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75 Cards in this Set
- Front
- Back
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What are the 3 Thrombolytics to know?
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-Tissue plasminogen activator
-Streptokinase -Aminocaproic acid |
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What are thrombolytic agents need for?
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Reducing the size of preformed fibrin clots such as those in coronary artery disease and atherosclerosis.
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What do Plasminogen activators activate?
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The fibrinolytic system
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What are 3 beneficial effects of timely reperfusion with thrombolytic agents in MI?
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-Reduced infarct size
-Maintained LV contractility -Reduced mortality |
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What drugs are ineffective in reducing the size of preformed fibrin clots?
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Heparin and Warfarin
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So what does the Fibrinolytic system do?
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Dissolves intravascular clots
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What is Plasmin?
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A nonspecific plasma serine protease enzyme that digests fibrin
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What is the inactive precursor of Plasmin?
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Plasminogen
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How is Plasminogen converted to Plasmin?
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By cleavage of a single peptide bond resulting in the generation of a 2-chained disulfide linked molecule with exposed kringles.
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What terms are used for the N- and C-termini of Plasmin?
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N-terminus: heavy chain
C-terminus: light chain |
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What does the N-terminus of Plasmin contain?
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5 disulfide-bonded loops which act as Lysine-binding sites
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What are these lysine binding sites called?
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Kringles
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What are the Kringles responsible for?
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Binding of plasmin to specific lysine residues in polymerized fibrin.
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What happens when the kringles (lys binding sites) bind to the lys residues on polymerized fibrin?
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Plasmin cleaves fibrin into Fibrin degradation products
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Where is the active catalytic site on Plasmin?
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The C-terminus (light chain)
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What is Plasminogen activated by?
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-Endogenous tPA and Prourokinase
-Exogenous Streptokinase |
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And how do the activators activate Plasminogen?
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By cleaving the Arg-Val bond
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What is the endogenous source of tPA?
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Vascular endothelial cells - it is released at local sites of thrombosis.
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How does tPA activate Plasminogen? (2 steps)
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1. Binds sites on Fibrin close to Plasminogen binding sites
2. Activates fibrin-bound Plasminogen into Fibrin-bound Plasmin |
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What does Fibrin-bound plasmin initiate?
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Clot resolution
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Why doesn't tPA prevent formation of clotting if it is released from EC's?
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Early during clot formation EC's also release PAI which allows for the clot to assemble.
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When does PAI production decrase and tPA production increase?
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At the end of clot formation when it is time to breakdown and recanalize the injured vessel.
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What other endogenous tissue activator can activate Plasminogen?
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Prourokinase
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How is Prourokinase converted to Urokinase?
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By kallikrein
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What is the mechanism of Urokinase like?
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Same as for tPA
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What is the exogenous Plasminogen activator?
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Streptokinase
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What are the products of Plasmin degradation of fibrin called?
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FDPs - fibrin degradation products
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What major side effect do Plasminogen activating drugs have the potential for?
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Too much activation of Plasminogen, thus too much clot lysis and hemorrhage.
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What protein prevents plasmin from circulating free in plasma?
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a2-Antiplasmin
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What does a2-antiplasmin inactivation of plasmin prevent?
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Prevents Inactivation of circulating fibrin and other clotting factors.
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What can result if plasmin generation exceeds the capacity of the a2-antiplasmin system?
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A systemic lytic state
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What 3 things will get consumed in such a systemic lytic state?
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-Fibrinogen
-Factor 8 -Factor 5 |
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So what are the 2 drugs that are used as activators of Fibrinolysis?
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-Streptokinase
-tPA |
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What is Streptokinase produced by?
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B-hemolytic streps
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What is Streptokinase NOT?
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It is NOT an enzyme.
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How does Streptokinase interact with Plasminogen?
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It forms a stable noncovalent 1:1 complex which undergoes conformational change to expose plasminogen's active site.
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What does the exposure of the active site of Plasminogen achieve?
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It catalyzes the activation of another plasminogen molecule to plasmin.
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What happens to the first Ska-Plasminogen complex after it catalyzes the activation of Plasminogen?
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It becomes Ska-Plasmin.
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What does the activated Plasmin consist of?
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Plasmin with its kringles available to interact with Lys residues on Fibrin.
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What kind of Plasminogen is activated by Streptokinase in contrast to that done by tPA?
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FREE plasminogen - not fibrin-bound.
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What can overabundant Streptokinase activation of plasminogen hence result in?
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A systemic lytic state
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What has to be done to overcome anti-streptococal Ab's from prior strep infections?
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Administer a large loading dose of Streptokinase
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What are common adverse effects of Streptokinase and what are they due to?
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Allergic reactions - fever, urticaria, anaphylaxis; due to its being a foreign protein from bacteria.
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What is the major difference of tPA in contrast to Ska?
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tPA IS an enzyme - a serine protease
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When is tPA a poor enzyme?
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In the absence of fibrin
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How is tPA made as a drug?
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By recombinant DNA technology
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What type of Plasminogen does tPA have a preference for activating? How do we know?
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Fibrin-bound Plasminogen - it has a 100X more rapid action on it than on free plasminogen.
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Where/how does tPA bind Fibrin?
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tPA binds to Fibrin via lysine binding residues at its N terminus.
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How is tPA cleared from plasma, and at what rate?
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By hepatic clearance at a VERY rapid rate - t1/2 = 1-4 minutes
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What sort of administration is required for tPA therapy?
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Continuous IV administration
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Which has more of a risk for systemic lytic state; Streptokinase or tPA? Why?
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Streptokinase - because it acts on free circulating plasminogen, not just that bound to the fibrin clot already made.
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Why is a systemic lytic state still a risk factor in tPA therapy though?
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Because required therapeutic doses are quite high and thus still carry the risk.
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How do side effects of tPA compare to Streptokinase?
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It is recombinant, so nonantigenic.
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What is the cost of tPA compared to streptokinase?
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tPA is 10X more expensive
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What is the most important complication of thrombolytic therapy?
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Hemorrhage
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What results from the systemic formation of plasmin?
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A systemic lytitic state
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What are the 2 abnormal processes that a systemic lytic state consists of?
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-Fibrinogenolysis
-Destruction of clotting factors especially V and VIII |
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What % of patients on thrombolytic therapy show minor bleeding and what is it primarily related to?
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3-4%; related to puncture or injection sites.
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What % show major bleeding requiring transfusion?
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1%
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What is the worst type of bleeding that is only seen in .1-.5% of patients?
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Intracerebral
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Despite the enhanced fibrin-bound plasminogen specificity of tPA, is there any less incidence of bleeding in patients on tPA vs Streptokinase?
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No; they both have similar incidence of bleeding.
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What is the incidence of hemorrhage in thrombolytic therapy proportional to?
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-Dose of thrombolytic agent
-Duration of therapy |
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What are 3 other complications of thrombolytic therapy?
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-Low grade fever
-Hypotension -Allergic reactions |
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What are the 3 major implications for thrombolytic therapy?
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1. Acute MI
2. DVT 3. Stroke |
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What are 3 positive effects that thrombolytics have in acute MI?
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-Reduction of infarct size
-Preservation of LV function -Reduction in mortality and morbidity |
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What is typically given along with thrombolytics in treating acute MI?
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Anticoagulants.
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When do thrombolytics have to be given if used for strokes?
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Within 3 hours
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What are major contraindications to thrombolytic therapy?
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-Active bleeding, GI bleeding within 3 months
-Recent surgery within 10 days -Recent CVA or cerebral surgery, mass, or aneurysm -Recent Ska therapy (5d-6mo) |
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What are 4 conditions that are contraindications to thrombolytic therapy?
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-Known hemorrhagic disorder
-Known hypersensitivity -Severe, uncontrolled hypertension -Pregnancy or postpartum |
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What is the 1 Procoagulant drug to know?
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Aminocaproic acid
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What is Aminocaproic acid?
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A potent inhibitor of fibrinolysis
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How does Aminocaproic acid act as an inhibitor of fibrinolysis?
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By acting as a synthetic lysine analog to bind the lysine binding sites of plasminogen and plasmin, preventing them from binding to fibrin.
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So what type of inhibitor is Aminocaproic acid of plasmin(ogen)?
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Competitive inhibitor
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What can Aminocaproic acid inhibition of plasminogen be used for?
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-Excess breakdown of fibrin
-Hemorrhage in surgery |
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How does the urine concentration of Aminocaproic acid typically compare to plasma levels and how is it useful?
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100X higher - useful for treating urinary tract bleeding.
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