Endothelium
Neil Herring, David J. Paterson in Levick's Introduction to Cardiovascular Physiology, 2018
The endothelial lining of blood vessels is now recognized to be central to preventing thrombosis in undamaged vessels by several mechanisms (Figure 9.11):It presents a physical barrier that separates platelets and coagulation factors in the blood from stimulatory collagen in the subendothelial layers of the blood vessel.Secretion of heparan sulphate on the luminal surface activates antithrombin III and prevents the activation of the clotting factors.Powerful inhibitors of platelet activation are synthesized. PGI2 and NO act synergistically to prevent the increase in intra-platelet Ca2+ essential for activation.The enzyme CD39 is expressed on the luminal surface to convert the platelet activator, ADP, to inactive AMP.Tissue plasminogen activator (tPA) is released to convert plasminogen to plasmin, which cleaves fibrin strands, earning tPA the title of ‘clot-buster’.
Optimizing Intra-Arterial tPA
Ying Yuan, Hoang Q. Nguyen, Peter F. Thall in Bayesian Designs for Phase I–II Clinical Trials, 2017
Acute ischemic stroke (AIS) is a major cause of death and disability in adults (Johnston et al., 2009). Intra-arterial (IA) fibrinolytic infusion is a treatment for AIS that must be carried out within six hours of the stroke. With this treatment regime, a thrombolytic agent is delivered via two telescoping catheters directly to the site in the brain artery where the clot that caused the stroke occurred. The aim is that the agent will dissolve the clot. A supportive catheter is positioned in the carotid artery, and a smaller microcatheter within it is positioned directly into the clot. These two telescoping catheters are introduced via a sheath placed into the femoral artery and, using X-ray fluoroscopic guidance, the catheters are moved through the carotid artery leading to the site of the clot. The agent is infused via the microcatheter. Tissue plasminogen activator (tPA) is a thrombolytic agent used for intravenous (IV) treatment of AIS in adults, where its effects are well understood. In contrast, safe and efficacious concentrations of IA tPA have not been established. The design described in this chapter provides a method to optimize IA tPA for rapid treatment of AIS.
Coagulation Theory, Principles, and Concepts
Harold R. Schumacher, William A. Rock, Sanford A. Stass in Handbook of Hematologic Pathology, 2019
Tissue plasminogen activator (tPA) is an enzyme released from cells which activates plasminogen to plasmin. The tPA secreted by cells is a single-chain protease. This single-chain form of tPA can be converted to a two-chain form by plasmin, kallikrein, or factor Xa. The conversion of plasminogen to plasmin by tPA is accelerated by the presence of fibrin. Both forms of tPA bind to fibrin, and it has been reported that single-chain tPA binds to fibrin better than two-chained tPA. This was thought to give single-chained tPA better clot selectivity than two-chained tPA, but this observation has been questioned recently. The two-chained form of tPA is more active in converting Glu-plasminogen to plasmin and is inactivated much more rapidly by inhibitors than is the single-chained tPA.
Hemostatic effect of acylated ghrelin in control and sleeve gastrectomy-induced rats: mechanisms of action
Published in Archives of Physiology and Biochemistry, 2020
Tissue factor (TF) is a membrane-bound glycoprotein secreted by the active vascular ECs to initiate the extrinsic pathway of blood coagulation (Hinsbergh 2012). On the cell surface, TF can activate circulatory factor VII leading to the formation of TF/VIIa complex which eventually induces the activation of circulating factors X and IX and deposition of insoluble fibrin (Nemerson 1988, Mackman 2009). On the opposite, vascular ECs also secrete an opposing anti-thrombotic protein named tissue factor pathway inhibitor (TFPI), which acts to inhibit TF directly (Hinsbergh 2012, Wood et al.2014). Similarly, tissue plasminogen activator (tPA) is the major fibrinolytic anti-coagulant protein released by the vascular ECs to degrade fibrin clots by increasing active plasmin levels in blood and body cavities (Rijken et al.2009). Plasminogen activator inhibitor-1 (PAI-1) is the most potent inhibitor of tPA activator and is also released by the vascular ECs (Hinsbergh 2012, Yau et al.2015).
Making a case for the right ‘-ase’ in acute ischemic stroke: alteplase, tenecteplase, and reteplase
Published in Expert Opinion on Drug Safety, 2019
Katleen Wyatt Chester, Megan Corrigan, J. Megan Schoeffler, Michelle Shah, Florence Toy, Barbara Purdon, George M. Dillon
Human tissue plasminogen activator is a serine protease that facilitates dissolution of blood clots by indirectly inducing degradation of fibrin. Tissue plasminogen activator catalyzes the conversion of fibrin-bound plasminogen to active plasmin, a proteolytic enzyme that degrades fibrin (Figure 1) [20,21]. Free tissue plasminogen activator has low intrinsic catalytic activity, which increases >100 times in the presence of fibrin [22,23]. The activity of tissue plasminogen activator is negatively regulated by plasminogen activator inhibitor-1 (PAI-1), which irreversibly inactivates tissue plasminogen activator by covalently binding within the active site of the protease domain [22,24]; this negative regulation prevents systemic activation of tissue plasminogen activator and plasminogen.
The potential association between metabolic syndrome and risk of post-surgical adhesion
Published in Archives of Physiology and Biochemistry, 2023
Gordon A Ferns, Milad Shahini Shams Abadi, Mohammad-Hassan Arjmand
Adhesion formation is a part of the wound healing process in tissues after trauma and surgeries. Both inflammation and fibrin clot deposition are the main mechanisms during the early phase of the normal or pathological healing process. Briefly, a rapid immune response begins with local and circulating immune cells, secretion of pro-inflammatory cytokines, and the formation of a fibrin matrix are an important mechanism in normal healing (diZerega & Campeau 2001). The balance between fibrin matrix deposition and degradation, or fibrinolytic activity, is important. The coagulation cascade is activated in response to injury to blood vessels and inflammation in the traumatised area with increases the permeability of vessels to increase exudate fluid and flow more inflammatory cells to the site. Fibrin matrix gel is lysed within a few days by the fibrinolytic system (Buckman et al. 1976). Plasmin is responsible for a physiological fibrinolytic sequence that result from plasminogen activation by tissue plasminogen activator (tPA) (Holmdahl et al. 1996). After surgery, a decrease of tPA activity is associated with an increased susceptibility to adhesions (Sulaiman et al. 2002).
Related Knowledge Centers
- Alteplase
- Enzyme
- Plasmin
- Protein
- Recombinant DNA
- Serine Protease
- Endothelium
- Blood Vessel
- Thrombolysis
- Reteplase