Thrombotic Disorders

Question 1

What are thrombotic disorders?

Answer 1

Thrombotic disorders are disorders involving thrombosis or platelets

Question 2

How does Ischaemic Heart Disease (IHD) manifest?

Answer 2

IHD manifests with stable and unstable angina, transient ischaemic attacks (TIA) and myocardial infarction

Question 3

What is ischaemia?

Answer 3

Starving tissue of oxygen that results in its death

Question 4

What is stable angina?

Answer 4

Blood vessels to the heart are narrowed and do not provide enough blood supply during exercise

Question 5

What is unstable angina?

Answer 5

Angina that comes and goes

Involves platelets

Dangerous

Question 6

What are the risk factors for IHD?

Answer 6

“Western” diet

Excessive bodyweight

Smoking

Lack of exercise

Age

Male sex

Question 7

Describe the epidemiology for IHD

Answer 7

Accounts for 30% of male and 22% female deaths in England and Wales

Question 8

What did the “Seven Countries” study show?

Answer 8

Mean serum cholesterol (particularly LDL) strongly associated with IHD death rate (r = 0.8)

BMI has variable association

“Central adiposity” (waist-hip ratio) strongly associated with IHD deaths

Question 9

What does post-mortem examination of the coronary arteries of MI victims show?

Answer 9

Ruptured atherosclerotic plaques

Platelet aggregates

Question 10

What is primary aggregation?

Answer 10

Primary aggregation is the response to the initiating stimulus for aggregation

Question 11

What is secondary aggregation?

Answer 11

Secondary aggregation is the further response to released ADP and TxA2

Question 12

Give examples of aggregating agents used in diagnosis

Answer 12

Collagen - potent aggregating agent

ADP moderate-strength aggregating agent, intermediate doses are dependent on TxA2 production and granule release

Adrenaline - weak aggregating agent, requires supraphysiological concentrations

Ristocetin - an antibiotic which triggers binding of VWF to GPIb/IX/V complex in absence of shear forces and thus agglutination of platelets

Arachidonic acid - precursor to TxA2 – passes into the platelet and is converted by COX-1

Question 13

What are the benefits of aspirin?

Answer 13

Reduces risk of serious secondary cardiac events by 20 – 40%

Reduces cardiac deaths in unstable angina by 50 – 70%

Beneficial in surgical intervention (PTCA, stents)

Benefit in reducing primary events not proved

Question 14

Is it better to give clopidogrel, aspirin, or both following an MI?

Answer 14

The CURE (2001) and MATCH (2004) studies showed that the occurrence of a second MI was reduced if both clopidogrel and aspirin were administered, instead of either one alone

Question 15

Are there any risks to giving both aspirin and clopidogrel?

Answer 15

Giving both drugs together leads to a slightly increased risk of hemorrhage

Question 16

How can you test whether clopidogrel is affecting platelets?

Answer 16

“Verify Now” test

Flow cytometry for VASP

Question 17

How does ADP act on the P2Y₁₂ receptor to activate platelets?

Answer 17

When ADP binds to P2Y₁₂, an G-protein moves across the membrane, and binds to Adenylate Cyclase, inhibiting it.

This prevents the conversion of ATP to cAMP, and so removes the inihibitory signal provided to the platelet, allowing the activation signal provided by ADP binding to the P2Y₁ receptor, making the activation signal dominant, leading to platelet activation.

Question 18

How does clopidogrel act on the P2Y₁₂ receptor?

Answer 18

It binds to the P2Y₁₂ receptor, inhibiting it, and so preventing the G-protein from moving across the membrane and inhibiting Adenylate Cyclase.

This prevents the removal of the inhibitory signal provided by P2Y₁₂, and so platelet activation remains inhibited.

Question 19

What did the ISIS-2 study (1988) show?

Answer 19

The ISIS-2 study showed that in patients with a recent suspected MI, patients who recieved aspirin (compared with placebo) had decreased incidence of vascular and non-vascular deaths, haemorrhagic and non-haemorrhagic strokes, and major and minor bleeding