platelet platelet platelets or thrombocytes (from greek θρόμβος, "clot" and κύτος, "cell") are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby initiating a blood clot. platelets have no cell nucleus; they are fragments of cytoplasm that are derived from the megakaryocytes of the bone marrow or lung, which then enter the circulation. platelets are found only in mammals, whereas in other vertebrates (e.g. birds, amphibians), thrombocytes circulate as intact mononuclear cells.: 3 the ligands, denoted by letter l, signal for platelets (p) to migrate towards the wound (site a). as more platelets gather around the opening, they produce more ligands to amplify the response. the platelets congregate around the wound in order to create a cap to stop blood flow out of the tissue. plateletsimage from a light microscope (500 ×) from a giemsa-stained peripheral blood smear showing platelets (purple dots) surrounded by red blood cells (pink circular structures)detailsprecursormegakaryocytesfunctionformation of blood clots; prevention of bleedingidentifierslatinthrombocytesmeshd001792fma62851anatomical terms of microanatomy one major function of platelets is to contribute to hemostasis: the process of stopping bleeding at the site of interrupted endothelium. they gather at the site and, unless the interruption is physically too large, they plug the hole. first, platelets attach to substances outside the interrupted endothelium: adhesion. second, they change shape, turn on receptors and secrete chemical messengers: activation. third, they connect to each other through receptor bridges: aggregation. formation of this platelet plug (primary hemostasis) is associated with activation of the coagulation cascade, with resultant fibrin deposition and linking (secondary hemostasis). these processes may overlap: the spectrum is from a predominantly platelet plug, or "white clot" to a predominantly fibrin, or "red clot" or the more typical mixture. some would add the subsequent retraction and platelet inhibition as fourth and fifth steps to the completion of the process and still others would add a sixth step, wound repair. platelets also participate in both innate and adaptive intravascular immune responses. structure structure structurally the platelet can be divided into four zones, from peripheral to innermost: peripheral zone – is rich in glycoproteins required for platelet adhesion, activation and aggregation. for example, gpib/ix/v; gpvi; gpiib/iiia. sol-gel zone – is rich in microtubules and microfilaments, allowing the platelets to maintain their discoid shape. organelle zone – is rich in platelet granules. alpha granules contain clotting mediators such as factor v, factor viii, fibrinogen, fibronectin, platelet-derived growth factor, and chemotactic agents. delta granules, or dense bodies, contain adp, calcium and serotonin, which are platelet-activating mediators. membranous zone – contains membranes derived from megakaryocyte smooth endoplasmic reticulum organized into a dense tubular system which is responsible for thromboxane a2 synthesis. this dense tubular system is connected to the surface platelet membrane to aid thromboxane a2 release. shape circulating inactivated platelets are biconvex discoid (lens-shaped) structures,: 117–18 2–3 µm in greatest diameter. activated platelets have cell membrane projections covering their surface. in a first approximation, the platelet shape can be considered similar to oblate spheroids, with a semiaxis ratio of 2 to 8. this approximation is often used to model the hydrodynamic and optical properties of a platelet population, as well as to restore the geometric parameters of individual measured platelets by flow cytometry. more accurate biophysical models of the platelet surface morphology, which model its shape from first principles, make it possible to obtain a more realistic platelet geometry in a calm and activated state. development platelets derive from totipotent marrow stem cells. megakaryocyte and platelet production is regulated by thrombopoietin, a hormone produced in the kidneys and liver. each megakaryocyte produces between 1,000 and 3,000 platelets during its lifetime. an average of 1011 platelets are produced daily in a healthy adult. reserve platelets are stored in the spleen and are released when needed by splenic contraction induced by the sympathetic nervous system. platelets extruded from megakaryocytes the average life span of circulating platelets is 8 to 9 days. life span of individual platelets is controlled by the internal apoptotic regulating pathway, which has a bcl-xl timer. old platelets are destroyed by phagocytosis in the spleen and liver. hemostasis 3d rendering of four inactivated and three activated platelets the fundamental function of platelets is to clump together to stop acute bleeding. this process is complex, as more than 193 proteins and 301 interactions are known to be involved in platelet dynamics. while there is much overlap, platelet function can be modeled in three steps: adhesion thrombus formation on an intact endothelium is prevented by nitric oxide, prostacyclin, and cd39. endothelial cells are attached to the subendothelial collagen by von willebrand factor (vwf), which these cells produce. vwf is also stored in the weibel-palade bodies of the endothelial cells and secreted constitutively into the blood. platelets store vwf in their alpha granules. when the endothelial layer is disrupted, collagen and vwf anchor platelets to the subendothelium. platelet gp1b-ix-v receptor binds with vwf; and gpvi receptor and integrin α2β1 bind with collagen. activation scanning electron micrograph of blood cells. from left to right: human erythrocyte, activated platelet, leukocyte. inhibition the intact endothelial lining inhibits platelet activation by producing nitric oxide, endothelial-adpase, and pgi2 (prostacyclin). endothelial-adpase degrades the platelet activator adp. resting platelets maintain active calcium efflux via a cyclic amp-activated calcium pump. intracellular calcium concentration determines platelet activation status, as it is the second messenger that drives platelet conformational change and degranulation (see below). endothelial prostacyclin binds to prostanoid receptors on the surface of resting platelets. this event stimulates the coupled gs protein to increase adenylate cyclase activity and increases the production of camp, further promoting the efflux of calcium and reducing intracellular calcium availability for platelet activation. adp on the other hand binds to purinergic receptors on the platelet surface. since the thrombocytic purinergic receptor p2y12 is coupled to gi proteins, adp reduces platelet adenylate cyclase activity and camp production, leading to accumulation of calcium inside the platelet by inactivating the camp calcium efflux pump. the other adp-receptor p2y1 couples to gq that activates phospholipase c-beta 2 (plcb2), resulting in inositol 1,4,5-trisphosphate (ip3) generation and intracellular release of more calcium. this together induces platelet activation. endothelial adpase degrades adp and prevents this from happening. clopidogrel and related antiplatelet medications also work as purinergic receptor p2y12 antagonists. data suggest that adp activates the pi3k/akt pathway during a first wave of aggregation, leading to thrombin generation and par‐1 activation, which evokes a second wave of aggregation. trigger (induction) platelet activation begins seconds after adhesion occurs. it is triggered when collagen from the subendothelium binds with its receptors (gpvi receptor and integrin α2β1) on the platelet. gpvi is associated with the fc receptor gamma chain and leads via the activation of a tyrosine kinase cascade finally to the activation of plc-gamma2 (plcg2) and more calcium release. tissue factor also binds to factor vii in the blood, which initiates the extrinsic coagulation cascade to increase thrombin production. thrombin is a potent platelet activator, acting through gq and g12. these are g protein-coupled receptors and they turn on calcium-mediated signaling pathways within the platelet, overcoming the baseline calcium efflux. families of three g proteins (gq, gi, g12) operate together for full activation. thrombin also promotes secondary fibrin-reinforcement of the platelet plug. platelet activation in turn degranulates and releases factor v and fibrinogen, potentiating the coagulation cascade. so, in reality, the process of platelet plugging and coagulation are occurring simultaneously rather than sequentially, with each inducing the other to form the final fibrin-crosslinked thrombus. gpiib/iiia activation collagen-mediated gpvi signalling increases the platelet production of thromboxane a2 (txa2) and decreases the production of prostacyclin. this occurs by altering the metabolic flux of platelet's eicosanoid synthesis pathway, which involves enzymes phospholipase a2, cyclo-oxygenase 1, and thromboxane-a synthase. platelets secrete thromboxane a2, which acts on the platelet's own thromboxane receptors on the platelet surface (hence the so-called "out-in" mechanism), and those of other platelets. these receptors trigger intraplatelet signaling, which converts gpiib/iiia receptors to their active form to initiate aggregation. granule secretion diagram of the structure of a platelet showing the granules platelets contain dense granules, lambda granules and alpha granules. activated platelets secrete the contents of these granules through their canalicular systems to the exterior. simplistically, bound and activated platelets degranulate to release platelet chemotactic agents to attract more platelets to the site of endothelial injury. granule characteristics: α granules (alpha granules) – containing p-selectin, platelet factor 4, transforming growth factor-β1, platelet-derived growth factor, fibronectin, b-thromboglobulin, vwf, fibrinogen, and coagulation factors v and xiii δ granules (delta or dense granules) – containing adp or atp, calcium, and serotonin γ granules (gamma granules) – similar to lysosomes and contain several hydrolytic enzymes λ granules (lambda granules) – contents involved in resorption during later stages of vessel repair morphology change as shown by flow cytometry and electron microscopy, the most sensitive sign of activation, when exposed to platelets using adp, are morphological changes. mitochondrial hyperpolarization is a key event in initiating changes in morphology. intraplatelet calcium concentration increases, stimulating the interplay between the microtubule/actin filament complex. the continuous changes in shape from the unactivated to the fully activated platelet is best seen on scanning electron microscopy. three steps along this path are named early dendritic, early spread and spread. the surface of the unactivated platelet looks very similar to the surface of the brain, with a wrinkled appearance from numerous shallow folds to increase the surface area; early dendritic, an octopus with multiple arms and legs; early spread, an uncooked frying egg in a pan, the "yolk" being the central body; and the spread, a cooked fried egg with a denser central body. these changes are all brought about by the interaction of the microtubule/actin complex with the platelet cell membrane and open canalicular system (ocs), which is an extension and invagination of that membrane. this complex runs just beneath these membranes and is the chemical motor that literally pulls the invaginated ocs out of the interior of the platelet, like turning pants pockets inside out, creating the dendrites. this process is similar to the mechanism of contraction in a muscle cell. the entire ocs thus becomes indistinguishable from the initial platelet membrane as it forms the "fried egg". this dramatic increase in surface area comes about with neither stretching nor adding phospholipids to the platelet membrane. platelet-coagulation factor interactions: coagulation facilitation platelet activation causes its membrane surface to become negatively charged. one of the signaling pathways turns on scramblase, which moves negatively charged phospholipids from the inner to the outer platelet membrane surface. these phospholipids then bind the tenase and prothrombinase complexes, two of the sites of interplay between platelets and the coagulation cascade. calcium ions are essential for the binding of these coagulation factors. in addition to interacting with vwf and fibrin, platelets interact with thrombin, factors x, va, viia, xi, ix, and prothrombin to complete formation via the coagulation cascade. six studies suggested platelets express tissue factor: the definitive study shows they do not. the platelets from rats were conclusively shown to express tissue factor protein and also it was proved that the rat platelets carry both the tissue factor pre-mrna and mature mrna. aggregation platelet clumps in a blood smear aggregation of platelets begins minutes after their activation, and occurs as a result of turning on the gpiib/iiia receptor, allowing these receptors to bind with vwf or fibrinogen. there are around 60,000 of these receptors per platelet. when any one or more of at least nine different platelet surface receptors are turned on during activation, intraplatelet signaling pathways cause existing gpiib/iiia receptors to change shape – curled to straight – and thus become capable of binding. since fibrinogen is a rod-like protein with nodules on either end capable of binding gpiib/iiia, activated platelets with exposed gpiib/iiia can bind fibrinogen to aggregate. gpiib/iiia may also further anchor the platelets to subendothelial vwf for additional structural stabilisation. classically it was thought that this was the only mechanism involved in aggregation, but three new mechanisms have been identified which can initiate aggregation, depending on the velocity of blood flow (i.e. shear range). immune function platelets have a central role in innate immunity, initiating and participating in multiple inflammatory processes, directly binding pathogens and even destroying them. this supports clinical data which show that many with serious bacterial or