Platelet


Platelets or thrombocytes are a part of blood whose function is to react to bleeding from blood vessel injury by clumping to form a blood clot. Platelets have no cell nucleus; they are fragments of cytoplasm from megakaryocytes which reside in bone marrow or lung tissue, and then enter the circulation. Platelets are found only in mammals, whereas in other vertebrates, thrombocytes circulate as intact mononuclear cells.
One major function of platelets is to contribute to hemostasis: the process of stopping bleeding at the site where the lining of vessels has been interrupted. Platelets gather at the site and, unless the interruption is physically too large, they plug it. 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 is associated with activation of the coagulation cascade, with resultant fibrin deposition and linking. 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 cytokines and growth factors which can promote wound healing and regeneration of damaged tissues.

Term

The term thrombocyte came into use in the early 1900s and is sometimes used as a synonym for platelet; but not generally in the scientific literature, except as a root word for other terms related to platelets. The term thrombocytes are proper for mononuclear cells found in the blood of non-mammalian vertebrates: they are the functional equivalent of platelets, but circulate as intact cells rather than cytoplasmic fragments of bone marrow megakaryocytes.
In some contexts, the word thrombus is used interchangeably with the word clot, regardless of its composition. 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.

Structure

Structurally the platelet can be divided into four zones, from peripheral to innermost:
Circulating inactivated platelets are biconvex discoid structures, 2–3 μm in greatest diameter. Activated platelets have cell membrane projections covering their surface.
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.

Development

  • 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.
  • 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

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 involved in platelet dynamics. Despite much overlap, platelet function can be modeled in three steps:

Adhesion

formation on an intact endothelium is prevented by nitric oxide, prostacyclin, and CD39.
Endothelial cells attach to the subendothelial collagen by von Willebrand factor, 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

Inhibition

Factors from the lining of vessels stop platelets from activating. An intact endothelial lining inhibits platelet activation by producing nitric oxide, endothelial-ADPase, and PGI2. 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. 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 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, resulting in inositol 1,4,5-trisphosphate 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 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 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 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.

Components (consequences)

GPIIb/IIIa activation
Collagen-mediated GPVI signalling increases the platelet production of thromboxane A2 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, and those of other platelets. These receptors trigger intraplatelet signaling, which converts GPIIb/IIIa receptors to their active form to initiate aggregation.
Granule secretion
Platelets contain dense granules, lambda granules, and alpha granules. 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: