New Pathway for Tissue-Type Plasminogen Activator Regulation

Circulating levels of tissue-type plasminogen activator (tPA) are correlated with risk of incident cardiovascular disease (CVD) among individuals with clinical atherosclerosis and in the general population, but a simple causal interpretation of this association belies epidemiological and regulatory complexity (eg, Ref. 1 and references therein). tPA, encoded by the PLAT gene, is an enzyme that is secreted from the vascular endothelium and cleaves circulating plasminogen to form plasmin, an enzyme with fibrinolytic activity. Most of the circulating tPA is bound in an inactive complex with its inhibitor PAI-1, encoded by the SERPINE1 gene. The association of higher levels of tPA with increased risk of incident CVD may thus seem paradoxical because formation rather than dissolution of a thrombus is the critical clinical event in clinical progression of atherosclerosis. Similarly, in the therapeutic setting, exogenous administration of tPA is an approved treatment for both myocardial infarction and acute ischemic stroke. The apparent discrepancy may be resolved by recognizing that elevated tPA may reflect, in …