31. Fibrinolytics, antifibrinolytics, hemostatic agents
Introduction to fibrinolysis
The fibrinolytic system is activated simultaneously with the coagulation cascade. The function of this system is to dissolve the clot after the bleeding has stopped and the damage has been repaired.
Many proteins are involved, most important tissue plasminogen activator (tPA), plasminogen and plasmin. tPA, factors XIa and XIIa and kallikrein all activate plasminogen into plasmin. Plasmin is a proteolytic enzyme similar to trypsin which then breaks down fibrin and coagulation factors, ultimately lysing the clot. After lysing the clot is plasmin quickly inactivated by plasmin inhibitors to prevent plasmin from lysing other clots that are not ready to be lysed yet in other parts of the body.
Fibrinolytics
Compounds
- Natural
- Streptokinase
- Urokinase
- Recombinant tPA analogues
- Alteplase
- Duteplase
- Tenecteplase
Fibrinolytics are also called plasminogen activators. The most frequently used fibrinolytics nowadays are tenecteplase and alteplase.
Indications
- Ischaemic stroke
- Massive pulmonary embolism
- STEMI (if PCI is unavailable)
Fibrinolytics are used to dissolve thrombi that have already been formed. They may be given systemically or administered directly adjacent to the thrombus by administration with a catheter.
Mechanism of action
These drugs activate plasminogen, converting it to plasmin. The historical drug is streptokinase, which is actually a virulence factor of streptococcus bacteria. Because it is a bacterial antigen it induces an immune reaction with a fever. It can therefore not be used for systemic use but only for local use with the help of a catheter.
Urokinase is found naturally in humans, named after being originally found in urine (but is also present in blood).
Alteplase, duteplase, and tenecteplase are recombinant TPA-like molecules. These molecules act mostly on plasminogen that is bound to fibrin, so they have lower risk of bleeding than streptokinase.
Because streptokinase activates plasminogen even if the plasminogen isn’t bound to fibrin, it has an increased risk of bleeding compared to other fibrinolytics.
Antifibrinolytics
Compounds
- Tranexamic acid
- Aprotinin
- Aminocaproic acid
Tranexamic acid is the most frequently used antifibrinolytic, which may be administered p.o. or i.v. Aprotinin may be applied topically.
Indications
- Stop severe haemorrhage
- Menorrhagia (severe menstrual bleeding)
- Antidote to fibrinolytic drugs
Mechanism of action
Tranexamic acid inhibits the conversion of plasminogen into plasmin. Aprotinin inhibits other proteolytic enzymes that convert plasminogen into plasmin.
Haemostatic drugs
These drugs stop bleeding by mechanisms other than inhibiting fibrinolysis. They can especially be used when patients who take anticoagulants or antiplatelets start bleeding externally, in which case the bleeding would take a long time to stop by itself.
Styptics are haemostatic agents that work by contracting tissue to seal damaged blood vessels. These agents contain astringents, which are compounds that cause vessels to contract. Adrenaline is often used as an astringent, either to allow for longer duration of action of local anaesthetic or to stop bleeding.
Spongostan is a type of sponge made of gelatine which induces haemostasis when applied directly to a bleeding. It’s also available as a powder.
Thrombin powder also induces haemostasis when applied directly to a bleeding.
For systemic use can plasma preparations, thrombocyte concentrates, coagulation factors and vitamin K be administered to prevent bleeding.
Ethamsylate is a drug that increases thrombocyte aggregation. It’s used to prevent parenchymal bleeding after surgery.