Platelet
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Platelets or thrombocytes are the cell fragments circulating in the blood that are involved in the cellular mechanisms of primary hemostasis leading to the formation of blood clots. Dysfunction or low levels of platelets predisposes to bleeding, while high levels, although usually asymptomatic, may increase the risk of thrombosis.
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[edit] Anatomy
Like red blood cells, platelets are anuclear (no cell nucleus) and discoid (disc shaped); they measure 1.5–3.0 μm in diameter. The body has a very limited reserve of platelets, so they can be rapidly depleted. They contain RNA, mitochondria, 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.
[edit] Physiology
[edit] Production
Platelets are produced in the bone marrow; the progenitor cell for platelets is the megakaryocyte. It is about twelve times larger than an erythrocyte, possesses a lobed nucleus and 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 marrow production.
[edit] Circulation
The circulating life of a platelet is 8–10 days. After this it is 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.
[edit] Function
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, receptors expressed on white blood cells or the endothelial cells of the blood vessels, a negatively charged surface (e.g., glass), or several other activating factors. Once activated, they release a number of different coagulation factors and platelet activating factors. 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. 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 haemostatic 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 abundant 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)
[edit] Activators
There are many known platelet activators. They include
- Collagen, which is exposed when endothelial blood vessel lining is damaged and binds to its receptors GPVI and alpha2b-beta1 on the platelet surface;
- von Willebrand factor which circulates in the blood and binds to its receptor GPIb-IX-V on the platelet surface.
- Thrombin, primarily through cleavage of the extracellular domain of PAR1 and PAR4;
- Thromboxane A2 (TxA2), which binds to its receptor, TP;
- ADP through an action on its two cell surface receptors, P2Y1 and P2Y12.
- Adrenaline that activates its receptor (alpha 2) on the platelet surface. Note that adrenaline will also activate an inhibitory beta2 receptor on platelets, but this effect is normally masked by its predominant effect on alpha 2.
- Serotonin that activates its receptor (5HT-2c) on the platelet surface.
- 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 and which is normally exposed on the surface of platelets following initial activation by other activators.
[edit] Inhibitors
- Prostacyclin opposes the actions of most if not all platelet agonists by increasing intracellular cAMP levels
- Adenosine through an action on its cell surface receptor (A2 receptor) by increasing intracellular cAMP levels
- Nitric oxide released by the endothelium (and platelets themselves in some instances)
- Clotting factors II, IX, X, XI, XII
- Nucleotidases such as CD39 ecto-ADP'ase break down ADP
[edit] Drugs that inhibit platelet function
- Aspirin irreversibly inhibits cyclooxygenase-1, preventing positive feedback
- Clopidogrel inhibits ADP receptors
- Non-steroidal anti-inflammatory drugs (NSAIDs) inhibit prostaglandin synthesis
- Abciximab blocks fibrinogen receptors
- β-lactam antibiotics alteration of agonist receptors
- Quinidine calcium channel blocker
[edit] Role in disease
[edit] High and low counts
A normal platelet count in a healthy person is between 150,000 and 400,000 per mm³ of blood (150–400 x 109/L). 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 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).
Low platelet counts are generally not corrected by transfusion unless the patient is bleeding or the count has fallen below 5 x 109/L; it is contraindicated in thrombotic thrombocopenic purpura (TTP) as it fuels the coagulopathy. In patients having surgery, a level below 50 x 109/L) is associated with abnormal surgical bleeding, and regional anaesthetic 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 (COX1), 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.
[edit] Diseases
Disorders leading to a reduced platelet count:
- Thrombocytopenia
- Idiopathic thrombocytopenic purpura - also known as immune thrombocytopenic purpura (ITP)
- Thrombotic thrombocytopenic purpura
- Drug-induced thrombocytopenia, e.g. heparin-induced thrombocytopenia (HIT)
- Gaucher's disease
- Aplastic anemia
Alloimmune disorders
- 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
Disorders that compromise platelet function:
[edit] Discovery
Brewer[1] 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[2]. 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[3].
[edit] Additional images
 Blood cell lineage |
[edit] References
- ^ Brewer DB. Max Schultze (1865), G. Bizzozero (1882) and the discovery of the platelet. Br J Haematol 2006;133:251-8. PMID 16643426.
- ^ Schultze M. Ein heizbarer Objecttisch und seine Verwendung bei Untersuchungen des Blutes. Arch Mikrosc Anat 1865;1:1-42.
- ^ Bizzozero J. Über einen neuen Forrnbestandteil des Blutes und dessen Rolle bei der Thrombose und Blutgerinnung. Arch Pathol Anat Phys Klin Med 1882;90:261-332.
