Thrombolytic agents Flashcards
Physiologic Activators of the fibrinolytic system
t-PA I - single chain tissue plasminogen activator
Urokinase
Factor XIIa
Physiologic Inhibitors of the fibrinolytic system
- PAI-1 (Rapid acting plasminogen activator inhibitor)
Thrombin activatable fibrinolytic inhibitor (TAFI) - α2-antiplasmin
α2-Macroglobulin
(inhibit plasmin from digesting fibrin)
how does α2-antiplasmin have its effects?
α2-antiplasmin complexes with plasmin blocking its active site
Plasminogen (Pro-fibrinolysin)
Zymogenic form of the active enzyme plasmin
2 types glu-plasminogen and lys-plasminogen
Plasmin (Fibrinolysin)
Active protease capable of digesting both fibrinogen and fibrin.
fibrin is formed by
thrombin acting on fibrinogen
fibrin is stabilized by
factor XIIIa
does plasmin act on stabilized or non-stabilized fibrin?
stabilized
D-Dimers
Fragments DDE,YD/DY and YYDD are formed by the action
of plasmin on polymerized fibrin monomers (clots).
Factors Which Promote Fibrinolysis
**Plasminogen incorporation into thrombus via fibrin binding
Clot retraction
Local release of t-PA by endothelial cells
**Binding of t-PA to fibrin
Enhanced t-PA or UK activity in the presence of fibrin
Protection of bound plasmin from antiplasmin
Factors Which Limit Fibrinolysis
- Fibrin crosslinking by Factor XIIIa
- Binding of α2-antiplasmin to fibrin
Low ratio of endothelial surface to thrombus volume in large vessels
Efficient inhibition of free plasmin by antiplasmin
Antiplasmin impairs plasmin binding to fibrin
effects of thrombolytic agents
- Reduction in thrombus size (thrombolytic)
- Reduction of fibrinogen levels
- Increase in fibrinogen and fibrin degradation products
Antiplatelet activators
most thrombolytic agents act by
activating plasminogen
Clinically Approved Thrombolytic Agents
Urokinase
Streptokinase
Recombinant tissue plasminogen activators (t-PA)
Recombinant tissue plasminogen activators available examples (3)
- Alteplase (Recombinant form of Human t-Pa, most used)
- Reteplase (Mutant nonglycosylated form of human t-Pa, more fibrin specific), longer half life
- Tenecteplase (Mutant form of human t-Pa with longer half life), high fibrin specificity.
other thrombolytic agents - not used in US
Single chain pro urokinase (Pro-UK, SCU-PA) (under development)
Plasmin (under development)
which thrombolytic agent has the most specificity?
t-PA more targeted to the clot (may have less bleeding associated as well)
biologic changed that occur after administering a thrombolytic agent
- Circulating plasminogen activator
- Plasminogen converted to plasmin
- Antiplasmin complexes with and inhibits plasmin
- Free plasmin
- Plasmin degradation of fibrinogen
- Degradation of other plasma clotting factors
- Hypocoagulable state
what is a side effect of thrombolytic agents and what causes it
systemic lytic state- degradation of plasma fibrinogen by circulating plasmin
what is a complication of thrombolytic agents and what causes it
bleeding - degredation of fibrin in hemostatic plugs (possibly also the hypocoagulable state)
Clinical Usage of Thrombolytic Agents
MI- due to a thrombus in the coronary vessels
or acute occlusion of coronary after leading to a fibrin-rich clot formation (may lead to an MI)
Peripheral Arterial Occlusion
DVT (localized or systemic treatment)
Pulmonary Embolism (streptokinase and urokinase only)
thrombotic stroke
catheter clearence
what factor may lead to decreased affectiveness of thrombolytic agents
Time- the older the clot the less susceptible it is to the lytic action of thrombolytic agents
Complications of Thrombolytic Therapy
Bleeding
Re-occlusion
Stroke
Others
Absolute Contraindications of Thrombolytic Therapy
Intracranial bleeding
Massive hemorrhage
Drug Interactions with Thrombolytic Agents
Antiplatelet Drugs
Heparin
Dextrans
Pharmacologic Antagonists for Thrombolytic Agents
- EACA (Epsilon-amino caproic acid)
- Tranexemic Acid (Trans-4-Aminoethylcyclohexane 1-Carboxylic Acid)
- Aprotonin (Trasylol)
can be used if there is too much bleeding due to thrombolytic use
DEFIBRINOGENATING ENZYMES can be found where
snake venom - digest fibrinogen
