Posts Tagged: hemostasis

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]

Animal Models of Thrombosis From Zebrafish to Nonhuman Primates: Use in the Elucidation of New Pathologic Pathways and the Development of Antithrombotic Drugs

Animal Models of Thrombosis From Zebrafish to Nonhuman Primates: Use in the Elucidation of New Pathologic Pathways and the Development of Antithrombotic Drugs

Pudur Jagadeeswaran, Brian C. Cooley, Peter L. Gross, Nigel Mackman

Formation of an occlusive thrombus. After vessel injury platelets rapidly adhere to collagen and deposited von Willebrand Factor. The adhered platelets are activated by primary and secondary activators that lead to platelet aggregation mediated by various ligands, including fibrinogen. In parallel to platelet activation, the clotting system is activated by exposure of tissue factor (TF) in the vessel wall. In addition, factor XII may contribute to the activation of coagulation. Thrombin is the central protease of the coagulation cascade and cleaves fibrinogen to fibrin monomers that are crosslinked into a network by factor XIIIa. There is cross talk between the platelet and coagulation cascades. For instance, activated platelets provide a thrombogenic surface for the assembly of various coagulation protease complexes and thrombin is a potent activator of platelets by cleavage of protease activated receptors. Formation of an occlusive thrombosis will block blood flow. [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]