TISSUE PLASMINOGEN ACTIVATOR INHIBITS THROMBIN-INDUCED AGGREGATION AND SHAPE CHANGE,BUT FACILITATES SECRETION,IN GEL-FILTERED PLATELETS ONLY

Prolonged administration of tissue plasminogen activator (t-PA) has caused bleeding problems in some patients, that did not necessarily correlate with a significant drop of fibrinogen levels. We have therefore evaluated the effect of t-PA on platelet function in vitro.

Incubation of gel-filtered platelets for one hour at 37°C with 180 μg/ml plasminogen and increasing concentrations of t-P(50-1600 ng/ml) significantly inhibited shapechange and aggregation induced by thrombinand the thromboxane mimetic U 46619 in a dose-dependent manner. In an EDTA milieu, whichbolishes aggregation, a dual effect of t-PA and plasminogen was observed in the aggregometer: the thrombin- or U 46619-elicited initial decrease in light transmission, reflectingthe disc-to-sphere transformation of platelets, was almost completely inhibited from 50 ng/ml t-PA upwards; the subsequent increase in light transmission, reflecting granule secretion, was however enhanced by small amounts of t-PA (up to 200 ng/ml). The latter finding was confirmed by direct measurement of secreted ATP:t-PA atconcentrations up to 200ng/ml enhanced thrombin- or U 46619-in-duced secretion. The amount of plasmin generated in the gel-filtered platelets-plasminogen-t-PA mixtures was quantified. The same amountsof plasmin, while also inhibiting the disc-to-sphere transformation of the platelets, did not enhance thrombin-or U 46619-induced ATP secretion. When whole blood or platelet-rich plasma or gel-filtered platelets resuspended in _α-antiplas-min-depleted plasma waspreincubated with t-PA, aggregation and/or shape change induced by ristocetin, arachidonic acid, the calcium ionophore A 23187, adenosine diphosphate, U 46619, thrombin, serotonin or platelet activating factor were not modified.

Our results suggest that in a purified system the effects of t-PA plus plasminogen onplatelets are distinct from those of plasmin;it appears that low pharmacological concentrations of t-PA enhance the secretory responses to stimuli.