ASPIRIN, HAEMOSTASIS AND THROMBOSIS

Aspirin has for long been a remarkable drug; two thousand tons are sold yearly and yet in spite of its numerous and diverse pharmacological effects it is surprisingly safe. There is great interest in it at present because it is helping to unravel the complexity of prostaglaiidin involvement in cell metabolism, and it may have a therapeutically beneficial effect on platelets. When a drug has widespread and different pharmacological effects and when many other drugs, some with little structural resemblance, have the same spectrum of effects, it is probable that all of them have a similar influence on a basic mechanism common to all the target organ cells. It now appears that the mechanism cominon to the aspirin-like drugs is the inhibition of prostaglandin (PG) biosynthesis (Vane, 1972). Prostaglandins have an effect on two clearly distinguishable platelet phenomena. When adenosine diphosphate (ADP) is added to citrated platelet-rich plasma the platelets become intensely sticky within 3 s so that they readily aggregate but the precise nature of the responsible nienibrane change remains obscure. Aspirin has no effect on this wave of primary aggregation so presumably PG synthesis is not involved; yet PGEi in nanogram quantities inhibits this kind of aggregation (Kloeze, 1967) though it is not understood how it does so; it is, however, probably relevant that it stimulates the formation of cyclic AMP (Ball et a/ , 1970). The second platelet phenomenon is the release reaction and when platelets stick, for example to collagen, this only occurs after a considerable delay (Holmsen et al , 1969). ADP and other substances stored in the dark granules in the platelets are extruded and this ADP causes other platelets to become sticky so that there is a delayed secondary wave of aggregation. In 1968 four groups of workers reported that aspirin inhibits the release reaction (Weiss rt ul, 1968 ; Evans et al , 1968 ; Zucker & Peterson, 1968 ; O’Brien, 1968). It is now known that prostaglandins E, and PGF,, are formed during the release reaction (Smith et al, 1973) and endoperoxide intermediates related to PGF,, (Smith et a2, 1974) or PGG, or PGH, (Hamberg et al , 1974) are also synthesized. It is not clear exactly how these prostaglandins influence the platelets, but they are probably concerned with energy metabolism since aspirin inhibits the breakdown of ATP (Ball et a l , 1969). Furthermore, arachnidonic acid, an esscntial fatty acid precursor of PGE, and of PGF,,, when injected into rabbits causes death by massive platelet aggregation which blocks the circulation; and aspirin protects this by preventing PG synthesis (Silver et al, 1974). Platelet niicrosonies in vitro are shown to use arachnidonate for the synthesis of ‘labile aggregation stimulating substance’ which is probably a PG endoperoxide, and this synthesis is also inhibited by aspirin (Willis, 1974). Two other findings may help unravel this complicated picture of platelet adhesion and release. It has been suggested that the platelet-collagen adhesion is mediated by an enzyme acceptor complex, glucosyl transferase which is inhibited by aspirin (Jamieson rt al , 1971). The dye alcian blue causes release which is not blocked by aspirin which suggests that aspirin may prevent the signal to release from reaching the platelet granule (O’Brien, 1972).