Ferric chlorideinduced carotid artery thrombosis in GPVI-deficient mice. Identification and Characterization of Novel Matrix-Derived Bioactive Peptides: A Role for Collagenase from Santyl Ointment in Post-Debridement Wound Healing? In this respect, therefore, platelet adhesion to vascular wall structures, to one another (aggregation), or to other blood cells, represent different aspects of the same fundamental biological process. In either case, no platelets are seen tethered to the surface. The images are single frames from a real-time recording representing an area of 65 536 m2. use prohibited. In the wild-type control shown here, flow begins to decrease 6 minutes after application of FeCl3 to the artery, and a complete occlusion (no flow) is established during the subsequent 3 minutes, with no successive resumption of flow. Different pathways of platelet adhesion are variably affected by increasing shear force depending on the biomechanical properties of each receptorligand pair. 
This is true in particular for insoluble proteins that exist only in the extracellular matrix, such as collagen, or for proteins that may exist in a soluble form in plasma, such as fibronectin, but differ in their structure and conformation when they assemble into complex matrices.24,25. In the absence of soluble VWF, single platelets adhere when the shear rate is 3000 sec1 (upper left), and fewer single platelets adhere at 24 000 sec1 (upper right). On a surface in which collagen and VWF form a functional unit, initial platelet tethering is mediated primarily by GPIb binding to VWF-A1 under high-flow conditions, otherwise by GPVI binding to collagen, specifically to the prototypic repeating sequence Gly-Pro-Hyp (where Hyp is hydroxyproline) typical of the fibril-forming collagens. Arterial flow is normal at the end of the observation period in the GPVI/ mouse (no occlusion). The fact that GPVI is not sufficient for adhesion to this substrate attests to the conformational disruption of its recognition site in partially degraded collagen. This response initiates thrombus formation that arrests hemorrhage and permits wound healing. Ongoing studies appear to confirm this hypothesis. Varying effects of tyrosine kinase inhibitors on platelet functionA need for individualized CML treatment to minimize the risk for hemostatic and thrombotic complications? Consequently, the interaction of circulating VWF with exposed vascular and perivascular tissues is a key early event in thrombus formation. Role of GPIb in platelet aggregation during thrombus growth. Can pretreatment platelet-to-lymphocyte and neutrophil-to-lymphocyte ratios predict long-term oncologic outcomes after preoperative chemoradiation followed by surgery for locally advanced rectal cancer? -lactic acid) nanosheets, Early Aging of Endothelial Function and PlateletVessel Wall Interactions, On-chip recalcification of citrated whole blood using a microfluidic herringbone mixer, Galectins in the Regulation of Platelet Biology, Anti-thrombotic effect of rutin isolated from Dendropanax morbifera Leveille, Roll, adhere, spread and contract: Structural mechanics of platelet function, Programmable 3D silk bone marrow niche for platelet generation ex vivo and modeling of megakaryopoiesis pathologies, Platelets in leucocyte recruitment and function, Force-induced on-rate switching and modulation by mutations in gain-of-function von Willebrand diseases, Platelet adhesion to podoplanin under flow is mediated by the receptor CLEC-2 and stabilised by Src/Syk-dependent platelet signalling, The sGC stimulator riociguat inhibits platelet function in washed platelets but not in whole blood, Deposition of fibrinogen on the surface of in vitro thrombi prevents platelet adhesion, Crosslinking decreases the hemocompatibility of decellularized, porcine small intestinal submucosa, Biomaterials-Based Strategies in Blood Substitutes, Loss of oligophrenin1 leads to uncontrolled Rho activation and increased thrombus formation in mice, Interaction of von Willebrand factor with platelets and the vessel wall, The functional role of platelets in the regulation of angiogenesis, New Approaches to Inhibiting Platelets and Coagulation, Platelet Glycoprotein Ib-IX as a Regulator of Systemic Inflammation, Atorvastatin Reduces the Proadhesive and Prothrombotic Endothelial Cell Phenotype Induced by Cocaine and Plasma From Cocaine Consumers In Vitro, Pre-activated blood platelets and a pro-thrombotic phenotype in APP23 mice modeling Alzheimer's disease, A factor VIII-derived peptide enables von Willebrand factor (VWF)-binding of artificial platelet nanoconstructs without interfering with VWF-adhesion of natural platelets, Baicalein inhibits agonist- and tumor cell-induced platelet aggregation while suppressing pulmonary tumor metastasis via cAMP-mediated VASP phosphorylation along with impaired MAPKs and PI3K-Akt activation, Engineered nanoparticles: thrombotic events in cancer, A comparative analysis of the bistability switch for platelet aggregation by logic ODE based dynamical modeling, Geometric design of microfluidic chambers: platelet adhesion versus accumulation, Potential value of targeting von Willebrand factor in atherosclerotic cardiovascular disease, Structural Basis of Regulation of von Willebrand Factor Binding to Glycoprotein Ib, The Relative Role of Soluble Guanylyl Cylase Dependent and Independent Pathways in Nitric Oxide Inhibition of Platelet Aggregation Under Flow, Platelet Dynamics in Three-Dimensional Simulation of Whole Blood, Platelet function inhibitors and platelet function testing in neurointerventional procedures: Table1, The potential role of anticoagulant therapy for the secondary prevention of ischemic events post-acute coronary syndrome, Matrix metalloproteinase-2 of human carotid atherosclerotic plaques promotes platelet activation, Organs on microfluidic chips: A mini review, Elevated Platelets Enhance Cancer Cell Migration, Promote Hematogenous Metastasis and Associate with a Poor Prognosis in Advanced Non-small Cell Lung Cancer Cases, Precise patterning of the SEBS surface by UV lithography to evaluate the platelet function through single platelet adhesion, von Willebrand factor, Jedi knight of the bloodstream, Platelet glycoprotein Ib ectodomain shedding and non-surgical bleeding in heart failure patients supported by continuous-flow left ventricular assist devices, The effects of PEG-based surface modification of PDMS microchannels on long-term hemocompatibility, Heteromultivalent ligand-decoration for actively targeted nanomedicine, Class I PI 3-kinases signaling in platelet activation and thrombosis: PDK1/Akt/GSK3 axis and impact of PTEN and SHIP1, Suppression of Aggrus/podoplanininduced platelet aggregation and pulmonary metastasis by a singlechain antibody variable region fragment, Highly reinforced structure of a C-terminal dimerization domain in von Willebrand factor, Identification of platelet function defects by multi-parameter assessment of thrombus formation, Role for Platelet Glycoprotein Ib-IX and Effects of its Inhibition in Endotoxemia-Induced Thrombosis, Thrombocytopenia, and Mortality, Phosphorylation of CalDAG-GEFI by protein kinase A prevents Rap1b activation, Platelets: bridging hemostasis, inflammation, and immunity, Tumor vascular disrupting agent 5,6-dimethylxanthenone-4-acetic acid inhibits platelet activation and thrombosis via inhibition of thromboxane A Leucocyte/endothelium interactions and microvessel permeability: coupled or uncoupled? Role of GPIb in platelet aggregation during thrombus growth. Among the substrates required for normal thrombus formation, VWF is unique for its role in initiating platelet adhesion and sustaining platelet aggregation under conditions of elevated shear stress.16,18 These functions are performed primarily through the tethering of GPIb in the platelet membrane GPIb-IX-V receptor complex26 to the A1 domain of immobilized VWF exposed to flowing blood. After a total perfusion time of 840 seconds, thrombus height was measured by confocal sections, as shown in the stacks in B. The flow rate was decreased such that the calculated shear rate was 300 sec1 at the collagen-coated surface but >1000 sec1 at the surface of thrombi with a height >20 m. Local Info It is of interest to note that no exception is known to the required participation of GPIb in the formation of occluding arterial thrombi.17Download figureDownload PowerPointFigure 5. The integrin IIb3, on the other hand, binds several ligands, in addition to VWF, that are key to the process of platelet adhesion and aggregation, primarily fibrinogen,64 fibronectin,65 and CD40 ligand.66. Modified from Ruggeri ZM et al130 and reprinted with permission. integrin-dependent adhesion to collagen, Bioinspired artificial platelets: past, present and future, Functional analysis and expression profile of human platelets infected by EBV in vitro, Flow driven vesicle unbinding under mechanosensitive adhesion, FluidFM-Based Fabrication of Nanopatterns: Promising Surfaces for Platelet Storage Application, Nano-Precision Tweezers for Mechanosensitive Proteins and Beyond, Method article: an Unauthorized B, Bar graph representation of the time to first occlusion, occurrence of embolization, and presence or absence of occlusion at the end of the observation period in 26 GPVI/ mice. 2 We gratefully acknowledge the many contributions that all of the colleagues in the laboratory of Z.M.R. It is important to note that the threshold discussed here is not a minimum shear rate value to engage the function of immobilized VWF-A1, which can mediate platelet tethering even under venous slow flow conditions18; rather, it is an upper limit for the function of most other platelet adhesive bonds in the absence of VWF. Adhesion to thrombospondin-1, however, has been proven to be independent of VWF albeit mediated by GPIb with a minor contribution by GPIV (CD36) only when platelets were activated. Studies with a specific antibody fragment,50 a nanobody, support the concept of a common active conformation in the VWF A1 domain of surface-bound multimers, soluble ultralarge multimers released by endothelial cells, and mutant type 2B plasma VWF, in contrast to the inactive conformation of normal plasma VWF. Platelets in HIV: A Guardian of Host Defence or Transient Reservoir of the Virus? This site uses cookies. We also discuss some key aspects of platelet adhesive functions that are relevant to inflammation, atherogenesis, and host defense mechanisms (see the online data supplement, available at http://circres.ahajournals.org). Collagen and VWF are represented by electron micrographs (not in scale). Adapted from Konstantinides et al17 and reprinted with permission. The extracellular matrix components that react with platelets include different types of collagen, VWF, fibronectin,19 and other adhesive proteins such as laminin,20 fibulin,21 and thrombospondin.22 Fibrinogen/fibrin18 and vitronectin23 are not synthesized by vascular wall cells but must be considered as potentially relevant thrombogenic substrates because they become immobilized onto extracellular matrix at sites of injury. 3 Platelet Integrins in Tumor Metastasis: Do They Represent a Therapeutic Target? This is best illustrated by the distinct consequences of blocking one of the platelet collagen receptors, the integrin 21, which impairs thrombus formation on spiral microfibrils but not on banded collagen fibers.74 In contrast, blocking the other receptor, GPVI, impairs thrombus formation on all types of collagen fibers.77,78 In fact, there appears to be a requirement for GPVI and 21 cooperation only when collagen fibers, and presumably their triple helical configuration, are not intact (Figure 4).74,77 As collagen is an insoluble matrix protein, preparations used in ex vivo experimental studies are often treated with proteases, such as pepsin, for solubilization, with the consequence of a functional behavior distinct from that of the native protein. Dallas, TX 75231 In agreement with other experimental findings, these results confirm that the pathways of platelet adhesion/stimulation in injured arteries, likely to influence the severity of thrombotic complications, are determined by the nature of the vascular lesion and of the substrates exposed to blood, including those leading to -thrombin generation. Figure 5. The platelet membrane is endowed with several collagen receptors, including the integrin 21,7981 GPVI,82,83 GPIV (CD-36),8486 and the 65-kDa protein (p65) reportedly specific for type I collagen.87 GPIV, which may be required for the interaction with collagen type V88 and is associated with Src kinases,89 is unlikely to make a major contribution to platelet activation because it is absent in approximately 5% of the Japanese population without hemostatic impairment. Thus, the fluid dynamic constraints that influence the adhesion of single platelets to the vessel wall affect also the recruitment of circulating platelets into a growing thrombus, as demonstrated by the required function of GPIb and VWF-A1 to support platelet aggregation above a threshold shear rate (Figure 1). The integrin 21 corresponds to the platelet membrane GPIa-IIa, originally identified as the very-late-activation antigen-2 on T cells91 and class II extracellular matrix receptor on fibroblasts.80 The expression of 21 on normal platelets varies by as much as 1 order of magnitude,92 and may positively correlate to the rapidity of the initial phase of platelet adhesion to collagen.93 Several collagen sequences have been identified as targets for 21 binding,36 and the most relevant appears to be Gly-Phe-Hyp-Gly-Glu-Arg (where Hyp is hydroxyproline), which has been crystallized in complex with the receptor.94 Like other integrins, 21 requires activation and divalent cations to engage its ligands with high affinity, and although this may be a requisite for signaling (see the online data supplement), it may not be necessary for the initial contact. Platelets also contain and secrete on activation laminins 8 and 10, as well as laminin 11 (521).123 It has been reported that platelets can adhere to laminin but are not directly activated following the interaction.123 Other investigators, however, found that human laminin stimulates formation of filopodia and lamellipodia in human and mouse platelets through an adhesion/activation pathway that involves the integrin 61, a well-known laminin receptor, and GPVI. Detailed studies by many investigators over the past several years have been aimed to dissect the complexity of these functions, and the results obtained now permit an attempt to integrate all the available information into a picture that highlights the balanced diversity and synergy of distinct platelet adhesive interactions. Following the initial events that lead to adhesion and activation at sites of vascular injury, platelets bind soluble adhesive proteins and form a reactive surface for continuing platelet deposition. + Fibrinogen Replacement Therapy for Traumatic Coagulopathy: Does the Fibrinogen Source Matter? As a consequence, the relative contribution of several adhesive interactions to the process of platelet adhesion to vascular surfaces remains to be elucidated in detail. After adding soluble VWF (20 g/mL), single platelets adhere at 3000 sec1 (lower left; an arrow points to a single platelet shown for reference), but aggregates form at 24 000 sec1 (lower right; arrows point to a rolling aggregate and an inset highlights a stretched aggregate during stationary adhesion). In the wild-type control shown here, flow begins to decrease 6 minutes after application of FeCl3 to the artery, and a complete occlusion (no flow) is established during the subsequent 3 minutes, with no successive resumption of flow. In particular, the GPIb-IX-V complex is a counter receptor for P-selectin62 and for the leukocyte integrin Mac-1 (2M),63 supporting 2 interactions that may contribute more to inflammatory responses4 than to platelet thrombus formation. In the absence of soluble VWF, single platelets adhere when the shear rate is 3000 sec1 (upper left), and fewer single platelets adhere at 24 000 sec1 (upper right). 1-800-242-8721 It remains to be determined whether such a conformation is dynamically transient or reflects one of the known crystallized structures.48,51,52 A particularly relevant active form of soluble VWF is represented by the ultralarge multimers43 released from the storage granules of stimulated endothelial cells and platelets.53,54 Ultralarge VWF multimers function locally, but under normal conditions, they do not accumulate in circulating blood55 because they are processed by a specific protease, ADAMTS-1356 (see the online data supplement). In this regard, it is noteworthy that the congenital deficiency of either 2181,98 or GPVI82 in humans results in a mild bleeding diathesis. Streptococcus gordonii In the GPVI/ mouse, in contrast, flow reduction begins between 8 and 9 minutes after FeCl3 application to the artery, and a complete obstruction develops over the next 1 to 2 minutes. Pathological conditions that cause vascular alterations and blood flow disturbances may turn this beneficial process into a disease mechanism that results in arterial occlusion, most frequently in atherosclerotic vessels of the heart and brain. Collagen and VWF are represented by electron micrographs (not in scale). Significant progress in genomics and proteomics has generated information relevant to elucidating the integrated processes that link plateletsubstrate interactions and signaling pathways to thrombus growth and stability. 3 The GPIb-mediated translocation velocity onto immobilized VWF is typically less than 2% of the free flow velocity of noninteracting platelets at the same distance from the luminal surface. Download figureDownload PowerPointFigure 2. The contrasting conclusions on the role of 21 in experimental arterial thrombosis cannot be reconciled at present with an objective explanation but likely reflect differences in the nature of the vascular lesion, including severity of the endothelial damage and exposure of extracellular matrix components. Thrombus development alters the hemodynamic conditions by restricting the lumen through which blood flows. As a constitutive component of the extracellular matrix of endothelial cells,27 in which it is associated with collagen type VI filaments,2830 subendothelial VWF can directly support platelet adhesion.3135 Nonetheless, hemostasis can be normal in the absence of endogenous endothelial VWF if plasma VWF is present (see the online data supplement). In the GPVI/ mouse, in contrast, flow reduction begins between 8 and 9 minutes after FeCl3 application to the artery, and a complete obstruction develops over the next 1 to 2 minutes. Perhaps the most relevant distinction is that GPIb-mediated, long-lasting adhesion and aggregation only occurs above a threshold shear rate of 10 000 sec1, a feature that highlights its potential importance for pathological arterial thrombosis. Arterial flow is normal at the end of the observation period in the GPVI/ mouse (no occlusion). extracellular vesicles-treated platelet adhesion on a blood vessel chip, Downregulated Platelet miR-1233-5p in Patients with Alzheimers Pathologic Change with Mild Cognitive Impairment is Associated with A-Induced Platelet Activation via P-Selectin, Platelets Role in Dentistry: From Oral Pathology to Regenerative Potential, Mechanobiology of Platelets: Techniques to Study the Role of Fluid Flow and Platelet Retraction Forces at the Micro- and Nano-Scale, Biomaterials-Mediated Tumor Infarction Therapy, Standardization and Validation of Fluorescence-Based Quantitative Assay to Study Human Platelet Adhesion to Extracellular-Matrix in a 384-Well Plate, Standard vs. leave extracts, Collagen scaffolds functionalized with triple-helical peptides support 3D HUVEC culture, Circulating tumor cells in cancer patients: developments and clinical applications for immunotherapy, Endothelial Dysfunction in Cardiovascular Diseases. 
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