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Platelet

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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.

Physiology

Production

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.

Circulation

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.

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, 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)

Activators

There are many known platelet activators. They include

Inhibitors

Drugs that inhibit platelet function

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.

Platelet dysfunction

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 [2] [3].

Diseases

Disorders leading to a reduced platelet count:

Alloimmune disorders

Disorders leading to platelet dysfunction or reduced count:

Disorders featuring an elevated count:

Disorders of platelet adhesion or aggregation:

Disorders of platelet metabolism

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

Discovery

Brewer[4] 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[5]. 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[6].

References

  1. Hillis LD, Lange RA (2009). "Optimal management of acute coronary syndromes.". N Engl J Med 360 (21): 2237-40. DOI:10.1056/NEJMe0902632. PMID 19458369. Research Blogging.
  2. Mannucci P, Remuzzi G, Pusineri F, Lombardi R, Valsecchi C, Mecca G, Zimmerman T (1983). "Deamino-8-D-arginine vasopressin shortens the bleeding time in uremia". N Engl J Med 308 (1): 8-12. PMID 6401193.
  3. Shapiro M, Kelleher S (1984). "Intranasal deamino-8-D-arginine vasopressin shortens the bleeding time in uremia". Am J Nephrol 4 (4): 260-1. PMID 6332534.
  4. Brewer DB. Max Schultze (1865), G. Bizzozero (1882) and the discovery of the platelet. Br J Haematol 2006;133:251-8. PMID 16643426.
  5. Schultze M. Ein heizbarer Objecttisch und seine Verwendung bei Untersuchungen des Blutes. Arch Mikrosc Anat 1865;1:1-42.
  6. 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.

See also