Metamorphosis is a biological process by which an animal physically develops after birth or hatching, involving a conspicuous and relatively abrupt change in the animal's body structure through cell growth and differentiation. Some insects, amphibians, mollusks, crustaceans, Cnidarians, echinoderms and tunicates undergo metamorphosis, which is usually accompanied by a change of habitat or behavior.
Scientific usage of the term is exclusive, and is not applied to general aspects of cell growth, including rapid growth spurts. References to "metamorphosis" in mammals are imprecise and only colloquial, but historically idealist ideas of transformation and monadology, as in Goethe's Metamorphosis of Plants, influenced the development of ideas of evolution.
Etymology
The word "metamorphosis" derives from Greek μεταμόρφωσις, "transformation, transforming"[1], from μετα- (meta-), "change" + μορφή (morphe) "form"[2].
Insect metamorphosis
Metamorphosis usually proceeds in distinct stages, starting with larva or nymph, optionally passing through pupa, and ending as adult or imago. There are two main types of metamorphosis in insects, hemimetabolism and holometabolism.
Incomplete metamorphosis in the grasshopper with different instar nymphs
The immature stages of a species that metamorphosises are usually called larvae, and in these stages may grow quite quickly. But in the complex metamorphosis of many insect species, only the first stage is called a larva and sometimes even that bears a different name; the distinction depends on the nature of the metamorphosis.
In hemimetabolism, the development of larva often proceeds in repeated stages of growth and ecdysis (moulting); these stages are called instars. The juvenile forms closely resemble adults, but are smaller and, if the adult has wings, lack wings. This process is also known as "simple", "gradual" or "incomplete" metamorphosis. The differences between juveniles in different instars are small, often just differences in body proportions and the number of segments.
In holometabolism, the larvae differ markedly from the adults. Insects which undergo holometabolism pass through a larval stage, then enter an inactive state called pupa, or chrysalis, and finally emerge as adults. Holometabolism is also known as "complete" and "complex" metamorphosis. Whilst inside the pupa, the insect will excrete digestive juices, to destroy much of the larva's body, leaving a few cells intact. The remaining cells will begin the growth of the adult, using the nutrients from the broken down larva. This process of cell death is called histolysis, and cell regrowth histogenesis.
Whether the insect spends more time in its adult stage or in its juvenile form depends on the species. Notable examples are the mayfly, whose non-eating, adult stage lives for one day, and the cicada, whose juvenile stage live underground for 13 or 17 years. These species have incomplete metamorphosis. Typically, though not exclusively, species in which the adult form outlives the juvenile form undergo complex metamorphosis.
Many observations have indicated that programmed cell death plays a considerable role during physiological processes of multicellular organisms, particularly during embryogenesis and metamorphosis.
Pieris rapae larva
Pieris rapae pupa
Pieris rapae pupa, ready to hatch.
A Pieris rapae adult
Hormonal control
Insect growth and metamorphosis are controlled by hormones synthesized by endocrine glands near the front of the body.
neurosecretory cells of an insect's brain secrete a hormone, the prothoracicotropic hormone that activates prothoracic glands, which secrete a second hormone, usually Ecdysone (a steroid), that induces metamorphosis.
Moreover, the corpora allata, a retrocerebral organ produces the juvenile hormone, whose effect is to prevent the development of adult characteristics while allowing ecdysis. Therefore, the insect is subject to a series of molting, controlled by Ecdysone, until the production of juvenile hormone ceases and metamorphosis occurs.
Amphibian metamorphosis
File:Greenfrog-male-tadpoles.jpg
A male northern green frog, Rana Clamitans Melanota with the year before's tadpoles
Just before metamorphosis, only 24 hours are needed to reach the stage in the next picture
Almost functional common frog with some remains of the gill sac and a not fully developed jaw
In typical amphibian development the eggs are laid in water and the larvae are adapted to an aquatic lifestyle. Both frogs, toads, and newts hatch from the egg as larvae with external gills. After that the newt larvae are starting a predatory lifestyle, the tadpoles are mostly scraping off food from surfaces with their horny tooth ridges. Metamorphosis in amphibians is regulated by thyroxin concentration in the blood, that stimulates metamorphosis and prolactin that counteracts its effect. The specific events are dependent of the threshold values for different tissues. Because most of the embryonic development is outside the parental body the development is subject to a lot of adaptations due to specific ecological circumstances. For this reason tadpoles can have horny ridges for teeth, whiskers and fins. They also make use of the lateral line organ. After metamorphosis these organs become redundant and will be resorbed by controlled cell death called apoptosis. The amount of adaptations to specific ecological circumstances is amazing and there are still discoveries being made.
Frogs and toads
With frogs and toads the external gills of the newly hatched tadpole are covered in a few days with a gill sac and lungs are quickly formed. Under the gill sac the front legs are formed and the hindlegs are also visible a few days later. Then there usually is a longer stage where the tadpole is growing on a vegetarian diet. The tadpoles use a spiral shaped relatively long gut to digest that diet.
After that, very quick changes in the body can be observed when the lifestyle of the frog changes completely. The trunk shaped mouth with horny tooth ridges is resorbed together with the spiral gut. The animal develops a big jaw, the gills disappear as well as the gill sac. The eyes grow at a very fast rate as well as the legs, a tongue is formed and all this is completed with the associated changes in the neural networks (development of stereoscopic vision, loss of the lateral line system etc.) All of this can happen in about a day, so it is truly a metamorphosis. A few days later also the tail is reabsorbed, due to the higher thyroxin concentrations required for tail resorption.
Newts
The large external gills of the crested newt
In newts there is not really such a thing as metamorphosis, because the larvae start feeding as predators always and continue to do so in the adult stage. The gills of newts are never covered by a gill sac and will be resorbed only just before the animal leaves the water. Just like in tadpoles the lungs are functional very soon also, but they don't make as much use of them as tadpoles do. Newts often have an aquatic phase in spring and summer and a land phase in winter. For adaptation to a water phase prolactin is the required hormone and for adaptations to the land phase thyroxin. The external gills do not return in subsequent aquatic phases because they are completely absorbed upon leaving the water for the first time.
Metamorphosis in fish and invertebrate aquatic animals
Little known is that also fish, i.e. bony fish, undergo metamorphosis. Fish metamorphosis is typically under strong control by thyroid hormone. Examples include the agnatha, salmon, and lamprey, which must change from a freshwater to saltwater lifestyle (diadromous). Additionally, the flatfish begins its life bilaterally symmetrical, and one eye must move to join the other side of the fish in its adult form.
Amphibians (class Amphibia, from Amphi- meaning "on both sides" and -bios meaning "life"), such as frogs, toads, salamanders, newts, and caecilians, are ectothermic (or cold-blooded) animals that metamorphose from a juvenile water-breathing form, either to an adult air-breathing form, or to a paedomorph that retains some juvenile characteristics. Proteidae (mudpuppies and waterdogs) are good examples of paedomorphic species. Though amphibians typically have four limbs, the caecilians are notable for being limbless. Unlike other land vertebrates (amniotes), most amphibians lay eggs in water. Amphibians are superficially similar to reptiles.
Amphibians are ecological indicators, and in recent decades there has been a dramatic decline in amphibian populations around the globe. Many species are now threatened or extinct.
Amphibians evolved in the Devonian Period and were top predators in the Carboniferous and Permian Periods, but many lineages were wiped out during the Permian–Triassic extinction. One group, the metoposaurs, remained important predators during the Triassic, but as the world became drier during the Early Jurassic they died out, leaving a handful of relict temnospondyls like Koolasuchus and the modern orders of Lissamphibia.
Etymology
Amphibian is derived from the Ancient Greek term ἀμφίβιος amphíbios which means both kinds of life, amphi meaning “both” and bio meaning life. The term was initially used for all kinds of combined natures. Eventually it was used to refer to animals that live both in the water and on land.[1]
Evolutionary history
The first major groups of amphibians developed in the Devonian Period from fish similar to the modern coelacanth and lungfish which had evolved multi-jointed leg-like fins that enabled them to crawl along the sea bottom. These amphibians were as much as one to five meters in length. However, amphibians never developed the ability to live their entire lives on land, having to return to water to lay their shell-less eggs.
In the Carboniferous Period, the amphibians moved up in the food chain and began to occupy the ecological position currently occupied by crocodiles. These amphibians were notable for eating the mega insects on land and many types of fishes in the water. During the Triassic Period, the better land-adapted proto-crocodiles began to compete with amphibians, leading to their reduction in size and importance in the biosphere.
Taxonomic history
Traditionally, amphibians have included all tetrapod vertebrates that are not amniotes. They are divided into three subclasses, of which two are only known as extinct subclasses:
Subclass Labyrinthodontia† (diverse Paleozoic and early Mesozoic group)
Subclass Lepospondyli† (small Paleozoic group, sometimes included in the Labyrinthodontia)
Of these only the last subclass includes recent species.
With the phylogenetic classification Labyrinthodontia has been discarded as it is a paraphyletic group without unique defining features apart from shared primitive characteristics. Classification varies according to the preferred phylogeny of the author, whether they use a stem-based or node-based classification. Generally amphibians are defined as the group that includes the common ancestors of all living amphibians (frogs, salamanders and caecilians) and all their descendants. This may also include extinct groups like the temnospondyls (traditionally placed in the subclass “Labyrinthodontia”), and the Lepospondyls. This means that cladistic nomenklature list a large number of basal Devonian and Carboniferous tetrapod groups, undoubtedly were “amphibians” in biology, that are formally placed in Amphibia in Linnaean taxonomy, but not in cladistic taxonomy.
All recent amphibians are included in the subclass Lissamphibia, superorder Salientia, which is usually considered a clade (which means that it is thought that they evolved from a common ancestor apart from other extinct groups), although it has also been suggested that salamanders arose separately from a temnospondyl-like ancestor.[2]
Authorities also disagree on whether Salientia is a Superorder that includes the order Anura, or whether Anura is a sub-order of the order Salientia. Practical considerations seem to favor using the former arrangement now. The Lissamphibia, superorder Salientia, are traditionally divided into three orders, but an extinct salamander-like family, the Albanerpetontidae, is now considered part of the Lissamphibia, besides the superorder Salientia. Furthermore, Salientia includes all three recent orders plus a single Triassic proto-frog, Triadobatrachus.
Class Amphibia
Subclass Lissamphibia
Family Albanerpetontidae — Jurassic to Miocene (extinct)
Superorder Salientia
Genus Triadobatrachus — Triassic (extinct)
Order Anura (frogs and toads): Jurassic to recent — 5,602 recent species in 48 families
Order Caudata or Urodela (salamanders, newts): Jurassic to recent — 571 recent species in 9 families
Order Gymnophiona or Apoda (caecilians): Jurassic to recent — 174 recent species in 3 families
The actual number of species partly also depends on the taxonomic classification followed, the two most common classifications being the classification of the website AmphibiaWeb, University of California (Berkeley) and the classification by herpetologist Darrel Frost and The American Museum of Natural History, available as the online reference database Amphibian Species of the World.[3] The numbers of species cited above follow Frost.
Respiration
The lungs in amphibians are primitive compared to that of the amniotes, possessing few internal septa, large alveoli and therefore a slow diffusion rate of oxygen into the blood. Ventilation is accomplished by buccal pumping. However, most amphibians are able to exchange gasses with the water or air via their skin. To enable sufficient cutaneous respiration, the surface of their highly vascularized skin must remain moist in order for the oxygen to diffuse at a sufficient rate. Because oxygen concentration in the water increases at both low temperatures and high flow rates, aquatic amphibians in these situations can rely primarily on cutaneous respiration, as in the Titicaca water frog or hellbender salamanders. In air, where oxygen is more concentrated, some small species can rely solely on cutaneous gas exchange, most famously the plethodontid salamanders which have neither lungs nor gills. Many aquatic salamanders and all tadpoles have gills in their larval stage, with some (such as the axolotl) retaining gills as aquatic adults.
Reproductive system
Caecilian from the San Antonio zoo
For the purpose of reproduction most amphibians require fresh water. A few (e.g. Fejervarya raja) can inhabit brackish water and even survive (though not thrive) in seawater, but there are no true marine amphibians. Several hundred frog species in adaptive radiations (e.g., Eleutherodactylus, the Pacific Platymantines, the Australo-Papuan microhylids, and many other tropical frogs), however, do not need any water for breeding in the wild. They reproduce via direct development, an ecological and evolutionary adaptation that has allowed them to be completely independent from free-standing water. Almost all of these frogs live in wet tropical rainforests and their eggs hatch directly into miniature versions of the adult, passing through the tadpole stage within the egg. Several species have also adapted to arid and semi-arid environments, but most of them still need water to lay their eggs. Symbiosis with single celled algae that lives in the jelly-like layer of the eggs has evolved several times. The larvae (tadpoles or polliwogs) breathe with exterior gills. After hatching, they start to transform gradually into the adult's appearance. This process is called metamorphosis. Typically, the animals then leave the water and become terrestrial adults, but there are many interesting exceptions to this general way of reproduction.
The most obvious part of the amphibian metamorphosis is the formation of four legs in order to support the body on land. But there are several other changes:
The gills are replaced by other respiratory organs, i.e., lungs.
The skin changes and develops glands to avoid dehydration.
The eyes develop eyelids and adapt to vision outside the water.
An eardrum is developed to lock the middle ear.
In frogs and toads, the tail disappears.
Conservation
The Golden Toad of Monteverde, Costa Rica was among the first casualties of amphibian declines. Formerly abundant, it was last seen in 1989.
Dramatic declines in amphibian populations, including population crashes and mass localized extinction, have been noted in the past two decades from locations all over the world, and amphibian declines are thus perceived as one of the most critical threats to global biodiversity. A number of causes are believed to be involved, including habitat destruction and modification, over-exploitation, pollution, introduced species, climate change, endocrine-disrupting pollutants, destruction of the ozone layer (ultraviolet radiation has shown to be especially damaging to the skin, eyes, and eggs of amphibians), and diseases like chytridiomycosis. However, many of the causes of amphibian declines are still poorly understood, and are a topic of ongoing discussion. A global strategy to stem the crisis has been released in the form of the Amphibian Conservation Action Plan (available at http://www.amphibians.org). Developed by over 80 leading experts in the field, this call to action details what would be required to curtail amphibian declines and extinctions over the next 5 years - and how much this would cost. The Amphibian Specialist Group of the World Conservation Union (IUCN) is spearheading efforts to implement a comprehensive global strategy for amphibian conservation.
On January 21, 2008, Evolutionarily Distinct and Globally Endangered (EDGE), as given by chief Helen Meredith, identified nature's most endangered species: "The EDGE amphibians are amongst the most remarkable and unusual species on the planet and yet an alarming 85% of the top 100 are receiving little or no conservation attention." The top 10 endangered species (in the List of endangered animal species) include: the Chinese giant salamander, a distant relative of the newt, the tiny Gardiner's Seychelles, the limbless Sagalla caecilian, South African ghost frogs, lungless Mexican salamanders, the Malagasy rainbow frog, Chile's Darwin frog (Rhinoderma rufum) and the Betic Midwife Toad
The ovary is an ovum-producing reproductive organ, often found in pairs as part of the vertebrate female reproductive system. Ovaries in females are homologous to testes in males, in that they are both gonads and endocrine glands.
Human anatomy
Ovaries are oval shaped and, in the human, measure approximately 3 cm x 1.5 cm x 1.5 cm (about the size of a Greek olive). The ovary (for a given side) is located in the lateral wall of the pelvis in a region called the ovarian fossa. The fossa usually lies beneath the external iliac artery and in front of the ureter and the internal iliac artery.
The ovaries aren't attached to the fallopian tubes but to the outer layer of the uterus via the ovarian ligaments. Usually each ovary takes turns releasing eggs every month; however, if there was a case where one ovary was absent or dysfunctional then the other ovary would continue providing eggs to be released.
Hormones
Ovaries secrete both estrogen and progesterone. Estrogen is responsible for the appearance of secondary sex characteristics of females at puberty and for the maturation and maintenance of the reproductive organs in their mature functional state. Progesterone functions with estrogen by promoting cyclic changes in the endometrium (it prepares the endometrium for pregnancy), as well as by helping maintain the endometrium in a healthy state during pregnancy.
Ligaments
In the human the paired ovaries lie within the pelvic cavity, on either side of the uterus, to which they are attached via a fibrous cord called the ovarian ligament. The ovaries are uncovered in the peritoneal cavity but are tethered to the body wall via the suspensory ligament of the ovary. The part of the broad ligament of the uterus that covers the ovary is known as the mesovarium. Thus, the ovary is the only organ in the human body which is totally invaginated into the peritonium, making it the only interperitoneal organ (not to be confused with intraperitoneal).
Extremities
There are two extremities to the ovary:
The end to which the uterine tube attach is called the tubal extremity.
The other extremity is called the uterine extremity. It points downward, and it is attached to the uterus via the ovarian ligament.
Histology
Cell Types
Follicular cells flat epithelial cells that originate from surface epithelium covering the ovary
granulosa cells - surrounding follicular cells have change from flat to cuboidal and proliferated to produce a stratified epithelium
Gametes[1]
Section of the ovary of a newly born child. Germinal epithelium is seen at top. Primitive ova are seen in their cell-nests. The Genital cord or genital ridge is still discernible in this young child. A blood vessel and an ovarian follicle is also seen
The outermost layer is called the ovarian surface epithelium (previously known as the germinal epithelium).
The tunica albuginea covers the cortex.
The ovarian cortex consists of ovarian follicles and stroma in between them. Included in the follicles are the cumulus oophorus, membrana granulosa (and the granulosa cells inside it), corona radiata, zona pellucida, and primary oocyte. The zona pellucida, theca of follicle, antrum and liquor folliculi are also contained in the follicle. Also in the cortex is the corpus luteum derived from the follicles.
The innermost layer is the ovarian medulla. It can be hard to distinguish between the cortex and medulla, but follicles are usually not found in the medulla.
In other animals
Ovaries of some kind are found in the female reproductive system of many animals that employ sexual reproduction, including invertebrates. However, they develop in a very different way in most invertebrates than they do in vertebrates, and are not truly homologous.[2]
Many of the features found in human ovaries are common to all vertebrates, including the presence of follicular cells, tunica albuginea, and so on. However, many species produce a far greater number of eggs during their lifetime than do humans, so that, in fish and amphibians, there may be hundreds, or even millions of fertile eggs present in the ovary at any given time. In these species, fresh eggs may be developing from the germinal epithelium throughout life. Corpora lutea are found only in mammals, and in some elasmobranch fish; in other species, the remnants of the follicle are quickly resorbed by the ovary. In birds, reptiles, and monotremes, the egg is relatively large, filling the follicle, and distorting the shape of the ovary at maturity.[2]
Amphibians and reptiles have no ovarian medulla; the central part of the ovary is a hollow, lymph-filled space. The ovary of teleosts is also often hollow, but in this case, the eggs are shed into the cavity, which opens into the oviduct.[2]
Although most normal female vertebrates have two ovaries, this is not the case in all species. In birds and platypuses, the right ovary never matures, so that only the left is functional. In some elasmobranchs, the reverse is true, with only the right ovary fully developing. In the primitive jawless fish, and some teleosts, there is only one ovary, formed by the fusion of the paired organs in the embryo.[2]
Cryopreservation
Cryopreservation of ovarian tissue, often called Ovarian Tissue Cryopreservation, is of interest to women who want to preserve their reproductive function beyond the natural limit, or whose reproductive potential is threatened by cancer therapy,[3] for example in hematologic malignancies or breast cancer.[4] The procedure is to take a part of the ovary and carry out slow freezing before storing it in liquid nitrogen whilst therapy is undertaken. Tissue can then be thawed and implanted near the fallopian, either orthotopic (on the natural location) or heterotopic (on the abdominal wall),[4] where it starts to produce new eggs, allowing normal conception to take place. [5] A study of 60 procedures concluded that ovarian tissue harvesting appears to be safe.[4] The ovarian tissue may also be transplanted into mice that are immunocompromised (SCID mice) to avoid graft rejection, and tissue can be harvested later when mature follicles have developed
A thrombus (Greek θρόμβος), or blood clot, is the final product of the blood coagulation step in hemostasis. It is achieved via the aggregation of platelets that form a platelet plug, and the activation of the humoral coagulation system (i.e. clotting factors). A thrombus is normal in cases of injury, but pathologic in instances of thrombosis.
Pathophysiology
Specifically, a thrombus is the inappropriate activation of the hemostatic process in an uninjured or slightly injured vessel. A thrombus in a large blood vessel will decrease blood flow through that vessel (termed a mural thrombus). In a small blood vessel, blood flow may be completely cut-off (termed an occlusive thrombus) resulting in death of tissue supplied by that vessel. If a thrombus dislodges and becomes free-floating, it is termed as an embolus.
Some of the conditions which elevate risk of blood clots developing include atrial fibrillation (a form of cardiac arrhythmia), heart valve replacement, a recent heart attack (also known as a myocardial infarction), extended periods of inactivity (see deep venous thrombosis), and genetic or disease-related deficiencies in the blood's clotting abilities.
Treatment
Blood clot prevention and treatment reduces the risk of stroke, heart attack and pulmonary embolism. Heparin and warfarin are often used to inhibit the formation and growth of existing thrombi; the former binds to and activates the enzyme inhibitor antithrombin III, while the latter inhibits vitamin K epoxide reductase, an enzyme needed to synthesize mature clotting factors.
Presentation
Virchow's triad describes the pathogenesis of thrombus formation:
Endothelial injury (injury to the endothelial cells that line enclosed spaces of the body, such as the inside of blood vessels) (e.g. trauma, atheroma)
Abnormal blood flow (loss of laminar flow resulting from stasis in veins or turbulence in arteries) (e.g. valvulitis, aneurysm)
Hypercoagulability (e.g. leukaemia, Factor V mutation (Leiden))
Disseminated intravascular coagulation (DIC) involves widespread microthrombi formation throughout the majority of the blood vessels. This is due to excessive consumption of coagulation factors and subsequent activation of fibrinolysis using all of the body's available platelets and clotting factors. The end result is hemorrhaging and ischaemic necrosis of tissue/organs. Causes are septicaemia, acute leukaemia, shock, snake bites, fat emboli from broken bones, or other severe traumas. DIC may also be seen in pregnant females. Treatment involves the use of fresh frozen plasma to restore the level of clotting factors in the blood, platelets and heparin to prevent further thrombi formation.
Prognosis
Thrombus formation can have one of four outcomes: propagation, embolization, dissolution or organization and recanalization. [1]
Propagation of a thrombus occurs towards the direction of the heart. This means that it is anterograde in veins or retrograde in arteries.
Embolization occurs when the thrombus breaks free from the vascular wall and becomes mobile. A venous emboli (most likely from deep venous thrombosis in the lower extremities) will travel through the systemic circulation, reach the right side of the heart, and travel through the pulmonary artery resulting in a pulmonary embolism. On the other hand, arterial thrombosis resulting from hypertension or atherosclerosis can become mobile and the resulting emboli can occlude any artery or arteriole downstream of the thrombus formation. This means that cerebral stroke, myocardial infarction, or any other organ can be affected.
Dissolution occurs when fibrinolytic mechanisms break up the thrombus and blood flow is restored to the vessel. This may be aided by drugs (for example after occlusion of a coronary artery). The best response to fibrinolytic drugs is within a couple of hours, before the fibrin meshwork of the thrombus has been fully developed.
Organization and recanalization involves the ingrowth of smooth muscle cells, fibroblasts and endothelium into the fibrin-rich thrombus. Recanalization provides capillary-sized channels through the thrombus for continuity of blood flow through the entire thrombus but may not restore sufficient blood flow for the metabolic needs of the downstream tissue.
Platelets, or thrombocytes (from Greek θρόμβος — «clot» and κύτος — «cell»), are small, irregularly-shaped anuclear cell fragments (i.e. cells that do not have a nucleus containing DNA), 2-3 µm in diameter[1], which are derived from fragmentation of precursor megakaryocytes. The average lifespan of a platelet is normally just 5 to 9 days. Platelets play a fundamental role in hemostasis and are a natural source of growth factors. They circulate in the blood of mammals and are involved in hemostasis, leading to the formation of blood clots.
If the number of platelets is too low, excessive bleeding can occur. However, if the number of platelets is too high, blood clots can form (thrombosis), which may obstruct blood vessels and result in such events as a stroke, myocardial infarction, pulmonary embolism or the blockage of blood vessels to other parts of the body, such as the extremities of the arms or legs. An abnormality or disease of the platelets is called a thrombocytopathy[2], which could be either a low number of platelets (thrombocytopenia), a decrease in function of platelets (thrombasthenia), or an increase in the number of platelets (thrombocytosis). There are disorders that reduce the number of platelets, such as heparin-induced thrombocytopenia (HIT) or thrombotic thrombocytopenic purpura (TTP) that typically cause thromboses, or clots, instead of bleeding.
Platelets release a multitude of growth factors including Platelet-derived growth factor (PDGF), a potent chemotactic agent, and TGF beta, which stimulates the deposition of extracellular matrix. Both of these growth factors have been shown to play a significant role in the repair and regeneration of connective tissues. Other healing-associated growth factors produced by platelets include basic 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) has been used as an adjunct to wound healing for several decades
Kinetics
Blood cell lineage
Platelets are produced in blood cell formation (thrombopoiesis) in bone marrow, by budding off from megakaryocytes.
The physiological range for platelets is 150-400 x 109 per liter.
Around 1 x 1011 platelets are produced each day by an average healthy adult.
The lifespan of circulating platelets is 5 to 9 days.
Megakaryocyte and platelet production is regulated by thrombopoietin, a hormone usually produced by the liver and kidneys.
Each megakaryocyte produces between 5,000 and 10,000 platelets.
Old platelets are destroyed by phagocytosis in the spleen and by Kupffer cells in the liver.
A reserve of platelets are stored in the spleen and are released when needed by sympathetically-induced splenic contraction.
Thrombus formation
Aggregation of platelets. Platelet rich human blood plasma (left vial) is a turbid liquid. Upon addition of ADP, platelets are activated and start to aggregate, forming white flakes (right vial).
The function of platelets is the maintenance of hemostasis. This is achieved primarily by the formation of thrombi, when damage to the endothelium of blood vessels occurs. On the converse, thrombus formation must be inhibited at times when there is no damage to the endothelium.
Activation
The inner surface of blood vessels is lined with a thin layer of endothelial cells that, in normal hemostasis, acts to inhibit platelet activation by producing nitric oxide, endothelial-ADPase, and PGI2. Endothelial-ADPase clears away the platelet activator, ADP.
Endothelial cells produce a protein called von Willebrand factor (vWF), a cell adhesion ligand, which helps endothelial cells adhere to collagen in the basement membrane. Under physiological conditions, collagen is not exposed to the bloodstream. vWF is secreted constitutively into the plasma by the endothelial cells, and is stored in granules within the endothelial cell and in platelets.
When the endothelial layer is injured, collagen, vWF and tissue factor from the subendothelium is exposed to the bloodstream. When the platelets contact collagen or vWF, they are activated (eg. to clump together). They are also activated by thrombin (formed with the help of tissue factor). They can also be activated by a negatively-charged surface, such as glass.
Platelet activation further results in the scramblase-mediated transport of negatively-charged phospholipids to the platelet surface. These phospholipids provide a catalytic surface (with the charge provided by phosphatidylserine and phosphatidylethanolamine) for the tenase and prothrombinase complexes. Calcium ions are essential for binding of these coagulation factors.
Shape change
Scanning electron micrograph of blood cells. From left to right: human erythrocyte, activated thrombocyte (platelet), leukocyte.
Activated platelets change in shape to become more spherical, and pseudopods form on their surface. Thus they assume a stellate shape.
Granule secretion
Platelets contain alpha and dense granules. Activated platelets excrete the contents of these granules into their canalicular systems and into surrounding blood. There are three types of granules:
delta granules (containing ADP or ATP, calcium, and serotonin)
lamda granules - similar to lysosomes and contain several hydrolytic enzymes.
α-granules (containing platelet factor 4, transforming growth factor-β1, platelet-derived growth factor, fibronectin, B-thromboglobulin, vWF, fibrinogen, and coagulation factors V and XIII).
Thromboxane A2 synthesis
Platelet activation initiates the arachidonic acid pathway to produce TXA2. TXA2 is involved in activating other platelets and its formation is inhibited by COX inhibitors, such as aspirin.
Adhesion and aggregation
Platelets aggregate, or clump together, using fibrinogen and vWF as a connecting agent. The most abundant platelet aggregation receptor is glycoprotein IIb/IIIa (gpIIb/IIIa); this is a calcium-dependent receptor for fibrinogen, fibronectin, vitronectin, thrombospondin, and von Willebrand factor (vWF). Other receptors include GPIb-V-IX complex (vWF) and GPVI (collagen).
Activated platelets will adhere, via glycoprotein (GP) Ia, to the collagen that is exposed by endothelial damage. Aggregation and adhesion act together to form the platelet plug. Myosin and actin filaments in platelets are stimulated to contract during aggregation, further reinforcing the plug.
Platelet aggregation is stimulated by ADP, thromboxane, and α2 receptor-activation, but inhibited by other inflammatory products like PGI2 and PGD2. Platelet aggregation is enhanced by exogenous administration of anabolic steroids.
Wound repair
The blood clot is only a temporary solution to stop bleeding; vessel repair is therefore needed. The aggregated platelets help this process by secreting chemicals that promote the invasion of fibroblasts from surrounding connective tissue into the wounded area to form a scar. The obstructing clot is slowly dissolved by the fibrinolytic enzyme, plasmin, and the platelets are cleared by phagocytosis.
Other functions
Clot retraction
Pro-coagulation
Inflammation
Cytokine signalling
Phagocytosis[10]
Cytokine signaling
In addition to being the chief cellular effector of hemostasis, platelets are rapidly deployed to sites of injury or infection, and potentially modulate inflammatory processes by interacting with leukocytes and by secreting cytokines, chemokines, and other inflammatory mediators[11][12][13][14]. Platelets also secrete platelet-derived growth factor (PDGF).
Role in disease
High and low counts
A normal platelet count in a healthy individual is between 150,000 and 450,000 per μl (microlitre) of blood (150–450 x 109/L)[15]. Ninety-five percent of healthy people will have platelet counts in this range. Some will have statistically abnormal platelet counts while having no demonstrable abnormality. However, if it is either very low or very high, the likelihood of an abnormality being present is higher.
Both thrombocytopenia and thrombocytosis may present with coagulation problems. In general, low platelet counts increase bleeding risks; however there are exceptions. For example, immune heparin-induced thrombocytopenia and thrombocytosis (high counts) may lead to thrombosis, although this is mainly when the elevated count is due to myeloproliferative disorder.
Low platelet counts are, in general, not corrected by transfusion unless the patient is bleeding or the count has fallen below 5 x 109/L. Transfusion is contraindicated in thrombotic thrombocytopenic purpura (TTP), as it fuels the coagulopathy. In patients undergoing surgery, a level below 50 x 109/L is associated with abnormal surgical bleeding, and regional anaesthetic procedures such as epidurals are avoided for levels below 80-100.
Normal platelet counts are not a guarantee of adequate function. In some states, the platelets, while being adequate in number, are dysfunctional. For instance, aspirin irreversibly disrupts platelet function by inhibiting cyclooxygenase-1 (COX1), and hence normal hemostasis. The resulting platelets are unable to produce new cyclooxygenase because they have no DNA. Normal platelet function will not return until the use of aspirin has ceased and enough of the affected platelets have been replaced by new ones, which can take over a week. Ibuprofen, another NSAID, does not have such a long duration effect, with platelet function usually returning within 24 hours[16], and taking ibuprofen before aspirin will prevent the irreversible effects of aspirin[17]. Uremia, a consequence of renal failure, leads to platelet dysfunction that may be ameliorated by the administration of desmopressin.
Medications
Oral agents, often used to alter/suppress platelet function:
aspirin
clopidogrel
cilostazol
ticlopidine
Intravenous agents, often used to alter/suppress platelet function:
abciximab
eptifibatide
tirofiban
Diseases
Disorders leading to a reduced platelet count:
Thrombocytopenia
Idiopathic thrombocytopenic purpura - also known as immune thrombocytopenic purpura (ITP)
Thrombotic thrombocytopenic purpura
Drug-induced thrombocytopenic purpura (for example heparin-induced thrombocytopenia (HIT))
Gaucher's disease
Aplastic anemia
Alloimmune disorders
Fetomaternal alloimmune thrombocytopenia
Some transfusion reactions
Disorders leading to platelet dysfunction or reduced count:
HELLP syndrome
Hemolytic-uremic syndrome
Chemotherapy
Dengue
Disorders featuring an elevated count:
Thrombocytosis, including essential thrombocytosis (elevated counts, either reactive or as an expression of myeloproliferative disease); may feature dysfunctional platelets
Disorders of platelet adhesion or aggregation:
Bernard-Soulier syndrome
Glanzmann's thrombasthenia
Scott's syndrome
von Willebrand disease
Hermansky-Pudlak Syndrome
Gray platelet syndrome
Disorders of platelet metabolism
Decreased cyclooxygenase activity, induced or congenital
Storage pool defects, acquired or congenital
Disorders that indirectly compromise platelet function:
Haemophilia
Disorders in which platelets play a key role:
Atherosclerosis
Coronary artery disease, CAD and myocardial infarction, MI
Cerebrovascular disease and Stroke, CVA (cerebrovascular accident)
Peripheral artery occlusive disease (PAOD)
Cancer [18]
Condition
Prothrombin time
Partial thromboplastin time
Bleeding time
Platelet count
Vitamin K deficiency or Warfarin
prolonged
prolonged
unaffected
unaffected
Disseminated intravascular coagulation
prolonged
prolonged
prolonged
decreased
Von Willebrand disease
unaffected
prolonged
prolonged
unaffected
Haemophilia
unaffected
prolonged
unaffected
unaffected
Aspirin
unaffected
unaffected
prolonged
unaffected
Thrombocytopenia
unaffected
unaffected
prolonged
decreased
Early Liver failure
prolonged
unaffected
unaffected
unaffected
End-stage Liver failure
prolonged
prolonged
prolonged
decreased
Uremia
unaffected
unaffected
prolonged
unaffected
Congenital afibrinogenemia
prolonged
prolonged
prolonged
unaffected
Factor V deficiency
prolonged
prolonged
unaffected
unaffected
Factor X deficiency as seen in amyloid purpura
prolonged
prolonged
unaffected
unaffected
Glanzmann's thrombasthenia
unaffected
unaffected
prolonged
unaffected
Bernard-Soulier syndrome
unaffected
unaffected
prolonged
decreased
Discovery
Brewer[19] traced the history of the discovery of the platelet. Although red blood cells had been known since van Leeuwenhoek (1632-1723), it was the German anatomist Max Schultze (1825-1874) who first offered a description of the platelet in his newly-founded journal Archiv für mikroscopische Anatomie[20]. He describes "spherules" to be much smaller than red blood cells that are occasionally clumped and may participate in collections of fibrous material. He recommends further study of the findings.
Giulio Bizzozero (1846-1901), building on Schultze's findings, used "living circulation" to study blood cells of amphibians microscopically in vivo. He is especially noted for discovering that platelets clump at the site of blood vessel injury, a process that precedes the formation of a blood clot. This observation confirmed the role of platelets in coagulation[21].
In transfusion medicine
Platelets are either isolated from collected units of whole blood and pooled to make a therapeutic dose or collected by apheresis, sometimes concurrently with plasma or red blood cells. The industry standard is for platelets to be tested for bacteria before transfusion to avoid septic reactions, which can be fatal.
Pooled whole-blood platelets, sometimes called "random" platelets, are made by taking a unit of whole blood that has not been cooled and placing it into a large centrifuge in what is referred to as a "soft spin." This splits the blood into three layers: the plasma, a "buffy coat" layer, which includes the platelets, and the white blood cells. These are expressed into different bags for storage.
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 not exposed to as many different donors and has less risk of transfusion-transmitted disease and other complications. Sometimes a person such as a cancer patient that requires routine transfusions of platelets will receive repeated donations from a specific donor to further minimize the risk.
Platelets are not cross-matched unless they contain a significant amount of red blood cells (RBCs), which results in a reddish-orange color to the product. This is usually associated with whole-blood platelets, as apheresis methods are more efficient than "soft spin" centrifugation at isolating the specific components of blood. An effort is usually made to issue type specific platelets, but this is not as critical as it is with RBCs.
Platelets collected by either method have a very short shelf life, typically five or seven days depending on the system used. This results in frequent problems with short supply, as testing the donations often requires up to a full day. Since there are no effective preservative solutions for platelets, they lose potency quickly and are best when fresh.
Platelets, either apheresis or random-donor platelets, can be processed through a volume reduction process. In this process, the platelets are spun in a centrifuge and the excess plasma is removed, leaving 10 to 100 ml of platelet concentrate. 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.[22] Volume reduced platelets have a shelf life of only four hours.
Metamorphosis 
