• 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 (< 1 second)
    • platelet adhesion and activation (several 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 excessive clotting
  • the fibrinolytic system comprises a group of activators and inhibitors linked by a series of positive and negative feedback loops, with 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 activate plasminogen to plasmin:
    • tissue-type plasminogen activator (tPA) is mainly involved in the lysis of thrombi in the 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 is crucial for maintaining hemostatic balance and preventing excessive clot breakdown, which could lead to bleeding
    • plasminogen activator inhibitors (PAI-1 and PAI-2) – primarily target and inhibit tPA and uPA, thereby reducing the conversion of plasminogen to plasmin
    • α2-antiplasmin  – a potent inhibitor of plasmin, which binds to plasmin and inhibits its fibrinolytic activity
    • α2-macroglobulin – a non-specific protease inhibitor
    • thrombin-activatable fibrinolysis inhibitor (TAFI) – removes the lysine residues from fibrin, which are necessary for plasminogen and tPA binding. This makes the fibrin clot less susceptible to lysis
    • plasminogen activator inhibitor-3 (PAI-3) – also known as protein C inhibitor PCI), inhibits tPA and activated protein C
  • fibrinolysis is fibrin-specific
    • high affinity of tPA for plasminogen in the presence of fibrin allows efficient activation of plasminogen on the fibrin barrier
    • at the same time, fibrin-bound plasmin is protected against rapid inhibition by plasmin inhibitors like α2-antiplasmin); in contrast, free plasmin is rapidly inhibited
    • 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
  • plasminogen is a zymogen (inactive precursor of an enzyme) that is synthesized primarily in the liver and circulates in the blood (plasma concentration ~ 1.5-2 pmol/L)
    • there are molecular variants of plasminogen, including a type known as Lp(a), which is structurally similar to plasminogen but has a different function and is considered a risk factor for cardiovascular disease
  • upon activation (via cleavage catalyzed by tPA, etc.), it is converted to plasmin, a serine protease that breaks down fibrin into soluble degradation products
  • the conversion of plasminogen to plasmin is tightly regulated by inhibitors (like α2-antiplasmin and PAIs)
  • disorders of the plasminogen-plasmin system can lead to either a hyperfibrinolytic state, which may result in bleeding, or a hypofibrinolytic state, which may result in thrombosis
  • tissue plasminogen activator (tPA) – a serine protease (alteplase, tenecteplase)
  • urokinase-type activator (uPA)
  • plasmin is a proteolytic enzyme that cleaves not only fibrin and fibrinogen but also factor V, factor VIII, and prothrombin
  • inhibition of fibrinolysis may occur at the level of plasmin inhibition or inhibition of plasminogen activators
  • α2 – antiplasmin is the main physiological inhibitor of plasmin in human plasma
    • a glycoprotein belonging to the serine protease inhibitors (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
  • plasminogen activator inhibitor-3 (PAI-3)
    • also known as Protein C Inhibitor (PCI), is a serine protease inhibitor (serpin) that plays a role in various physiological processes including coagulation and fibrinolysis
    • it is known to inhibit activated protein C and tissue-type plasminogen activator (t-PA), among other proteases
    • it may also have roles in modulating inflammation and tumor invasion
  • thrombin-activatable fibrinolysis inhibitor (TAFI)
    • TAFI is activated by thrombin, thrombin in complex with thrombomodulin, or plasmin. When activated, it’s termed activated TAFI (TAFIa)
    • TAFIa exerts its anti-fibrinolytic activity by removing C-terminal lysine residues from partially degraded fibrin, hence slowing down the process of fibrinolysis
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Overview of plasminogen activators (fibrinolytics)

  • all fibrinolytic agents act as plasminogen activators

1st generation thrombolytics

  • urokinase
  • streptokinase
    • no specificity for fibrin
    • streptokinase activates plasminogen to plasmin indirectly – initially, streptokinase forms a complex with plasminogen, which is then 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), administrated as a 1-hour infusion (with an initial bolus)
    • the most widely used thrombolytic in stroke therapy to date → intravenous thrombolysis in acute stroke
    • the high affinity of alteplase for plasminogen in the presence of fibrin allows effective activation on the fibrin barrier, whereas, in plasma, plasminogen activation by alteplase is ineffective
      • theoretically, alteplase should only induce thrombolysis of the fibrin clot and not lead to a hypocoagulable state and hypofibrinogenemia; practical experiences reveal that elevated risk of bleeding and a decrease in fibrinogen levels can be observed

3rd generation thrombolytics
selective binding to fibrin, no systemic fibrinolysis, faster onset of action than generation II

  • tenecteplase (METALYSE)
    • a genetically engineered variant of tPA
    • a longer half-life (17 ± 7 min) allows a single bolus injection
    • greater affinity for fibrin, greater resistance to PAI
    • significant stroke trials:
      • EXTEND-IA TNK  demonstrated superior results of TNK compared to alteplase in patients with LVO and subsequent EVT
      • NOR-TEST   – similar results to alteplase
    • up to 4.5 hours, it can be used as an alternative to alteplase (ESO guidelines 2021)
  • reteplase (RAPILYSIN / RETAVASE)
    • recombinant plasminogen activator with a longer half-life than alteplase (15-18 minutes), allowing for bolus administration
    • fibrinogen depletion after reteplase is less pronounced than after streptokinase but more pronounced than after alteplase
    • reteplase may hold potential, but its role in stroke therapy is not yet well-established; it is used primarily in the management of acute myocardial infarction

4th generation thrombolytics

  • desmoteplase
    • fibrin-specific thrombolytic protein derived from the saliva of the vampire bat Desmodus rotundus
    • approx. 180-fold more fibrin selective than alteplase ⇒ does not significantly affect systemic coagulation
    • no effect on BBB, no neurotoxicity, and longer plasma half-life than alteplase (4 hours)
    • not used in clinical practice (DEDAS, DIAS, DIAS2 trials)
Fibrinolytic drugs
Comparison of alteplase,reteplase, and tenecteplase

Synthetic antifibrinolytics

(Exacyl / Traxyl / Transamin) usually 1ml/100mg

 

  • slow IV injection 10mg/kg (vial=5mL/500 mg) over 10 min every 8 hours  (infusion speed < 100mg/min to avoid hypotension)
  • cardiac surgery – 10-20 mg/kg bolus + continuous IV infusion 1-2 mg/kg/h
  • reduce dose in nephropathy
  • no dosage adjustment is required for hepatic impairment

(Trasylol / Antilysin)

 

  • vial = 10 000 TIJ (trypsin inhibitory units) / 1 mL
  • a bolus of 100 000 TIJ (10 mL) IV followed by infusion of 200-300 000 TIJ (diluted in 5% glucose) within 3-4 hours
  • 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

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Fibrinolytic drugs
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