viral infections have thrombocytopenia, thus reducing their contribution to inflammation. platelet-leukocyte aggregates (plas) found in circulation are typical in sepsis or inflammatory bowel disease, showing the connection between thrombocytes and immune cells. the platelet cell membrane has receptors for collagen. following the rupture of the blood vessel wall, the platelets are exposed and they adhere to the collagen in the surrounding connective tissue. immunothrombosis as hemostasis is a basic function of thrombocytes in mammals, it also has its uses in possible infection confinement. in case of injury, platelets, together with the coagulation cascade, form the first line of defense by forming a blood clot. thus, hemostasis and host defense were intertwined in evolution. for example, in the atlantic horseshoe crab (living fossil estimated to be over 400 million years old), the only blood cell type, the amebocyte, facilitates both the hemostatic function and the encapsulation and phagocytosis of pathogens by means of exocytosis of intracellular granules containing bactericidal defense molecules. blood clotting supports immune function by trapping the pathogenic bacteria within. although 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, directed thrombosis, called immunothrombosis, can locally control the spread of the infection. the thrombosis is directed in concordance of platelets, neutrophils and monocytes. 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. in turn, the 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 its negatively charged surface to the factor xii. other neutrophil secretions, such as proteolytic enzymes which cleave coagulation inhibitors, also bolster the process. in case of imbalance throughout the regulation of immunothrombosis, this process can quickly become aberrant. regulatory defects in immunothrombosis are suspected to be a major factor in causing pathological thrombosis in many forms, such as disseminated intravascular coagulation (dic) or deep vein thrombosis. dic in sepsis is a prime example of both the disregulated coagulation process as well as an undue systemic inflammatory response, resulting in a multitude of microthrombi of similar composition to that in physiological immunothrombosis – fibrin, platelets, neutrophils and nets. inflammation platelets are rapidly deployed to sites of injury or infection, and potentially modulate inflammatory processes by interacting with leukocytes and secreting cytokines, chemokines, and other inflammatory mediators. platelets also secrete platelet-derived growth factor (pdgf). platelets modulate neutrophils by forming platelet-leukocyte aggregates (plas). these formations induce upregulated production of αmβ2 (mac-1) integrin in neutrophils. interaction with plas also induce degranulation and increased phagocytosis in neutrophils. platelets are also the largest source of soluble cd40l which induces production of reactive oxygen species (ros) and upregulate expression of adhesion molecules, such as e-selectin, icam-1 and vcam-1, in neutrophils, activates macrophages and activates cytotoxic response in t and b lymphocytes. recently, the belief that mammalian platelets lacking nucleus are unable of autonomous locomotion was disproven. in fact, the 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, being able to fully envelop them in their open canalicular system (ocp), leading to proposed name of the process being "covercytosis", rather than phagocytosis, as ocs is merely an invagination of outer plasma membrane. these platelet-bacteria bundles are then used as an interaction platform for neutrophils which destroy the bacteria using the netosis and phagocytosis. platelets also participate in chronic inflammatory disease, such as synovitis or rheumatoid arthritis. platelets are activated by collagen receptor glycoprotein iv (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, maintaining the microvesicle production. adaptive immunity activated platelets are able to participate in adaptive immunity, interacting with antibodies. they are able to specifically bind igg through fcγriia, a receptor for the constant fragment (fc) of igg. when activated and bound to igg opsonised bacteria, the platelets subsequently release reactive oxygen species (ros), antimicrobial peptides, defensins, kinocidins and proteases, killing the bacteria directly. platelets also secrete proinflammatory and procoagulant mediators such as inorganic polyphosphates or platelet factor 4 (pf4), connecting innate and adaptive immune responses. signs and symptoms of disorders spontaneous and excessive bleeding can occur because of platelet disorders. this bleeding can be caused by deficient numbers of platelets, dysfunctional platelets, or very excessive numbers of platelets: over 1.0 million/microliter. (the excessive numbers create a relative von willebrand factor deficiency due to sequestration.) one can get a clue as to whether bleeding is due to a platelet disorder or a coagulation factor disorder by the characteristics and location of the bleeding.: 815, table 39-4 all of the following suggest platelet bleeding, not coagulation bleeding: the bleeding from a skin cut such as a razor nick 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 site of thrombosis. measurement and testing measurement platelet concentration in the blood (i.e. platelet count), is measured either manually using a hemocytometer, or by placing blood in an automated platelet analyzer using particle counting, such as a coulter counter or optical methods. most common blood testing methods include platelet count in their measurements, usually reported as (plt). platelet concentrations vary between individuals and over time, with the population average being between 250,000 and 260,000 cells per mm3 (equivalent to per microliter), but the typical laboratory accepted normal range is between 150,000 to 400,000 cells per mm3 or 150–400 × 109 per liter. on for example optical densitometry, a first and second wave of platelet aggregation is seen, in this case for an adp-initiated aggregation. on a stained blood smear, platelets appear as dark purple spots, about 20% the diameter of red blood cells. the smear is used to examine platelets for size, shape, qualitative number, and clumping. a healthy adult typically has 10 to 20 times more red blood cells than platelets. bleeding time bleeding time was first developed as a test of platelet function by duke in 1910. duke's test measured the time taken for bleeding to stop from a standardized wound in the ear lobe which was blotted every 30 seconds. the normal time for bleeding to stop was less than 3 minutes. more modern techniques are now used. a normal bleeding time reflects sufficient platelet numbers and function, plus normal microvasculature. multiple electrode aggregometry main article: multiple electrode aggregometry in multiple electrode aggregometry, anticoagulated whole blood is mixed with saline and a platelet agonist in a single-use cuvette with two pairs of electrodes. the increase in impedance between the electrodes as platelets aggregate onto them, is measured and visualized as a curve. platelet aggregation function by disorders and agonists adpepinephrinecollagenristocetin p2y receptor defect (including clopidogrel) decreasednormalnormalnormal adrenergic receptor defect normaldecreasednormalnormal collagen receptor defect normalnormaldecreased or absentnormal von willebrand disease bernard–soulier syndrome normalnormalnormaldecreased or absent glanzmann's thrombasthenia afibrinogenemia decreaseddecreaseddecreasednormal or decreased storage pool deficiency absent second wavepartial aspirin or aspirin-like disorder absent second waveabsentnormal light transmission aggregometry in light transmission aggregometry (lta), platelet-rich plasma is placed between a light source and a photocell. unaggregated plasma allows relatively little light to pass through. after adding an agonist, the platelets aggregate, resulting in greater light transmission, which is detected by the photocell. pfa-100 the pfa-100 (platelet function assay - 100) is a system for analysing platelet function in which citrated whole blood is aspirated through a disposable cartridge containing an aperture within a membrane coated with either collagen and epinephrine or collagen and adp. these agonists induce platelet adhesion, activation and aggregation, leading to rapid occlusion of the aperture and cessation of blood flow termed the closure time (ct). an elevated ct with epi and collagen can indicate intrinsic defects such as von willebrand disease, uremia, or circulating platelet inhibitors. the follow-up test involving collagen and adp is used to indicate if the abnormal ct with collagen and epi was caused by the effects of acetyl sulfosalicylic acid (aspirin) or medications containing inhibitors. disorders adapted from:: vii low platelet concentration is called thrombocytopenia, and is due to either decreased production or increased destruction. elevated platelet concentration is called thrombocytosis, and is either congenital, reactive (to cytokines), or due to unregulated production: one of the myeloproliferative neoplasms or certain other myeloid neoplasms. a disorder of platelet function is called a thrombocytopathy or a platelet function disorder. 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: namely, 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 tissue death. the three broad categories of platelet disorders are "not enough", "dysfunctional", and "too many".: vii thrombocytopenia immune thrombocytopenia (itp) – formerly known as immune thrombocytopenic purpura and idiopathic thrombocytopenic purpura splenomegaly gaucher's disease familial thrombocytopenia chemotherapy babesiosis dengue fever onyalai thrombotic thrombocytopenic purpura hellp syndrome hemolytic–uremic syndrome drug-induced thrombocytopenic purpura (five known drugs – most problematic is heparin-induced thrombocytopenia (hit) pregnancy-associated neonatal alloimmune associated aplastic anemia transfusion-associated pseudothrombocytopenia vaccine-induced immune thrombotic thrombocytopenia (vitt) altered platelet function (thrombocytopathy) congenital disorders of adhesion bernard–soulier syndrome disorders of activation disorders of granule amount or release hermansky–pudlak syndrome gray platelet syndrome adp receptor defect decreased cyclooxygenase activity platelet storage pool deficiency disorders of aggregation glanzmann's thrombasthenia wiskott–aldrich syndrome disorders of coagulant activity coat platelet defect scott syndrome acquired disorders of adhesion paroxysmal nocturnal hemoglobinuria asthma aspirin-exacerbated respiratory disease (aerd/samter's triad) cancer malaria decreased cyclooxygenase activity thrombocytosis and thrombocythemia reactive chronic infection chronic inflammation malignancy hyposplenism (post-splenectomy) iron deficiency acute blood loss myeloproliferative neoplasms – platelets are both elevated and activated essential thrombocythemia polycythemia vera associated with other myeloid neoplasms congenital pharmacology anti-inflammatory drugs some drugs used to treat inflammation have the unwanted side effect of suppressing normal platelet function. these are the non-steroidal anti-inflammatory drugs (nsaids). 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, and taking ibuprofen before aspirin prevents the irreversible effects of aspirin. drugs that suppress platelet function these drugs are used to prevent thrombus formation. oral agents aspirin clopidogrel cilostazol ticlopidine ticagrelor prasugrel drugs that stimulate platelet production thrombopoietin mimetics desmopressin factor viia intravenous agents abciximab eptifibatide tirofiban others: oprelvekin, romiplostim, eltrombopag, argatroban therapies transfusion main article: platelet transfusion indications platelet transfusion is most frequently used to correct unusually low platelet counts, either to prevent spontaneous bleeding (typically at counts below 10×109/l) or in anticipation of medical procedures that will necessarily involve some bleeding. for example, in patients undergoing surgery, a level below 50×109/l is associated with abnormal surgical bleeding, and regional anaesthetic procedures such as epidurals are avoided for levels below 80×109/l. platelets may also be transfused when the platelet count is normal but the platelets are dysfunctional, such as when an individual is taking aspirin or clopidogrel. finally, platelets may be transfused as part of a massive transfusion protocol, in which the three major blood components