Posts Tagged: blood platelets

Translational Implications of Platelets as Vascular First Responders

Translational Implications of Platelets as Vascular First Responders

Richard C. Becker, Travis Sexton, Susan S. Smyth

Platelet participation in neutrophil extracellular trap formation (NETosis). Activated platelets interact with neutrophils via platelet P-selectin and neutrophil PSGL-1 (P-selectin glycoprotein ligand-1), with interactions stabilized by a series of secondary adhesion interactions, including the ones mediated by platelet GP (glycoprotein) Ib and leukocyte Mac-1 (αMβ2). This interaction can contribute to trigger the release of NETs, consisting of chromatin containing citrullinated histones complexed with antimicrobial proteases, such as elastase and myeloperoxidase, in a process called NETosis. NETs serve to enhance the clearance of pathogens. They also contribute to clot formation by forming a mesh with platelets and fibrin and accumulating coagulation factors, such as tissue factor (TF). [Powerpoint File]

Translational Implications of Platelets as Vascular First Responders

Translational Implications of Platelets as Vascular First Responders

Richard C. Becker, Travis Sexton, Susan S. Smyth

Role for platelets in inflammation and response to pathogens. At sites of damaged or inflamed endothelium, platelet adhesion occurs through various interactions, such as with exposed subendothelium, P-selectin expression on activated endothelium, and release of ultralarge vWF (von Willebrand factor). Adherent platelets, in turn, recruit white blood cells (WBCs), which can subsequently transmigrate across the endothelium. Heterotypic cell interactions between platelets and WBCs or red blood cells (RBCs) can occur and are associated with increases in systemic inflammation. Activated platelets can trigger the release of neutrophil extracellular traps (NETs), which contribute to microbial clearance and clot formation. Platelets also interact with viral and bacterial pathogens to contribute to their clearance and respond to gut microbiota that can modulate platelet function. [Powerpoint File]

Circulating Platelets as Mediators of Immunity, Inflammation, and Thrombosis

Circulating Platelets as Mediators of Immunity, Inflammation, and Thrombosis

Milka Koupenova, Lauren Clancy, Heather A. Corkrey, Jane E. Freedman

Platelet and circulating cell interactions during infection initiate the innate or adaptive immune response. Platelets achieve cell-to-cell communication during bacterial or viral infection either by direct interaction with white blood cells (WBCs) through surface expression of platelet proteins or through indirect protein release from their α- or δ-granules. Encephalomyocarditis virus (EMCV)–activated platelets interact with neutrophils in a TLR7 (Toll-like receptor 7)-dependent manner. Coxsackievirus B (CVB)–activated platelets bind to neutrophils in a phosphatidylserine (PS)-dependent manner. Dengue and influenza increase microparticle release; dengue-mediated microparticles contain IL-1β (interleukin 1β). Human cytomegalovirus (HCMV)–activated platelets interact with neutrophils, monocytes, B cells, T cells, and dendritic cells (DCs), suggesting activation of innate and adaptive immune responses. Vaccinia-bound platelets have reduced aggregation potential in the presence of ADP, collagen, or thrombin. The specific pathways by which platelets respond to herpes simplex virus (HSV) 1 or HSV2 are currently unknown. During bacterial infection, platelet interactions with complement C3 opsonized bacteria through GP1b (glycoprotein 1b; CD42) lead to slowing of bacterial clearance. DCs recognize the platelet–bacterial complexes, thereby inducing adaptive immunity. These platelet–bacterial interactions are true for Gram-positive or Gram-negative bacteria. 5HT includes serotonin; and VEGF, vascular endothelial growth factor. [Powerpoint File]

Circulating Platelets as Mediators of Immunity, Inflammation, and Thrombosis

Circulating Platelets as Mediators of Immunity, Inflammation, and Thrombosis

Milka Koupenova, Lauren Clancy, Heather A. Corkrey, Jane E. Freedman

Platelet-mediated interactions with vascular or circulating cells. Platelets interact with endothelial and immune cells in the circulation, orchestrating a response to microbes, inflammatory stimuli, and vessel damage. Through their TLRs (Toll-like receptors; or inflammatory signals), platelets can change their surface expression and release their granule content, thereby engaging different immune cells. Platelets form heterotypic aggregates (HAGs) and initiate innate immune responses in the presence of TLR agonists and viruses such as encephalomyocarditis virus (EMCV), coxsackievirus B (CVB), dengue, flu, HIV. Platelets can interact with dendritic cells (DC) through their P-selectin (platelet selectin), activate them to become antigen (Ag) presenting through their CD154. By releasing α- or δ-granule content which leads to IgG (IgG1, IgG2, IgG3) production and control of T-cell function, platelets engage the adaptive immune response. Similarly, platelets are able to activate the endothelium, make it more permeable, and mediate leukocyte trafficking to the inflamed endothelium. Proteins in bold represent changes of expression on the platelet surface. Continuous lines represent direct binding; dotted lines represent interaction through secretion. 5HT indicates serotonin; CMV, cytomegalovirus; ICAM-1, intercellular adhesion molecule 1; IL, interleukin; PF4, platelet factor 4; PSGL1, P-selectin glycoprotein ligand 1; RANTES, regulated on activation, normal T cell expressed and secreted; TGF-β; transforming growth factor-β; and VCAM-1, vascular cell adhesion molecule 1. [Powerpoint File]

Systems Analysis of Thrombus Formation

Systems Analysis of Thrombus Formation

Scott L. Diamond

Systems biology of thrombosis. The computer simulation of clotting requires a multiscale and integrated description of platelet signaling and adhesion, coagulation kinetics, and hemodyamics. Platelet signaling is driven by soluble activators (ADP, thromboxane A2 [TXA2], thrombin), soluble inhibitors (NO, prostacyclin [PGI2] and insoluble activators (collagen) to drive intracellular calcium mobilization. Calcium mobilization occurs rapidly through IP3-mediated release and store-operated calcium entry (STIM1-Orai1). Dense platelet deposits in clots result in significant ADP and thromboxane and thrombin-driven signaling, often targeted by inhibition of P2Y12, cyclooxygenase (COX)-1, and PAR1, respectively. During coagulation, the generation of thrombin (FIIa) is primarily driven by TF/FVIIa (extrinsic tenase) via subsequent engagement of the FIXa/VIIIa (intrinsic tenase) and FXaVa (prothrombinase). Thrombin has significant regulatory control on its own production through activation of FVIIIa, FVa, FXIa, as well as regulation of fibrin through activation of FXIIIa that crosslinks fibrin. Local hemodynamics (inset; reprinted from Taylor et al3 with permission of the publisher. Copyright ©2013, Elsevier.) can be determined by computational fluid dynamics to define locations with at-risk plaque burden, stenosis, and high wall shear stress. Full systems biology models of platelet activation and coagulation in a patient-specific flow field are directed at simulation of acute coronary syndromes (bottom). AC indicates adenylate cyclase; AP, antiplasmin; APC, activated protein C; ATIII, antithrombin III; catG, cathepsin G; CTI, corn trypsin inhibitor; DTS, dense tubular system; EC, endothelial cell; FDP, fibrin degradation product; GC, guanylate cyclase; GPVI, glycoprotein VI; HMWK, high molecular weight kininogen; HNE, human neutrophil elastase; IP, prostacyclin receptor; MG, macroglobulin; NO, nitric oxide; P2Y purinergic receptor type 2; PAI, plasminogen activator inhibitor; PAR, protease activated receptor; PC, protein C; PLC, phospholipase; PMCA, plasma membrane calcium ATPase; PN2, proteonexin 2; PS, protein S; TM, thrombomodulin; TP, thromboxane receptor; tPA, tissue-type plasminogen activator; and uPA, urokinase plasminogen activator. [Powerpoint File]

Platelet Lipidomics: Modern Day Perspective on Lipid Discovery and Characterization in Platelets

Platelet Lipidomics: Modern Day Perspective on Lipid Discovery and Characterization in Platelets

Valerie B. O’Donnell, Robert C. Murphy, Steve P. Watson

Examples of mass spectrometry (MS) instrument configurations. A, Triple quadrupole instrument. Ions are selected in Q1, fragmented in Q2, and daughter ions scanned out in Q3. B, Fourier transform Orbitrap MS. Ion trajectories in an Orbitrap mass spectrometer. C, Time-of-flight (ToF) MS. In the example shown, matrix-assisted laser desorption ionization is used to generate ions that are selected in an electric field and m/z determined based on time taken to reach the detector. [Powerpoint File]

What Can Proteomics Tell Us About Platelets?

What Can Proteomics Tell Us About Platelets?

Julia M. Burkhart, Stepan Gambaryan, Stephen P. Watson, Kerstin Jurk, Ulrich Walter, Albert Sickmann, Johan W.M. Heemskerk, René P. Zahedi

What proteomics can tell us about human platelets. A, Schematic overview of several classes of proteins that have been identified by platelet proteomics, including low abundant membrane receptors and their glycosylation sites. Estimated copy numbers per platelet taken from Burkhart et al42 are color coded. B, Summary of present and potential future applications of platelet proteomics, which may help to improve the understanding of physiological and pathological conditions. In platelets, protein–protein interaction, sub(cellular)-proteomes, post-translational modifications (PTM), and in vitro signaling have already been addressed using proteomics. This work can comprise the characterization of resting and activated platelets from healthy donors, as well as of platelets in pathophysiological conditions. Using quantitative proteomics, changes in the respective protein or PTM patterns can reveal novel insights into platelet (dys)function. ACSA indicates acetyl-coenzyme A synthetase; DTS, dense tubular system; ER, endoplasmic reticulum; FG, fibrinogen, FN, fibronectin; GPVI, platelet glycoprotein VI; LAMP, lysosome-associated membrane glycoprotein; LDH, L-lactate dehydrogenase; MYH, myosin; PAR, proteinase-activated receptor; PDI, platelet disulfide isomerase; PF-4, platelet factor 4; SERCA, sarcoplasmic endoplasmic reticulum Ca2+ ATPase; and TSP, thrombospondin. [Powerpoint File]

Platelet Immunoreceptor Tyrosine-Based Activation Motif (ITAM) Signaling and Vascular Integrity

Platelet Immunoreceptor Tyrosine-Based Activation Motif (ITAM) Signaling and Vascular Integrity

Yacine Boulaftali, Paul R. Hess, Mark L. Kahn, Wolfgang Bergmeier

Platelet-dependent hemostasis after vascular injury and at sites of inflammation. Schematic representation of important molecular mechanisms regulating platelet-dependent hemostasis. At sites of vascular injury, platelet activation and adhesion is strongly dependent on soluble agonists and their respective G protein–coupled receptors (GPCRs) expressed on the platelet surface. Engagement of GPCRs leads to the rapid activation of phospholipase Cβ2 (PLCβ2) and phosphatidyl inositol-3 kinase (PI3K), events that are critical for the activation of the small GTPase Rap1, affinity regulation in platelet integrins, and platelet aggregate formation. The contribution of immunoreceptor tyrosine-based activation motif (ITAM)–coupled receptors to platelet activation at sites of vascular injury is weak when compared with GPCRs. In contrast, hemostasis at sites of inflammation depends primarily on platelet ITAM signaling and is independent of major platelet adhesion receptors. These findings suggest a model in which platelets get activated under low-/no-flow conditions in the extravascular space, leading to the release of soluble factors that secure vascular integrity. Both the signaling response downstream of PLCγ2 and the platelet-derived mediator(s) critical for vascular integrity in inflammation are currently unknown. CLEC2 indicates C-type lectin 2; ECM, extracellular matrix; FcRγ, Fc receptor γ chain; GPVI, glycoprotein VI; LAT, linker for activation of T cells; PAR, protease activated receptor; PDPN, podoplanin; SLP-76, SH2 containing leukocyte protein of 76 kDa; TP, TxA2 receptor; and TxA2, thromboxane A2. [Powerpoint File]

Thiol Isomerases in Thrombus Formation

Thiol Isomerases in Thrombus Formation

Bruce Furie, Robert Flaumenhaft

Colocalization of protein disulfide isomerase (PDI) with toll-like receptor 9 (TLR9) in T-granules. Electron microscopy demonstrates (A) TLR9, (B) PDI, or (C and D) colocalization of both TLR9 and PDI to electron-dense membrane-encapsulated regions adjacent to the plasma membrane of platelets (Adapted from Thon et al46). [Powerpoint File]

ATP-Binding Cassette Transporters, Atherosclerosis, and Inflammation

ATP-Binding Cassette Transporters, Atherosclerosis, and Inflammation

Marit Westerterp, Andrea E. Bochem, Laurent Yvan-Charvet, Andrew J. Murphy, Nan Wang, Alan R. Tall

Contribution of ATP-binding cassette A1 (ABCA1) and ABCG1 deficiency to atherogenesis. A, Abca1−/−Abcg1−/− hematopoietic stem and multipotential progenitor cells (HSPCs) show increased proliferation, stimulating monocyte production. B, Abca1/g1-deficient mice show enhanced bone marrow (BM) HSPC mobilization into the blood and organs, including the spleen. HSPC accumulation in the spleen leads to enhanced monocyte production. C, Abca1−/−Abcg1−/− monocytes and macrophages in the spleen show increased expression of macrophage colony-stimulating factor (M-CSF) and monocyte chemoattractant protein 1 (MCP-1), increasing M-CSF and MCP-1 plasma levels and monocyte production in the BM and monocyte release from the BM, respectively. Abcg1−/− endothelium (D) and Abca1−/−Abcg1−/− macrophages (E) in the atherosclerotic plaque show increased foam cell formation and cytokine levels, which enhances monocyte infiltration. All processes contribute to atherosclerotic lesion formation. Figure artwork by Derek Ng. CMP indicates common myeloid progenitor; GMP, granulocyte macrophage progenitor; ICAM-1, intracellular adhesion molecule-1; IL-1β, interleukin-1β; and MIP-1α, macrophage inflammatory protein-1α. [Powerpoint File]