L10 - Antiplatelets

Question 1

Venous thrombosis

Answer 1

• associated with stasis of blood +/- damage to the vein
• high RBC content
• high fibrin content
• low platelet content
• red
• soft and gelatinous

Question 2

Arterial thrombosis

Answer 2

Forms at site of atherosclerosis following plaque rupture

• low fibrin content
• higher platelet content
• white
• lines of Zahn

Question 3

Healthy endothelium

Answer 3

1. Proastacyclin (PGI2) produced and released by endothelium cells
2. PGI2 binds to the platelet receptors and increases cAMP in platelets
3. The increased cAMP inhibits the release of sequestration calcium from stores
4. Less calcium means less platelet aggregation
5. Less release of platelet aggregatory mediators
6. Glycoprotein IIb/IIIa receptors remains inactive

Question 4

Glycoproteins IIb/IIIa

Answer 4

• Integrin receptor complex found on platelets

- binds with fibrinogen and vWF to aid platelet aggregation

Question 5

Platelet activation and aggregation

Answer 5

1. Damage to endothelium e.g. by fibrous cap rupture exposes collagen fibres
2. Adhesion and activation of platelets
3. Chemical mediators are released by platelets granules e.g. thromboxane A2, ADP, serotonin, thrombin and platelet activation factor
4. Further cascade of platelet aggregation as GP IIb/IIIa are activated which binds to fibrinogen and another platelet
5. Ca2+ is released from its stores and cAMP decreases in platelets

Question 6

Drug type for arterial and venous thrombi

Answer 6

Arterial thrombi: platelet rich, white

• anti-platelet drugs
• lesser extent fibrinolysis drugs

Venous thrombi: loser platelet content, red

• parenteral anticoagulants - heparin
• oral anticoagulants - warfarin

Question 7

Secondary prevention in acute coronary syndrome

Answer 7

Combination of both anticoagulants, antiplatelets and fibrinolytics

Question 8

Aspirin mechanism of action

Answer 8

Cyclo-oxygenase inhibitor

• inhibits COX-1 mediated production of thromboxane A2 and irreversibly reduces platelet aggregation

Question 9

Why does aspirin not completely inhibit platelet aggregation

Answer 9

There are other methods that platelets use to aggregate, independent of COX 1

Question 10

COX 1

Answer 10

Normally converts arachidonic acid into prostaglandin H2

Prostaglandin H2 is converted to thromboxane A2

Question 11

Where is arachidonic acid produced from

Answer 11

Produced and accumulates around the phospholipid membrane

Question 12

Dose actions of aspirin

Answer 12

Low dose - inhibits platelet aggregation

High dose

• loading dose
• analgesic
• inhibits prostacyclin

Question 13

Absorption of aspirin

Answer 13

Passive diffusion - hepatic hydrolysis when metabolised to salicylic acid

Question 14

Side effects of aspirin

Answer 14

Prolonged bleeding time

• haemorrhagic stroke
• GI bleeding
• peptic ulcers - to lesser extent
• Reye’s syndrome
• hypersensitivity
• early closure of the ductus arteriosus in the 3rd trimester

Question 15

Reye’s syndrome

Answer 15

Occurs after a viral infection in children given aspirin
Can be fatal
Causes oedema and hepatic issues

Therefore do not give aspirin to children under 16

Question 16

Cautionary measures with aspirin

Answer 16

Taken with other antiplatelets and and anticoagulants

Question 17

Why does inhibitory effects of aspirin last the lifespan of a platelet (7-10 days)?

Answer 17

Platelets do not have nuclei therefore cannot reproduce COX - 1

Question 18

COX 1 polymorphism

Answer 18

Can cause lack of efficacy

May not acetylate COX 1 therefore reduces efficacy

Question 19

When is aspirin used?

Answer 19

In secondary prevention of:

• stroke - initial 300mg daily for 2 weeks
• TIA
• acute coronary syndrome - initial once only chewable loading dose
• MI in stable angina or peripheral vascular disease

Used in:
- post primary percutaneous coronary intervention (PCI) and stents to reduce ischaemic complications

Question 20

What is also given with long term aspirin?

Answer 20

PPI e.g. omeprazole form gastric protection

Question 21

ADP receptor antagonist examples

Answer 21

Clopidogrel
Prasugrel
Ticagrelor

Question 22

ADP receptor antagonists

Answer 22

Inhibits binding of ADP to P2Y12 receptor on platelets therefore less calcium release from stores, inhibiting the activation of GP IIb/IIIa receptors

(Independent of COX -1)

Question 23

Clopidogrel and prasugrel

Answer 23

Irreversible inhibitors of P2Y12

Pro drugs - require hepatic metabolites to activate them (CYPS)

Question 24

Onset speed for ADP receptor antagonists

Answer 24

Clopidogrel - slow onset of action without loading dose
Prasugrel - rapid onset but slower than ticagrelor
Ticagrelor - rapid onset (1-2 hours)

Question 25

Ticagrelor

Answer 25

Acts reversibly at different sites to clopidogrel | Has active metabolites

Question 26

Side effects of ADP receptor antagonists

Answer 26

- Bleeding - GI upset - dyspepsia and diarrhoea - possible thrombocytopenia - clopidogrel needs stopping 7days prior to surgery

Question 27

Cautions with ADP receptor antagonists

Answer 27

Renal and hepatic impairment - due to excretion and activation Clopidogrel requires CYPs for activation therefore (CYP inhibitors) - omeprazole - ciprofloxacin - erythromycin - SSRI Ticagrelor can interact with CYP inhibitors and inducers Co-prescribed with other antiplatelets and anticoagulant agents or NSAIDS

Question 28

When are ADP receptor antagonists used?

Answer 28

- clopidogrel is used as monotherapy when aspirin is contraindicated - NSTEMI patients - up to 12months - STEMI with stent - up to 12 months Long term secondary prevention for: - ischaemic stroke - TIA Prasugrel with aspirin in ACS patients undergoing PCI for up to 12 months

Question 29

Glycoprotein IIb/IIIa inhibitors example

Answer 29

Abciximab - monoclonal antibody | Given as IV with bolus

Question 30

Glycoprotein IIb/IIIa inhibitor mechanism of action

Answer 30

Blocks the glycoproteins IIb/IIIa receptors therefore blocks the binding of fibrinogen and vWF to GP IIb/IIIa Therefore inhibits aggregation of platelets at the terminal step - better efficacy

Question 31

Side effects and cautions of abciximab

Answer 31

- bleeding (highest risk) - dose adjustments with body weight - thrombocytopenia - hypotension - bradycardia Caution with other antiplatelets and anticoagulants Specialist use in high risk percutaneous transluminal coronary angioplasty patients

Question 32

Phosphodiesterase inhibitor example

Answer 32

Dipyridamole

Question 33

Phosphodiesterase inhibitor mechanism

Answer 33

Inhibits the cellular reuptake of adenosine Increased plasma adenosine Inhibits platelet aggregation via A2 receptors Also: Prevents cAMP degradation Less calcium released from stored Less GP IIb/ IIIa receptor activation

Question 34

Side effects and cautions of dipyridamole

Answer 34

Flushing Headache Hypersensitivity Caution with: - antihypertensives (higher adenosine plasma conc) - antiplatelets - anticoagulants

Question 35

Uses of dipyridamole

Answer 35

Secondary prevention of ischaemic stroke and TIAs | Adjunct for prophylaxis of thromboembolism following valve replacement

Question 36

Fibrinolytic agents

Answer 36

Streptokinase - promotes plasminogen expression Alteplase - plasminogen activator Plasmin causes fibrinolysis of a fibrin clot into fibrin degradation products

Question 37

Fibrinolysis inhibitor

Answer 37

Tranexamic acid

Question 38

When is Alteplase used

Answer 38

In acute ischaemic stroke - less that 4.5 hours

Question 39

Side effects of fibrinolytics

Answer 39

Bleeding

Question 40

Why can streptokinase only be used once?

Answer 40

Developed from streptococci therefore body will produce antibodies