morphology of mature platelet

Finally, it is possible that even low-affinity fibrinogen interactions with integrin αIIbβ3 are sufficient to initiate integrin interactions with the cytoskeleton such that actin-myosin-induced contraction provides the energy required for the conformational changes needed to achieve higher affinity binding.250, Fibrinogen and/or fibrin have been identified on the surface of damaged blood vessels; thus it is possible that integrin αIIbβ3 mediates platelet adhesion under those circumstances.939 In contrast, integrin αIIbβ3 on resting platelets does not appear to be able to mediate adhesion to VWF or fibronectin940; if platelets are activated, however, integrin αIIbβ3 can support adhesion to these glycoproteins.930 In models of platelet accumulation under flowing conditions, αIIbβ3 acts in synergy with GPIb/IX, VWF, and fibrinogen at the apex of thrombi, where shear forces are greatest.28,941,942 The integrin αIIbβ3 has also been implicated in platelet spreading after adhesion,227,228,943 and it is necessary for clot retraction (see above) and the uptake of plasma fibrinogen into platelet α granules.818,944, Less-well-defined roles for integrin αIIbβ3 have been suggested in the binding of plasminogen,688 calcium transport across the platelet membrane,945,946,947 IgE binding to platelets leading to parasite cytotoxicity,948 and interactions with the Borrelia species spirochetes that cause Lyme disease949 and hantavirus.950 Integrin αIIbβ3 also mediates factor XIIIa binding to platelets, but this is primarily as a result of factor XIII’s association with fibrinogen.456 Factor XIIIa and calpain have also been implicated in limiting platelet–platelet interactions after activation by adhesion to collagen.951, Integrin α2β1 (GPIa/IIa) is widely distributed on different cell types and can mediate adhesion to collagen.19,20,952,953,954,955,956,957 The integrin α2 subunit (GPIa) contains a region of 220 amino acids inserted in the aminoterminal β-propeller region (I domain) that is homologous to similar regions in other proteins that are known to interact with collagen, including VWF and cartilage matrix protein.958 This region has a MIDAS and crystallographic data of the α2 I domain in complex with a CRP containing the type I collagen sequence GFOGER (where O indicates hydroxyproline) demonstrated that the glutamic acid in the peptide coordinates Mg2+ binding in the MIDAS.959,960,961 The integrin α2β1 I domain can assume a variety of conformations, going from inactive (closed), through intermediate or low affinity, to active high affinity.952,962, Both integrin α2β1 and GPVI appear to participate in platelet interactions with collagen.963,964,965 Bleeding defects have been described in patients with decreased levels of integrin α2β1 and GPVI, but the precise contributions of the decreases in these receptors is uncertain (Chap. Platelets have been reported to contain at least 11 Rabs, although only a few have been shown to be functionally relevant. The narrowest constrictions observed were about 0.2 micrometer in diameter and several microns in length. Thick bundles of microtubules fill the shafts and cortex of broad pseudopodia that are subsequently extended by the megakaryocyte. Plasmin can cause redistribution and/or cleavage of platelet glycoprotein Ib. The platelets lose their discoid shape and become spiny spheres with long extensions, variably referred to as filopodia or pseudopodia. Thus, both involve the self-assembly of elongated spectrin strands that interconnect through their binding to actin filaments, generating triangular pores. The approximately 1 trillion platelets that circulate in an adult human are small anucleate cell fragments adapted to adhere to damaged blood vessels, to aggregate with one another, and to facilitate the generation of thrombin. MVBs contained the secretory proteins von Willebrand factor (vWF) and β-thromboglobulin (β-TG), the platelet-specific membrane protein P-selectin, and the lysosomal membrane protein CD63. The integrin αIIbβ3 receptors in α granules appear to cycle to and from the plasma membrane.817 This recycling helps to explain the ability of the integrin to take up fibrinogen from plasma and transport it to α granules, where it is concentrated.375,818. Second, tropomodulins are not present at suffic. Large platelet masses are generally found on the feathered edge of push preparations (Fig. mediated by the major membrane glycoprotein IIbIIIa (Coller et al. The ligated integrins may then cluster (not shown). depression. Platelets contain approximately 2,000 spectrin molecules (Hartwig and, OCS and plasma membrane systems. Unlike erythrocytes whi. Components include the exterior coat (E.C. Forty perc, the actin subunits assemble to form the 2,000–5,000 linear filaments p, maintained in storage as a 1-to-1 complex with, filaments during platelet activation to drive cell spreading (Safer and, various points into a stiff cytoplasmic network, as platelets expre, concentrations of actin crosslinking proteins including filamin and, Filamin subunits are elongated strands composed primarily of 24 repe, ~100 amino acids in length that are folded into IgG-like, filamin genes on chromosomes 3, 7, and X. Filamin A (on X) and filamin B (on 3), are expressed in platelets with filamin A present at greater, filamin B. Filamin is recognized to be a prototypical scaffolding prot. Deficiencies of this enzymatic activity have been identified in the cerebrorenal Zellweger syndrome, and the platelet activity can be used to diagnose the disorder.195,196, Mitochondria Platelets contain approximately four to seven mitochondria of relatively small size, often located near the plasma membrane; they are involved in oxidative energy metabolism.197,198,199 Control of mitochondrial Bcl-2 family proteins, including Bcl-x1 and Bak, directly affects a platelet’s life span and alterations in these proteins can produce thrombocytopenia (Chaps. The anucleate nature of platelets also enables the effect of mtDNA variation to be determined without interference from the nuclear genome, ... Platelets are released from megakaryocyte cells in the bone marrow and lungs, with size of 2-4 mm in diameter, lifespan of 7-10 days, and normal count of about 150-450  10 3 /ml in the human bloodstream, requiring a continuous platelet clearance and production of 100 billion platelets (70 million/min) daily to maintain a physiological platelet concentration. isolated from the hemipteran Oncopeltus varicolor were monitored by light and electron microscopy. There are subtle differences in the binding of each of these ligands, however, with regard to divalent cation preference and competent activating agents. Blood morphology adds greatly to the value of a routine blood count. 112–11). Double immunofluorescence microscopy of resting platelets using antibodies against vascular endothelial growth factor (VEGF) (A) and endostatin (B) and an overlay (C). These nucleation sites are generated de novo by the activation of the Arp2/3 complex or by the exposure of the barbed ends of preexisting filaments.217 Because barbed ends have a higher affinity for actin molecules than do the actin sequestering proteins, they have the capacity to initiate actin filament polymerization. is seen as a continuous band beneath the plasma membrane on the equatorial section and as small open cylinders at the ends of the platelet on the cross-section. Blood, Bluteau D, Lordier L, Di Stefano A, Chang Y, Raslova H, Debili N, Vainchenker W (2009) R, of megakaryocyte maturation and platelet formation. Microtubules located adjacent to the inside wall layer of the ascospore initials appeared to contribute to an elliptical shape. Inhibition of platelet aggregation by the depletion of plasma fibrinogen, if severe, and generation of fibrin (ogen) degradation products. 121).318 The LYST gene product may associate with the AP3 complex.305, The abnormalities of in vitro platelet function in patients with HPS suggest that released dense granule contents contribute to platelet activation through a positive feedback mechanism. Platelets also express Mer, a tyrosine kinase receptor for Gas6, and mice deficient in Mer demonstrate both abnormalities in platelet aggregation and protection from thrombosis, but not to the same extent as mice deficient in Gas6.413,414 Other Gas6 receptors in the same family as Mer also appear to contribute to platelet thrombus stability.413,414,415,416,417, Platelet-derived growth factor (PDGF) is a disulfide-linked dimeric molecule of approximately Mr 30,000 that is mitogenic for smooth muscle cells.418 Platelet α granules contain a mixture of the homodimer PDGF-BB (30 percent) and the heterodimer PDGF-AB (70 percent); the different forms appear to have different functional activities.419 PDGF may play a role in normal cell proliferation, as well as in the development of atherosclerosis, tumor growth, wound repair, and fibroproliferative responses.420,421,422 After it was discovered in platelets and termed PDGF, other tissues were found to produce the same factor; thus, despite its name, PDGF is not exclusively derived from platelets. Proplatelet formation begins when these. However, data from mice suggest a minor role for platelet thrombospondin in either TGF-β1 packaging or activation.481,482,483 Only a very small percentage of the TGF-β1 released from platelets with thrombin stimulation becomes activated, but this amount is sufficient to activate synthesis of PAI-1.479,481,482,484 Based on animals models, TGF-β1 released from platelets has been implicated in promoting tumor metastases and cardiac fibrosis in response to constriction of the aorta or aortic valve stenosis.485,486,487 Active TGF-β can bind to three different cell surface proteins, a proteoglycan (β-glycan), and two serine/threonine kinases.471,485,486,487,488, Platelets may also release proteins that affect the uptake of oxidized low-density lipoproteins by macrophages, furnishing another potential link between platelet activation and atherosclerosis.489, In addition to the contents of α granules, activated platelets release both microparticles (see “Platelet Coagulant Activity” below), which are derived from the plasma membrane, and exosomes, which are internal membrane MVBs.490 Exosomes are smaller than microparticles (40 to 100 nm vs. 100 to 1000 nm), enriched in CD63 and tetraspanins (see section “Platelet Membrane Glycoproteins” below), and relatively deficient in membrane proteins such as GPIb/IX and platelet-endothelial cell adhesion molecule (PECAM)-1. While MAC provides short-term (days to weeks) support and long-term (months to years) for the heart and/or lungs, the blood is inevitably exposed to non-physiological shear stress (NPSS) due to mechanical pumping action and in contact with artificial surfaces. Moreover, tropomodulins, which are abundant in erythrocytes, are not expressed at significant levels in platelets and thus are unlikely to play a role in capping the pointed ends of actin filaments. (Adapted with permission from Michelson A: Platelets. Studies examining the internalization. To assess the individual contributions of the platelet glycoprotein (GP) IIb/IIIa receptor and the alpha v beta 3 vitronectin receptor to platelet levels of fibrinogen and vitronectin, we analyzed the platelets from two groups of Glanzmann thrombasthenic patients: Iraqi- Jews, whose platelets lack both receptors, and Arab patients in Israel, whose platelets lack GPIIb/IIIa, but have normal or increased numbers of alpha v beta 3 vitronectin receptors. tion proposed by our lab predicts that megakaryocytes will releas, sinusoidal blood vessels where they undergo successive rounds of abscission along, their midbody and at their ends to produce smaller barbell-shaped proplatelets and, furrow at the point of division and results in platelet release from the proplatelet, ends at an increasing rate in time as more ends become available, abscission event. Start studying CAP 2018 Assessment: Platelet Testing, Morphology, and Disorders. Integrin αIIbβ3 ectodomain chain separation, headpiece extension, and integrin β3 swing out then follow, either spontaneously or as a result of the traction force generated by the cytoskeleton on integrin β3 through talin.149 Outside-in signaling is presumed to be initiated by loss of ectodomain interactions between the membrane-proximal regions of integrins αIIb and β3, perhaps as a result of ligand binding producing even greater integrin β3 swing out, resulting in disruption of the outer membrane clasp and subsequent dissociation of the transmembrane helices. (Adapted with permission from Varga-Szabo D, Braun A, Nieswandt B: Calcium signaling in platelets. Philadelphia, PA: Williams & Wilkins; 2001. Platelets can synthesize and release PAF, which can activate leukocyte αMβ2. Platelet clumping is usually a collection artifact that can produce a false decrease in platelet count. Glycoprotein (GP) Ib binding to VWF plays a prominent role, but integrin α2β1 (GPIa/IIa) and GPVI binding to collagen and other platelet receptors (see Table 112–4) probably also play a role. develop into burst- and colony-forming precursors, both of which, antigen, and which continue to mature along an increasingly restricted lineage. A. Endothelial cells limit platelet deposition because they separate platelets from the adhesive proteins in the subendothelial area, produce two inhibitors of platelet function (nitric oxide [NO] and prostacyclin [PGI2]), and contain a potent enzyme (CD39) that can digest adenosine diphosphate (ADP) released from platelets. Tubulin an, network, and an expansive and interconnected membranous network of cisternae and, reorganization remains largely unknown, the invaginated membra, thought to supply membrane during proplatelet fo. 112–8 illustrate several features of the human platelet transcriptome: (1) estimates of expressed protein-coding genes are more similar amongst different subjects for high abundance genes (leftwards in Fig. Arterioscler Thromb Vasc, Folkman J, Browder T, Palmblad J (2001) Angiogenesis research: guidelines for translation to, clinical application. Nitric oxide, which is synthesized by endothelial cells, is a potent inhibitor of ex vivo platelet adhesion and aggregation. This is the first description of an in vitro culture system that sequentially demonstrates megakaryocyte growth, development, and platelet production. Intravital microscopy and ex vivo flow chamber studies indicate that discoid platelets that show minimal or no evidence of activation can form the initial layers of platelet aggregates when laminar flow is disrupted by a stenotic lesion, but that stable thrombus development requires the generation and/or release of soluble activators.6 Membrane tethers, which can undergo restructuring and stabilization, are important in achieving interactions with matrix proteins and other platelets. Thrombospondin, a plasminogen-binding protein, is expressed on the surface of platelets after activation. (Used with permission of Matt Hazard, Teaching and Academic Support Center, The University of Kentucky. 126); (3) activation of factor XI by thrombin on the platelet surface,676,677 with the dimeric structure of factor XI allowing it to interact both with the platelet and factor IX simultaneously678; (4) a factor XI-like protein associated with platelet membranes, which may be an alternatively spliced form of factor XI lacking exon V; the level of this factor appears to correlate better with hemorrhagic symptoms than does the level of plasma factor XI399,679; (5) the presence of cytoplasmic factor XIII (Chap. Microtubule bundles in the proplatelet shaft serve, as tracks along which these granules move individually (Blair and Flaumenhaft, culminating at the proplatelet tips where the cargo becomes, series of events occurs as megakaryocytes transition from immature cells (. Components include the open canalicular and dense. An elaborate intracellular program of, nuclear amplification and protein production in maturing megakaryocytes precedes the mechanical, extension of proplatelet elongations into the sinusoidal blood vessels of the bone marrow. Nevertheless, proplatelets have been identified both in vitro and in vivo (Leven. Platelet dense granules contain polyphosphate, a linear polymer of inorganic phosphate synthesized by inositol hexakisphosphate 6 kinase. The MVBs were prominent in cultured megakaryocytes and the megakaryoblastic cell line CHRF-288, but were less numerous in bone marrow megakaryocytes and platelets, whereas α-granules were most prominent in mature bone marrow megakaryocytes and in platelets. These structural differences reflect the different signals initiated by the adhesion process, and both PIs and the small GTPase molecules Rac and Cdc42 appear to be particularly important in this process.154 In platelets, Rac is activated by thrombin receptor ligation and it stimulates actin filament uncapping.230 Proteins that have been implicated in organizing the tips of the filopodia where the actin bundles attach to the plasma membrane are the small GTPase Cdc42, the exchange protein WASP, vinculin, vasodilator-stimulated protein (VASP), zyxin, and profilin.111 Pleckstrin, a platelet protein that is phosphorylated during platelet activation, appears to participate in this process by binding to PIs and affecting Rac via an exchange factor.231,232 Platelets from mice deficient in pleckstrin have a defect in granule secretion, integrin αIIbβ3 activation, and aggregation mediated by protein kinase C. Thrombin can overcome this abnormality via a pathway involving PI3K.233 Signaling after adhesion results from the assembly of protein complexes on the cytoplasmic surfaces of the receptor(s) involved in the adhesion process, including focal adhesion kinase (FAK), which is activated by integrin ligation and colocalizes with a number of cytoskeletal proteins. Tubulin. Italiano JE Jr, Bergmeier W, Tiwari S, Falet H, Hartwig JH, Hoffmeister KM, Andre P, Wagner, DD, Shivdasani RA (2003) Mechanisms and implications of platelet discoid shape. 112–2).95,212 In the aggregometer, it has been generally assumed that the initial decrease in light transmission immediately after adding certain agonists is a reflection of platelets undergoing shape change,213 but this interpretation has been challenged by the suggestion that microaggregation rather than shape change accounts for this phenomenon.214 Although the reason platelets undergo shape change is unclear, one possibility is that it reduces electrostatic repulsion between two negatively charged platelets or between a platelet and a negatively charged surface or cell without the need to reduce surface charge density. EMBO J 28(9):1351–1361, 2009. We studied neutrophil interactions with activated, surface-adherent platelets as a model for leukocyte binding in vascular shear flow and emigration at thrombogenic sites. 112–9. In turn, thrombopoietin induces both increased megakaryocyte production and megakaryocyte expression of TGF-β receptors. Further evidence for a beta 2-integrin-dependent neutrophil/platelet interaction is demonstrated by the complete inhibition of interleukin (IL)-8-induced neutrophil transmigration across platelets bound to fibronectin-coated polycarbonate filters by mAbs to Mac-1. α Granules are the most abundant granule type of platelets, numbering approximately 50 to 80 per platelet.323,324 They are approximately 200 nm in diameter on cross-section and demonstrate internal variation in electron density, often with an eccentric area of accentuated electron density, termed a nucleoid, in which β-thromboglobulin, platelet factor 4 (PF4), and proteoglycans are concentrated (see Fig. Fibroblasts ?Endothelial cells Megakaryocytes Monocytes, etc. Ultimately, the vessel either becomes fully occluded or loses its thrombogenic reactivity; that is, it becomes passivated. The platelet expresses many receptors that participate in adhesive interactions (Table 112–1). TGF-β1 released from platelets can stimulate smooth muscle cells to express and release VEGF, thus perhaps supporting reendothelialization after vascular injury.473, TGF-β1 released from platelets is inactive (latent) because it is complexed with the remaining portion of its precursor protein (latency-associated peptide [LAP]).474 LAP, in turn, is covalently coupled to another protein, the latent TGF-β–binding protein-1 (LTBP-1), which localizes the complex to the extracellular matrix.475 Activation of latent TGF-β1 is a complex process that is thought to involve a conformational change in LAP that results in altering its ability to shield the active site in TGF-β1.475 Activation of latent TGF-β1 can be achieved by several different mechanisms, including acidification; proteolysis by plasmin, a furin-like enzyme, or other enzymes; traction produced by LTBP-1 binding to extracellular matrix and LAP interaction with integrin αVβ6 or αVβ8; interaction with thrombospondin-1 or a small peptide derived from thrombospondin-1; or exposure to stirring or shear.475,476,477,478,479 The interaction of LAP with integrin receptors via its RGD sequence probably plays a dominant role as mice with a mutation in this sequence have a phenotype like that of TGF-β1 null mice.480 The ability of thrombospondin-1 to activate TGF-β1 is of special interest because both TGF-β1 and thrombospondin-1 are present in α granules. Integrin receptors mediate interactions between cells and proteins or proteins on cells; they are also involved in protein trafficking in cells. A complex system of four laminated oval discs (rhizanchora), microtubule rootlets and fibrous material anchor the flagellar apparatus and rhizoplasts to the plasma membrane and theca. How immature platelets give origin to mature ones is not understood but it has been shown that ex-vivo generated murine megakaryocytes infused into mice ��� After platelets adhere, they undergo an activation process that leads to a conformational change in integrin αIIbβ3 receptors involving headpiece extension and leg separation (see Fig. Once assembly is complete, capZ recaps the barbed filament ends. Platelets contain approximately 2000 molecules of spectrin.133,134,135,136 The spectrin network coats the cytoplasmic surfaces of both the plasma membrane and the open canalicular system. To accomplish these tasks, platelets have surface receptors that can bind adhesive glycoproteins; these include the GPIb/IX/V complex, which supports platelet adhesion by binding von Willebrand factor, especially under conditions of high shear, and the αIIbβ3 (GPIIb/IIIa) receptor, which is platelet-specific and mediates platelet aggregation by binding fibrinogen and/or von Willebrand factor. J Cell Sci 97(Pt 1):59–70. Second, because a large fraction of filamin is also bound to actin, it aligns the GPIb-IX-V complexes into rows on the plasma membrane surface of the platelet over the underlying actin filaments. © 2008-2021 ResearchGate GmbH. Platelets contain 5 μM each of gelsolin219 and capZ,220 and 3 mM of adducin.221 Uncapping of the actin filaments appears to be accomplished by the inactivation of capping proteins by phosphoinositides that are produced during platelet activation, including PI-3,4-bisphosphate (PI3,4P2), PI4,5P2, and PI3,4,5P3.216 The uncapped actin filaments act as nuclei onto which actin monomers (which are maintained in an available pool by association with thymosin-β4) can assemble on the barbed ends of the filaments. Even though the cells did not have the classical morphology of mature platelet-forming megakaryocytes, 90% of the cells within a cell line were positive by direct or indirect immunofluorescence for the platelet membrane glycoproteins IIb and IIIa; for surface markers HLA-Dr and B2-microglobulin; for intracellular platelet-derived growth factor and platelet factor IV; and for membrane affinity or binding with serum platelet-derived growth factor and platelet ��� No unbiased GWAS has been performed using documented arterial thrombosis as the clinical phenotype, but many have been performed with coronary artery disease (CAD). Initially, wall materials and (or) precursors were deposited between the closely spaced double membranes from within the ascospore initials. The three major cytoskeletal elements are the spectrin membrane skeleton, the marginal microtubule coil, and the actin cytoskeleton. ), trilaminar unit membrane (CM), and submembrane area containing the specialized filaments of the membrane skeleton (SMF). membrane skeleton; an actin-based cytoskeletal network; microtubules; and numerous organelles including. Many mechanisms of platelet–leukocyte interactions have been defined, but the initial interaction appears to be mediated primarily by the interaction between P-selectin (CD62P) expressed on the surface of activated platelets and PSGL-1 on the surface of neutrophils and monocytes.755,756,757,758,759,760,761 P-selectin–PSGL-1 interactions are characterized by rapid on-and-off rates that promote tethering and rolling of leukocytes along adherent platelets. Therefore, the, spectrin lattice is assembled into a continuous network by, filaments. The presence of a centriole in each cytoplasmic process was revealed by serial sectioning. Rupture at sites of constriction is thought to release platelets. Cellular stimulation induces migfilin to displace filamin from the integrin β3 cytoplasmic domain as well as a conformational change in talin that alters the interactions between the talin head and rod domains and exposes the talin head domain. bound by filamin members include the small GTPases, rho, rac. Trapping of serotonin must differ from that of adenine nucleotides, however, because dense granule serotonin exchanges readily with external serotonin.197 Transport and delivery of platelet-derived serotonin may play an important role in a variety of biologic phenomena including vasospasm, platelet coagulant activity, and liver regeneration.315, The membrane of dense granules contains glycoproteins that are also found on the plasma membrane and the membranes of α granules and lysosomes, including CD36, LAMP-2, CD63, P-selectin, αIIbβ3, and GPIb/IX. Munc13–4 has drawn particular attention based on its involvement in familial hemophagocytic lymphohistiocytosis (FHL) and Griscelli syndrome. Control of platelet actin assembly. The relationship between ultrastructure and photosensitivity of pigmented neurons of the abdominal ganglion of Aplysia californica was investigated using electron microscopy and electrophysiological methods.

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