Anti-platelets and anti-thrombotics

Question 1

Process of haemostasis?

Answer 1

1. Vasoconstriction
2. Platelet plug formation (adhesion, activation and aggregation)
3. Coagulation cascade
4. Fibrin mesh to stabilise platelet plug

Question 2

Types of anti-clotting drugs

Answer 2

1. Anti-platelets
2. Anti-coagulants
3. Thrombolytics

Question 3

4 main classes of anti-platelets

Answer 3

1. NSAIDs (e.g. aspirin)
2. Platelet GP IIB/IIIA receptor blockers
3. ADP receptor blockers
4. PDE inhibitor

Question 4

Role of prostacyclin in inhibiting platelet aggregation?

Answer 4

• Prostacyclin (PGI2) binds to platelet membrane receptors causing synthesis of cAMP from ATP
  -cAMP inhibits release of granules containing platelet aggregating agents

Question 5

Role of thromboxane A2 in activating platelet aggregation?

Answer 5

-Thromboxane A2 causes release of arachidonic acid from the platelet membrane
-Increased synthesis of TXA2
-Binds to receptors on neighbouring platelets, initiating release of aggregating agents

Question 6

Mechanism of action of aspirin in inhibiting platelet aggregation

Answer 6

-Irreversible COX inhibitor that decreases the synthesis of TXA2 from arachidonic acid

Question 7

How long does the effect of aspirin last?

Answer 7

-Lifespan of the platelet as it is an irreversible COX inhibitor (7-10 days)

Question 8

Clinical uses of aspirin

Answer 8

1. Prophylactic treatment of transient cerebral ischaemia
2. Reduce incidence of recurrent myocardial infarction
3. Decrease mortality in post myocardial infarction in patients

Question 9

Adverse effects of aspirin

Answer 9

1. Bleeding (PGI2)
2. Gastric upset and ulcers / GI bleeding (PGE2)

Question 10

What 4 molecules do GPIIB/IIIA bind to activate platelet aggregation?

Answer 10

1. Fibronectin
2. Fibrinogen
3. Vitronectin
4. von Willebrand factor

Question 11

MOA of GP IIB/IIIA blockers?

Answer 11

-Bind to GPIIB/IIIA, preventing the binding of fibrinogen and other ligands that promote platelet aggregation

Question 12

Name the 3 GPIIB/IIIA blockers.

Answer 12

1. Abciximab (monoclonal antibody; reversible inhibitor)
2. Eptifibatide (analogue of the sequence at the carboxyl terminal of the delta chain of fibrinogen)
3. Tirofiban (small molecule blocker)

Question 13

2 clinical uses of GP IIB/IIIA blockers

Answer 13

1. Prevent restenosis after coronary angioplasty
2. Acute coronary syndromes

Question 14

Name the 2 ADP receptor blockers that inhibit platelet activation

Answer 14

1. Clopidogrel
2. Ticlopidine

Question 15

Name the phosphodiesterase inhibitor.

Answer 15

Dipyridamole (increases cAMP which inhibits granule release)

Question 16

Name the 4 types of anticoagulants.

Answer 16

1. Heparin derivatives
2. Warfarin
3. Lepirudin, hirudin
4. Antithrombin III

Question 17

Describe 4 actions of thrombin

Answer 17

1. Further thrombin generation by activating FV, VIII and IX
2. Cleaves fibrinogen, forming fragments that polymerise to fibrin
3. Activates FXIII, a fibrinoligase that forms fibrin-fibrin links, stabilising coagulum
4. Platelet aggregation, smooth muscle cell proliferation and contraction

Question 18

Function of antithrombin III

Answer 18

Irreversibly inactivates IIa, IXa and Xa by forming equilimolar stable complexes with them

Question 19

What are heparins?

Answer 19

Sulfated glycosaminoglycans (mucopolysaccharides)

Question 20

Do LMWHs or unfractionated heparins have a longer duration of action?

Answer 20

LMWHs

Question 21

MOA of heparin

Answer 21

-Binds to ATIII, induces a conformational change that exposes its active site for more rapid interaction with clotting factor proteases
-To inactivate IIa, needs to bind to IIa and ATIII
-To inactivate Xa, only needs to bind to ATIII

Question 22

MOA of LMWHs

Answer 22

-Increases action of ATIII on Xa but not IIa

Question 23

Clinical uses of heparin

Answer 23

1. DVT, PE and AMI (Prevents worsening and spread of thrombus)
2. Combined with thrombolytics for revascularisation
3. Combined with GP IIa/IIIb inhibitors for angioplasty and placement of coronary stents
4. Anticoagulant of choice in pregnancy

Question 24

How is heparin administered?

Answer 24

IV or subcutaneously (NO IM as it predisposes to haematoma formation)

Question 25

Two adverse effects of heparin

Answer 25

1. Haemorrhage (Stop heparin and administer protamine sulfate) 2. Thrombosis and thrombocytopaenia (Ig M and Ig G mediated)

Question 26

What is Vitamin K used for in the body?

Answer 26

Reduced vitamin K is an essential cofactor in the carboxylation (post-translational modification) of glutamate residues (FII, VII, IX and X)

Question 27

Two clinical uses of Vitamin K?

Answer 27

1. Treatment and/or prevention of bleeding resulting from use of oral anticoagulants (e.g. warfarin) and prevention of haemorrhagic disease of the newborn; give reduced Vit K 2. Vitamin K deficiencies in adults

Question 28

MOA of warfarin

Answer 28

Inhibits Vit K reductase, preventing the formation of reduced Vitamin K and thus the post-translational modification of FII, VII, IX and X

Question 29

Clinical uses of warfarin

Answer 29

Same as heparin but MUST NOT be used in pregnancy

Question 30

PK factors of warfarin

Answer 30

1. Small and lipid-soluble, good oral bioavailbility 2. Small Vd, >99% bound to plasma albumin 3. Elimination by CYP450

Question 31

Three adverse effects of warfarin

Answer 31

1. Bleeding 2. Contraindicated in pregnancy due to fetal haemorrhagic disorder and effects on fetal proteins with gamma carboxyglutamate residues in bone and blood 3. DDIs (CYP450)

Question 32

Name the 4 thrombolytic agents

Answer 32

1. t-PA (alteplase) 2. Urokinase 3. Streptokinase 4. Anistreplase

Question 33

MOA of thrombolytic agents

Answer 33

Activate plasminogen, forming plasmin which degrades fibrin to form fibrin degradation products

Question 34

Three clinical uses of thrombolytics

Answer 34

1. Emergency treatment of coronary artery thrombosis 2. Peripheral arterial thrombosis and emboli (e.g. PE) 3. Ischaemic stroke (<4.5h)

Question 35

How are thrombolytic agents administered?

Answer 35

Intracoronary or IV injection

Question 36

Two adverse effects of thrombolytic agents?

Answer 36

1. Bleeding 2. CI: healing wound, pregnancy