Fibrinolytics

Question 1

What is Physiological fibrinolysis/thrombolysis? What enzyme is required for it? And how is it formed?

Answer 1

Fibrin clots are dissolved endogenously by the action of plasmin, a proteolytic enzyme formed by the cleavage of the plasma protein plasminogen
Plasminogen is activated endogenously by tissue plasminogen activator (tPA) which is released from endothelial cells
tPA binds preferentially to the plasminogen bound to fibrin and activates it with less effect on circulating plasminogen

Question 2

What are Fibrinolytic drugs? What are their indications?

Answer 2

Fibrinolytic drugs, sometimes called “clot busters” are used to dissolve fibrin clots whenever the presence of a clot causes imminent danger to the patient

Acute treatment of myocardial infarction is the primary indication for these agents
Also used in the setting of thrombotic stroke, PE and for catheter patency
The earlier the drug is given to dissolve the blockage in the vessel, the better the patient prognosis

Question 3

What ensures the best outcome witht the drug? What is the maximun time? What is it’s major disadvantage?

Answer 3

Best outcome occurs with drug administration within one hour of onset
Protocols allow administration of the fibrinolytic agent up to six hours from the onset of MI
Risk of hemorrhage with these drugs is great, even more than with antiplatelet and anticoagulant agents

Question 4

List examples of available fibrinolytic drugg?

Answer 4

Streptokinase
Anistreplase (anisoylated streptokinase activator complex)
Urokinase
Tissue plasminogen activator (tPA; alteplase)
Reteplase

Question 5

What is Streptokinase?

Answer 5

Enzyme derived from beta hemolytic streptococcus

Forms a complex with plasminogen via 1:1 stable, non-covalent binding to induce a conformational change that exposes the active site of plasminogen leading to its activation

Administered by IV infusion, intracoronary infusion and into occluded cannulae

Available as powder for injection; dosed in international units

Question 6

What are the indications and adverse effects of streptokinase? Is it affordable?

Answer 6

Indications:
acute evolving transmural MI, DVT, arterial embolism and occluded AV cannulae

Adverse effects:
Allergic reactions including bronchospasm, breathing difficulty, itching, rash, flushing
Hemorrhage
Least expensive of the treatment alternatives

Question 7

What is Anistreplase? What is the half-life? How is it administered? What is its indications? What are the adverse effects?

Answer 7

A complex of streptokinase and plasminogen with the catalytic center of the complex blocked by an anisoyl group

Deacylation of the complex occurs in vivo ; half-life of fibrinolytic activity is approximately 94 minutes compared to 23 minutes for streptokinase alone

Administered by IV injection over 2-5 minutes
Indicated for management of acute myocardial infarction
Adverse effects: hemorrhage

Question 8

What is Urokinase?

Answer 8

Acts directly on plasminogen to enzymatically activate it to plasmin

Administered similarly to streptokinase
Protein is of human origin from urine or kidney cell cultures -
not as antigenic as streptokinase
Considerably more expensive than streptokinase

Question 9

What is tPA?

Answer 9

Genetically engineered version of human tPA
100-fold more potent at activating plasminogen bound to fibrin than circulating plasminogen
Should limit the risk of widespread fibrinolysis and hemorrhage
Cleared by hepatic metabolism with a half-life of 5-10 minutes

Question 10

Indications and adverse effects of tPA

Answer 10

Indications:
indicated for acute MI
more recently approved for treatment of acute ischemic stroke within 3 hours of onset of symptoms
Adverse effects:
hemorrhage

Question 11

What are tPA-absolute contraindications?

Answer 11

• > 3 hours onset of symptoms (stroke indication)
• Sustained Blood pressure >185/100
• History of intracranial neoplasm, arteriovenous malformation (AVM), Aneurysm, or intracranial hemorrhage
• Active internal bleeding
• Gl bleeding with/in 21 days
• Recent MI
• Major surgery w/in 14 days
• Platelets <100,000
• Glucose <50 or >400
• Elevated aPTT or PT/INR
• Prior stroke within 90 days
• Prior head trauma within 90 days

Question 12

What is Aminocaproic acid?

Answer 12

Fibrinolytic antagonist
Inhibits plasminogen activator substances
Used to treat excessive bleeding due to hyperfibrinolysis
Can be given orally or IV

Question 13

Which drugs bind directly to fibrin-bound plasminogen?

Answer 13

Alteplase
Reteplase
Telecteplase

Question 14

Which drugs bind directly to circulating plasminogen? What is a risk?

Answer 14

Urokinase
Streptokinase
Anistreplase

They are associated with a higher risk of systemic bleeding