Pharmacology of Platelet-affecting Drugs

Our present knowledge is incomplete concerning the mechanisms that initiate different types of thrombosis and the dominant reactions involved. Exposed collagen, released adenosine diphosphate (ADP), thromboxane A₂, epinephrine and thrombin may all take part in thrombus formation, but their relative importance in each situation has not been assessed. Drugs that affect one type of thrombosis may have little effect on another type of thrombosis. Although occlusive thrombi and thromboembolism may contribute to some of the clinical complications of atherosclerosis, other mechanisms may also operate. Drugs that inhibit the arachidonate pathway block the formation of the aggregating agent, thromboxane A₂, by platelets and also block synthesis of prostaglandin 1₂ (PGI₂) (a potent inhibitor of platelet function) by the vessel wall. These drugs include ones that inhibit phospholipase, thromboxane synthetase, and cyclooxygenase. The last group includes the nonsteroidal anti-inflammatory drugs aspirin, indomethacin, phenylbutazone and the uricosuric agent sulfinpyrazone. These drugs do not prevent platelet adherence to damaged vessel walls or release of granule contents from these adherent platelets, but in some situations they may inhibit thrombus formation. Aspirin irreversibly acetylates platelet cyclooxygenase so that its effects on platelets are permanent; the cells of the vessel wall can resynthesize cyclooxygenase and thus regenerate their capacity to form PGI₂. These observations, as well as the suggestion that platelet cyclooxygenase is more readily inhibited than the enzyme in the vessel wall, have led to the suggestion that a low dose of aspirin given once daily may be beneficial. Clinically, males seem to benefit more than females from aspirin administration for prevention of the complications of atherosclerosis. Differences are apparent between the effects of aspirin and sulfinpyrazone. Agents that increase cyclic adenosine monophosphate levels in platelets, and thereby inhibit platelet function, include PGE₂, PGD₂, and PGI₂, and phosphodieterase inhibitors, notably dipyridamole; inhibition of thrombosis in experimental animals and man has been observed in some situations. Agents that inhibit thrombin (oral anticoagulants and heparin) may prevent thrombosis under conditions in which thrombin makes a major contribution to the formation of thrombi. The elfects of heparin on platelets are complex and reports are contradictory, possibly because of the heterogeneity of this drug. Other drugs that have received less attention include propranolol and other β blockers, clofibrate and halofenate, ticlopidine, vitamin E, hydroxychloroquine and many others. Some tests of combinations of drugs have been done. Many questions remain concerning the relative importance of the different mechanisms of thrombosis, and of thromboembolism, in the clinical complications of atherosclerosis, suitable ways of screening drugs, subgroups to be studied, and dosage.