Streptokinase (SK) frequently induced platelet aggregation when added to citrated whole blood in vitro, but aggregation did not occur in corresponding samples of platelet-rich plasma (PRP). The aggregation occurred at concentrations of SK that are achieved after systemic infusion and was significantly more extensive in blood from men than women. SK-induced aggregation was accompanied by TXB2formation and release of14C-5HT and was inhibited by aspirin, by sulotroban, a TXA2antagonist, and by apyrase, an enzyme which removed ADP from plasma. Aggregation was also inhibited by each of three agents that interrupt the fibrinolytic pathway: epsilon-aminocaproic acid (ACA), aprotinin and alpha-2-antiplasmin. It is suggested that the aggregation is consequent to platelet activation by plasmin formed on the platelet surface, with ADP from red cells playing a part.In contrast to results obtained in vitro, prior administration of SK to man resulted in inhibition of the aggregation that occurs when this agent is added to whole blood. This effect was reproduced in vitro by pre-incubating blood with SK prior to carrying out aggregation studies. Similar inhibition was obtained when plasmin was added to blood and it is suggested that this effect of SK may be mediated by plasmin formed in plasma.In contrast to the pro-aggregatory effects of SK in vitro, recombinant tissue plasminogen activator (rt-PA) only inhibited platelet aggregation in whole blood. rt-PA inhibited the aggregation induced by a wide range of agents suggesting a central mechanism of action. Inhibition of aggregation was prevented by ACA, suggesting that this is also mediated by plasmin formed in plasma.The relevance of these observations is discussed in relation to the increasing use of fibrinolytic therapy in acute thrombosis in man. It is suggested that slow infusion of SK should always be performed so as to maximise the inhibitory rather than potentiatory effect of this agent on platelet aggregation, and that SK should only be used after prior administration of an anti-platelet agent.