocytes. THC2 is an autosomal dominant disorder presenting as mild-to-moderate thrombocytopenia with minimal symptoms, with an increased risk of myeloproliferative malignancies. In our study of a family with suspected IT, three affected individuals harbored the c.-118C>T <i>ANKRD26</i> variant, while four healthy members carried the c.-140C>G <i>ANKRD26</i> variant. We performed a functional analysis by studying platelet-specific <i>ANKRD26</i> gene expression levels using quantitative real-time polymerase-chain reaction. Functional analysis of the c.-118C>T variant showed a significant increase in <i>ANKRD26</i> expression in affected individuals, supporting its pathogenicity. On the contrary, carriers of the c.-140C>G variant exhibited normal platelet counts and no significant elevation in the <i>ANKRD26</i> expression, indicating the likely benign nature of this variant. Our findings provide evidence confirming the pathogenicity of the c.-118C>T <i>ANKRD26</i> variant in THC2 and suggest the likely benign nature of the c.-140C>G variant.</p>","PeriodicalId":20268,"journal":{"name":"Platelets","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142111212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-08-22DOI: 10.1080/09537104.2024.2389967
Dean Pym, Amanda J Davies, Jessica O Williams, Christine Saunders, Chloë E George, Philip E James
The impact of the biophysical environment on the platelet storage lesion (PSL) has mainly focused on reduced temperature storage, overlooking the significance of storage-induced shear stress. Shear stress in platelet storage refers to the frictional force acting parallel to the bag surface and exists solely through the implementation of agitation. This study investigates whether minimizing exposure to agitation-induced shear stress can alleviate the unexplained loss of function in stored platelet concentrates for neonatal transfusion (neonatal PCs). Using particle tracking analysis, fluid motion was measured in neonatal and adult platelet storage bags under agitation frequencies ranging from 20-60 rpm. Platelets stored at 20-60 rpm agitation over 8 days were examined by biochemical analysis, aggregation, and expression of activation markers. Results indicate that neonatal PCs experience significantly higher storage-induced shear stress compared to adult doses, leading to reduced functionality and increased activation from day 2 of storage. Adjusting the neonatal PC agitation frequency to 20 rpm improved functionality in early storage, while 40 rpm maintains this improvement throughout storage with reduced activation, compared to 60 rpm storage. This study confirms that small volume PC storage for neonatal use contributes to the PSL through the induction of shear stress, suggesting further evaluation of the recommended agitation frequency for neonatal PCs or postponement of the production of neonatal PCs until requested for neonatal transfusion.
生物物理环境对血小板储存病变(PSL)的影响主要集中在低温储存上,忽略了储存引起的剪切应力的重要性。血小板储存中的剪切应力是指平行于袋子表面的摩擦力,仅通过搅拌而存在。本研究探讨了尽量减少搅拌引起的剪切应力是否能减轻新生儿输注用浓缩血小板(新生儿 PC)储存过程中出现的无法解释的功能丧失。利用粒子追踪分析法,测量了新生儿和成人血小板储存袋在 20-60 转/分的搅拌频率下的液体运动。通过生化分析、聚集和活化标记物的表达,对在 20-60 rpm 搅拌下储存 8 天的血小板进行了检测。结果表明,与成人剂量相比,新生儿 PC 所承受的储存诱导剪切应力明显更高,导致其功能降低,并从储存的第 2 天起活化增加。将新生 PC 的搅拌频率调整到 20 转/分钟可改善储存早期的功能,而 40 转/分钟则可在整个储存过程中保持这种改善,同时与 60 转/分钟的储存相比,活化程度降低。这项研究证实,用于新生儿的小容量 PC 存储会通过诱导剪切应力而导致 PSL,因此建议进一步评估推荐的新生儿 PC 搅拌频率,或推迟新生儿 PC 的生产,直到需要用于新生儿输血时再进行。
{"title":"Small volume platelet concentrates for neonatal use are more susceptible to shear-induced storage lesion.","authors":"Dean Pym, Amanda J Davies, Jessica O Williams, Christine Saunders, Chloë E George, Philip E James","doi":"10.1080/09537104.2024.2389967","DOIUrl":"https://doi.org/10.1080/09537104.2024.2389967","url":null,"abstract":"<p><p>The impact of the biophysical environment on the platelet storage lesion (PSL) has mainly focused on reduced temperature storage, overlooking the significance of storage-induced shear stress. Shear stress in platelet storage refers to the frictional force acting parallel to the bag surface and exists solely through the implementation of agitation. This study investigates whether minimizing exposure to agitation-induced shear stress can alleviate the unexplained loss of function in stored platelet concentrates for neonatal transfusion (neonatal PCs). Using particle tracking analysis, fluid motion was measured in neonatal and adult platelet storage bags under agitation frequencies ranging from 20-60 rpm. Platelets stored at 20-60 rpm agitation over 8 days were examined by biochemical analysis, aggregation, and expression of activation markers. Results indicate that neonatal PCs experience significantly higher storage-induced shear stress compared to adult doses, leading to reduced functionality and increased activation from day 2 of storage. Adjusting the neonatal PC agitation frequency to 20 rpm improved functionality in early storage, while 40 rpm maintains this improvement throughout storage with reduced activation, compared to 60 rpm storage. This study confirms that small volume PC storage for neonatal use contributes to the PSL through the induction of shear stress, suggesting further evaluation of the recommended agitation frequency for neonatal PCs or postponement of the production of neonatal PCs until requested for neonatal transfusion.</p>","PeriodicalId":20268,"journal":{"name":"Platelets","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142018324","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-06-21DOI: 10.1080/09537104.2024.2369766
Carol Dangelmaier, Hymavathi Reddy Vari, Dhruv N Vajipayajula, Manal Elzoheiry, Monica Wright, Ashvin Iyer, Alexander Y Tsygankov, Satya P Kunapuli
Receptor-induced tyrosine phosphorylation of spleen tyrosine kinase (Syk) has been studied extensively in hematopoietic cells. Metabolic mapping and high-resolution mass spectrometry, however, indicate that one of the most frequently detected phosphorylation sites encompassed S297 (S291 in mice) located within the linker B region of Syk. It has been reported that Protein kinase C (PKC) phosphorylates Syk S297, thus influencing Syk activity. However, conflicting studies suggest that this phosphorylation enhances as well as reduces Syk activity. To clarify the function of this site, we generated Syk S291A knock-in mice. We used platelets as a model system as they possess Glycoprotein VI (GPVI), a receptor containing an immunoreceptor tyrosine-based activation motif (ITAM) which transduces signals through Syk. Our analysis of the homozygous mice indicated that the knock-in platelets express only one isoform of Syk, while the wild-type expresses two isoforms at 69 and 66 kDa. When the GPVI receptor was activated with collagen-related peptide (CRP), we observed an increase in functional responses and phosphorylations in Syk S291A platelets. This potentiation did not occur with AYPGKF or 2-MeSADP, although they also activate PKC isoforms. Although there was potentiation of platelet functional responses, there was no difference in tail bleeding times. However, the time to occlusion in the FeCl3 injury model was enhanced. These data indicate that the effects of Syk S291 phosphorylation represent a significant outcome on platelet activation and signaling in vitro but also reveals its multifaceted nature demonstrated by the differential effects on physiological responses in vivo.
{"title":"Phosphorylation of (Ser 291) in the linker insert of Syk negatively regulates ITAM signaling in platelets.","authors":"Carol Dangelmaier, Hymavathi Reddy Vari, Dhruv N Vajipayajula, Manal Elzoheiry, Monica Wright, Ashvin Iyer, Alexander Y Tsygankov, Satya P Kunapuli","doi":"10.1080/09537104.2024.2369766","DOIUrl":"10.1080/09537104.2024.2369766","url":null,"abstract":"<p><p>Receptor-induced tyrosine phosphorylation of spleen tyrosine kinase (Syk) has been studied extensively in hematopoietic cells. Metabolic mapping and high-resolution mass spectrometry, however, indicate that one of the most frequently detected phosphorylation sites encompassed S297 (S291 in mice) located within the linker B region of Syk. It has been reported that Protein kinase C (PKC) phosphorylates Syk S297, thus influencing Syk activity. However, conflicting studies suggest that this phosphorylation enhances as well as reduces Syk activity. To clarify the function of this site, we generated Syk S291A knock-in mice. We used platelets as a model system as they possess Glycoprotein VI (GPVI), a receptor containing an immunoreceptor tyrosine-based activation motif (ITAM) which transduces signals through Syk. Our analysis of the homozygous mice indicated that the knock-in platelets express only one isoform of Syk, while the wild-type expresses two isoforms at 69 and 66 kDa. When the GPVI receptor was activated with collagen-related peptide (CRP), we observed an increase in functional responses and phosphorylations in Syk S291A platelets. This potentiation did not occur with AYPGKF or 2-MeSADP, although they also activate PKC isoforms. Although there was potentiation of platelet functional responses, there was no difference in tail bleeding times. However, the time to occlusion in the FeCl<sub>3</sub> injury model was enhanced. These data indicate that the effects of Syk S291 phosphorylation represent a significant outcome on platelet activation and signaling <i>in vitro</i> but also reveals its multifaceted nature demonstrated by the differential effects on physiological responses <i>in vivo</i>.</p>","PeriodicalId":20268,"journal":{"name":"Platelets","volume":null,"pages":null},"PeriodicalIF":2.5,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11322839/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141432636","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-12-01Epub Date: 2024-06-07DOI: 10.1080/09537104.2024.2358244
Veronika Dill, Kilian Kirmes, Jiaying Han, Melissa Klug, Marc Rosenbaum, Giacomo Viggiani, Moritz von Scheidt, Markus List, Peter Herhaus, Jürgen Ruland, Florian Bassermann, Karl-Ludwig Laugwitz, Katharina S Götze, Philipp J Jost, Stefanie Jilg, Conor J Bloxham, Philip W J Raake, Isabell Bernlochner, Dario Bongiovanni
Thromboembolic events are common in patients with essential thrombocythemia (ET). However, the pathophysiological mechanisms underlying the increased thrombotic risk remain to be determined. Here, we perform the first phenotypical characterization of platelet expression using single-cell mass cytometry in six ET patients and six age- and sex-matched healthy individuals. A large panel of 18 transmembrane regulators of platelet function and activation were analyzed, at baseline and after ex-vivo stimulation with thrombin receptor-activating peptide (TRAP). We detected a significant overexpression of the activation marker CD62P (p-Selectin) (p = .049) and the collagen receptor GPVI (p = .044) in non-stimulated ET platelets. In contrast, ET platelets had a lower expression of the integrin subunits of the fibrinogen receptor GPIIb/IIIa CD41 (p = .036) and CD61 (p = .044) and of the von Willebrand factor receptor CD42b (p = .044). Using the FlowSOM algorithm, we identified 2 subclusters of ET platelets with a prothrombotic expression profile, one of them (cluster 3) significantly overrepresented in ET (22.13% of the total platelets in ET, 2.94% in controls, p = .035). Platelet counts were significantly increased in ET compared to controls (p = .0123). In ET, MPV inversely correlated with platelet count (r=-0.96). These data highlight the prothrombotic phenotype of ET and postulate GPVI as a potential target to prevent thrombosis in these patients.
血栓栓塞事件在原发性血小板增多症(ET)患者中很常见。然而,血栓风险增加的病理生理机制仍有待确定。在这里,我们首次使用单细胞质谱法对六名 ET 患者和六名年龄与性别匹配的健康人的血小板表达进行了表型鉴定。我们分析了基线和体内外凝血酶受体活化肽(TRAP)刺激后血小板功能和活化的 18 种跨膜调节因子。我们发现,在未受刺激的 ET 血小板中,活化标志物 CD62P(p-选择素)(p = 0.049)和胶原受体 GPVI(p = 0.044)明显过表达。相比之下,ET 血小板中纤维蛋白原受体 GPIIb/IIIa 的整合素亚基 CD41 (p = .036) 和 CD61 (p = .044) 以及 von Willebrand 因子受体 CD42b (p = .044) 的表达较低。利用 FlowSOM 算法,我们确定了 ET 血小板中具有促血栓形成表达谱的 2 个亚群,其中一个亚群(第 3 群)在 ET 中的比例明显偏高(ET 血小板占血小板总数的 22.13%,对照组为 2.94%,p = .035)。与对照组相比,ET 患者的血小板计数明显增加(p = .0123)。在 ET 中,MPV 与血小板计数成反比(r=-0.96)。这些数据突显了 ET 的促血栓形成表型,并推测 GPVI 是预防这些患者血栓形成的潜在靶点。
{"title":"Platelet mass cytometry reveals dysregulation of prothrombotic pathways in essential thrombocythemia.","authors":"Veronika Dill, Kilian Kirmes, Jiaying Han, Melissa Klug, Marc Rosenbaum, Giacomo Viggiani, Moritz von Scheidt, Markus List, Peter Herhaus, Jürgen Ruland, Florian Bassermann, Karl-Ludwig Laugwitz, Katharina S Götze, Philipp J Jost, Stefanie Jilg, Conor J Bloxham, Philip W J Raake, Isabell Bernlochner, Dario Bongiovanni","doi":"10.1080/09537104.2024.2358244","DOIUrl":"https://doi.org/10.1080/09537104.2024.2358244","url":null,"abstract":"<p><p>Thromboembolic events are common in patients with essential thrombocythemia (ET). However, the pathophysiological mechanisms underlying the increased thrombotic risk remain to be determined. Here, we perform the first phenotypical characterization of platelet expression using single-cell mass cytometry in six ET patients and six age- and sex-matched healthy individuals. A large panel of 18 transmembrane regulators of platelet function and activation were analyzed, at baseline and after <i>ex-vivo</i> stimulation with thrombin receptor-activating peptide (TRAP). We detected a significant overexpression of the activation marker CD62P (p-Selectin) (<i>p</i> = .049) and the collagen receptor GPVI (<i>p</i> = .044) in non-stimulated ET platelets. In contrast, ET platelets had a lower expression of the integrin subunits of the fibrinogen receptor GPIIb/IIIa CD41 (<i>p</i> = .036) and CD61 (<i>p</i> = .044) and of the von Willebrand factor receptor CD42b (<i>p</i> = .044). Using the FlowSOM algorithm, we identified 2 subclusters of ET platelets with a prothrombotic expression profile, one of them (cluster 3) significantly overrepresented in ET (22.13% of the total platelets in ET, 2.94% in controls, <i>p</i> = .035). Platelet counts were significantly increased in ET compared to controls (<i>p</i> = .0123). In ET, MPV inversely correlated with platelet count (<i>r</i>=-0.96). These data highlight the prothrombotic phenotype of ET and postulate GPVI as a potential target to prevent thrombosis in these patients.</p>","PeriodicalId":20268,"journal":{"name":"Platelets","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141284593","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Currently, the standard treatment for patients who have undergone percutaneous coronary intervention (PCI) following acute myocardial infarction (MI) involves dual antiplatelet therapy (DAPT) with ...
目前,对急性心肌梗死(MI)后接受经皮冠状动脉介入治疗(PCI)的患者的标准治疗方法包括使用...
{"title":"The safety and efficacy of indobufen or aspirin combined with clopidogrel in patients with acute myocardial infarction after percutaneous coronary intervention","authors":"Wen-Bo Dai, Jia-Yi Ren, Su-Tao Hu, Yu-Kun Zhang, Tian-Shu Gu, Xue Wu, Jing-Kun Zhang, Jing-Jin Che, Xiang-Hong Ma, Tong Liu, Guang-Ping Li, Kang-Yin Chen","doi":"10.1080/09537104.2024.2364748","DOIUrl":"https://doi.org/10.1080/09537104.2024.2364748","url":null,"abstract":"Currently, the standard treatment for patients who have undergone percutaneous coronary intervention (PCI) following acute myocardial infarction (MI) involves dual antiplatelet therapy (DAPT) with ...","PeriodicalId":20268,"journal":{"name":"Platelets","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-06-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141509900","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pub Date : 2024-04-24DOI: 10.1080/09537104.2024.2327835
Kailun Yan, Jiawen Li, Yulong Li, P. Zhu, Xiaofang Tang, D. Yuan, Yuejin Yang, Runlin Gao, Jinqing Yuan, Xueyan Zhao
Percutaneous coronary intervention (PCI) patients combined with thrombocytopenia (TP) are usually considered to be at low ischemic risk, receiving less proper antiplatelet therapy. However, recent studies reported a paradoxical phenomenon that PCI patients with TP were prone to experience thrombotic events, while the mechanisms and future treatment remain unclear. We aim to investigate whether inflammation modifies platelet reactivity among these patients. Consecutive 10 724 patients undergoing PCI in Fuwai Hospital were enrolled throughout 2013. High-sensitivity C-reactive protein (hsCRP) ≥2 mg/L was considered inflammatory status. TP was defined as platelet count <150×109/L. High on-treatment platelet reactivity (HTPR) was defined as adenosine diphosphate-induced platelet maximum amplitude of thromboelastogram >47mm. Among 6617 patients finally included, 879 (13.3%) presented with TP. Multivariate logistic regression demonstrated that patients with TP were associated with a lower risk of HTPR (odds ratio [OR] 0.64, 95% confidence interval [CI] 0.53-0.76) than those without TP in the overall cohort. In further analysis, among hsCRP <2 mg/L group, patients with TP exhibited a decreased risk of HTPR (OR 0.53, 95% CI 0.41-0.68); however, in hsCRP ≥2mg/L group, TP patients had a similar risk of HTPR as those without TP (OR 0.83, 95% CI 0.63-1.08). Additionally, these results remain consistent across subgroups, including patients presenting with acute coronary syndrome and chronic coronary syndrome. Inflammation modified the platelet reactivity of PCI patients with TP, providing new insights into the mechanisms of the increased thrombotic risk. Future management for this special population should pay more attention to inflammation status and timely adjustment of antiplatelet therapy in TP patients with inflammation.
{"title":"Inflammation modifies the platelet reactivity among thrombocytopenia patients undergoing percutaneous coronary intervention.","authors":"Kailun Yan, Jiawen Li, Yulong Li, P. Zhu, Xiaofang Tang, D. Yuan, Yuejin Yang, Runlin Gao, Jinqing Yuan, Xueyan Zhao","doi":"10.1080/09537104.2024.2327835","DOIUrl":"https://doi.org/10.1080/09537104.2024.2327835","url":null,"abstract":"Percutaneous coronary intervention (PCI) patients combined with thrombocytopenia (TP) are usually considered to be at low ischemic risk, receiving less proper antiplatelet therapy. However, recent studies reported a paradoxical phenomenon that PCI patients with TP were prone to experience thrombotic events, while the mechanisms and future treatment remain unclear. We aim to investigate whether inflammation modifies platelet reactivity among these patients. Consecutive 10 724 patients undergoing PCI in Fuwai Hospital were enrolled throughout 2013. High-sensitivity C-reactive protein (hsCRP) ≥2 mg/L was considered inflammatory status. TP was defined as platelet count <150×109/L. High on-treatment platelet reactivity (HTPR) was defined as adenosine diphosphate-induced platelet maximum amplitude of thromboelastogram >47mm. Among 6617 patients finally included, 879 (13.3%) presented with TP. Multivariate logistic regression demonstrated that patients with TP were associated with a lower risk of HTPR (odds ratio [OR] 0.64, 95% confidence interval [CI] 0.53-0.76) than those without TP in the overall cohort. In further analysis, among hsCRP <2 mg/L group, patients with TP exhibited a decreased risk of HTPR (OR 0.53, 95% CI 0.41-0.68); however, in hsCRP ≥2mg/L group, TP patients had a similar risk of HTPR as those without TP (OR 0.83, 95% CI 0.63-1.08). Additionally, these results remain consistent across subgroups, including patients presenting with acute coronary syndrome and chronic coronary syndrome. Inflammation modified the platelet reactivity of PCI patients with TP, providing new insights into the mechanisms of the increased thrombotic risk. Future management for this special population should pay more attention to inflammation status and timely adjustment of antiplatelet therapy in TP patients with inflammation.","PeriodicalId":20268,"journal":{"name":"Platelets","volume":null,"pages":null},"PeriodicalIF":3.3,"publicationDate":"2024-04-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140661159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}