Haemostasis and Thrombosis

Question 1

What are the initial stages of thrombosis

Answer 1

Small-scale thrombin production

1. Tissue factor bearing cells activate FX and FV forming a prothombinase complex
2. Prothrombinase complex activates FII (prothrombin) to FIIa (thrombin)
3. Antithrombin (AT-III) inactivates VIIa and FXa

Question 2

What are the mechanisms by which drugs can be used to inhibit the initial stages of thrombosis and give examples of each

Answer 2

Inhibit factor IIa e.g. Dabigatran
Inhibit factor Xa e.g. Rivaroxaban
Increase AT-III activity e.g. heparin
Reduce levels of other factors e.g. warfarin

Question 3

What are the risk factors of Virchow’s triad

Answer 3

Rate of blood flow
Consistency of blood
Blood vessel wall integrity

Question 4

How does rate of blood flow contribute to DVT and pulmonary embolism risk

Answer 4

Blood flow is slow/stagnating -> no replenishment of anticoagulant factors + balance adjusted in favour of coagulation

Question 5

How does consistency of blood contribute to DVT and pulmonary embolism risk

Answer 5

Natural imbalance between procoagulation + anticoagulation factors

Question 6

How does blood vessel wall integrity contribute to DVT and pulmonary embolism risk

Answer 6

Damaged endothelia -> blood exposed to procoagulation factors

Question 7

How does DVT and pulmonary embolism present

Answer 7

Swollen leg + pitting oedema

Question 8

How is DVT investigated

Answer 8

2-level Wells score
D-dimer
Ultrasound to confirm

Question 9

How is DVT treated

Answer 9

Positive D-dimer test - given interim treatment with parenteral anticoagulant (dalteparin)

Ultrasound scan confirms DVT - given maintenance treatment with oral anticoagulant (rivaroxaban/warfarin)

Question 10

How do acute coronary syndromes present

Answer 10

History of hypertension + hyperlipidaemia

Shortness of breath, sweating, dizziness + chest pain

Question 11

What are the investigations done for acute coronary syndromes present

Answer 11

ECG (no changes)

Troponin (elevated)

Question 12

What is the treatment for acute coronary syndrome

Answer 12

Antiplatelet therapy -> ASPIRIN + CLOPIDOGREL

Used to stop the thrombus from growing larger

Question 13

What is a NSTEMI

Answer 13

Non-ST elevated myocardial infarction (MI)

‘White’ thrombus -> partially occluded coronary artery

Question 14

What is the treatment for NSTEMI

Answer 14

Antiplatelets

aspirin and clopidogrel as well as heparin to reduce DVT risk

Question 15

What is a STEMI

Answer 15

ST elevated myocardial infarction

‘White’ thrombus -> fully occluded coronary artery

Question 16

What is the treatment for STEMI

Answer 16

antiplatelets + thrombolytics

Aspirin and clopidogrel and thrombolysis (if within 12 hours of onset)

Question 17

What are NSTEMIs and STEMIs caused by

Answer 17

Damage to endothelium
Atheroma formation
Platelet aggregation

Question 18

Describe amplification stage of thrombosis

Answer 18

Platelet activation + aggregation

1. Factor IIa (Thrombin) activates platelets
2. Activated platelet changes shape and becomes ‘sticky’ and attaches other platelets

Question 19

Explain how platelets become activated by thrombin during amplification

Answer 19

1. thrombin binds to protease-activated receptor (PAR) on the platelet surface
2. PAR activation causes a rise in intracellular calcium
3. Calcium rises
4. Exocytosis of ADP from dense granules
5. ADP activates P2Y12 receptors
6. platelet activation/ aggregation
7. PAR activation liberates arachidonic acid (AA)
8. Cyclo-oxygenase (COX) generates thromboxane A2 (TXA2) from AA
9. TXA2 activation leads to expression of GPIIb/IIIa integrin receptor on platelet surface (involved in platelet aggregation)

Question 20

What are the ways in which the amplification stage of thrombosis can be inhibited by drugs

Answer 20

Prevent platelet activation/aggregation e.g. clopidogrel
Inhibit production of TXA2 e.g. aspirin
Prevent platelet aggregation e.g. abciximab

Question 21

Describe what occurs in the propagation stage of thrombolysis

Answer 21

Generation of fibrin strands

1. Activated platelets cause large-scale thrombin production
2. Factor IIa (thrombin) binds to fibrinogen and converts to fibrin strands

Question 22

What is the mechanism of action for thrombolytics and give an example

Answer 22

Convert plasminogen to plasmin (protease degrades fibrin) e.g. Alteplase (IV) -

Question 23

What are the risk factors for a DVT

Answer 23

Surgery
Prolonged immobility
Obesity

Question 24

How are PEs treated

Answer 24

Same way as DVTs

Question 25

How are PEs treated when the patient is at a severe risk of a cardiac arrest

Answer 25

thromboylysis with a 50mg bolus of a tPA such as alteplase

Question 26

Describe warfarin (class, pharmacokinetics, pharmacodynamics and side effects)

Answer 26

Vitamin K epoxide reductase inhibitor Given orally Reduces vitamin K epoxide (Needed for the conversion of glutamate to gamma-carboxyglutamate. This conversion normally activates factors 2, 7, 9 and 10) No side effects

Question 27

Describe Dalteparin (class, pharmacokinetics, pharmacodynamics and side effects)

Answer 27

Heparin IV or subcutaneous Potentiates activity of antithrombin III No side effects

Question 28

Describe Dabigatran (class, pharmacokinetics, pharmacodynamics and side effects)

Answer 28

Direct oral anticoagulant (DOAC) Oral admin Thrombin (IIa) inhibitor Can cause excessive bleeding

Question 29

Describe Rivaroxaban (class, pharmacokinetics, pharmacodynamics and side effects)

Answer 29

DOAC Oral admin Factor Xa inhibitor No side effects

Question 30

What are ischaemic strokes caused by

Answer 30

Thrombosis in one of the arteries supplying the brain or embolism from somewhere in the body (e.g. in AF)

Question 31

What is the treatment for ischaemic strokes

Answer 31

Thrombolysis with alteplase may be considered if within 4.5 hours of onset >4.5 hours of onset ->aspirin and clopidogrel are given as well as heparin if the patient is at a high risk of more emboli

Question 32

Describe aspirin (class, pharmacokinetics, pharmacodynamics and side effects)

Answer 32

Antiplatelet/NSAID/COX-1 inhibitor Oral admin Covalent binding to COX-1, preventing TXA2 production Side effects: GI irritation and ulceration, bronchospasm, prolonged bleeding, nephrotoxicity

Question 33

Describe Clopidogrel (class, pharmacokinetics, pharmacodynamics and side effects)

Answer 33

Antiplatelet Oral admin P2Y12 (ADP receptor) antagonist -> stops platelets activation No side effects

Question 34

Describe Abciximab (class, pharmacokinetics, pharmacodynamics and side effects)

Answer 34

Antiplatelet IV or SC Monoclonal antibody against GIpIIIa/IIb No side effects

Question 35

Describe Alteplase (class, pharmacokinetics, pharmacodynamics and side effects)

Answer 35

Recombinant tissue type plasminogen activator (rt-PA) IV Converts plasminogen into plasmin (Protease that degrades fibrin) Excessive bleeding at higher doses

Question 36

How do heparins work and how are they administered and why are they used as interim treatment

Answer 36

Activates AT-III (Reduces FIIa and FXa) IV, SC (parenteral) Rapid action to prevent immediate issues