IC3 Fibrinolytics

Question 1

State a fibrinolytic drug

Answer 1

🥨 Alteplase

Question 2

Which factor is important for clot stabilization?

Answer 2

Factor XIIIa

Question 3

Which stage of hemostasis does fibrinolytics act on?

Answer 3

• Clot stabilization
• Fibrinolytics or thrombolytics breakdown fibrin crosslinking to reverse clot stabilization

Question 4

Explain what happens in endogenous thrombolysis

Answer 4

1. Tissue-type plasminogen activator, tPA activates the conversion of plasminogen to plasmin
2. Plasmin is an enzyme that mediates fibrinolysis → breaks down the fibrin network stabilizing thrombus
3. Trapped platelets & RBC are slowly released back into bloodstream

Question 5

What is Alteplase? Describe its MOA

Answer 5

• Recombinant tPA (-teplases)
• Produced by recombinant DNA technology
• Promote conversion of plasminogen to plasmin

Question 6

What is the risk of fibrinolytics?

Answer 6

• If fibrin network is broken down too quickly, the clot may break into clumps instead of a gradual release of trapped RBC & platelets
• These clot fragments may circulate in bloodstream → embolism → block smaller vessels

Question 7

Due to the risk of fibrinolytics, they are only used for ______?

Answer 7

• Pre-existing clots causing imminent risk of irreversible damage/death e.g. PE, thrombotic stroke
• Other clots like DVT → leave it to endogenous tPA + aggressive Tx w anticoagulants to prevent further clot growth

Question 8

What is the difference between native & recombinant tPA?

Answer 8

Longer plasma half-lives → allow convenient IV dosing (Alteplase has DOA of 20 to 30 min)

Question 9

What is an advantage of -teplases over kinases like urokinase & streptokinase (also fibrinolytics)?

Answer 9

They bind preferentially to clot-associated plasminogen, activating plasmin at the clot

Question 10

What are the adverse effects of Alteplase?

Answer 10

• Haemorrhage/bleeding
• Ventricular arrhythmias, hypotension, oedema (can be managed, not a major impediment)
• Cholesterol embolization, venous thromboembolism
• Hypersensitivity & anaphylaxis
  (Rare but severe as -teplases are recombinant proteins = risk of Ab production against them)

Question 11

What are the reversal agents for excessive fibrinolysis? Explain how they work

Answer 11

• 🥨 Tranexamic acid
• 🥨 Aminocaproic acid
• Compete for lysine binding sites on plasminogen & plasmin → thus blocking their interaction with fibrin

Question 12

What are the contraindications of Alteplase?

Answer 12

• Active bleeding
• Prior intracranial haemorrhage or recent (within last 3 months) intracranial or intraspinal surgery
• Serious head injury or stroke

Question 13

In whom should caution be taken for the use of Alteplase?

Answer 13

• Major surgery within 10 days
• Risk of bleeding (e.g., peptic ulcer) Cerebrovascular disease
• Mitral stenosis
• Atrial fibrillation
• Acute pericarditis or subacute bacterial endocarditis
• Presence of stable clots that can cause embolism (when rapidly fragmented & mobilized)

Question 14

What are the drug interactions with Alteplase that may increase bleeding risks?

Answer 14

• Antiplatelets (especially Dipyridamole & Aspirin)
• Anticoagulants (especially Warfarin & Heparin)

Question 15

What are the drug interactions with Alteplase that may decrease Alteplase levels?

Answer 15

Nitroglycerin