Platelet

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Platelets
Platelets2.JPG
Image from a light microscope (500 ×) from a Giemsa-stained peripheral blood smear showing platelets (blue) surrounded by red blood cells

Platelets (also called "thrombocytes") are biconvex discs, fragments of cytoplasm 2–3 µm in diameter,[1] found only in the blood of mammals. Platelets form by budding off from megakaryocytes[2] in the bone marrow, and then entering the circulation. They help stop bleeding.

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.

The main function of platelets is to contribute to hemostasis: the process of stopping bleeding at the site of interrupted endothelium. Hemostasis is a two-step process; primary hemostasis involves platelets coming together to form a platelet plug, while in secondary hemostasis the coagulation factors form a fibrin meshwork. During primary hemostasis, platelets go through three stages: first, they stick to substances outside the interrupted endothelium (adhesion); second, they change shape, turn on receptors and secrete chemical messengers (activation); and third, they stick to each other (aggregation). Addition of coagulation factors to this platelet plug via the coagulation cascade results in fibrin deposition, which both cross-links and links to platelets to complete formation of the clot.

Any abnormality of platelets is a thrombocytopathy.[3] Low platelet concentration is thrombocytopenia and is due to either decreased production or increased destruction. Elevated platelet concentration is thrombocytosis and is either reactive such as to blood loss, or due to unregulated production: one of the myeloprolerative neoplasms.

Normal platelets can respond to an abnormality on the vessel wall rather than to hemorrhage, resulting in inappropriate platelet adhesion/activation and thrombosis. Examples are: extending the fibrin clot of venous thrombosis; extending an unstable or ruptured arterial plaque, causing arterial thrombosis; and responding to arteritis with thrombi. An arterial thrombus may partially obstruct blood flow, causing downstream ischemia; or completely obstruct it, causing downstream infarction.

Discovery and naming[edit]

The German anatomist Max Schultze (1825–1874) was the first to describe what he called "spherules", which he noted were much smaller than red blood cells, occasionally clumped, and were sometimes found in collections of fibrin material[4][5] .

Osler observed them and called them blood plaques.

Giulio Bizzozero (1846–1901), building on Schultze's findings, in 1882 used "living circulation" to study the blood of amphibians microscopically in vivo.  He named Schultz's spherules (It.) piastrine: little plates, which later became platelets. He observed that platelets clump at the site of blood vessel injury, a process that precedes the formation of a clot. This observation confirmed the role of platelets in coagulation.[6]

The term thrombocyte (clot cell) arose in the early 1900's and is sometimes used as a synonym for platelet; but not generally in the scientific literature, especially since the discovery in non-mammalian vertebrates of nucleated cells that have a hemostatic function and were given the name thrombocyte.

Measurement[edit]

Platelet concentration is measured either manually using a hemacytometer or by placing blood in an automated analyzer, which uses light scattering or electrical impedance to count the platelets. The normal range (95% of population) for platelets is 150,000 to 400,000 per cubic millimeter, (the same as per microliter).[7]  or 150 - 400 X 109/L. This normal range varies slightly in different laboratories.

The platelet concentration is often referred to informally as the platelet count without stating the units.

Symptoms of platelet disorders[edit]

Spontaneous bleeding can be caused by deficient numbers of platelets, dysfunctional platelets, or very excessive numbers of platelets: over 1.5 million/microliter. The bleeding from skin cuts is prompt and excessive and can be controlled by pressure. Spontaneous bleeding into the skin causes petechiae; into mucous membranes causes bleeding gums, nose bleed, and gastrointestinal bleeding. Intraretinal bleeding and intracranial bleeding can also occur.

Excessive numbers of platelets, and normal platelets responding to abnormal vessel walls, can result in venous thrombosis and arterial thrombosis. The symptoms depend on the site of thrombosis.

Kinetics[edit]

Platelets derive from blood stem cells
  • Megakaryocyte and platelet production is regulated by thrombopoietin, a hormone produced in the liver and kidneys.
  • Each megakaryocyte produces between 5,000 and 10,000 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 life span of circulating platelets is 8 to 9 days[8].
  • Old platelets are destroyed by phagocytosis in the spleen and liver.

Dynamics[edit]

3D Rendering of Platelets

The separation of platelet dynamics into three stages is useful, but artificial. In fact, each stage is initiated in rapid succession, and each continues until the trigger for that stage is no longer present, so there is overlap.

Adhesion[edit]

Endothelial cells produce von Willebrand factor (vWF), a cell adhesion ligand, which adheres endothelial cells to collagen in the basement membrane. vWF is secreted constitutively into the bloodstream by the endothelial cells, and is stored in endothelial cell and platelet granules.

When the endothelial layer is injured, collagen and vWF anchor platelets to the subendothilium. Platelet GP-V-IX receptor binds with vWF; and GPVI receptor with collagen. (In vitro, platelets can adhere to any negatively charged surface, such as glass.)

Activation[edit]

Scanning electron micrograph of blood cells. From left to right: human erythrocyte, activated platelet, leukocyte.

The intact endothelial lining inhibits platelet activation by producing nitric oxide, endothelial-ADPase, and PGI2.  Endothelial-ADPase degrades the platelet activator, ADP.

Platelet activation begins seconds after adhesion occurs.

Platelet activating substances (ligands) operate through surface G protein coupled receptors to turn on signaling pathways within the platelet. Families of three G proteins (Gi, Gq, G12) operate together for full activation. Most, but not all, effects are mediated via cAMP. Another important ligand for activation is the thrombin receptor.

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.

Non-physiological flow conditions (especially high values of shear stress) caused by arterial stenosis, or artificial devices such mechanical heart valves and blood pumps, can lead to platelet activation.[9]

Shape change[edit]

Intraplatelet calcium concentration increases, stimulating actin and myosin filaments, resulting in platelets becoming more spherical and with pseudopods on their surface.  Thus they assume a stellate shape: morphological evidence of the activated platelet.

Granule secretion[edit]

Diagram of the structure of a platelet showing the granules

Platelets contain dense granules, lambda granules and alpha granules. Activated platelets secrete the contents of these granules through their canalicular systems to the exterior.  Granule characteristics:

Thromboxane A2 synthesis[edit]

Platelet activation initiates the arachidonic acid pathway to synthesize and secrete TXA2.  TXA2 acts on both its own thromboxane receptors, and those of other platelets.

Aggregation[edit]

Platelet clumps in a blood smear

Aggregation begins minutes after activation, and occurs as a result of turning on the GPIIb/IIIa receptor, which allows it to bind with vWF or fibrinogen.[10] There are 50-100 receptors per platelet[11]. They can be turned on by stimulation of any one of at least nine different platelet surface receptors: existing GpIIb/IIIa receptors change shape (curled to straight) and thus become capable of binding.

Classically it was thought that this was the only mechanism involved in aggregation, but three new mechanisms have been identified which can initiate aggregation, depending on the velocity of blood flow (i.e. shear range)[12].

Platelet-coagulation factor interactions[edit]

In addition to interacting with vWF and fibrin, platelets interact with thrombin, Factors X, Va, VIIa, XI, IX, and prothrombin to complete clot formation via the coagulation cascade. (Citations to follow)

Wound repair[edit]

The blood clot is only a temporary solution to stop bleeding; vessel repair is needed. The aggregated platelets secrete substances that promote the invasion of fibroblasts from surrounding connective tissue into the wound to resorb the clot and form a scar. The fibrin is slowly dissolved by the fibrinolytic enzyme, plasmin, and the platelets are cleared by phagocytosis.[13]

Clot formation in non-mammalian vertebrates[edit]

Non-mammalian vertebrates instead of having platelets have thrombocytes which have a nucleus and resemble B lymphocytes in morphology. They aggregate in response to thrombin (but not to ADP, serotonin, nor adrenaline, as platelets do).[14][15]

Role in inflammation[edit]

In addition to being the 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.[16][17][18][19] Platelets also secrete platelet-derived growth factor (PDGF).

Disorders of platelets[edit]

Disorders associated with a reduced platelet count:

Alloimmune disorders

Disorders associated with platelet dysfunction or reduced count:

Disorders associated with an elevated platelet count:

Disorders of platelet adhesion or aggregation:

Disorders of platelet activation:

  • ADP Receptor defect

Disorders of platelet granule amount or release

Disorders of platelet metabolism

  • Decreased cyclooxygenase activity, induced or congenital
  • Storage pool defects, acquired or congenital

Disorders associated with compromised platelet signaling:

Platelet rich plasma in wound healing[edit]

Platelets release platelet-derived growth factor (PDGF), a potent chemotactic 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 to wound healing.[24]

Drugs affecting platelets[edit]

Some drugs used to treat inflammation have the unwanted side effect of suppressing normal platelet function. These are the non-steroidal anti-inflammatory agents (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,[25] and taking ibuprofen before aspirin prevents the irreversible effects of aspirin.[26] 

Uremia, a consequence of renal failure, leads to platelet dysfunction that may be ameliorated by the administration of desmopressin.

Drugs which suppress platelet function are used to prevent thrombus formation. The oral agents are aspirin, clopidogrel, cilostazol, ticlopidine, ticagrelor and prasugrel. The intravenous agents are abciximab, eptifibatide, and tirofiban.

Drugs which stimulate production of platelets and thus increase platelet count are Oprelvekin, Romiplostim, Eltrombopag.

Platelet transfusion[edit]

Platelet transfusion is most frequently used to correct unusually low platelet counts, either to prevent spontaneous bleeding (typically at counts below (10–15)×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.[27] 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.[28] Finally, platelets may be transfused as part of a massive transfusion protocol, in which the three major blood components (red blood cells, plasma, and platelets) are transfused to address severe hemorrhage. Platelet transfusion is contraindicated in thrombotic thrombocytopenic purpura (TTP), as it fuels the coagulopathy.

Platelet concentrate.

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. Recently the AABB Industry Standards for Blood Banks and Transfusion Services (5.1.5.1) has allowed for use of pathogen reduction technology as an alternative to bacterial screenings in platelets.[29]

Pooled whole-blood platelets, sometimes called “random” platelets, are made primarily by two methods.[30] 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 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 who requires routine transfusions of platelets will receive repeated donations from a specific donor to further minimize the risk. Pathogen reduction of platelets using for example, riboflavin and UV light treatments can also be carried out to reduce the infectious load of pathogens contained in donated blood products, thereby reducing the risk of transmission of transfusion transmitted diseases.[31][32]

Platelets do not need to be cross-matched to ensure immune compatibility between donor and recipient unless they contain a significant amount of red blood cells (RBCs). The presence of RBCs results in a reddish-orange color to the product, and is usually associated with whole-blood platelets. Apheresis methods are more efficient than “soft spin” centrifugation at isolating the specific components of blood needed. 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 days. 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 are stored under constant agitation at 20–24 °C (68-75.2 °F). Storage at room temperature provides an environment where any bacteria that are introduced to the blood component during the collection process may proliferate and subsequently cause bacteremia in the patient. Regulations are in place in the United States that require products to be tested for the presence of bacterial contamination before transfusion.[33]

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 the excess 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.[34] Volume reduced platelets have a shelf life of only four hours.[35]

References[edit]

  1. ^ Campbell, Neil A. (2008). Biology (8th ed.). London: Pearson Education. p. 912. ISBN 978-0-321-53616-7. "Platelets are 2–3µm diameter." 
  2. ^ Stenberg, P. E.; Levin, J (1989). "Mechanisms of platelet production". Blood cells 15 (1): 23–47. PMID 2649182. 
  3. ^ Maton, Anthea; Jean Hopkins, Charles William McLaughlin, Susan Johnson, Maryanna Quon Warner, David LaHart, Jill D. Wright (1993). Human Biology and Health. Englewood Cliffs NJ: Prentice Hall. ISBN 0-13-981176-1. 
  4. ^ Brewer DB (2006). "Max Schultze (1865), G. Bizzozero (1882) and the discovery of the platelet". Br. J. Haematol. 133 (3): 251–8. doi:10.1111/j.1365-2141.2006.06036.x. PMID 16643426. 
  5. ^ Schultze M (1865). "Ein heizbarer Objecttisch und seine Verwendung bei Untersuchungen des Blutes". Arch Mikrosc Anat 1 (1): 1–42. doi:10.1007/BF02961404. 
  6. ^ Bizzozero, J. (1882). "Über einen neuen Forrnbestandteil des Blutes und dessen Rolle bei der Thrombose und Blutgerinnung". Arch Pathol Anat Phys Klin Med 90 (2): 261–332. doi:10.1007/BF01931360. 
  7. ^ Parveen June Kumar, Michael L. Clark (2005). "8". Clinical Medicine (6th ed.). Elsevier Saunders. p. 469. ISBN 0-7020-2763-4. 
  8. ^ Harker, L. A.; Roskos, L. K.; Marzec, U. M.; Carter, R. A.; Cherry, J. K.; Sundell, B; Cheung, E. N.; Terry, D; Sheridan, W (2000). "Effects of megakaryocyte growth and development factor on platelet production, platelet life span, and platelet function in healthy human volunteers". Blood 95 (8): 2514–22. PMID 10753829.  edit
  9. ^ Kroll, M., J. Hellums, et al. (1996). "Platelets and shear stress." Blood 88(5) 1525-1541
  10. ^ Yip, J.; Shen, Y.; Berndt, MC.; Andrews, RK. (Feb 2005). "Primary platelet adhesion receptors.". IUBMB Life 57 (2): 103–8. doi:10.1080/15216540500078962. PMID 16036569. 
  11. ^ Phillips, D. R.; Charo, I. F.; Scarborough, R. M. (1991). "GPIIb-IIIa: The responsive integrin". Cell 65 (3): 359–62. PMID 2018971.  edit
  12. ^ Coller, B. S.; Cheresh, D. A.; Asch, E; Seligsohn, U (1991). "Platelet vitronectin receptor expression differentiates Iraqi-Jewish from Arab patients with Glanzmann thrombasthenia in Israel". Blood 77 (1): 75–83. PMID 1702031.  edit
  13. ^ Movat, HZ; Weiser, WJ; Glynn, MF; Mustard, JF (December 1965). "Platelet phagocytosis and aggregation.". The Journal of Cell Biology 27 (3): 531–43. doi:10.1083/jcb.27.3.531. PMID 4957257. 
  14. ^ Blood v. 118 no. 13, 3661-3669 (29 September 2011); doi:10.1182/blood-2011-02-338244 Occlusive thrombi arise in mammals but not birds in response to arterial injury: evolutionary insight into human cardiovascular disease. Alec A. Schmaier, et al. [1]
  15. ^ Nature 220, 509 - 510 (2 November 1968); doi:10.1038/220509a0 ADP is not Involved in Thrombin-Induced Aggregation of Thrombocytes of a Non-mammalian Vertebrate FRANK A. BELAMARICH, DAVID SHEPRO & MARJA KIEN Biology Department, Boston University, Massachusetts.[2]
  16. ^ Weyrich AS, Zimmerman GA (2004). "Platelets: signaling cells in the immune continuum". Trends Immunol. 25 (9): 489–95. doi:10.1016/j.it.2004.07.003. PMID 15324742. 
  17. ^ Wagner, DD; Burger, PC (December 2003). "Platelets in inflammation and thrombosis.". Arteriosclerosis, thrombosis, and vascular biology 23 (12): 2131–2137. doi:10.1161/01.ATV.0000095974.95122.EC. PMID 14500287. 
  18. ^ Diacovo, TG; Puri, KD; Warnock, RA; Springer, TA; von Andrian, UH (Jul 12, 1996). "Platelet-mediated lymphocyte delivery to high endothelial venules.". Science 273 (5272): 252–5. doi:10.1126/science.273.5272.252. PMID 8662511. 
  19. ^ Iannacone M. et al. (2005). "Platelets mediate cytotoxic T lymphocyte-induced liver damage". Nat Med 11 (11): 1167–9. doi:10.1038/nm1317. PMC 2908083. PMID 16258538. 
  20. ^ Erpenbeck L, Schön MP (2010). "Deadly allies: the fatal interplay between platelets and metastasizing cancer cells". Blood 115 (17): 3427–36. doi:10.1182/blood-2009-10-247296. PMC 2867258. PMID 20194899. 
  21. ^ Pleass RJ (2009). "Platelet power: sticky problems for sticky parasites?". Trends Parasitol. 25 (7): 296–9. doi:10.1016/j.pt.2009.04.002. PMC 3116138. PMID 19539528. 
  22. ^ Kornerup, KN; Page, CP (August 2007). "The role of platelets in the pathophysiology of asthma.". Platelets 18 (5): 319–28. doi:10.1080/09537100701230436. PMID 17654302. 
  23. ^ Laidlaw, TM; Kidder, MS; Bhattacharyya, N; Xing, W; Shen, S; Milne, GL; Castells, MC; Chhay, H; Boyce, JA (Apr 19, 2012). "Cysteinyl leukotriene overproduction in aspirin-exacerbated respiratory disease is driven by platelet-adherent leukocytes.". Blood 119 (16): 3790–8. doi:10.1182/blood-2011-10-384826. PMC 3335383. PMID 22262771. 
  24. ^ Gawaz, M; Vogel, S (2013). "Platelets in tissue repair: Control of apoptosis and interactions with regenerative cells". Blood 122 (15): 2550–4. doi:10.1182/blood-2013-05-468694. PMID 23963043. 
  25. ^ "Platelet Function after Taking Ibuprofen for 1 Week". Annals of internal medicine 142 (7): I54. 2005. PMID 15809457. 
  26. ^ Rao, GH; Johnson, GG; Reddy, KR; White, JG (1983). "Ibuprofen protects platelet cyclooxygenase from irreversible inhibition by aspirin". Arteriosclerosis (Dallas, Tex.) 3 (4): 383–8. doi:10.1161/01.ATV.3.4.383. PMID 6411052. 
  27. ^ Van Veen, Joost J.; Nokes, Timothy J.; Makris, Mike (1 January 2010). "The risk of spinal haematoma following neuraxial anaesthesia or lumbar puncture in thrombocytopenic individuals". British Journal of Haematology 148 (1): 15–25. doi:10.1111/j.1365-2141.2009.07899.x. PMID 19775301. 
  28. ^ Roback J, Grossman B, Harris T, Hillyer C, eds. (2011). Technical Manual, 17th ed. Bethesda, MD: AABB. p. 580. ISBN 978-1-56395-315-6. 
  29. ^ American Association of Blood Banks Standards for Blood Banks and Transfusion Services, Bethesda, MD: 22nd ed, AABB, 2003, Section 5.1.5.1.
  30. ^ Hogman, C. F. (1992). "New trends in the preparation and storage of platelets". Transfusion 32 (1): 3–6. doi:10.1046/j.1537-2995.1992.32192116428.x. PMID 1731433. 
  31. ^ Ruane, Patrick H.; Edrich, Richard; Gampp, Deanna; Keil, Shawn D.; Leonard, R. Lynne; Goodrich, Raymond P. (1 June 2004). "Photochemical inactivation of selected viruses and bacteria in platelet concentrates using riboflavin and light". Transfusion 44 (6): 877–885. doi:10.1111/j.1537-2995.2004.03355.x. PMID 15157255. 
  32. ^ Perez-Pujol, S. et al. (2005). "Effects of a New Pathogen-Reduction Technology (Mirasol PRT) on Functional Aspects of Platelet Concentrates". Transfusion 45 (6): 911–919. doi:10.1111/j.1537-2995.2005.04350.x. PMID 15934989. 
  33. ^ AABB Standards for Blood Banks and Transfusion Services 26th Edition Bethesda, MD: AABB, 2009.
  34. ^ Schoenfeld H, Spies C, Jakob C (2006). "Volume-reduced platelet concentrates". Curr. Hematol. Rep. 5 (1): 82–8. PMID 16537051. 
  35. ^ CBBS: Washed and volume-reduced Plateletpheresis units. Cbbsweb.org (2001-10-25). Retrieved on 2011-11-14.

External reading[edit]

Michelson, Alan D. (2013). Platelets. London ; Waltham, MA: Academic Press. ISBN 0-12-387837-3.