A brief history of platelets and their measurements: Donné, a French physiologist, described platelets in 1842 as lymph particles (`globulins du chyle'). He believed them to coalesce to form white cells, while others dismissed them as cell débris or artefacts (Donné 1842). Osler, Regius Professor of Medicine in Oxford, seems to have been the first, in 1874, to suggest a possible role for platelets, and he described platelet pseudopodia and their adhesion to fibrin (Osler 1874).
A bleeding time test was first described 1901 and this stimulated the study of platelet adhesion. The tests were however very poorly reproducible but the development of methods to measure platelet aggregation in 1962 gave a considerable stimulus to platelet research (O'Brien 1962). By then there was general agreement on the key role of platelets in thrombosis.
Pharmacologists and haematologists then began an intensive search for drugs to reduce platelet aggregation. Many drugs were tried, including anti-malarial and anti-histamine compounds, heroin, and `a strong solution of sodium salicylate', but for most substances the dose likely to be required to reduce the risk of thrombosis were judged likely to be `incompatible with life'. Morris in 1967 appears to have been the first to test aspirin against platelet aggregation and as a result he suggested that aspirin might `play a therapeutic role in the management of pathological thrombosis' (Morris 1967).
Developments followed quickly and interest was heightened when a number of reports described how an extremely small dose of aspirin has a permanent effect on the exposed platelets, and a reduction in aggregation could be detected up to about ten days later. Calls were then made for trials of Aspirin in Cardiovascular Disease (O'Brien 1968).
Aspirin was originally derived from salicylic acid and it has been used for over 100 years in clinical practice. A range of salicylates occur throughout nature and have a wide variety of essential functions in plants (Pierpoint 1976). It should not surprise therefore that salicylates, including aspirin, have a number of effects in humans. In fact, some have suggested that the beneficial effect of fruit and vegetables on cardiovascular disease and on cancer may be due, in part, to their salicylate content (Paterson et al. 1998).
A break-through in the understanding of the mechanism of action of aspirin was achieved in the early 1970's when Sir John Vane discovered the effect of aspirin on prostaglandin synthesis (Vane 1971). Many of the effects of aspirin, including analgesia, anti-inflammatory and antipyretic effects are due to an inhibition of prostaglandin production by cyclo-oxygenase, an enzyme which catalyses the formation of prostaglandin and thromboxane precursors from arachidonic acid.
Low doses of aspirin affect platelet function by primarily inhibiting platelet cyclo-oxygenase, thereby preventing the formation of the aggregating agent thromboxane A2. This action is uniquely irreversible in platelets, it lasts for the life of the platelets, and there is no evidence that long-term therapy leads to either tolerance, or dependence. Salicylates, including aspirin, have other effects on haemostatic mechanisms, some due to interference with vitamin K in the hepatic synthesis of the coagulation factors VII, IX and X.
- acetylates cyclo-oxygenase
- acetylates fibrinogen
- modulates thrombolysis
- affects membrane proteins
- affects inter-cell interactions
- reduces cell-platelet interactions
- reduces factors VII, IX and X Other than the first of these actions, they are dose-dependent. Based on Rocca & Fitzgerald (1997)
Aspirin also causes a dose-dependent reduction in an interaction between erythrocytes and platelets, and this has led to the suggestion that `...in addition to daily low-dose aspirin... a loading dose of 500 mg soluble aspirin, repeated every two weeks, may amplify the therapeutic potential of aspirin by blocking the capacity of the erythrocytes to promote platelet reactivity' (Santos et al. 1997).
Pursuit of Longevity
Platelets, Aspirin and Prostaglandins
Aspirin and Vascular Disease
Dose and Formulation
The Way Ahead