Induction of plasminogen activator inhibitor by products released from platelets

Abstract

Activation of platelets and augmentation of plasma plasminogen activator inhibitor (PAI) type I activity accompany acute myocardial infarction. To determine whether the two may be related, platelet compounds including epidermal growth factor and transforming growth factor β as well as platelet lysates were studied in rabbits in vivo. After intravenous infusion of epidermal growth factor (1 and 5 μg/kg), plasma PAI activity increased sevenfold and 20-fold, peaking at 2 hours. After infusions of transforming growth factor β (0.2 and 0.5 μg/kg), plasma PAI activity increased sevenfold and 12-fold but peaked more slowly (at 5 hours). After infusion of platelet lysates (lysates from 2.8 and 5.6×108 platelets/kg), the increase was 19-fold and 35-fold, with a peak at 4 hours. Platelet lysates induced a pronounced increase of plasma PAI type 1 messenger RNA (Northern blots) in aorta, liver, and myocardium. Anti-transforming growth factor β neutralizing antibody markedly attenuated the plasma PAI increase. Concentrations in plasma of fibrinogen and α2-antiplasmin were virtually unaffected under all conditions. Thus, platelet-associated growth factors and platelet lysates, shown previously to increase plasma PAI type 1 messenger RNA expression and protein production in cultured hepatocytes and vascular endothelial cells in vitro, augment plasma PAI in vivo as well. Accordingly, activation of platelets and release of platelet-associated growth factors appear to contribute to the increased plasma PAI seen after myocardial infarction.