ISCHEMIC STROKE / RECANALISATION THERAPY
Fibrinolytic drugs
Created 26/10/2021, last revision 13/02/2023
- blood clotting is a fundamental homeostatic mechanism
- the participation of different systems is necessary:
- vascular wall (vasoconstriction)
- platelets (adhesion → activation → aggregation) with the formation of a primary plug
- plasma coagulation factors → thrombin formation → fibrin formation → definitive plug
- plasma inhibitors
- fibrinolytic system
Timing of successive steps of hemostasis:
- primary hemostasis:
- vasoconstriction (fractions of seconds)
- platelet adhesion and activation (tenths to units of seconds)
- platelet aggregation and primary plug formation (seconds to minutes)
- coagulation:
- activation of coagulation factors (seconds to minutes)
- formation of a solid fibrin coagulum (minutes)
- fibrinolysis:
- activation of fibrinolysis (minutes)
- dissolution of fibrin coagulum (hours to tens of hours)
Fibrinolysis
- the fibrinolytic system has two functions in the process of hemostasis:
- dissolves the fibrin plug (within hours)
- limits coagulum formation
- the fibrinolytic system comprises a group of activators and inhibitors that are linked by a series of positive and negative feedback loops and has four main components:
- plasminogen
- plasmin
- plasminogen activators
- plasminogen inhibitors
- the main component is the inactive proenzyme plasminogen, which is a precursor of plasmin protease
- plasmin hydrolytically cleaves fibrin to form degradation products
- several plasminogen activators are required to activate plasminogen to plasmin:
- tissue-type (tPA) is mainly involved in the dissolution of thrombi in circulation
- urokinase-type (uPA) is involved in extravascular proteolysis
- plasminogen activation can also be mediated by streptokinase (a product of bacteria) or other fibrinolytics, kallikrein, and factor XIIa
- Inhibition of fibrinolysis occurs at the level of inhibition of activators (PAI 1,2) and the level of inhibition of plasminogen (α2-antiplasmin and non-specifically α2-macroglobulin)
- fibrinolysis is fibrin specific
- the high affinity of tPA for plasminogen in the presence of fibrin allows efficient activation of plasminogen on the fibrin barrier, whereas in plasma, plasminogen activation by tPA is ineffective
- at the same time, fibrin-bound plasmin is protected against rapid inhibition by α2-plasminogen. In contrast, free plasmin is rapidly inhibited.
- the fibrinolytic system is triggered and conditioned by fibrin in the above ways
- streptokinase and urokinase are non-specific fibrinolytics and activate both circulating and fibrin-bound plasminogen, leading to widespread systemic activation of the fibrinolytic system, leading to degradation of other plasma proteins, including fibrinogen, factor V or factor VII
Components of the fibrinolytic system
| molecular weight (Da) | effect | |
| plasminogen | 88000 | proenzyme |
| plasmin | 88000 | active enzyme |
| tPA | 70000 | tissue enzyme |
| EPA | 54000 | urokinase-type |
| α2-antiplasmin | 70000 | specific fast-acting plasma inhibitor |
| PAI-1 | 43000 | endothelium-produced rapid inhibitor of both t-PA and u-PA |
- glycoprotein present in plasma at a concentration of 1.5-2 pmol/L
- contains “lysine-binding surfaces” that specifically react with amino acids such as lysine and 6-aminohexanoic acid. They mediate the specific binding of plasminogen to fibrin and the interaction of plasmin with α2-antiplasmin and play a key role in the control of fibrinolysis
- tissue plasminogen activator (tPA) – a serine protease (alteplase, tenecteplase)
- urokinase-type activator (uPA)
- plasmin, as a proteolytic enzyme, cleaves not only fibrin and fibrinogen but also factor V, factor VIII, and prothrombin
- inhibition of fibrinolysis may occur at the level of inhibition of plasmin or inhibition of plasminogen activators
- α2 – antiplasmin is the main physiological inhibitor of plasmin in human plasma
- a glycoprotein belonging to the serine protease inhibitor proteins (serpins)
- forms a complex with plasmin without protease activity
- the main inhibitor of tPA and uPA is the plasminogen activator inhibitor (PAI 1,2)
- glycoprotein belonging to serine protease inhibitors (serpins)
- is the primary inhibitor of tPA and uPA in human plasma
- reacts with tPA and urokinase, but not with pro-urokinase
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Overview of plasminogen activators (fibrinolytics)
- all fibrinolytic agents act as plasminogen activators
- alteplase and recently tenecteplase became a standard treatment for an acute ischemic stroke → intravenous thrombolysis
1st generation thrombolytics
- urokinase
- streptokinase
- no specificity for fibrin
- streptokinase activates plasminogen to plasmin indirectly – in the first step, streptokinase forms a complex with plasminogen, then plasminogen-streptokinase is converted to plasmin-streptokinase complex
- contraindicated in stroke due to a higher incidence of intracranial bleeding
2nd generation thrombolytics
- alteplase (ACTILYSE)
- recombinant human tissue plasminogen activator (tPA)
- short half-life (3-6 minutes), administration by infusion (with initial bolus) is necessary
- the most widely used thrombolytic in stroke therapy to date → intravenous thrombolysis in acute stroke
- the high affinity of tPA for plasminogen in the presence of fibrin allows effective activation on the fibrin barrier, whereas, in plasma, plasminogen activation by tPA is ineffective
- theoretically, alteplase should therefore only induce thrombolysis of the fibrin clot and not a hypocoagulable state and hypofibrinogenemia – we know from practice that even here we have to take into account the increased risk of bleeding and a decrease in fibrinogen levels
3rd generation thrombolytics
selective binding to fibrin, no systemic fibrinolysis, faster onset of action than generation II
- tenecteplase (METALYSE)
- genetically engineered tPA
- longer half-life (17 ± 7 min) allows bolus administration
- higher affinity for fibrin, higher resistance to PAI-1
- significant trials:
- EXTEND-IA TNK demonstrated superior results of TNK compared to tPA in patients with LVO and subsequent EVT
- NOR-TEST – similar results to tPA
- up to 4.5h. it can be given as an alternative to tPA (ESO guidelines 2021
- reteplase (RAPILYSIN / RETAVASE)
- recombinant plasminogen activator, which has a longer half-life than tPA (15-18 minutes), allowing for bolus administration
- fibrinogen depletion after reteplase is less pronounced than after streptokinase, but more pronounced than after tPA
- approved for thrombolysis in myocardial infarction
4th generation thrombolytics
- desmoteplase
- genetically engineered thrombolytic protein from the saliva of the bat Desmodus rotundus
- approx. 180 times more fibrin-selective than tPA, so it does not significantly affect systemic coagulation
- no effect on HEB, no neurotoxicity, and longer plasma half-life than tPA (4 h)
- DEDAS, DIAS, DIAS2 trials
Synthetic antifibrinolytics
- antifibrinolytics block the binding of plasmin to fibrin
- aminocaproic acid and tranexamic acid are the commonly used antifibrinolytic drugs in the EU
- tranexamic acid (EXACYL vial 5mL/500mg)
- IV injection 10mL (10 ml = 2 amp =1000 mg) over 10 min every 8h
- in cardiac surgery 10-20 mg/kg bolus + continuous infusion 1-2 mg/kg/h
- reduce dose in nephropathy!
- ε-aminocaproic acid (AMICAR 250 mg/mL)
- aprotinin (ANTILYSIN SPOFA, TRASYLOL) INJ (10 000 trypsin inhibitory units -TIJ in 1 mL)
- non-specific inhibitor – interferes with the active center of serine proteases, inhibits kallikrein, trypsin, urokinase, and elastase, interferes with the contact system (f.X), inhibition of f.XII and thrombin
