Sentence to add to lead regarding mechanism of action:
Alteplase causes the breakdown of a clot through inducing fibrinolysis.[1]
History
In 1995, a study by the National Institute of Neurological Disorders and Stroke showed the effectiveness of administering intravenous alteplase to treat ischemic stroke.[2] This sparked a medical paradigm shift as it redesigned stroke treatment in the emergency department to allow for timely assessment and therapy for ischemic stroke patients.[2]
Commercialization and large scale manufacture of human t-PA was made possible through the generation of Chinese hamster ovary cells, which are capable of producing recombinant human t-PA (alteplase) with the use of recombinant DNA technology.[3] Prominent commercial brands include Activase® manufactured by Genentech Inc. from San Francisco, USA, as well as Actilyze® manufactured by Boehringer Ingelheim from Ingelheim, Germany.[3]
Alteplase is the same as the normal human plasminogen activator and is synthesized via recombinant DNA technology from vascular endothelial cells.[4]
Medical uses
Generally, alteplase is delivered intravenously into the body. To treat blocked catheters, alteplase is administered directly into the catheter.[1]
Mechanism of action
Alteplase binds to fibrin in a blood clot and activates the clot-bound plasminogen. Alteplase cleaves plasminogen at the site of its Arg561-Val562 peptide bond to form plasmin. Plasmin is a fibrinolytic enzyme that cleaves the cross-links between polymerized fibrin molecules, causing the blood clot to break down and dissolve. Fibrinolysis by plasmin is extremely short-lived due to plasmin inhibitors, which inactivate and regulate plasmin activity. Plasminogen activator inhibitor 1 binds to alteplase and stops its activity by forming an inactive complex, which is removed from the bloodstream by the liver.
Pulmonary embolism
As of 2019, alteplase is the most commonly used medication to treat pulmonary embolism (PE). Alteplase has a short infusion time of 2 hours and a half-life of 4-6 minutes. Alteplase has been approved by the FDA, and treatment can be done via systemic thrombolysis or catheter-directed thrombolysis.
Systemic thrombolysis can quickly restore right ventricular function, heart rate, and blood pressure in patients with acute PE. However, standard doses of alteplase used in systemic thrombolysis may lead to massive bleeding, such as intracranial hemorrhage, particularly in older patients. A systematic review has shown that that low-dose alteplase is safer than and as effective as the standard amount.
Catheter-directed thrombolysis may be more efficient than systemic thrombolysis, as alteplase is locally administered to the occlusion site, and wash-away of the medication into other blood vessels is minimized. This procedure involves positioning a multi-sidehole catheter into the blood clot.
Blocked catheters
Alteplase can be used in small doses to clear blood clots that obstruct a catheter, reopening the catheter so it can continue to be used. Catheter obstruction is commonly observed with a central venous catheter (CVC). Currently, the standard treatment for CVC obstructions in the United States is alteplase administration. Alteplase is effective and low risk for treating blocked catheters in adults and children. Overall, adverse effects of alteplase for clearing blood clots are rare. Novel alternatives to treat CVC occlusion, such as tenecteplase, reteplase, and recombinant urokinase, offer the advantage of shorter dwell times than alteplase.
Synthesis
Alteplase is synthesized via recombinant DNA technology from vascular endothelial cells.
Mechanism of action
Alteplase is a serine protease that catalyzes the conversion of clot-bound plasminogen to plasmin.
The standard dose for PTE is 100mg within 2 hours. NO DOSAGE.
Adverse effects:
Symptomatic intracerebral hemorrhage is a prominent potential adverse effect of alteplase use.[5]
Contraindications:
The safety of alteplase in the pediatric population has not been determined definitively.[5] Alteplase is contraindicated in those with bleeding disorders that increase a person's tendency to bleed.[5] An example of this includes thrombocytopenia which is defined by an abnormally low platelet count.[5] Active internal bleeding and high blood pressure are additional contraindications for alteplase.[5]
Contraindications for Alteplase used specifically for acute ischemic stroke include current intracranial hemorhage and subarachnoid hemorrhage.[6]
- ^ a b Jilani, Talha N.; Siddiqui, Abdul H. (2020), "Tissue Plasminogen Activator", StatPearls, Treasure Island (FL): StatPearls Publishing, PMID 29939694, retrieved 2020-11-10
- ^ a b Campbell Bruce C.V.; Meretoja Atte; Donnan Geoffrey A.; Davis Stephen M. (2015-08-01). "Twenty-Year History of the Evolution of Stroke Thrombolysis With Intravenous Alteplase to Reduce Long-Term Disability". Stroke. 46 (8): 2341–2346. doi:10.1161/STROKEAHA.114.007564.
- ^ a b Collen, D.; Lijnen, H. R. (2004-04). "Tissue-type plasminogen activator: a historical perspective and personal account". Journal of Thrombosis and Haemostasis. 2 (4): 541–546. doi:10.1111/j.1538-7933.2004.00645.x. ISSN 1538-7933.
{{cite journal}}: Check date values in:|date=(help) - ^ Baskin, Jacquelyn L.; Pui, Ching-Hon; Reiss, Ulrike; Wilimas, Judith A.; Metzger, Monika L.; Ribeiro, Raul C.; Howard, Scott C. (2009-07-11). "Management of occlusion and thrombosis associated with long-term indwelling central venous catheters". Lancet (London, England). 374 (9684): 159–169. doi:10.1016/S0140-6736(09)60220-8. ISSN 1474-547X. PMC 2814365. PMID 19595350.
- ^ a b c d e Demaerschalk, Bart M.; Kleindorfer, Dawn O.; Adeoye, Opeolu M.; Demchuk, Andrew M.; Fugate, Jennifer E.; Grotta, James C.; Khalessi, Alexander A.; Levy, Elad I.; Palesch, Yuko Y.; Prabhakaran, Shyam; Saposnik, Gustavo (2016-02). "Scientific Rationale for the Inclusion and Exclusion Criteria for Intravenous Alteplase in Acute Ischemic Stroke: A Statement for Healthcare Professionals From the American Heart Association/American Stroke Association". Stroke. 47 (2): 581–641. doi:10.1161/STR.0000000000000086. ISSN 1524-4628. PMID 26696642.
{{cite journal}}: Check date values in:|date=(help) - ^ Parker, Sarah; Ali, Yasmin (2015-10). "Changing Contraindications for t-PA in Acute Stroke: Review of 20 Years Since NINDS". Current Cardiology Reports. 17 (10): 81. doi:10.1007/s11886-015-0633-5. ISSN 1523-3782.
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