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Platelets or thrombocytes () are a part of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping to form a thrombus. Platelets have no cell nucleus; they are fragments of cytoplasm from which reside in bone marrow or Lung, and then enter the circulation. Platelets are found only in mammals, whereas in other (e.g. , ), thrombocytes circulate as intact agranulocyte.
One major function of platelets is to contribute to hemostasis: the process of stopping bleeding at the site where the lining of vessels (endothelium) has been interrupted. Platelets 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. Berridge adds retraction and platelet inhibition as fourth and fifth steps, while others would add a sixth step, wound repair. Platelets participate in both innate and adaptive intravascular immune responses.
In addition to facilitating the clotting process, platelets contain and which can promote wound healing and regeneration of damaged tissues.
In some contexts, the word thrombus is used interchangeably with the word clot, regardless of its composition (white, red, or mixed). In other contexts it is used to contrast a normal from an abnormal clot: thrombus arises from physiologic hemostasis, thrombosis arises from a pathologic and excessive quantity of clot. In a third context it is used to contrast the result from the process: thrombus is the result, thrombosis is the process.
In a first approximation, the shape can be considered similar to oblate spheroids, with a semiaxis ratio of 2 to 8. This approximation can be used to model the hydrodynamic and optical properties of a population, as well as to restore the geometric parameters of individual measured platelets by flow cytometry. More accurate biophysical models of platelet surface morphology that model its shape from first principles, make it possible to obtain a more realistic platelet geometry in a calm and activated state.
Endothelial cells attach 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.
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. 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.
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. Platelet plugging and coagulation occur simultaneously, with each inducing the other to form the final fibrin-crosslinked thrombus.
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 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.
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. Human platelets do not express tissue factor. Rat platelets do express tissue factor protein and carry both tissue factor pre-mRNA and mature mRNA.
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 other mechanisms have been identified which can initiate aggregation, depending on the velocity of blood flow (i.e. shear range).
The platelet cell membrane has receptors for collagen. Following rupture of the blood vessel wall, platelets are exposed and adhere to the collagen in the surrounding tissue.
Thrombosis (blood coagulation in intact blood vessels) is usually viewed as a pathological immune response, leading to obturation of lumen of blood vessel and subsequent hypoxic tissue damage. In some cases, however, directed thrombosis (or immunothrombosis) can locally control the spread of an infection. The thrombosis is directed in concordance with platelets, and . The process is initiated either by immune cells by activating their pattern recognition receptors (PRRs), or by platelet-bacterial binding. Platelets can bind to bacteria either directly through thrombocytic PRRs and bacterial surface proteins, or via plasma proteins that bind both to platelets and bacteria. Monocytes respond to bacterial pathogen-associated molecular patterns (PAMPs), or damage-associated molecular patterns (DAMPs) by activating the extrinsic pathway of coagulation. Neutrophils facilitate the blood coagulation by NETosis, while platelets facilitate neutrophils' NETosis. NETs bind tissue factor, binding the coagulation centers to the location of infection. They also activate the intrinsic coagulation pathway by providing a negatively charged surface for factor XII. Other neutrophil secretions, such as proteolytic enzymes which cleave coagulation inhibitors, also bolster the process.
In case of imbalance in the regulation of immunothrombosis, this process can become aberrant. Regulatory defects in immunothrombosis are suspected to be a major factor in pathological thrombosis in forms such as disseminated intravascular coagulation (DIC) or deep vein thrombosis. DIC in sepsis is a prime example of both the dysregulated coagulation process and an undue systemic inflammatory response. It results in a multitude of microthrombi. These are similar in composition to the thrombi produced in native immunothrombosis — they are made up of fibrin, platelets, neutrophils and NETs.
Platelets modulate neutrophils by forming platelet-leukocyte aggregates (PLAs). These formations induce upregulated production of the complement receptor αmβ2 (Mac-1) integrin in neutrophils. Interaction with PLAs also induces degranulation and increased phagocytosis in neutrophils.
Platelets are the largest source of soluble CD40L (CD154) which induces production of reactive oxygen species (ROS) and upregulates expression of adhesion molecules (such as E-selectin, ICAM-1, and VCAM-1) in neutrophils. CD40L also activates macrophages and activates cytotoxic response in T lymphocyte and B lymphocytes.
Mammalian platelets lacking nucleus are able to conduct autonomous locomotion. Platelets are active scavengers, scaling walls of blood vessels and reorganising the thrombus. They are able to recognize and adhere to many surfaces, including bacteria, and can envelop them in their open canalicular system (OCP), leading to a proposal to name the process as covercytosis (OCS) rather than phagocytosis, as OCS is merely an invagination of outer plasma membrane. These platelet-bacteria bundles provide an interaction platform for neutrophils that destroy bacteria using NETs and phagocytosis.
Platelets also participate in chronic inflammatory disease, such as synovitis or rheumatoid arthritis. Platelets are activated by collagen receptor GPVI (GPVI). Proinflammatory platelet microvesicles trigger constant cytokine secretion from neighboring fibroblast-like synoviocytes, most prominently Il-6 and Il-8. Inflammatory damage to the surrounding extracellular matrix continuously reveals more collagen, binding receptors on platelets and maintaining microvesicle production.
Platelet concentrations vary between individuals and over time, with the population average between 250,000 and 260,000 cells per mm3 (equivalent to per microliter), but the typical laboratory accepted normal range is between 150,000 and 400,000 cells per mm3 or 150–400 billion per liter.
On a stained blood smear, platelets appear as dark purple spots, about 20% of the diameter of red blood cells. The smear reveals size, shape, qualitative number, and clumping. A healthy adult typically has 10 to 20 times more red blood cells than platelets.
Bleeding due to a platelet disorder or a coagulation factor disorder can be distinguished by the characteristics and location of the bleeding. Platelet bleeding involves bleeding from a cut that is prompt and excessive, but can be controlled by pressure; spontaneous bleeding into the skin which causes a purplish stain named by its size: petechiae, purpura, ecchymoses; bleeding into mucous membranes causing bleeding gums, nose bleed, and gastrointestinal bleeding; menorrhagia; and intraretinal and intracranial bleeding.
Excessive numbers of platelets, and/or normal platelets responding to abnormal vessel walls, can result in venous thrombosis and arterial thrombosis. The symptoms depend on the thrombosis site.
Low platelet concentration is called thrombocytopenia, and is due to either decreased production, increased destruction of platelets, or platelets being sequestered in another part of the body. Elevated platelet concentration is called thrombocytosis, and is either congenital, reactive (to ), or due to unregulated production: one of the myeloproliferative neoplasms or certain other myeloid .
Normal platelets can respond to an abnormality on the vessel wall rather than to hemorrhage, resulting in inappropriate platelet adhesion/activation and thrombosis: the formation of a clot within an intact vessel. This type of thrombosis arises by mechanisms different from those of a normal clot: extending the fibrin of venous thrombosis; extending an unstable or ruptured arterial plaque, causing arterial thrombosis; and microcirculatory thrombosis. An arterial thrombus may partially obstruct blood flow, causing downstream ischemia, or may completely obstruct it, causing downstream infarction.:
Pooled whole-blood platelets, sometimes called "random" platelets, are separated by one of two methods. In the US, a unit of whole blood is placed into a large centrifuge in what is referred to as a "soft spin". At these settings, the platelets remain suspended in the plasma. The platelet-rich plasma (PRP) is removed from the red cells, then centrifuged at a faster setting to harvest the platelets from the plasma. In other regions of the world, the unit of whole blood is centrifuged using settings that cause the platelets to become suspended in the "buffy coat" layer, which includes the platelets and the white blood cells. The "buffy coat" is isolated in a sterile bag, suspended in a small amount of red blood cells and plasma, then centrifuged again to separate the platelets and plasma from the red and white blood cells. Regardless of the initial method of preparation, multiple donations may be combined into one container using a sterile connection device to manufacture a single product with the desired therapeutic dose.
Apheresis platelets are collected using a mechanical device that draws blood from the donor and centrifuges the collected blood to separate out the platelets and other components to be collected. The remaining blood is returned to the donor. The advantage to this method is that a single donation provides at least one therapeutic dose, as opposed to the multiple donations for whole-blood platelets. This means that a recipient is exposed to fewer donors and has less risk of transfusion-transmitted disease and other complications. Sometimes a person such as a cancer patient who requires routine transfusions of platelets receives repeated donations from a specific donor to minimize risk. Pathogen reduction of platelets using for example, riboflavin and UV light treatments can reduce the infectious load of pathogens contained in donated blood products. Another photochemical treatment process utilizing amotosalen and UVA light has been developed for the inactivation of viruses, bacteria, parasites, and leukocytes. In addition, apheresis platelets tend to contain fewer contaminating red blood cells because the collection method is more efficient than "soft spin" centrifugation.
Platelets are stored under constant agitation at . Units cannot be refrigerated as this causes platelets to change shape and lose function. Storage at room temperature provides an environment where any introduced bacteria may proliferate and subsequently cause bacteremia. The United States requires products to be tested for the presence of bacterial contamination before transfusion.
Prior to issuing platelets to the recipient, they may be irradiated to prevent transfusion-associated graft versus host disease or they may be washed to remove the plasma.
The change in the recipient's platelet count after transfusion is termed the "increment" and is calculated by subtracting the pre-transfusion platelet count from the post-transfusion count. Many factors affect the increment including body size, the number of platelets transfused, and clinical features that may cause premature destruction of the transfused platelets. When recipients fail to demonstrate an adequate post-transfusion increment, this is termed platelet transfusion refractoriness.
Platelets, either apheresis-derived or random-donor, can be processed through a volume reduction process. In this process, the platelets are spun in a centrifuge and plasma is removed, leaving 10 to 100 mL of platelet concentrate. Such volume-reduced platelets are normally transfused only to neonatal and pediatric patients when a large volume of plasma could overload the child's small circulatory system. The lower volume of plasma also reduces the chances of an adverse transfusion reaction to plasma proteins. Volume reduced platelets have a shelf life of four hours. CBBS: Washed and volume-reduced Plateletpheresis units . Cbbsweb.org (2001-10-25). Retrieved on 2011-11-14.
Platelets release platelet-derived growth factor (PDGF), a potent chemotaxis agent; and TGF beta, which stimulates the deposition of extracellular matrix; fibroblast growth factor, insulin-like growth factor 1, platelet-derived epidermal growth factor, and vascular endothelial growth factor. Local application of these factors in increased concentrations through platelet-rich plasma (PRP) is used as an adjunct in wound healing.
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