The tenecteplase is a tissue plasminogen activator the (tPA) synthesized by the pharmaceutical industry by recombinant DNA techniques applied in a cell line derived from Chinese hamster ovary cells.
The blood clotting process, which ends with the formation of a thrombus and the retraction of the clot, is continued with a phase called fibrinolysis. This phase is characterized by the dissolution of the thrombus through the fragmentation of the fibrin polymer into smaller and more soluble peptides, and the recanalization of the vessel, or vessels, where coagulation occurred.
Summary of the fibrinolytic process (Source: Jfdwolff at en.wikipedia / CC BY-SA (http://creativecommons.org/licenses/by-sa/3.0/) via Wikimedia Commons)
This fibrinolytic process requires the participation of a blood protein from the group of plasma globulins called plasminogen or profibrinolysin, of about 81 kDa, synthesized in the liver and normally present in circulating blood. This plasminogen is trapped during coagulation between the fibrin networks that make up the thrombus.
Plasminogen per se lacks any fibrinolytic action, an action that only appears when the original molecule is activated and converted into plasmin or fibrinolysin, which is a serine protease very similar to trypsin, which is the most important digestive proteolytic enzyme in secretion. pancreatic.
Plasmin has a high affinity for fibrin, which it breaks down into small soluble peptides, which in turn inhibit the action of thrombin and the subsequent production of more fibrin. It also exerts a proteolytic action on fibrinogen, prothrombin and coagulation factors V, VIII, IX, XI and XII, which also reduces the coagulatory capacity of the blood.
From this table, it can be deduced that plasmin influences blood coagulation processes in two ways, since on the one hand it produces the dissolution of the thrombus through its fibrinolytic action, and on the other it interferes with coagulation through its proteolytic action. on key factors of the coagulation process.
What is tenecteplase for?
Plasminogen activation occurs by the individual or combined action of a set of substances that are generically called plasminogen activators, and which, according to their origin, are grouped into plasminogen activators: blood, urinary, tissue and from microorganisms.
Being a tissue plasminogen activator that converts it into plasmin, and plasmin being the fibrinolytic agent par excellence, since tenecteplase is used for therapeutic fibrinolysis in acute myocardial infarction, thromboembolic strokes and pulmonary thromboembolism.
Structure of the molecule
Tenecteplase is a glycoprotein that has 527 amino acids in its primary structure and in which two basic domains are distinguished, one called the kringle domain and the other corresponding to the protease domain.
The kringle domain is an area of the protein that folds into large loops that are stabilized by disulfide bonds. This type of domain is very important because it allows protein-protein interactions that occur with blood clotting factors and receives its name from a Scandinavian cake whose shape it resembles.
The protease domain is the area of the molecule that has the proteolytic activity that confers on the enzyme its activating function itself.
The structure of the molecule is very similar to that of natural human tPA, however, recombinant DNA technology allowed the introduction of some modifications in its complementary DNA (cDNA) that provide the protein encoded in it with some therapeutic advantages.
Said modifications include the substitution of threonine at position 103 for asparagine and for asparagine 117 for glutamine, changes that are located in the kringle domain; while in the protease domain a tetra-alanine assembly was achieved in the positional range 296-299.
Mechanism of action
The mechanism of action of tenecteplase is similar to that of natural tPA. Once the thrombus is formed, plasminogen in its inactive form binds to fibrin without exerting any proteolytic action on it.
The tPA produced by endothelial cells binds to fibrin, thereby acquiring its plasminogen activating property in plasmin, a substance that triggers fibrinolysis.
Structure of plasminogen (Source: Jcwhizz / CC BY-SA (https://creativecommons.org/licenses/by-sa/3.0) via Wikimedia Commons)
The modifications produced in the tPA molecule and incorporated into tenecteplase make the activating action of this substance on plasminogen more sensitive to the presence of fibrin. Fibrin specificity that limits its action to thrombus sites and reduces systemic plasminogen activation and the resulting degradation of plasma fibrinogen.
Presentation
The dosage or potency of the substance is expressed in mg and in units (U) of tenecteplase. The units represent a specific reference standard for the drug and is not comparable with the units of other thrombolytic agents. One mg equals 200 units (U).
A commercial form is Metalyse, which comes in two presentations, each of which has a vial with the product in the form of a white powder and a pre-filled syringe with the solvent, clear and colorless, for reconstitution.
In one of them the vial contains 8000 units (40 mg) and the syringe 8 ml of solvent. In the other, the vial contains 10,000 U (50 mg) and the syringe 10 ml. In both cases, once the solution has been reconstituted by adding the contents of the syringe to the corresponding vial, it will contain 1000 units (5 mg) for each ml and will appear clear and colorless, or slightly yellow.
Dose
Treatment with tenecteplase should be started as quickly as possible, within 6 hours of the onset of symptoms. Due to the implicit risks of bleeding or hemorrhage, it should be prescribed by physicians with experience in thrombolytic treatment and in institutions with the means to monitor and counteract this type of side effects.
Image by HeungSoon at www.pixabay.com
The dosage of the substance should be based on body weight, with a minimum dose of 6000 units, equivalent to 30 mg dissolved in a volume of 6 ml of the reconstituted solution, to be administered in patients with body weight below 60 kg.
The maximum dose is 10,000 U (50 mg / 10 ml solution) reserved for patients with body weight of 90 kg and up.
The dosage schedule for patients whose weights are in the range between 60 and below 90 kg is as follows:
- ≥ 60 to <70 = 7000 U (35 mg / 7 ml)
- ≥ 70 to <80 = 8000 U (40 mg / 8 ml)
- ≥ 80 to <90 = 9000 U (45 mg / 9 ml)
The required dose should be administered as a single intravenous bolus and over a period of about 10 seconds. It can be administered through a previously connected intravenous circuit and through which a physiological solution of 0.9% sodium chloride (9 mg / ml) is being passed.
The drug is incompatible with glucose solutions, and although, according to current therapeutic criteria, adjuvant antithrombotic treatment that could include antiplatelet agents and anticoagulants should be administered in parallel, no other medication should be added to the injectable solution of tenecteplase.
References
- Balsera, EC, Palomino, M. Á. P., Ordoñez, JM, Caler, CL, Paredes, TG, & García, GQ (2011). Effectiveness and safety of alteplase versus tenecteplase in fibrinolysis of ST-elevation acute coronary syndrome. Cardiocore, 46 (4), 150-154.
- Bauer C and Walzog B: Blut: ein Flüssiges Organsystem, in: Physiologie, 6th ed; R Klinke et al (eds). Stuttgart, Georg Thieme Verlag, 2010.
- Fatovich, DM, Dobb, GJ, & Clugston, RA (2004). A pilot randomized trial of thrombolysis in cardiac arrest (The TICA trial). Resuscitation, 61 (3), 309-313.
- Guyton AC, Hall JE: Hemostasis and Blood Coagulation, in: Textbook of Medical Physiology, 13th ed, AC Guyton, JE Hall (eds). Philadelphia, Elsevier Inc., 2016.
- Haley Jr, EC, Lyden, PD, Johnston, KC, Hemmen, TM, & TNK in Stroke Investigators. (2005). A pilot dose-escalation safety study of tenecteplase in acute ischemic stroke. Stroke, 36 (3), 607-612.
- Jelkman W: Blut, in: Physiologie des Menschen mit Pathophysiologie, 31 th ed, RF Schmidt et al (eds). Heidelberg, Springer Medizin Verlag, 2010.