Posts Tagged: thrombosis

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]

Bioresorbable Scaffold: The Emerging Reality and Future Directions

Bioresorbable Scaffold: The Emerging Reality and Future Directions

Yohei Sotomi, Yoshinobu Onuma, Carlos Collet, Erhan Tenekecioglu, Renu Virmani, Neal S. Kleiman, Patrick W. Serruys

Strut thickness and platelet activation. The thick protruding strut disrupts the laminar flow and induces flow disturbances, and thereby endothelial shear stress (ESS) microgradients (upper panel). The shear microgradients can induce the formation of stabilized discoid platelet aggregates, the size of which is directly regulated by the magnitude and spatial distribution of the gradient.72,73 Shear microgradient–dependent platelet aggregation requires 3 principal features: shear acceleration phase, peak shear phase, and shear deceleration phase. During shear acceleration, platelets in the central regions of blood flow exposed to laminar flow (constant physiological shear) are suddenly accelerated through the shear microgradient. During the peak shear phase, a proportion of the discoid platelets that are accelerated into the peak shear zone adhere to exposed thrombogenic surfaces through platelet membrane glycoprotein (GP) Ib/IX/V. Exposure of these platelets to elevated hemodynamic drag leads to the extrusion of thin filamentous membrane tethers. Membrane tether formation initiates discoid platelet adhesion with the thrombogenic surface and also facilitates the recruitment of discoid platelets into the downstream deceleration zone. During the shear deceleration phase, platelets transitioning into the flow deceleration zone experience decreasing hemodynamic drag forces. Reduced shear within this zone progressively favors the formation of integrin αIIbβ3 adhesion contacts. Integrin αIIbβ3 engagement is associated with low-frequency calcium spikes that trigger tether restructuring, leading to the stabilization of discoid platelet aggregates. Ongoing discoid platelet recruitment drives the propagation of the thrombus in the downstream deceleration zone, which may in turn amplify the shear microgradient and promote further platelet aggregation. Thus, the shear microgradients caused by the thick struts induce platelet aggregation, formation of microthrombi with potential embolization, and micromyocardial necrosis (so-called a nidus of thrombus). The magnitude of flow disturbance depends on the degree of protrusion of the strut into the lumen. Therefore, thin struts could be a potential solution for the less flow disturbance and thus less thrombogenic status (lower panel). There is another cascade of von Willebrand factor (VWF)/GPIb activation, namely agglutination-elicited GPIb signaling.73 In contrast to shear stress–induced GPIb-elicited signaling, agglutination-elicited GPIb signaling that activates integrin αIIbβ3 requires thromboxane A2 (TXA2). Agglutination-elicited TXA2 production is independent of Ca2+ influx and mobilization of internal Ca2+ stores. [Powerpoint File]

Bioresorbable Scaffold: The Emerging Reality and Future Directions

Bioresorbable Scaffold: The Emerging Reality and Future Directions

Yohei Sotomi, Yoshinobu Onuma, Carlos Collet, Erhan Tenekecioglu, Renu Virmani, Neal S. Kleiman, Patrick W. Serruys

Design and optical coherence tomography (OCT) appearance of first and next generation bioresorbable scaffolds (BRSs). [Powerpoint File]

Neutrophil Extracellular Traps in Atherosclerosis and Atherothrombosis

Neutrophil Extracellular Traps in Atherosclerosis and Atherothrombosis

Yvonne Döring, Oliver Soehnlein, Christian Weber

Emerging roles of neutrophil extracellular traps (NETs) in atherosclerosis and atherothrombosis. (A) Luminally netting neutrophils activate leukocytes, platelets, and endothelial cells creating a proinflammatory milieu presumably resulting in endothelial dysfunction, the initial trigger of lesion development. (B/C) Lesional NETs may initiate a interleukin-1β/TH17 (T helper 17) and type I interferon response, which leads to further activation of lesional leukocytes, releasing more proinflammatory mediators. (D/E) Furthermore, it may be assumed that NET-driven proinflammatory responses will cause an inflammatory environment that favors plaque destabilization and rupture. During atherothrombosis, NETs may trigger activation of the coagulation cascade and increase thrombus stability thus orchestrating arterial occlusion. [Powerpoint File]

Purinergic Signaling in the Cardiovascular System

Purinergic Signaling in the Cardiovascular System

Geoffrey Burnstock

Central vagal cardiocardiac reflex triggered by ATP.230 Illustration Credit: Ben Smith. [Powerpoint File]

Purinergic Signaling in the Cardiovascular System

Purinergic Signaling in the Cardiovascular System

Geoffrey Burnstock

Three P2 receptor subtypes, P2X1, P2Y1, and P2Y12, are involved in ADP-induced platelet activation. Clopidogrel is a P2Y12 receptor blocker that inhibits platelet aggregation and is in highly successful use for the treatment of thrombosis and stroke. A P2Y1 receptor antagonist, MRS 2500, inhibits shape change.234 Illustration Credit: Ben Smith. [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]

MicroRNAs for Restenosis and Thrombosis After Vascular Injury

MicroRNAs for Restenosis and Thrombosis After Vascular Injury

Clarice Gareri, Salvatore De Rosa, Ciro Indolfi

The cartoon represents the hypothetical structure of a vascular scaffold able to elute microRNAs (miRNAs). The scaffold (blue) is coated by poly-lactic-co-glycolic acid (PLGA) (green). At the bottom of the figure, the most promising miRNAs to be modulated for therapeutic use are listed. [Powerpoint File]

MicroRNAs for Restenosis and Thrombosis After Vascular Injury

MicroRNAs for Restenosis and Thrombosis After Vascular Injury

Clarice Gareri, Salvatore De Rosa, Ciro Indolfi

The figure illustrates specific vascular (upper section) or platelet-derived (lower section) microRNAs that can be measured in the flowing bloodstream. [Powerpoint File]

MicroRNAs for Restenosis and Thrombosis After Vascular Injury

MicroRNAs for Restenosis and Thrombosis After Vascular Injury

Clarice Gareri, Salvatore De Rosa, Ciro Indolfi

Schematic representation of the most relevant microRNAs (miRNAs) that modulate vascular smooth muscle cell (VSMCs) proliferation, with their direct molecular targets. The red area includes miRNAs that inhibit VSMCs proliferation (thus preventing ISR), whereas the green area indicates miRNAs that promote the synthetic phenotype of VSMCs. BMPR2 indicates bone morphogenetic protein receptor type II; Cdc-42, cell division control protein 42; FOXO4, Forkhead box protein O4; KLF-4, Kruppel-like factor 4; KLF-5, Kruppel-like factor 5; PTEN, phosphatase and tensin homolog; SMAD3, small mother against decapentaplegic; uPA, urokinase-type plasminogen activator; and WWP1, NEDD4-like E3 ubiquitin-protein ligase. [Powerpoint File]

MicroRNAs for Restenosis and Thrombosis After Vascular Injury

MicroRNAs for Restenosis and Thrombosis After Vascular Injury

Clarice Gareri, Salvatore De Rosa, Ciro Indolfi

Representative case of arterial restenosis, observed by means of intravascular optical coherence tomography (OCT). The picture shows a human artery with intimal hyperplasia 2 years after PCI with implantation of a coronary scaffold (struts-remnants indicated by yellow arrows). A thick neointimal layer is evident at the adluminal side of the struts-remnants (neointimal area included between the yellow dotted line and the green line). [Powerpoint File]

Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis

Endothelial Cell Dysfunction and the Pathobiology of Atherosclerosis

Michael A. Gimbrone Jr, Guillermo García-Cardeña

Endothelial-derived nitric oxide: production and biological actions. Endothelial cells rapidly produce nitric oxide (NO) via a unique isoform of NO synthase (eNOS) in response to agonists (eg, acetylcholine and bradykinin) and fluctuations in blood flow. Once generated, NO rapidly diffuses through the endothelial plasma membrane to activate guanylate cyclase in several cell types present in the blood (platelets and leukocytes) and also within the vessel wall (smooth muscle). Activation of guanylate cyclase in platelets results in inhibition of activation, adhesion, and aggregation; in leukocytes, decreased adhesivity; in smooth muscle cells, dephosphorylation of myosin light chain and vasorelaxation. NO also reacts with hemoglobin in erythrocytes, enhancing oxygen delivery to tissues. Chronic exposure of endothelial cells to laminar flow results in transcriptional upregulation of eNOS, thus increasing their NO-forming capacity (Illustration Credit: Ben Smith). [Powerpoint File]