Anticoagulants

Question 1

Name 3 serious medical problems caused by clots and give examples of conditions for each

Answer 1

1. Venous thromboembolism
   e.g deep vein thrombosis, pulmonary embolism
2. Myocardial infarction
   e.g. atherosclerosis
3. Stroke
   e.g. atrial fibrillation

Question 2

Describe the 3 main stages of the haemostatic process

Answer 2

1. Vasoconstriction - this reduces the blood flow to reduce blood loss
2. Platelet plug formation - this involves platelet adhesion, activation and aggregation
3. Stable clot formation - the coagulation cascade process. This causes the activation of a thrombin which converts soluble fibrinogen to insoluble fibrin. More platelet recruitment and activation occurs

Question 3

At which stage of the haemostatic process do anticoagulants exert their effect?

Answer 3

The coagulation cascade

Question 4

Why was the waterfall model revised and what was the new name?

Answer 4

New name:
amplification model

Why:
- found that thrombin (FII) activates FXIII, FXI, FVIII, FV
- so patients with FXII deficiency didn’t have a bleeding tendency and they could still form blood clots so it was deemed that factor 12 was not a convincing pathological activation to clotting
- tissue factor (FIII) was deemed the key trigger for physiological haemostasis (damage directly to the tissue)

Question 5

What are the 3 steps of the amplification model

Answer 5

1. initiation
   - hole in the endothelium which causes the tissue factor to become exposed and bind with FVII in the tissue factor pathway
   - This activates factor X to Xa, which converts prothrombin (II) to thrombin (IIa)
2. Amplification
   - thrombin burst - thrombin recruits more platelets by activating VIII, V and XI
3. Propagation
   - prothrombin is converted to thrombin
   - thrombin burst causes fibrinogen to fibrin which crosslinks with XIII to form a clot

Question 6

What did the mouse models for F XII deficient mice show for physiological clotting ?

Answer 6

FXII deficient mice did not suffer haemorrhage as FXII was deemed not to be a pathological activator for clotting

Question 7

What did the mouse models for FXII and FXI deficient mice show for pathological clotting ?

Answer 7

Formation of the thrombus was severely impaired

Question 8

Why were the mouse models important

Answer 8

FXII and FXI are important for pathological clotting cascade but not physiological

Question 9

What can be a pathological activator of FXII

Answer 9

polyanions that are generated at sites of inflammation and infection

Question 10

What is the mechanism of action of Heparin

Answer 10

Binds to antithrombin which inhibits thrombin (FIIa) and FXa

Question 11

What is the main side effect of Heparin

Answer 11

thrombocytopenia (low platelet count in the blood)

Question 12

What is the mechanism of action of Warfarin

Answer 12

Blocks the vitamin K cycle by blocking the epoxide reductase enzyme
This stops the recycling of vitamin K which is essential to the carboxylation activation of factors 2,7,9,10

Question 13

How are DOACs different to Warfarin in their MoA

Answer 13

DOACs have direct and specific inhibition of clotting factor II of X

Warfarin inhibits multiple factors 2,7,9,10

Question 14

Describe the mechanism of action of LMWH and give a drug example

Answer 14

anticoagulant activity of factor X

e.g. Dalteparin, Enoxaparin

Question 15

Describe the mechanism of action of Hirudins and give a drug example

Answer 15

direct thrombin (II) inhibitor

e.g. Bivalirudin

Question 16

Describe the mechanism of action of Fondaparinux

Answer 16

It is a super low molecular weight heparin which precisely and irreversible binds to factor X active site

Question 17

What are the different types of DOACs and give drug examples for each

Answer 17

1. Direct thrombin (II) inhibitors e.g. Dabigatran
2. Direct Xa inhibitors e.g. Rivaroxaban, Edoxaban, apixaban

Question 18

Which has a longer half-life, Warfarin or DOACs? What are the implications of this?

Answer 18

Warfarin - it can be taken less often, DOACs have shorter half-life so drug adherence is needed

Question 19

What is the route of elimination of warfarin

Answer 19

Hepatic

Question 20

What is the route of elimination of DOACs

Answer 20

renal - this is not good for people with renal impairment

Question 21

What are 4 future anticoagulant treatments

Answer 21

1. Antisense oligonucleotides
2. Antibodies
3. Small molecule inhibitors
4. Aptamers

Question 22

What type of drug is IONIS FXI-LRx and what is the mechanism of action

Answer 22

It is an antisense oligonucleotide
It binds to the mRNA and prevents protein synthesis of CF FXI

Question 22

What type of drug is IONIS FXI-LRx and what is the mechanism of action

Answer 22

It is an antisense oligonucleotide
It binds to the mRNA and prevents protein synthesis of CF FXI

Question 23

What type of drug is Osocimab and what is the mechanism of action

Answer 23

fully human monoclonal antibody

binds to factor XI and blocks function

Question 24

What is the mechanism of action of antisense oligonucleotides

Answer 24

they bind to the mRNA which causes it to become degraded and prevent protein synthesis

Question 25

What did the FOXTROT trial show about Osocimab

Answer 25

it was compared with enoxaparin (LMWH) on its safety and efficacy

that it can be given as a one-time dose as it had a long half-life

When given before surgery it was superior to enoxaparin

Question 26

What is the mechanism of action of small molecule inhibitors as anticoagulants, give a drug example

Answer 26

they bind to the targets active site and inhibit

e.g. Milvexian which is a factor XI inhibitor

Question 27

What is the mechanism of action of Aptamers

Answer 27

a single-stranded nucleic acid that forms a secondary structure which then binds and inhibits with high affinity and specificity