Platelets are cell fragments circulating in the blood. Specifically, they are the fragments of a very large bone marrow cell called a megakaryocyte (mega=big, karyo=nucleus, cyte=cell). Normally, a multitude of platelets flow through the blood stream without sticking to each other, or any other cell. However, when platelets are stimulated by the proteins (and other chemicals) that are released by tissue injuries, they aggregate together to form plugs that can fill breaks in blood vessels and stop bleeding. Platelets also form the substrate for the function of the soluble protein clotting cascade, and platelets can help activate this important hemostasis mechanism.
When the number of circulating platelets is very low, or when the functional quality of even a perfectly adequate number of platelets is poor, excessive bleeding can occur. Very high numbers of circulating platelets may increase the risk of thrombosis, or paradoxically increase the risk of bleeding.
Anatomy of a platelet
Like red blood cells, platelets have no cell nucleus. Both platelets and erythrocytes (another name for red blood cells) are discoid (disc shaped), but the shape of red blood cells is smooth and the shape of platelets is irregular. Platelets are relatively small compared to other blood cells, and measure 1.5–3.0 μm in diameter. Unlike red blood cells, platelets contain no pigment and are both clear and colorless.
The body has a very limited reserve of platelets, so they can be rapidly depleted. They contain RNA, a canalicular system, and several different types of granules; lysosomes (containing acid hydrolases), dense bodies (containing ADP, ATP serotonin and calcium) and alpha granules (containing fibrinogen, factor V, vitronectin, thrombospondin and von Willebrand factor), the contents of which are released upon activation of the platelet. These granule contents play an important role in both hemostasis and in the inflammatory response.
Platelets are produced in the bone marrow; the progenitor cell for platelets is the megakaryocyte. This large, multinucleated cell sheds platelets into the circulation. Thrombopoietin (c-mpl ligand) is a hormone, mainly produced by the liver, that stimulates platelet production. It is bound to circulating platelets; if platelet levels are adequate, serum levels remain low. If the platelet count is decreased, more thrombopoeitin circulates freely and increases bone marrow platelet production. Pharmacological analogues of thrombopoetin are clinically available in the United States.
The circulating life of a platelet is 9–10 days. After this time period, platelets are sequestered in the spleen. Decreased function (or absence) of the spleen may increase platelet counts, while hypersplenism (overactivity of the spleen, e.g. in Gaucher's disease, leukemia and cirrhosis) may lead to increased elimination and hence low platelet counts.
Platelets are activated when brought into contact with collagen (which is exposed when the endothelial blood vessel lining is damaged), thrombin (primarily through PAR-1), ADP, with receptors expressed on white blood cells or the endothelial cells of the blood vessels, among other activators. Once activated, they release a number of different coagulation factors and platelet activating factors, and activated platelets also release their granule contents rapidly. 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 protein coagulation cascade complexes. The platelets adhere to each other via adhesion receptors or integrins, and to the endothelial cells in the wall of the blood vessel forming a hemostatic plug in conjunction with fibrin. The high concentration of myosin and actin filaments in platelets are stimulated to contract during aggregation, further reinforcing the plug. The most common platelet adhesion receptor is glycoprotein (GP) IIb/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)
There are many known platelet activators. They include
- Collagen, especially with von Willebrand factor which is exposed when endothelial blood vessel lining is damaged and binds to GPVI on the platelet;
- Thrombin, primarily through cleavage of the extracellular domain of PAR1 and PAR4;
- Thromboxane A2 (TxA2), which binds to TP;
- ADP through creation of TxA2, which can be blocked by conversion of ADP to cAMP;
- Human neutrophil elastase (HNE) cleaves the αIIbβ3 integrin on the platelet surface;
- P-selectin, which binds to PSGL-1 on endothelial cells and white blood cells
- SFLLRN, which activates the PAR-1 receptor
- AYPGKF, which activates the PAR-4 receptor; and
- Convulxin, (a purified protein from snake venom) which binds to GPVI.
- Prostacyclin opposes the actions of Thromboxane A2
- Nitric oxide
- Clotting factors II, IX, X, XI, XII
- Nucleotidases by breaking down ADP
Drugs that inhibit platelet function
- Aspirin inhibits cyclooxygenase-1, preventing positive feedback
- Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis
- Inhibitors of ADP purinoceptor P2Y12 cell surface receptors
- Abciximab blocks fibrinogen receptors and is used with percutaneous coronary intervention
- Glycoprotein IIb-IIIa inhibitors include eptifibatide and tirofiban. These medication block the platelet glycoprotein GPIIb-IIIa complex and are used for treating acute coronary syndromes.
- β-lactam antibiotics alteration of agonist receptors
- Calcium channel blocker
Role in disease
High and low counts
A normal platelet count in a healthy person is between 150,000 and 400,000 per mm3 of blood. 95% of healthy people will have platelet counts in this range. Some will have statistically abnormal platelet counts while having no abnormality, although the likelihood increases if the platelet count is either very low or very high.
Both thrombocytopenia (or thrombopenia) and thrombocytosis (or thrombocythemia) may present with coagulation problems. Generally, low platelet counts increase bleeding risks (although there are exceptions, e.g. 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). High platelet counts, especially in the context of a myeloproliferative disorder, may paradoxically lead to an increased risk of bleeding.
Low platelet counts are generally not corrected by transfusion unless the patient is bleeding or the count has fallen below 10 (x 109/L); it is relatively contraindicated in thrombotic thrombocytopenic purpura (TTP) as it fuels the platelet consumption. In patients having surgery, a level below 50 (x 109/L) is associated with abnormal surgical bleeding, and regional anesthetic 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 and -2 (COX1 and COX2), and hence normal hemostasis; normal platelet function may not return until the aspirin has ceased and all the affected platelets have been replaced by new ones, which can take over a week. Similarly, uremia (a consequence of renal failure) leads to platelet dysfunction that may be ameliorated by the administration of desmopressin  .
Disorders leading to a reduced platelet count:
- Gaucher's disease
- Aplastic anemia
- Fetomaternal alloimmune thrombocytopenia
- Some transfusion reactions
Disorders leading to platelet dysfunction or reduced count:
Disorders featuring an elevated count:
- Thrombocytosis, including benign 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
Disorders of platelet metabolism
- Decreased cyclooxygenase activity, induced or congenital
- Storage pool defects, acquired or congenital
Brewer traced the history of the discovery of the platelet. Although red blood cells had been known since van Leeuwenhoek, 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. He describes "spherules" 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. One of his findings was the fact that platelets clump at the site of blood vessel injury, which precedes the formation of a blood clot. This observation confirmed the role of platelets in coagulation.
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