Haemostasis and thrombosis

Question 1

What are the differences between haemostasis and thrombosis?

Answer 1

Haemostasis is physiological (blood coagulation to prevent excessive blood loss), whereas thrombosis is pathophysiological (blood coag within BV –> obstructs blood flow)

Question 2

Summarise the steps of coagulation

Answer 2

3 steps:

1. Initiation - small scale thrombin production on TF bearing cells
2. Amplification - large scale thrombin production on platelet surface
3. Propagation - thrombin mediated generation of fibrin strands

Question 3

What happens in the first step of coagulation?

Answer 3

Initiation:

• Small scale thrombin production
• Tissue factor bearing cells activate factors X and V forming prothrombinase complex
• Prothrombinase complex activates factor II (prothrombin) –> IIa (thrombin)
• Antithrombin in blood inactivates factors IIa, Xa

Question 4

How can step 1 of coagulation be targeted pharmacologically?

Answer 4

ANTI-COAGULANTS:
1. Factor IIa inhibitor - dabigatran

2. Factor Xa inhibitor - rivaroxaban
3. Increase activity of antithrombin - heparin, dalteparin (low MW heparin)
4. Reduce levels of other factors - warfarin (vit K antagonist)

Question 5

Explain the process of platelet activation

Answer 5

• Thrombin binds to protease-activated receptor (PAR) on platelet surface
• PAR activation –> rise in IC Ca2+
• Ca2+ rise –> platelet shape change + exocytosis of ADP from dense granules

1. ADP activates P2Y12 receptors (paracrine/autocrine) –> platelet activation/aggregation
2. COX
   - PAR activation liberates arachidonic acid
   - COX generates thromboxane A2 from AA
3. GPIIb/IIIa receptor
   - TXA2 activation –> expression of GPIIb/IIIa integrin receptor on platelet surface
   - GPIIb/IIIa involved in platelet aggregation

Question 6

What major clinical conditions are antiplatelet drugs indicated for in?

Answer 6

Arterial thrombosis

• Acute coronary syndromes - STEMI and NSTEMI
• AF - prophylaxis of stroke

Question 7

What major clinical conditions are anticoagulant drugs indicated for in?

Answer 7

DVT
PE
Thrombosis during surgery
AF - prophylaxis of stroke

Question 8

What major clinical conditions are thrombolytics indicated for in?

Answer 8

Stroke - first line
ST-elevated MI

Only used within certain time period o/w ineffective and too dangerous (excessive bleeding)

Question 9

What is haemostasis?

Answer 9

Essential physiological process - blood coagulation prevents excessive blood loss

Question 10

What is thrombosis?

Answer 10

Pathophysiological process - blood coagulates within blood vessel –> obstructs blood flow

Question 11

What step of coagulation do anticoagulants target?

Answer 11

Step 1 - initiation

Question 12

What step of coagulation do antiplatelets target?

Answer 12

Step 2 - amplification

Question 13

What step of coagulation do thrombolytics target?

Answer 13

Step 3 - propagation

Question 14

Under pathological conditions, what can happen during the initiation step of coagulation?

Answer 14

Too much thrombin can be formed

Question 15

How can step 2 of coagulation be targeted pharmacologically?

Answer 15

1. Prevent platelet activation/aggregation - clopidogrel - P2Y12 receptor antagonist
2. Inhibit TXA2 production - aspirin - irreversible COX-1 inhibitor
3. Prevent platelet aggregation - abciximab

Question 16

What happens in the second step of coagulation?

Answer 16

Amplification: platelet activation and aggregation:

• Thrombin (factor IIa) activates platelets
• Activated platelet changes shape, becomes sticky and attaches other platelets

Question 17

What kind of drug is clopidogrel? How does it work?

Answer 17

Anti-platelet drug
P2Y12 (ADP) receptor antagonist
Prevents platelet activation and aggregation

Question 18

What kind of drug is aspirin? How does it work?

Answer 18

Anti-platelet drug
Irreversible COX-1 inhibitor
Inhibits production of thromboxane A2

Question 19

What kind of drug is abciximab? How does it work?

Answer 19

Anti-platelet

Prevents platelet aggregation

Question 20

What kind of drug is dabigatran? How does it work?

Answer 20

Anti-coagulant
Factor IIa (thrombin) inhibitor

Question 21

What kind of drug is rivaroxaban? How does it work?

Answer 21

Anti-coagulant

Factor Xa inhibitor

Question 22

What kind of drug is heparin? How does it work?

Answer 22

Anti-coagulant

Potentiates action of antithrombin

Question 23

What kind of drug is dalteparin? How does it work?

Answer 23

Anti-coagulant
Low MW heparin
Potentiates action of antithrombin
Activates portion of antithrombin concerned w/breakdown of factor Xa more than IIa
Longer half life than heparin

Question 24

What kind of drug is warfarin? How does it work?

Answer 24

Anti-coagulant
Vit K epoxide reductase antagonist
Vit K required in gamma-carboxylation of factors II, VII, IX, X
Stops production of clotting factors

Question 25

What happens in the thirdstep of coagulation?

Answer 25

Propagation: generation of fibrin strands:

• Large scale thrombin production on platelet surface
• Thrombin (factor IIa) binds to fibrinogen and converts fibrin strands
• Net of fibrin traps all platelets within it

Question 26

How can step 3 of coagulation be targeted pharmacologically?

Answer 26

Thrombolytics
Convert plasminogen to plasmin (anticoag factor) - breaks down preformed clots

ALTEPLASE - recombinant tissue type plasminogen activator (tPA)