Fibrinolytics Flashcards
What is the fibrinolytic system?
It is the system where clots are resolved and removed by the body
- When heamostasis has been restored and blood loss is prevented
What happens during clot removal in the fibrinolytic system?
The fibrinolytic pathways occurs where it degrades fibrin, resulting in plasmin activation and fibrin breakdown. Plasmin has a potent proteolytic enzyme and it attacks fibrin at 50 different sites, it cuts in different places.
Plasmin is formed from the proenzyme plasminogen.
- It has a very high affinity for fibrin but has to be activated and can be activated by:
1. Tissue plasmin activators (tPA)
2. Urokinase plasminogen activator (uPA)
3. Kallikrein
What happens in the clot/thrombosis?
Thrombosis occurs which then leads to this fibrin clot, and in this clot plasmin is being trapped in the clot as well. However the plasmin needs to be activated as well. When inactive it will bind to the fibrin but it won’t cleave it until it’s activated. So there’s plasmin circulating in the blood and theres a free plasmin that circulates and becomes trapped in the clot when the clot forms. It can be inhibited in the circulation by antiplasmin binding to form antiplasmin-plasmin complexes that are inactive. It can be stimulated by the release of tissue plasminogen activator and urokinase from the endothelial cells upon damage. These activators will stimulate the catalytic activity of plasmin and this will then lead to the breakdown of fibrin. There are also inhibitors secreted by the endothelial cells and this activation is a balance between activation and the inhibition pathways. Once activated the plasmin will degrade the fibrin polymers to fibrin breakdown/degradation products and start to breakdown the clots.
How does the fibrinolytic system work?
- Plasminogen is the proenzyme which is inactive.
- It gets cleaved to Plasmin by plasminogen activators such as tissue plasminogen activators and urokinase.
- Plasmin is then free to bind and degrade fibrin once these activators bind to the plasmin to activate it.
- Once activated, plasmin degrades fibrin into fibrin degradation products
- Antiplasmin can bind to plasmin to inhibit it as well, which takes place in the general circulation and not in the clot.
What drugs can be used to stimulate fibrinolysis?
There are drugs that can convert plasminogen to plasmin, hence they’ll be more plasmin that can degrade the fibrin polymers. Examples include:
- Streptokinase
- Recombinant human tPA (activators) (e.g. Reteplase, Alteplase, Tenecteplase)
- Urokinase
What is Streptokinase?
- It is purified from streptococci
- It is cleared by the liver
- Bad side effect: you will generate antigenic antibodies after 4 days
- Half life about 20 minutes
- Due to the antibody production, it can’t be used for a year after one dose is given otherwise you will have a reaction towards it.
What is Alteplase?
- It is a plasminogen activator
- Reduces mortality in Myocardial infarction
- First line treatment of acute ischemic stroke, DVT and PE
- More active on fibrin-bound plasminogen than plasma plasminogen, therefore “clot selective” and fibrin is in the clot so more active on the fibrin bound plasminogen and will activate plasmin and breakdown of fibrin in the clot rather than in the circulation.
- Not antigenic so you don’t make antibodies against it
- Given IV - half life of 5mins
- Given within 6-12hrs, ideally within 1hr, it will work instantly to restore blood flow through the blood vessel.
What is Reteplase and Tenecteplase?
- Reduce mortality in myocardial infarction
- More active on fibrin-bound plasminogen than plasma plasminogen, therefore “clot selective”
- Not antigenic - no antibodies
- Reteplase given within 12hrs, ideally <1hr
- Tenecteplase given within 6hrs, ideally <1hr
Why is Urokinase not as useful as the other activators?
Not selective for clot-bound fibrin so less useful. most likely to target the circulating fibrin.
