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| Open AccessA let-7 microRNA-RALB axis links the immune properties of iPSC-derived megakaryocytes with platelet producibility
The authors pioneered the iPSC-derived platelet transfusion in human. Here they employ miRNA switches, identifying RALB as a determinant of immune megakaryocytes and a marker for quality control, advancing standardization of iPSC-platelet production.
- Si Jing Chen
- , Kazuya Hashimoto
- & Koji Eto
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Article
| Open AccessMTH1 protects platelet mitochondria from oxidative damage and regulates platelet function and thrombosis
MTH1 hydrolyzes oxidized nucleotides to prevent their mis-incorporation into DNA under oxidative stress. Here, the authors show that MTH1 is expressed in platelets and its deficiency increases mitochondrial DNA oxidative damage, impairs platelet function and hemostasis.
- Yangyang Ding
- , Xiang Gui
- & Jianlin Qiao
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| Open AccessHighly efficient platelet generation in lung vasculature reproduced by microfluidics
Highly efficient generation of platelets in the vasculature. Here, Zhao et al. show that the mouse platelet precursor cell, megakaryocytes, generate physiological numbers of functional platelets when passaged repeatedly through pulmonary vasculature.
- Xiaojuan Zhao
- , Dominic Alibhai
- & Alastair W. Poole
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| Open AccessCargo-free particles divert neutrophil-platelet aggregates to reduce thromboinflammation
Platelet-neutrophil aggregates are a hallmark of thromboinflamation. Here, the authors use cargo-free particles to block platelet-neutrophil aggregates’ vascular wall adhesion, which could become an effective thromboinflammation therapy, regardless of disease cause.
- Alison L. Banka
- , M. Valentina Guevara
- & Omolola Eniola-Adefeso
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| Open AccessSVEP1 is an endogenous ligand for the orphan receptor PEAR1
SVEP1 is linked to numerous human diseases, though its disease-promoting mechanism has remained unclear. Here, the authors identify SVEP1 as a ligand for the orphan receptor PEAR1 and provide insight into the role of this interaction in cardiovascular disease.
- Jared S. Elenbaas
- , Upasana Pudupakkam
- & Nathan O. Stitziel
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| Open AccessFate mapping of hematopoietic stem cells reveals two pathways of native thrombopoiesis
Hematopoietic stem cells produce diverse cell lineages. Here, the authors apply single-cell RNA-seq, computational integration of non-perturbative approaches for fate-mapping, and mitotic tracking to chart lineage decisions in native hematopoiesis and identify megakaryocyte progenitors that directly link HSCs to megakaryocytes.
- Mina N. F. Morcos
- , Congxin Li
- & Alexander Gerbaulet
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Article
| Open AccessCell-specific and divergent roles of the CD40L-CD40 axis in atherosclerotic vascular disease
Previous studies have shown that the CD40L-CD40 signaling axis plays a role in atherosclerosis. Here the authors investigate the cell-specific functions of the most relevant CD40L-expressing cell types in atherosclerosis. Deficiency of T cell-derived CD40L reduces and stabilizes plaques through impaired Th1 polarization while platelet-derived CD40L ameliorates atherothrombosis.
- Michael Lacy
- , Christina Bürger
- & Esther Lutgens
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Article
| Open AccessGenome sequencing unveils a regulatory landscape of platelet reactivity
Platelet aggregation is associated with myocardial infarction and stroke. Here, the authors have conducted a whole genome sequencing association study on platelet aggregation, discovering a locus in RGS18, where enhancer assays suggest an effect on activity of haematopoeitic lineage transcription factors.
- Ali R. Keramati
- , Ming-Huei Chen
- & Andrew D. Johnson
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| Open AccessThe C5a/C5a receptor 1 axis controls tissue neovascularization through CXCL4 release from platelets
As more intersection points between platelets and the immune system are found, the role of platelets for vessel growth in the adult organism remains unclear. The authors demonstrate that platelets negatively modulate revascularization through CXCL4 secretion induced by activation C5aR1 on their surface.
- Henry Nording
- , Lasse Baron
- & Harald F. Langer
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Article
| Open AccessTargeting Gα13-integrin interaction ameliorates systemic inflammation
Bacterial or viral infection can lead to lethal systemic inflammation and thrombosis. Here, the authors show that inhibiting integrin outside-in signaling in leukocytes and platelets alleviates inflammation/clotting and improved survival in septic mice.
- Ni Cheng
- , Yaping Zhang
- & Xiaoping Du
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Article
| Open AccessDeletion of Mfsd2b impairs thrombotic functions of platelets
The mechanisms by which platelets release sphingosine-1-phosphate (S1P) is not well characterized. Here the authors show that Mfsd2b is required for S1P release from both resting and activated platelets and that deletion of Mfsd2b impairs thrombotic functions of platelets.
- Madhuvanthi Chandrakanthan
- , Toan Quoc Nguyen
- & Long N. Nguyen
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Article
| Open AccessVascular surveillance by haptotactic blood platelets in inflammation and infection
Breakdown of vascular barriers is a major complication of inflammatory diseases. However, the mechanisms underlying platelet recruitment to inflammatory micro-environments remains unclear. Here, the authors identify haptotaxis as a key effector function of immune-responsive platelets
- Leo Nicolai
- , Karin Schiefelbein
- & Florian Gaertner
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| Open AccessPlatelet-derived microparticles enhance megakaryocyte differentiation and platelet generation via miR-1915-3p
Platelets derive from megakaryocytes, which differentiate from hematopoietic stem/progenitor cells (HSPCs). Here, Qu et al show that platelet-derived microparticles carrying miR-1915-3p target HSPCs and promote megakaryopoiesis by suppressing RHOB expression levels.
- Mingyi Qu
- , Xiaojing Zou
- & Xuetao Pei
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| Open AccessThe choline transporter Slc44a2 controls platelet activation and thrombosis by regulating mitochondrial function
Genetic association studies have identified loci including the choline transporter SLC44A2 as a potential regulator of thrombosis. Here the authors report that loss of SLC44A2 impairs platelet activation and thrombosis in mice via a reduction of mitochondrial ATP production.
- J. Allen Bennett
- , Michael A. Mastrangelo
- & Charles J. Lowenstein
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| Open AccessUsing proteolysis-targeting chimera technology to reduce navitoclax platelet toxicity and improve its senolytic activity
Senolytics have the potential to extend healthspan by selectively killing senescent cells (SCs), but senolytics that target Bcl-xl may cause platelet toxicity. Here, the authors generated a Bcl-xl proteolysis-targeting chimera (PROTAC) senolytic, which effectively clears SCs and rejuvenates tissue stem and progenitor cells in naturally aged mice without causing severe thrombocytopenia.
- Yonghan He
- , Xuan Zhang
- & Daohong Zhou
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Article
| Open AccessThe platelet receptor CLEC-2 blocks neutrophil mediated hepatic recovery in acetaminophen induced acute liver failure
The molecular mechanisms that drive irreversible acute liver failure remain poorly characterized. Here, the authors show that the recently discovered platelet receptor CLEC-2 (C-type lectin-like receptor) perpetuates and worsens liver damage during acute liver injury by blocking restorative neutrophil driven inflammation.
- Abhishek Chauhan
- , Lozan Sheriff
- & Patricia F. Lalor
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| Open AccessRed blood cell-derived semaphorin 7A promotes thrombo-inflammation in myocardial ischemia-reperfusion injury through platelet GPIb
Reperfusion injury following myocardial ischemia is aggravated by inflammation and platelet–neutrophil complex formation. Here the authors show that semaphorin 7A binds to platelet GPIb, enhancing platelet–neutrophil interaction and increasing post-ischemic myocardial tissue injury, and that blockage of semaphorin 7A is protective.
- David Köhler
- , Tiago Granja
- & Peter Rosenberger
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Article
| Open Accessβ4GALT1 controls β1 integrin function to govern thrombopoiesis and hematopoietic stem cell homeostasis
Mutations affecting sialylation and galactosylation affect megakaryocyte function and thrombopoiesis. Here the authors show that the enzyme β4GalT1 regulates thrombopoiesis and hematopoietic stem cell homeostasis by controlling beta-1 integrin function.
- Silvia Giannini
- , Melissa M. Lee-Sundlov
- & Karin M. Hoffmeister
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| Open AccessThe transcription factor ERG regulates a low shear stress-induced anti-thrombotic pathway in the microvasculature
The endothelium actively maintains an anticoagulant surface through expression of thrombomodulin. Here, Peghaire et al. identify an anti-thrombotic pathway that controls thrombomodulin expression selectively in regions of low shear stress, via cooperation of the transcription factors ERG and KLF2.
- C. Peghaire
- , N. P. Dufton
- & A. M. Randi
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| Open AccessThe role of platelets in mediating a response to human influenza infection
Influenza viremia is rare in human blood and not well studied. Here, the authors show that influenza can be found in human platelets and that platelet engulfment of influenza A results in TLR7-dependent C3 release, which in turn promotes neutrophil-DNA release and formation of platelet-DNA aggregates.
- Milka Koupenova
- , Heather A. Corkrey
- & Jane E. Freedman
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| Open AccessNeutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia
The pathogenesis of heparin-induced thrombocytopenia and thrombosis (HIT) is mediated by heparin-reactive autoantibodies binding to platelets (thrombocytes). Here the authors show neutrophil activation and NETosis are elevated in patients with HIT, and are essential for thrombosis in HIT mouse models.
- José Perdomo
- , Halina H. L. Leung
- & Beng H. Chong
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| Open AccessContractile forces in platelet aggregates under microfluidic shear gradients reflect platelet inhibition and bleeding risk
Platelet aggregates generate contractile forces that contribute to their cohesion and adhesion. Here, Ting et al. develop a microfluidic device to measure contractile forces generated by platelet aggregates, and find it can detect the response of platelets to pharmacological agents and predict bleeding risk in trauma patients.
- Lucas H. Ting
- , Shirin Feghhi
- & Nathan J. Sniadecki
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| Open AccessA shear-dependent NO-cGMP-cGKI cascade in platelets acts as an auto-regulatory brake of thrombosis
Nitric oxide (NO) inhibits thrombosis in part by stimulating cyclic guanosine monophosphate (cGMP) production and cGMP-dependent protein kinase I (cGKI) activity in platelets. Here, Wen et al. develop a cGMP sensor mouse to follow cGMP dynamics in platelets, and find that shear stress activates NO-cGMP-cGKI signaling during platelet aggregation to limit thrombosis.
- Lai Wen
- , Susanne Feil
- & Robert Feil
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Article
| Open AccessVariants in exons 5 and 6 of ACTB cause syndromic thrombocytopenia
Genetic variants in ACTB and ACTG1 have been associated with Baraitser-Winter Cerebrofrontofacial syndrome. Here, the authors report of a syndromic thrombocytopenia caused by variants in ACTB exons 5 or 6 that compromise the organization and coupling of the cytoskeleton, leading to impaired platelet maturation.
- Sharissa L. Latham
- , Nadja Ehmke
- & Nataliya Di Donato
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Article
| Open AccessApolipoprotein A-IV binds αIIbβ3 integrin and inhibits thrombosis
Activation of integrin αIIbβ3 at the surface of platelets is required for their aggregation and for thrombus formation. Here Xu et al. identify apolipoprotein A-IV as a novel ligand for platelet αIIbβ3 integrin, and find it inhibits platelet aggregation and thrombosis.
- Xiaohong Ruby Xu
- , Yiming Wang
- & Heyu Ni
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Article
| Open AccessCathelicidins prime platelets to mediate arterial thrombosis and tissue inflammation
Cathelicidins are antimicrobial peptides that eliminate pathogens and contribute to the innate immune response. Here the authors show that neutrophil-derived LL-37/CRAMP induces platelet activation and promotes arterial thrombosis and thrombo-inflammation.
- Joachim Pircher
- , Thomas Czermak
- & Christian Schulz
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| Open AccessCompression force sensing regulates integrin αIIbβ3 adhesive function on diabetic platelets
Diabetes is associated with an increased thrombotic response, but the mechanism is unknown. Here the authors demonstrate that compressive force activates integrin αIIbβ3 on discoid diabetic platelets and that platelet aggregates can be eliminated by PI 3-kinase inhibition, but not by anti-thrombotics aspirin or clopidogrel.
- Lining Ju
- , James D. McFadyen
- & Shaun P. Jackson
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| Open AccessThe podoplanin-CLEC-2 axis inhibits inflammation in sepsis
Sepsis is a life-threatening condition where exaggerated inflammatory responses lead to severe tissue damage. Here, Rayes and colleagues show that the interaction between podoplanin and its receptor CLEC-2 on platelets plays a critical role in limiting inflammation during sepsis.
- Julie Rayes
- , Siân Lax
- & Steve P. Watson
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Article
| Open AccessCritical role of the HDAC6–cortactin axis in human megakaryocyte maturation leading to a proplatelet-formation defect
Histone deacetylase (HDAC) inhibitors, a class of cancer therapeutics, cause thrombocytopenia via an unknown mechanism. Here, the authors show that HDAC6 inhibition impairs proplatelet formation in human megakaryocytes, and show that this is linked to hyperacetylation of the actin-binding protein cortactin.
- Kahia Messaoudi
- , Ashfaq Ali
- & Najet Debili
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| Open AccessQuantitative structural mechanobiology of platelet-driven blood clot contraction
Blood clot contraction is a cellular (patho)physiological process essential for wound healing, hemostasis, and thrombosis. Here, the authors describe the physical structural mechanism by which platelet filopodia pull “hand-over-hand” on fibrin fibers to compact them into bundled agglomerates.
- Oleg V. Kim
- , Rustem I. Litvinov
- & John W. Weisel
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| Open AccessThrombopoiesis is spatially regulated by the bone marrow vasculature
Megakaryocyte maturation is thought to occur as the cells migrate from a vessel-distant (endosteal) niche to the vessel within the bone. Here, the authors show that megakaryocytes represent largely sessile cells in close contact with the vasculature and homogeneously distributed in the bone marrow.
- David Stegner
- , Judith M. M. vanEeuwijk
- & Katrin G. Heinze
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| Open AccessPlatelet function is modified by common sequence variation in megakaryocyte super enhancers
Numerous genetic variants, including those located in the non-coding regions of the genome, are known to be associated with blood cells traits. Here, Frontini and colleagues investigate their potential regulatory functions using epigenomic data and promoter long-range interactions.
- Romina Petersen
- , John J. Lambourne
- & Mattia Frontini
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| Open AccessLeukocyte integrin Mac-1 regulates thrombosis via interaction with platelet GPIbα
The binding of the leukocyte integrin Mac1 to the platelet receptor GPIbα is important for the physiological response to tissue injury. Here the authors show that this interaction also regulates thrombosis, without influencing bleeding time, which may provide clues for the development of new anti-thrombotic drugs.
- Yunmei Wang
- , Huiyun Gao
- & Daniel I. Simon
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| Open AccessLoss of the Arp2/3 complex component ARPC1B causes platelet abnormalities and predisposes to inflammatory disease
ARPC1B is a component of the actin-related protein 2/3 complex (Arp2/3), which is required for actin filament branching. Kahret al. show that ARPC1B deficiency in humans is associated with severe multisystem disease that includes platelet abnormalities, eosinophilia, eczema and other indicators of immune disease.
- Walter H. A. Kahr
- , Fred G. Pluthero
- & Aleixo M Muise
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| Open AccessDirected transport of neutrophil-derived extracellular vesicles enables platelet-mediated innate immune response
Interaction between platelets and neutrophils promotes neutrophil activation. Here the authors show that neutrophils initiate the cross-talk with platelets by shuttling arachidonic acid via extracellular vesicles, which platelets convert to thromboxane A2that then elicits neutrophil activation.
- Jan Rossaint
- , Katharina Kühne
- & Alexander Zarbock
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Article
| Open Access14-3-3ζ regulates the mitochondrial respiratory reserve linked to platelet phosphatidylserine exposure and procoagulant function
Platelets express negatively charged phosphatidylserine (PS) on their plasma membrane when propagating coagulation within a developing thrombus. Here the authors show that an adaptor protein 14-3-3 regulates mitochondrial function and PS exposure and thus platelet procoagulant activity, promising a new therapy to reduce thrombosis.
- Simone M. Schoenwaelder
- , Roxane Darbousset
- & Shaun P. Jackson
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Article
| Open AccessPlatelet clearance via shear-induced unfolding of a membrane mechanoreceptor
The platelets detect and respond to shear stress generated by blood flow. Here the authors show that the binding of the soluble von Willebrand factor to its receptor GPIba under physiological shear stress induces receptor's domain unfolding on the platelet and signalling into the platelet, leading to platelets clearance.
- Wei Deng
- , Yan Xu
- & Renhao Li
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Article
| Open AccessNeutralizing blood-borne polyphosphate in vivo provides safe thromboprotection
The inorganic procoagulant polymer polyphosphate participates in thrombosis via factor XII. Here the authors use recombinant probes that specifically bind or degrade circulating polyphosphate to protect mice in arterial and venous thrombosis models without an increased bleeding risk, the primary complication of all currently used anticoagulants.
- Linda Labberton
- , Ellinor Kenne
- & Thomas Renné
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Article
| Open AccessSingle-cell RNA sequencing reveals molecular and functional platelet bias of aged haematopoietic stem cells
With age, haematopoietic stem cells (HSCs) produce more myeloid than lymphoid cells, affecting adaptive immunity. By combining HSC single cell transcriptomics with functional studies, Grover et al. find that platelet production is also increased in old murine HSCs and show that the FOG-1 transcription factor contributes to the age-dependent platelet bias.
- Amit Grover
- , Alejandra Sanjuan-Pla
- & Claus Nerlov
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Article
| Open AccessA shear gradient-activated microfluidic device for automated monitoring of whole blood haemostasis and platelet function
The current hemostasis assays are unable to predict thrombotic or bleeding risk in clinics. Here, Jain et al. present a novel microfluidic device mimicking stenosed arterioles that determines clotting times in vitroand in extracorporeal circuits, offering a simple and reliable monitoring of blood homeostasis and platelet function.
- Abhishek Jain
- , Amanda Graveline
- & Donald E. Ingber
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Article
| Open AccessDesialylation is a mechanism of Fc-independent platelet clearance and a therapeutic target in immune thrombocytopenia
Immune thrombocytopenia (ITP) is caused by autoantibody-mediated platelet clearance, but refractoriness to current immunomodulatory therapies is common. Here the authors show that desialylated platelets can be cleared via hepatic Ashwell–Morell receptor, a process that can be attenuated by sialidase inhibitors, suggesting a new therapy for ITP.
- June Li
- , Dianne E. van der Wal
- & Heyu Ni
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Article
| Open AccessPlatelet actin nodules are podosome-like structures dependent on Wiskott–Aldrich syndrome protein and ARP2/3 complex
During early platelet spreading a novel F-actin structure forms, called the actin nodule. Here Poulter et al.demonstrate that actin nodule formation depends on WASp and the Arp2/3 complex, and using super-resolution microscopy they show that nodules bear a structural resemblance to podosomes.
- Natalie S. Poulter
- , Alice Y. Pollitt
- & Steven G. Thomas
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The class II PI 3-kinase, PI3KC2α, links platelet internal membrane structure to shear-dependent adhesive function
The lipid kinase PI3KC2α is essential for embryogenesis, yet its role in adult homeostasis is unknown. Here, the authors show that PI3KC2α regulates the structure of the internal membrane reserves of murine megakaryocytes and platelets, affecting the platelets’ adhesiveness and prothrombotic function.
- Jessica K. Mountford
- , Claire Petitjean
- & Shaun P. Jackson
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Platelets promote tumour metastasis via interaction between TLR4 and tumour cell-released high-mobility group box1 protein
Factors affecting the fate of disseminating tumour cells in the circulation play a critical role in metastasis. Here the authors show that TLR4 on platelets promotes their adhesion to tumour cells and enhances metastasis.
- Le-Xing Yu
- , Lei Yan
- & Hong-Yang Wang
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Megakaryocyte-specific Profilin1-deficiency alters microtubule stability and causes a Wiskott–Aldrich syndrome-like platelet defect
Patients with mutations in the gene encoding the cytoskeleton regulator WAS have platelet defects. Here the authors show that the WAS-binding protein, Profilin1, is essential for platelet formation in mice, and that its deficiency reproduces the bleeding disorder of patients with WAS mutations.
- Markus Bender
- , Simon Stritt
- & Bernhard Nieswandt
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| Open AccessIdentification of platelet function defects by multi-parameter assessment of thrombus formation
Platelets from patients with bleeding disorders often display altered adherence to surface proteins. In this study, de Witt et al.design a flow chamber for the systematic interrogation of platelets attaching to 52 adhesive surfaces, which may be helpful for the diagnosis of platelet disorders.
- Susanne M. de Witt
- , Frauke Swieringa
- & Judith M.E.M. Cosemans
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Platelet production proceeds independently of the intrinsic and extrinsic apoptosis pathways
Platelet production has been suggested to occur by apoptosis of megakaryocytes, but mitochondrially mediated apoptosis is known to be dispensable. Here, the authors show that death receptor-mediated apoptosis in mouse megakaryocytes is also not required for platelet biogenesis.
- Emma C. Josefsson
- , Deborah L. Burnett
- & Benjamin T. Kile
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Platelets protect from septic shock by inhibiting macrophage-dependent inflammation via the cyclooxygenase 1 signalling pathway
Sepsis in patients is often accompanied by thrombocytopenia, but the exact role of platelets in the pathogenesis of septicaemia has not been elucidated. Here, Xiang et al. present evidence that platelets may act as anti-inflammatory cells and protect from septic shock.
- Binggang Xiang
- , Guoying Zhang
- & Zhenyu Li
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Article
| Open AccessConnexin40 regulates platelet function
Hemichannels and gap junctions containing the connexin Cx37 are required for platelet functions such as aggregation and granule secretion through poorly defined mechanisms. Vaiyapuri et al. show that Cx40 is also required and can act independently of Cx37 in mouse platelets.
- Sakthivel Vaiyapuri
- , Leonardo A. Moraes
- & Jonathan M. Gibbins