Editing Platelet (section)

===Activation===
[[File:Red White Blood cells.jpg|thumb|Scanning electron micrograph of blood cells. From left to right: human [[red blood cell|erythrocyte]], activated platelet, [[leukocyte]].]]

====Inhibition====
Factors from the lining of vessels stop platelets from activating. An intact endothelial lining ''inhibits'' platelet activation by producing [[nitric oxide]], endothelial-[[apyrase|ADPase]], and [[prostacyclin|PGI<sub>2</sub>]] (prostacyclin). Endothelial-ADPase degrades the platelet activator [[adenosine diphosphate|ADP]].{{citation needed|date=December 2021}}

Resting platelets maintain active calcium [[efflux (microbiology)|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 [[prostacyclin receptor|prostanoid]] receptors on the surface of resting platelets. This event stimulates the coupled [[Gs alpha subunit|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.{{citation needed|date=December 2021}}

ADP on the other hand binds to [[purinergic receptor]]s on the platelet surface. Since the thrombocytic purinergic receptor [[P2Y12]] is coupled to [[Gi alpha subunit|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]] [[receptor antagonist|antagonists]].{{citation needed|date=December 2021}} Data suggest that ADP activates the [[PI3K/Akt]] pathway during a first wave of aggregation, leading to thrombin generation and [[protease-activated receptor 1|PAR‐1]] activation, which evokes a second wave of aggregation.<ref name="JiangXu2013">{{cite journal |last1=Jiang |first1=L. |last2=Xu |first2=C. |last3=Yu |first3=S. |last4=Liu |first4=P. |last5=Luo |first5=D. |last6=Zhou |first6=Q. |last7=Gao |first7=C. |last8=Hu |first8=H. |title=A critical role of thrombin/PAR-1 in ADP-induced platelet secretion and the second wave of aggregation |journal=Journal of Thrombosis and Haemostasis |volume=11 |issue=5 |year=2013 |pages=930–940 |issn=1538-7933 |doi=10.1111/jth.12168 |pmid=23406164 |doi-access=free}}</ref>

====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.{{citation needed|date=December 2021}}

[[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 receptor]]s 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.{{citation needed|date=December 2021}}

====Components (consequences)====

=====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]], [[PTGS1|cyclo-oxygenase 1]], and [[thromboxane-A synthase]]. Platelets secrete thromboxane A2, which acts on the platelet's own [[thromboxane receptor]]s 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''.<ref name="pmid16036569"/>

=====Granule secretion=====
[[File:Platelet structure.png|right|thumb|Diagram of the structure of a platelet showing the granules]]
Platelets contain [[dense granules]], lambda granules, and [[alpha granule]]s. Activated platelets secrete the contents of these granules through their canalicular systems to the exterior. Bound and activated platelets degranulate to release platelet [[chemotactic]] agents to attract more platelets to the site of endothelial injury. Granule characteristics:
* [[Platelet alpha-granule|α granules (alpha granules)]] — containing [[P-selectin]], [[platelet factor 4]], [[TGF beta 1|transforming growth factor-β1]], [[platelet-derived growth factor]], [[fibronectin]], [[B-thromboglobulin]], [[von Willebrand factor|vWF]], [[fibrinogen]], and [[coagulation factor]]s [[factor V|V]] and [[factor XIII|XIII]]
* [[dense granule|δ granules (delta or dense granules)]] — containing [[adenosine diphosphate|ADP]] or [[adenosine triphosphate|ATP]], [[calcium]], and [[serotonin]]
* γ granules (gamma granules) — similar to [[lysosome]]s 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.<ref>{{cite journal |vauthors=Litvinov RI, Weisel JW, Andrianova IA, Peshkova AD, Minh GL |title=Differential Sensitivity of Various Markers of Platelet Activation with Adenosine Diphosphate |journal=BioNanoScience |volume=9 |issue=1 |pages=53–58 |date=2018 |doi=10.1007/s12668-018-0586-4 |pmid=31534882 |pmc=6750022}}</ref> Mitochondrial hyperpolarization is a key event in initiating morphology changes.<ref>{{cite journal |vauthors=Matarrese P, Straface E, Palumbo G, Anselmi M, Gambardella L, Ascione B, Del Principe D, Malorni W |title=Mitochondria regulate platelet metamorphosis induced by opsonized zymosan A — activation and long-term commitment to cell death |journal=The FEBS Journal |volume=276 |issue=3 |pages=845–856 |date=February 2009 |pmid=19143843 |doi=10.1111/j.1742-4658.2008.06829.x |doi-access=free}}</ref> 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 are best seen via [[scanning electron microscopy]]. The three steps along this path are named ''early dendritic'', ''early spread,'' and ''spread''. The surface of the unactivated platelet looks similar to the surface of the brain–a wrinkled appearance from numerous shallow folds that increase the surface area; ''early dendritic'', an octopus with multiple arms and legs; ''early spread'', an uncooked frying egg in a pan, the "yolk" is 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 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]].<ref>{{cite journal |vauthors=White JG |title=An overview of platelet structural physiology |journal=Scanning Microsc. |volume=1 |issue=4 |pages=1677–1700 |date=December 1987 |pmid=3324323}}</ref> 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.<ref>{{cite journal |vauthors=Behnke O |title=The morphology of blood platelet membrane systems |journal=Series Haematologica |volume=3 |issue=4 |pages=3–16 |date=1970 |pmid=4107203}}</ref>

=====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 [[phospholipid]]s 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.<ref name=Bouchard10>{{cite journal |vauthors=Bouchard BA, Mann KG, Butenas S |title=No evidence for tissue factor on platelets |journal=Blood |volume=116 |issue=5 |pages=854–5 |date=August 2010 |pmid=20688968 |pmc=2918337 |doi=10.1182/blood-2010-05-285627}}</ref><ref>{{cite journal |vauthors=Ahmad SS, Rawala-Sheikh R, Walsh PN |title=Components and assembly of the factor X activating complex |journal=Seminars in Thrombosis and Hemostasis |volume=18 |issue=3 |pages=311–323 |date=1992 |pmid=1455249 |doi=10.1055/s-2007-1002570|s2cid=28765989 }}</ref> Human platelets do not express [[tissue factor]].<ref name=Bouchard10/> Rat platelets do express tissue factor protein and carry both tissue factor pre-mRNA and mature mRNA.<ref>{{cite journal |vauthors=Tyagi T, Ahmad S, Gupta N, Sahu A, Ahmad Y, Nair V, Chatterjee T, Bajaj N, Sengupta S, Ganju L, Singh SB, Ashraf MZ |title=Altered expression of platelet proteins and calpain activity mediate hypoxia-induced prothrombotic phenotype |journal=Blood |volume=123 |issue=8 |pages=1250–60 |date=February 2014 |pmid=24297866 |doi=10.1182/blood-2013-05-501924 |doi-access=free}}</ref>