Term
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Definition
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•Know the mechanism of action of fibrinolytic drugs
•Know the major toxicities and contraindications of fibrinolytic drugs
•Know the major therapeutic uses of fibrinolytic drugs
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Term
Fibrinolytic (Thrombolytic) Agents
(5) |
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Definition
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•In contrast to the antiplatelet and anticoagulant drugs which prevent thrombus formation, the fibrinolytic drugs break down existing clots
–They are commonly called the ‘clot buster’ drugs
•The fibrinolytic drugs act by increasing the formation of the serine protease, plasmin, from its precursor zymogen, plasminogen
–Plasmin is part of the endogenous fibrinolytic system that breaks down clots in the normal hemostatic process
•These agents are typically used in combination with antiplatelet and anticoagulant drugs in the treatment of serious fibrin-containing thromboemboli (e.g., MI, ischemic stroke, DVT), but this multi-drug approach can increase the risk of hemorrhage
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Term
The Fibrinolytic System
(5) |
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Definition
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•The role of the endogenous fibrinolytic system is to dissolve unwanted fibrin thrombi and to dissolve old fibrin plugs
•Plasmin, a serine protease that digests fibrin, is the key component of the fibrinolytic system
–Plasmin is formed from its inactive precursor, plasminogen, by cleavage of a single bond (Arg560)
–Plasmin is a relatively non-specific protease that also cleaves other plasma proteins, including fibrinogen and several clotting factors
•Plasminogen can be activated by a number of endogenous proteases including tissue plasminogen activator (tPA), urokinase (uPA), and factor XIIa
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Term
Regulation of Fibrinolysis
(5) |
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Definition
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•Plasminogen (and plasmin) contain high-affinity binding sites for fibrin which enhances fibrinolysis
•Fibrin-bound plasmin is resistant to inactivation by circulating a2-antiplasmin
–Some a2-antiplasmin is bound covalently to fibrin protecting fibrin from premature lysis
•Circulating a2-antiplasmin rapidly inactivates plasmin outside the clot
-There is only enough a2-antiplasmin to inhibit ~50% of potential plasmin, so the system can be overwhelmed if massive activation of plasminogen occurs, resulting in a “systemic lytic state |
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Term
Regulation of Fibrinolysis: tPA
(6) |
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Definition
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•The most important endogenous activator of fibrinolysis is normally tPA
•tPA is released by endothelial cells in response to stimuli such as blood stasis, exercise, and stress
•tPA normally only activates plasminogen in clots for several reasons:
–tPA binds fibrin with high affinity where it activates fibrin-bound plasminogen
–tPA is rapidly cleared from the blood
–Free tPA is inhibited by circulating inhibitors, PAI-1 (plasminogen activator inhibitor-1) and PAI-2
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Term
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Definition
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•Tissue plasminogen activator (tPA; alteplase, ACTIVASE) and its derivatives (reteplase, RETAVASE; tenekteplase; TNKase)
–tPA is serine protease that activates plasminogen in a fibrin-specific manner (activates fibrin-bound plasminogen several hundred-fold faster than circulating plasminogen)
–Genetically engineered tPA derivatives are designed to have improved pharmacokinetic and pharmacodynamic properties
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Term
Fibrinolytic Drugs
tPA and Its Derivatives
(9) |
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Definition
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•tPA (alteplase, Activase) is a recombinant single chain serine protease
–It is cleaved at Arg275 by plasmin to a 2-chain form
•The N-terminal chain contains fibrin-binding determinants and domains important for hepatic clearance
•The C-terminal chain contains the serine protease domain
•Genetically engineering derivatives of tPA have been developed with prolonged half-lives (allowing bolus administration), enhanced fibrin specificity, and increased resistance to inhibition by PAI-1
–Reteplase (rPA; RETAVASE)
–Tenecteplase (TNK-tPA; tenecteplase; TNKASE)
•tPA and its derivatives have similar efficacy and toxicity, but have different dosing regimens
–Medication errors are possible if the wrong dosing is used
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Term
Fibrinolytic Drugs
Derivatives of Tissue Plasminoigen Activator (tPA)
Structural Features
(7) |
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Definition
- Fibronectin Finger: high affinity fibrin binding
- EGF: hepatic clearance
- Kringle 1: receptor binding (liver)
- Kringle 2: low affinity fibrin binding
- Serine Protease: catalytic activity, plasminogen activator inhibitor-1 (PAI-1) binding
- Glycosylation sites: clearance
- Ala296-299: enhanced fibrin specificity and PAI-1 resistance
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Term
Fibrinolytic Agents:
Administration
(8) |
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Definition
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•All agents are administered IV or intra-arterially
•All agents are most effective when given as soon as possible after the thromboembolic event
–Maximal benefit is obtained if tPA treatment is started within 4 to 6 hours of onset of MI symptoms
•Some patients may benefit if treated later
–Up to 4.5 hours after onset of stroke symptoms
•tPA is administered as a bolus (15 mg), followed by infusion over the next 90 min
•Single-bolus (tenectaplase, 5 sec) or double-bolus (reteplase, 2 min, wait 30 min, then 2 min) administration of tPA agents would appear to offer advantages over constant infusion of tPA, though clinical studies indicate similar efficacy to tPA
•Agents are typically administered in combination with aspirin and heparin (abxicimab may also be administered)
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Term
Thrombolytic Agents: Toxicity
(5) |
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Definition
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•Bleeding is the major toxicity of all the thrombolytic agents
–Due to lysis of fibrin in physiological thrombi at sites of vascular injury
–Due to systemic formation of plasmin which results in degradation of fibrinogen and clotting factors
•Intracranial hemorrhage is the most serious bleeding problem and occurs with all regimens
–Risk of hemorrhagic stroke increases with co-administration of heparin
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Term
Fibrinolytic Agents:
Indications
(3) |
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Definition
- Acute thromboembolic stroke
- Acute myocardial infarction
- Central deep vein thrombosis (DVT)
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Term
Fibrinolytic Agents:
Indications
Acute Thromboembolic Stroke
(2) |
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Definition
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Treatment of choice if patients present within 3 hours of symptoms.
Rigorous therapeutic protocols must be followed to minimize the chance of hemorrhagic stroke.
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Term
Fibrinolytic Agents:
Indications
Acute Myocardial Infarction
(4) |
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Definition
–In combination with aspirin, tPA and its derivatives result in ~30% reduction in death and reinfarction
–Patients with ST segment elevation and BBB do best
–Patients with ST segment depression or normal ECG do less well; non-Q-wave AMI may be harmed by treatment
–Clinical studies indicate angioplasty (with or without stent) is superior to thrombolytic therapy, but this treatment option may not always be feasible
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Term
Fibrinolytic Therapy:
Contraindications
(9) |
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Definition
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•Recent surgery, including organ biopsy, puncture of noncompressible vessels, serious trauma (especially head/face), CPR within 3 weeks
•Serious GI bleeding or ischemic stroke within 3 months
•Uncontrolled hypertension (systolic >180, diastolic >110)
•Active bleeding or hemorrhagic disorder
•Previous CVA or active intracranial process
•Suspected aortic dissection
•Acute pericarditis
•Current use of warfarin and INR >1.7
•Invasive procedures (such as cardiac catheterization, arterial blood gases draw) should be avoided in patients receiving fibrinolytic therapy
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Term
Fibrinolytics
Key Concepts
(4) |
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Definition
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•Fibrinolytic drugs act by increasing the amounts of plasmin, the protease that breaks down fibrin
•Fibrinolytic drugs are based on the endogenous activator of plasminogen, tissue plasminogen activator (tPA)
•Fibrinolytic drugs are most effective breaking down clots when used soon after fibrin clots are formed
•Bleeding is the most common risk of fibrinolytic therapy
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