Regulation of local availability of active tissue‐type plasminogen activator in vivo in man

Abstract

Free, biologically active tissue-type plasminogen activator (tPA) is the main initiator of intravascular fibrinolysis, but little is known about the regulation of active tPA on the organ level. The aim was to investigate if the local availability of active tPA on the organ level depends on the local release rate of tPA or the arterial input of tPA and plasminogen activator inhibitor type 1 (PAI-1). Also, we wanted to evaluate if plasma levels predict capacity for endothelial release of fibrinolytic proteins. Invasive perfused-forearm studies were performed in 96 healthy subjects. Local release rates of fibrinolytic proteins were assessed at baseline and during endothelial stimulation. Stimulation by methacholine and desmopressin induced a 6-and 12-fold increase in total tPA release rates, respectively. With increasing local release rates of tPA a gradually closer correlation emerged between the total tPA secretion and the forearm output of active tPA (from r ¼ 0.102, ns to r ¼ 0.85, P < 0.0001). Forearm availability of active tPA was not related to arterial input of either tPA or PAI-1. Release rates and plasma levels of tPA were not correlated. Baseline release rates of active tPA increased to noon. The major determinant for the local availability of active tPA is the capacity of the endothelium to release tPA rather than the arterial input of PAI-1 or tPA. Despite a molar excess of PAI-1, the majority of tPA released during stimulation does not undergo local inactivation. The capacity to release tPA locally cannot be predicted from its plasma concentration.

Characterization of a Small Molecule Inhibitor of Plasminogen Activator Inhibitor Type 1 That Accelerates the Transition into the Latent Conformation

“…complex with VN (28 -30) and is active (31). Upon activation of platelets, this stored PAI-1 is released to protect the primary clot from fibrinolysis (28,31) by inhibiting tPA secreted from nearby endothelium (32). Although an inhibitor for PAI-1 that neutralizes the activity of both PAI-1 in complex with VN and of free PAI-1 may yield the most effective inhibition, it is still possible that selective inhibition of free PAI-1 could provide therapeutic benefit.…”

Hypothermia in cardiogenic shock reduces systemic t-PA release

“…The release of t-PA is triggered by various injurious stimuli including ischemia, and is mediated by a variety of substances including thrombin, ADP, serotonin, bradykinin, and epinephrine [9,12,13,10,11,[37][38][39][40][41]. It is possible that the release of t-PA was triggered by the shock related metabolic compromise.…”

“…It is synthesized and stored in endothelial cells and vascular neurons [7,8], and is released in response to ischemia and other injurious stimuli [9][10][11][12][13]. Interestingly, t-PA has also been found to have proinflammatory properties that could contribute to tissue injury in ischemia-reperfusion injury [14,15].…”

Assessment of the relation between initial culprit vessel patency in acute ST-elevation myocardial infarction and endothelial function

“…In the presence of developing thrombus, endogenous fibrinolysis is rapidly initiated by the local endothelium that tightly regulates plasmin generation, fibrin degradation, and dissolution of the thrombus 18,19 . As a result, thrombus growth is limited and reperfusion is promoted; however, the efficacy of this system depends on functional endothelium 20,21 . Endothelial dysfunction, on the other hand, disturbs various homeostatic pathways and predisposes to vasoconstriction, platelet activation, and thrombus formation 4,18 .…”