Search

Schuermans et al. discovered that genetic predisposition to thromboembolism is associated with a greater risk of post-acute sequelae after SARS-CoV-2 infection, including long COVID, and downstream analyses implicated PAR-1 as a potential contributor to long COVID.

Platelets are known to have functions beyond those in thrombosis and haemostasis. Here the authors use multi-colour flow cytometry and proteomics to analyse platelet phenotypes in psoriatic disease and proteins that are potentially involved in the interaction of platelets with immune cells.

Sepsis may progress into lethal septic shock, but the cellular mechanisms are still unclear. Here the authors show that, in septic mice, platelets activate perivascular mast cells to cause systemic hypotension and vascular pathology, while inhibiting platelets or mast cell activation suppresses septic shock induction, thereby implicating potential therapy targets.

In this Review, Kaiser and Nicolai summarize our understanding of procoagulant platelets, describing the signalling pathways that control platelet procoagulant activation and discussing the role of procoagulant platelets in venous and arterial thrombosis, as well as potential therapeutic approaches to target these platelets in thrombotic and thromboinflammatory disorders, including cardiovascular disease, septic inflammation and immune complex-mediated diseases.

Non-variceal upper gastrointestinal bleeding (NVUGIB) is an often life-threatening bleeding in the oesophagus, stomach or proximal duodenum. This PrimeView focuses on the pathophysiology of NVUGIB, which is most often caused by peptic ulcers associated with Helicobacter pylori infection or use of NSAIDs or low-dose aspirin.

This PrimeView highlights the difficulty in reaching a conclusive diagnosis of thrombotic thrombocytopenic purpura (TTP), a rare but potentially lethal microangiopathy characterized by thrombocytopenia, haemolytic anaemia and ischaemic organ damage.

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.

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.

Myasthenia gravis (MG) is an autoimmune condition leading to extreme muscle weakness due to autoantibodies targeting the neuromuscular junctions. Here authors assign a critical role for platelets in amplifying the pro-inflammatory response in AChR+ immunotherapy-naïve MG (nMG) patients and thus contributing to disease pathology.

To stop bleeding from an injured vessel, platelets adhere and form a clot despite high shear stress from the flow. Here, the authors show that platelet actin disassembly is a key step that enables a receptor to translocate to membrane lipid rafts, enhancing its adhesive function under shear stress.

Vascular protein disulfide isomerase (PDI) regulates thrombosis and targeting extracellular PDI remains a promising antithrombotic approach. Here, the authors show that PDI cleaves allosteric disulfides on histidine-rich glycoprotein to influence its functions during coagulation and thus fine-tune the kinetics of thrombus formation.

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.

Arterial thrombosis is a leading cause of death and disability with no clinical bioassay for prediction. Here, the authors develop an assay that monitors the multi-dimensional attributes of thrombi forming in its physiologically mimicking rheological condition to predict arterial thrombotic risks

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.

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.

Meral Gunay-Aygun and colleagues report that NBEAL2 is mutated in gray platelet syndrome (GPS). GPS is a recessive platelet disorder that can lead to severe bleeding.

Zhang et al. report that alkaline ceramidase 1–mediated ceramide degradation in platelets alleviated platelet-involved vascular inflammation and abdominal aortic aneurysm formation but without affecting hemostasis 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.

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.

Barrachina et al. present an extensive lipidomic analysis at different stages of thrombopoiesis and, through in vitro and in vivo experiments, demonstrate that fatty acid uptake, largely dependent on the scavenger receptor CD36, and its regulation are essential for megakaryocyte maturation and platelet production.

Chen et al. provide cryo-EM structures of ABC transporter ABCC4 in human platelets and, through a combination of structural and biochemical assays, demonstrate that platelet agonist TXA₂ and antagonist aspirin are substrates of ABCC4 and reveal a specific transmembrane substrate-binding pocket of ABCC4. They also found that dipyridamole is a strong competitive inhibitor against ABCC4, which supports the co-administration of dipyridamole with aspirin in clinic.

Jacobsen and colleagues elucidate the nonhierarchical relationship between two types of stem cells: Vwf⁻ hematopoietic stem cells that stably replenish all blood cell lineages without a platelet bias, and Vwf⁺ stem cells that replenish almost exclusively platelets, and demonstrate that the two types utilize cellularly and molecularly distinct progenitor trajectories for replenishment of platelets.

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.

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.

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.

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.

Pharmacological targeting of de novo lipogenesis is an attractive clinical target for a wide range of diseases. Kelly et al. report that de novo lipogenesis is essential for platelet production in primates, but not in dogs and rats.

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.

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.

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.

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.

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.

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.

Through genetic mouse models, pharmacological interventions and in vitro assays, Beck et al. show that thrombin-mediated platelet glycoprotein V (GPV) shedding does not affect platelet activation but prevents excessive thrombin-mediated fibrin deposition and thereby controls hemostasis, thrombosis and thrombo-inflammation. The GPV-mediated spatio-temporal control of fibrin formation on thrombogenic surfaces could be targeted to restrict thrombosis while preserving hemostasis.

Platelets are formed from megakaryocytes but the exact mechanisms are unknown. Thonet al.describe circular preplatelets and barbell shaped proplatelets in human blood and demonstrate, with the aid of a mathematical model, a role for microtubule-based forces in regulating final platelet size.

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.

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.

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.

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.

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.