This regimen was associated with a 91% patency rate at 90 minutes, and it has now been approved by the US Food and Drug Administration (FDA). Neuhaus and coworkers introduced “front-loaded” dosing (i.e., 15 mg bolus with 50 mg given by infusion over the first 30 minutes, followed by 35 mg over the next 60 minutes). 28,29,35 tPA is available commercially as Alteplase. Unlike SK, tPA is not associated with immunogenicity. The relative fibrin specificity of tPA accounts for the more rapid clot lysis seen with tPA compared with SK. An important advantage of tPA compared with SK is its affinity for fibrin-bound plasminogen.
tPA is metabolized by the liver and inhibited in plasma by plasminogen activator inhibitor type 1 (PAI-1). The plasma half-life of tPA is 5 minutes, but fibrinolytic activity persists within clots for 7 hours. TPA is an endogenous serine protease synthesized and secreted by human vascular endothelium and numerous other cells. Sobel, in Cardiac Intensive Care (Third Edition), 2019 Tissue-Type Plasminogen Activator. These results clearly outline a role for tPA exocytosis from neurons in the normal growth and sprouting of neurites as well as that potentially caused by TLE. The mechanism of how Pld1 might promote vesicular tPA release is unclear, likely involving the activation of protein kinase C (PKC) through generation of phosphatidic acid, and possibly diacylglycerides, both of which can stimulate PKC at the cell membrane.
Some of these pathways have implicated phospholipase-D1 (Pld1) as the driver of tPA secretion from the growth cone in an excitation-dependent manner, thus regulating the neurite outgrowth necessary during normal hippocampal development, as well as aberrant growth due to excitotoxic insult. tPA has been shown to degrade ECM components through the generation of plasmin, allowing the extension of neurites under normal developmental cues or following temporal lobe epilepsy (TLE). Low levels of sc-tPA and tc-tPA are thought to mediate this cross talk, which clearly points to an antiexcitotoxic effect of tPA on neurons, as opposed to that seen with high-level administration of tPA.Īnother pointed role for tPA involves its effect on neurite outgrowth either during development and/or neurogenesis, or following injury. Both sc-tPA and tc-tPA modulate the cross talk between EGFR and NMDA receptors on neurons: tPA-mediated EGFR activation leads to a downregulation of NMDAR function. Proteolytic activation of tPA does not preclude sc-tPA from being proteolytically active, as the single-chain form can act as an effector of epidermal growth factor receptor (EGFR) and N-methyl- d-aspartate (NMDA) signaling. TPA is secreted in a single-chain form (sc-tPA) from neurons and glial cells and processed into a two-chain form (tc-tPA) by plasmin or kallikreins. Tsirka, in Primer on Cerebrovascular Diseases (Second Edition), 2017 Signaling Through Proteolytic Cleavage of ECM