Pharm 16 - Haemostasis and Thrombosis

Question 1

What is interim treatment for DVT?

Answer 1

Parenteral anticoagulant

Question 2

What happens in the initial stages of thrombosis

Answer 2

1. Tissue factor (TF) - TF bearing cells activate Factor 5 and factor 10 - f5a and f10a form prothrombinase complex
2. Prothrombinase complex activates f2 (prothrombin) - which creates f2a (thrombin)
3. Antithrombin (AT-3) - inactivates f2a and f10a

Question 3

What are the 4 classes of anticoagulant drugs?

Answer 3

1. Factor 2a inhibitors - Dabigatran (oral) (BUT IT HAS A DANGEROUS SIDE EFFECT PROFILE)
2. Factor 10a inhibitor - Rivaroxaban (oral)
3. Drugs that increase the activity of Antithrombin (AT-3) -
4. Heparin (IV, SC) - decreases f2a and f10a.
5. Low molecular weight Heparin (LMWH) - Dalteparin (decreases f10a)
6. Drugs that Reduce levels of other factors -
   e. g. Warfarin - Vitamin K antagonist

Question 4

What factors does Vitamin K help generate?

So warfarin prevents these factors being produced

Answer 4

2, 7, 9, 10

Question 5

What is the difference in pharmacological treatment when a DVT progresses to a PE?

Answer 5

Parenteral treatment - goes from Dalteparin (DVT) to Dalteparin and Heparin (PE)

Maintenance treatment - goes from Rivaroxaban (DVT) to Rivaroxaban and/or warfarin (PE)

Question 6

What are the 3 risk factors for Virchows Triad.

Virchows triad = RFs for DVT and PE

Answer 6

1. Rate of blood flow - slow/stagnating blood means no replenishment of anticoagulant factors - balance adjusted in favour of coagulation
2. Consistency of blood - natural imbalance between procoagulant and anticoagulant factors
3. Blood vessel wall integrity - Damaged endothelia - blood exposed to pro coagulation factors

Question 7

What is the difference between a red and white thrombus?

Answer 7

Red thrombus = forms in vein —> partial occlusion of vein

White thrombus = forms in (coronary) arteries –> partial occlusion in (coronary) artery (white due to presence of foam cells taking up lipids) - associated with atherosclerosis

Question 8

Which 2 drugs are always offered as part of anti platelet therapy for an NSTEMI?

Answer 8

Aspirin and Clopidogrel

Question 9

What are 3 risk factors for acute coronary syndromes?

Answer 9

1. Damage to endothelium
2. Atheroma formation
3. Platelet aggregation

Question 10

What is the difference between NSTEMI and STEMI?

Answer 10

STEMI = fully occluded coronary artery (white thrombus) - Treated with anti platelets and thrombolytics

NSTEMI = partially occluded coronary artery (white thrombus) - Treated with anti platelets

Question 11

STEMI and NSTEMI are both examples of?

Answer 11

Acute coronary syndromes

Question 12

Thrombin is which factor?

Answer 12

f2a

Question 13

On a molecular level, how does amplification of a clot (i.e. platelet activation occur)

Answer 13

1. F2a (thrombin) activates Protease Activated Receptor (PAR)
2. PAR activation - rise in intracellular Ca
3. Increased intracellular Ca - exocytosis of ADP
4. ADP activates P2Y12 receptors - causing platelet activation
5. Activated P2Y12 and PAR stimulate COX to generate Thromboxane A2 (TXA2) from AA
6. TXA2 activation causes expression of GP2B/GP3A integrin receptor on platelet surface (acts like velcro)
7. GP2b/GP3a involved in platelet aggregation

Question 14

Activation of which receptor causes Arachadonic acid to be liberated?

Answer 14

PAR

Question 15

What 3 classes of drugs can be used to prevent platelet activation

Answer 15

1. Prevent platelet activation - Clopidogrel (oral) - ADP (P2Y12) receptor antagonist
2. Inhibit production of TXA2 - Aspirin (oral) - irreversible COX-1 inhibitor
3. Prevent platelet aggregation - Abciximab (IV, SC) - monoclonal antibody that binds to GP2b/GP3a receptors - Abciximab is 3rd line drug

Question 16

What does D-dimer test for?

Answer 16

Fibrin degradation products

Question 17

What is the treatment for ischaemic stroke?

Answer 17

Thrombolytic therapy - Alteplase (tPA)

tPA = Tissue Plasminogen Activator

Question 18

Which 2 atrial problems can cause increased likelihood of blood clot?

Answer 18

Atrial fibrillation and flutter

Question 19

On a cellular level, how does propagation of a clot occur?

Answer 19

Essentially through generation of fibrin strands

1. Large scale thrombin production (activated platelets)
2. Large amounts of thrombin bind to lots of fibrinogen and converts into fibrin strands

Question 20

How do thrombolytics work? (e.g. Alteplase)

Answer 20

1. Convert plasminogen into plasmin
2. Plasmin is a protease that degrades fibrin
3. Alteplase (IV) - recombinant tissue type plasminogen activator (rt-PA)
4. Causes dissolution of the clot

Question 21

Why are thrombolytics not given if they can remove preformed clots (unlike anticoagulants and anti-platelets)

Answer 21

Thrombolytics can cause excessive bleeding and may cause death later on

Question 22

Aside from ischaemic stroke, when else are thrombolytics prescribed

Answer 22

In STEMI

Question 23

What are the stages of coagulation

Answer 23

1. Initially, TF presentation, prothrombinase-mediated formation of f2a
2. Amplification - thrombin mediated platelet activation - ADP activates P2Y12 receptor - COX and GP2B/3A
3. Propagation - thrombin mediated conversion of fibrinogen - fibrin strands