VOL: 101, ISSUE: 44, PAGE NO: 26
Ken Campbell, MSc clinical oncology, is clinical information officer, Leukaemia Research Fund (written in a private capacity)
This article, the last in a series on blood cells, describes platelets. These small yet complex structures are important in coagulation and also have a significant role in the immune system, particularly in relation to inflammation.
Platelets are the smallest formed elements of the blood at 2-4µm in diameter. Although only about 1/14th of the volume of a red blood cell, they are more complex. Like red cells, platelets (thrombocytes) have no nucleus. However, unlike red cells that originate in the marrow as nucleated cells and lose their nucleus, platelets are produced by budding off from a giant multinucleated marrow cell called a megakaryocyte. Each megakaryocyte produces about 4,000 platelets (Hoffbrand et al, 2002).
Platelets appear smaller than their actual size under the microscope as the outer layer of their cytoplasm, the hyalomere, scarcely stains. The inner region, the granulomere, contains densely staining granules, alpha granules and dense bodies. The granules are so numerous and small that a platelet appears on microscopy as a small homogeneous blue cell fragment.
Platelets have a complex internal structure, with granules, internal channels and microtubule arrays (Kern, 2002) that maintain their shape. The resting shape of a platelet is a flat disc (Fig 1), but when it is activated, it transforms into a prickly sphere with long projections (Fig 2).
Platelets normally have a lifespan of about 9-10 days. However, there is a steady consumption of platelets, at a rate of about 8,000/ml per day (Harker et al, 2000), as a consequence of formation and removal of clots at sites of minor tissue damage throughout the body. This consumption is independent of the platelet count, and a reduction in the count (thrombocytopenia) effectively shortens the mean platelet lifespan.
The normal platelet count ranges from about 150 to 450x109/L. The count can drop markedly below this level without serious consequences.
Platelets are essential for the normal blood clotting process. The first stage of normal clotting is the formation of a platelet plug, in which platelets are enmeshed in a fibrin web (Fig 3). When a blood vessel is damaged, the resulting breach in the endothelium exposes water-wettable surfaces and collagen fibrils - either of which is capable of activating platelets. Activation can also be induced by von Willebrand’s factor (Schmugge et al, 2003), which is released by damaged endothelial cells.
Once a platelet is activated it attracts other nearby platelets, which in turn become activated. Platelet adherence and aggregation are driven by the prostaglandin thromboxane A2, which is synthesised within the platelet from arachidonic acid. It is this synthetic pathway that is blocked by aspirin (Schror, 1997). ADP plays a key role in haemostasis and thrombosis.
One of the major functions of the shape change during activation is to facilitate the binding together of platelets in a three-dimensional jigsaw. This generates a friable but quite strong clot and triggers activation of the coagulation cascade.
The coagulation cascade is a process involving a number of clotting factors in the plasma - the end product of which is conversion of soluble fibrinogen to fibrin. This forms a mesh that locks in the platelets and gradually contracts and dries out to form a strong, protective scab under which wound healing can progress.
Although many older or more basic textbooks discuss platelets exclusively in terms of their coagulation function, it is now clear that they also play a significant role in the immune system, particularly in relation to inflammation (Danese et al, 2004).
They are involved in the development of atheromatous plaques in vessels and even in metastasis of malignant tumours.
Their immunological capabilities may be the mechanism by which they contribute to atherosclerosis.
In patients with coronary heart disease (CHD), exercise appears to increase platelet aggregation and activation. This has obvious implications for the advice on physical activity given to such patients.
It has been suggested that such effects may play a part in sudden cardiac death during exercise (Smith, 2003). There is also a correlation between platelet activation and stroke but here the direction of cause and effect is not entirely clear (Smith et al, 1999). Increased platelet activation is a well-recognised feature of migraine.
It has been recognised for over a century that platelets are increased in patients with malignant disease and that such patients commonly have a hypercoaguable state.
Drugs affecting platelets
Aspirin is a highly active anti-platelet drug. It binds to the enzyme that normally converts arachidonic acid to the prostaglandin thromboxane A2. This potently inhibits platelet adhesion and aggregation.
However, although it has great therapeutic potential in preventing thrombosis, it has a narrow therapeutic window - any effective anti-platelet dose of aspirin is associated with an increased risk of bleeding (Schror, 1997).
Interestingly, aspirin appears ineffective against the platelet sensitisation induced by exercise (Smith, 2003). Because of this potent antiplatelet activity, aspirin and aspirin-containing compounds should be avoided by any patient with compromised platelet numbers or function.
Some ADP-selective antiaggregation drugs (ticlopidine and clopidogrel) have been shown to reduce the incidence of stroke, myocardial infarction and vascular death (Malinin et al, 2003).
Anagrelide was originally used as an antibiotic but was observed to cause a reduction in platelet numbers in a consistent and reproducible fashion. This led to a UK trial (MRC PT-1) of its use to block platelet production in essential thrombocythaemia, as it was expected that anagrelide would be a safe, highly specific inhibitor of platelet synthesis.
The component of the trial comparing anagrelide with hydroxyurea was closed early because patients in the anagrelide group experienced a higher frequency of arterial thrombosis, significant haemorrhage and myelofibrosis, although their incidence of venous thrombosis was reduced.
Based on these results, hydroxyurea is now recommended as a frontline treatment of essential thrombocythaemia, although anagrelide may be useful in patients who cannot tolerate hydroxyurea (Harrison et al, 2005).
This article has been double-blind peer-reviewed.
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