Platelets最新文献

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.

This trial targeted to analyze the effects of different doses of tirofiban combined with dual antiplatelet drugs on platelet indices, vascular endothelial function, and major adverse cardiovascular events (MACE) in patients with acute ST-segment elevated myocardial infarction (STEMI) undergoing percutaneous coronary intervention (PCI). A total of 180 patients with STEMI who underwent PCI were divided into Group A, Group B, and Group C (60 cases per group). Group A was given conventional medication, and Groups B and C were given a standard dose (10 μg/kg) and a high dose (20 μg/kg) of tirofiban on the basis of Group A, respectively. Thrombolysis in myocardial infarction (TIMI) myocardial perfusion grade and TIMI blood flow grade were compared. Myocardial enzymes, platelet indices, vascular endothelial function, inflammatory factors, and cardiac function indices were detected. In-hospital bleeding events and follow-up MACE were recorded. After PCI, Group C had a higher number of TIMI myocardial perfusion grade III and TIMI blood flow grade III versus Group A. Group C achieved the greatest changes in myocardial enzymes, platelet indices, vascular endothelial function-related factors, inflammatory factors, and cardiac function indices, followed by Group B and Group A. The incidence of bleeding events was higher in Group C than in Group A, and that of MACE in Group C was lower than in Group A. The addition of high-dose tirofiban to PCI and dual antiplatelet drugs for STEMI patients can improve myocardial blood perfusion, cardiac function, and vascular endothelial function, inhibit platelet activation and aggregation, and reduce the occurrence of MACE.

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.

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 in vitro 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.

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.

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.

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.

Severe thermal injury significantly impacts upon hemostasis and is associated with classical changes to the circulating platelet count with a nadir followed by a rebound thrombocytosis at days ~3 and ~15 post-injury, respectively. To date, few studies have assessed platelet function following thermal injury as platelet tests often require large quantities of blood, are not representative of normal platelet pathophysiology, and are usually dependent on a normal platelet count. The purpose of this study was to measure platelet thrombus formation in vitro using a whole blood flow chip-based system following thermal injury and to study how platelet counts may impact upon the measurement. Adult (≥16 years) patients (N = 10) with ≥ 20% total burn surface area (TBSA) burn were recruited within 24 h of injury. Healthy controls (N = 25) were also recruited. Whole blood counts were measured using a hematology analyzer (Sysmex XN-1000). Platelet function was measured using the Total Thrombus-formation Analyzer System (T-TAS) within chips coated with tissue factor and collagen at shear rates of either 600 sec^-1 (AR chips) or 1200 sec^-1 (HD chips), the latter test being independent of platelet count. We confirmed the classical nadir in platelet counts following severe thermal injury at days 2, 3, 4 (p < 0.0001) and day 5 (p < 0.01) post-injury compared to healthy controls. Physiological platelet thrombus formation was significantly (p < 0.01) abnormal at day 3 post-injury using the AR chips but was related to the platelet count. However, although platelet dysfunction was not significant using HD chips, some of the results were independent of platelet count. A small number of samples, however, still gave abnormal results suggesting that there can be an underlying acquired platelet functional abnormality. Furthermore, the AR chip Area Under the Curve (AUC) was significantly lower on day 1 post-injury and negatively associated with severity of injury (TBSA, p < 0.05) and higher platelet function (AUC) positively associated with survival (p < 0.05). This study suggests that measuring platelet dysfunction within a more physiological in vitro test may have potential clinical utility. Larger studies are required to fully understand the impact of platelet dysfunction following severe thermal injury.