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Summary: Platelets are anucleate blood cells that contain mitochondria and regulate blood clotting in response to injury. Mitochondria contain their own gene expression machinery that relies on nuclear-encoded factors for the biogenesis of the oxidative phosphorylation system to produce energy required for thrombosis. The autonomy of the mitochondrial gene expression machinery from the nucleus is unclear, and platelets provide a valuable model to understand its importance in anucleate cells. Here, we conditionally delete Elac2, Ptcd1, or Mtif3 in platelets, which are essential for mitochondrial gene expression at the level of RNA processing, stability, or translation, respectively. Loss of ELAC2, PTCD1, or MTIF3 leads to increased megakaryocyte ploidy, elevated circulating levels of reticulated platelets, thrombocytopenia, and consequent extended bleeding time. Impaired mitochondrial gene expression reduces agonist-induced platelet activation. Transcriptomic and proteomic analyses show that mitochondrial gene expression is required for fibrinolysis, hemostasis, and blood coagulation in response to injury.

Epidemiological studies have demonstrated that survivors of acute burn trauma are at long-term increased risk of developing a range of morbidities. The mechanisms underlying this increased risk remain unknown. This study aimed to determine whether burn injury leads to sustained immune dysfunction that may underpin long-term morbidity. Plasma and peripheral blood mononuclear cells were collected from 36 pediatric burn survivors >3 years after a non-severe burn injury (

Abstract Low‐grade inflammation, endothelial dysfunction, and platelet hyper‐reactivity to agonists are associated with an increased risk of cardiovascular events. In vitro and animal studies infer an inverse mechanistic relationship between platelet activation and the production of endothelium‐derived nitric oxide and prostacyclin. This concept is supported by evidence of an inverse relationship between endothelial function and platelet activation in high‐risk cardiac patients. The aim of this study was to investigate what relationship, if any, exists between platelet and endothelial function in healthy, middle‐aged, and elderly adults. In 51 participants (18 male, 33 post menopausal female), endothelial function was assessed by flow‐mediated dilation (FMD). Platelet function was assessed by flow cytometric determination of glycoprotein IIb/IIIa activation (measured by PAC‐1 binding), granule exocytosis (measured by surface P‐selectin expression), and monocyte‐platelet aggregates (MPAs), with and without stimulation by canonical platelet agonists adenosine diphosphate (ADP), arachidonic acid (AA), and collagen. Correlation analysis indicated there was no significant (all P => 0.05) relationship between FMD and any marker of in vivo platelet activation (MPAs R = 0.193, PAC‐1 R = −0.113, anti‐CD62P R = −0.078) or inducible platelet activation by ADP (MPA R = −0.128, anti‐CD62P R = −0.237), AA (MPA R = −0.122, PAC‐1 R = −0.045, anti‐CD62P R = −0.142), or collagen (MPA R = 0.136, PAC‐1 R = 0.174, anti‐CD62P R = −0.077). Our findings contrast with two previous studies performed in high‐risk cardiac patients, which reported inverse relationships between platelet activation and endothelial function, suggesting that some compensatory redundancy may exist in the relationship between platelet and endothelial function in preclinical populations.

AbstractTranscription factor 3 (TCF3) is a DNA transcription factor that modulates megakaryocyte development. Although abnormal TCF3 expression has been identified in a range of hematological malignancies, to date, it has not been investigated in myelofibrosis (MF). MF is a Philadelphia-negative myeloproliferative neoplasm (MPN) that can arise de novo or progress from essential thrombocythemia [ET] and polycythemia vera [PV] and where dysfunctional megakaryocytes have a role in driving the fibrotic progression. We aimed to examine whether TCF3 is dysregulated in megakaryocytes in MPN, and specifically in MF. We first assessed TCF3 protein expression in megakaryocytes using an immunohistochemical approach analyses and showed that TCF3 was reduced in MF compared with ET and PV. Further, the TCF3-negative megakaryocytes were primarily located near trabecular bone and had the typical “MF-like” morphology as described by the WHO. Genomic analysis of isolated megakaryocytes showed three mutations, all predicted to result in a loss of function, in patients with MF; none were seen in megakaryocytes isolated from ET or PV marrow samples. We then progressed to transcriptomic sequencing of platelets which showed loss of TCF3 in MF. These proteomic, genomic and transcriptomic analyses appear to indicate that TCF3 is downregulated in megakaryocytes in MF. This infers aberrations in megakaryopoiesis occur in this progressive phase of MPN. Further exploration of this pathway could provide insights into TCF3 and the evolution of fibrosis and potentially lead to new preventative therapeutic targets.

Platelets are subcellular fragments which circulate in blood and have well established roles in thrombosis and haemostasis in adults. Upon activation, platelets undergo granule exocytosis and express P-Selectin on the cell membrane which binds a ligand on monocytes, leading to monocyte-platelet aggregation. Elevated circulating monocyte-platelet aggregates in adults are linked to atherothrombosis, but have not been investigated in children where thrombosis is less common. This study aimed to measure monocyte-platelet aggregate formation in children using whole blood flow cytometry. Monocyte-platelet aggregates as well as activation and granule exocytosis of platelets were measured in healthy adults (n = 15, median age 28 years) and healthy children (n = 28, median age 7 years). Monocyte-platelet aggregates in healthy children were elevated compared to healthy adults (37.8±4.4% vs 15.5±1.9% respectively, p