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Case 4 > The role of platelet activation and thrombosis in the pathophysiology of acute coronary syndrome- how does this influence treatment > Flashcards

The role of platelet activation and thrombosis in the pathophysiology of acute coronary syndrome- how does this influence treatment Flashcards

1
Q

What is the triad of conditions in acute coronary syndromes

A

Unstable angina (UNSA), non ST elevation myocardial infarction (NSTEMI) and ST elevation myocardial infarction (STEMI)

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2
Q

What can occur before an infarct is fully evolved

A

Sudden cardiac death

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3
Q

What happens in unstable angina

A

A quiescent plaque ruptures resulting in the underlying fatty material being exposed to blood

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4
Q

What happens when underlying fatty material is exposed to blood

A

Blood is intensely thrombogenic resulting in activation of the platelet cascade which can cause sub or complete occlusion

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5
Q

Describe occlusion

A

Occlusions can be micro or macro. Microvascular occlusions occur in the micro circulation

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6
Q

What can be used to study plaque rupture

A

OCT real time imaging

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7
Q

Describe OCT real time imaging

A

OCT is an angiogram which requires a catheter into the lumen of the artery from the brachial artery and are used to monitor erosion and plaque rupture

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8
Q

Describe the ‘vulnerable plaque’ and inflammation in ACS

A

Active plaques are vulnerable. An undiscovered virus may result in inflammation. In patients with ACS vulnerable plaques are numerous and inflammation is widespread

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9
Q

What would happen if a filling defect is seen on an angiogram catheter from the radial artery

A

It would be aspirated then stented

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10
Q

What keeps the stent in place

A

Platelet recruitment and adhesion at the site of injury forming a monolayer

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11
Q

Why does a clot arise

A

Due to activation of the clotting cascade resulting in tissue factor formation and activation of the coagulation cascade

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12
Q

What type of clots and clots in coronary arteries

A

Platelet clots

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13
Q

What treatment do platelet clots need

A

Antiplatelet medication

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14
Q

Describe the overlap between the coagulation and platelet cascade

A

Thrombin aggregates platelets

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15
Q

What do aspirin, clopidogrel, prasugrel and GPII/IIIa inhibitors target

A

Platelet cascade, are anti-platelets

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16
Q

What are the two types of drugs used as antithrombotics

A

Anti-coagulation and anti-platelet

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17
Q

What do fondaparinus. LMWH, heparin and bivalirudin target

A

Coagulation cascade so are anti-coagulation

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18
Q

What happens to platelets during activation

A

They change from the smooth, discoid shape they are at rest into spiny and spheric when activated

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19
Q

What can unstable angina result in

A

Either STEMI or NSTEMI

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20
Q

How do you treat a patient with a NSTEMI

A

NSTEMI= clopidogrel, prasugrel and ticagrelor

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21
Q

How do you treat a patient with STEMI

A

Immediate intervention is required meaning that you give IV drugs as well, the drugs given are Prasugrel, Ticagrelor and IV Gp2b3a inhibitors.

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22
Q

What is the first antiplatelet drug

A

Aspirin

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23
Q

Describe the antithrombotic trialists’ collaboration on efficacy of aspirin on vascular events in high risk patients

A

All studies show aspirin is better than the control by 22%. In unstable angina those with aspirin were 44% better

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24
Q

Describe the MOA of aspirin

A

Aspirin inhibits cyclo-oxygenase meaning that thromboxane is inhibited

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25
Q

Describe the MOA of new drugs thienopyridine

A

They block the ADP receptors on the surface of platelets and therefore inhibit platelet aggregation by blocking the pro-aggregatory effects of ADP

26
Q

Describe the MOA of GP IIb/ IIIa inhibitors

A

They inhibit the final common pathway

27
Q

What are the three types of thienopyridines

A

Ticlopidine, Clopidogrel and Prasugrel

28
Q

Describe the MOA of clopidogrel

A

Clopidogrel is an oral anti-platelet receptor that blocks ADP receptors and works synergistically with aspirin. Aspirin acts on thrombin and therefore the coagulation pathway as well

29
Q

What did the CURE trial find in relation to Clopidogrel and aspirin

A

Clopidogrel has a further 20% improvement rate when with aspirin (instead of aspirin on its own) post ACS

30
Q

How long do people continue to benefit for when treated with both aspirin and clopidogrel

A

Up to 12 months

31
Q

How much does clopidogrel cost per month

A

£20

32
Q

When does clopidogrel have to be stopped before surgery

A

7-10 days

33
Q

What are the three categories of clopidogrel response variability

A

Clinical factors, genetic factors and cellular factors

34
Q

What are the clinical factors that affect of response to Clopidogrel

A

Failure to prescribe/ poor compliance, under-dosing, poor absorption, drug-drug interactions involving CYP3A4, ACS, diabetes mellitus/ insulin resistance, elevated body mass index

35
Q

What are the genetic factors that affect of response to Clopidogrel

A

Polymorphisms of CYP, polymorphisms of GPIa, polymorphisms of P2Y12, polymorphisms of GPIIIa

36
Q

What are the cellular factors that affect of response to Clopidogrel

A

Accelerated platelet turnover, reduced CYP3A metabolic activity, increased ADP exposure, up-regulation of the P2Y12 pathway, up-reguation of the P2Y-independent pathways (collagen, epinephrine, TXA2, thrombin)

37
Q

Describe repsonse to Prasugrel compared to Clopidogrel

A

With Prasugrel 80% of people responded. Even those who responsed to Clopidogrel to begin with only had a response of up to 80% inhibition of platelet aggregation. When give Prasugrel all non-responders to Clopidogrel were responders and all resposnder to Prasugrel increased in response

38
Q

What does the fact that prasugrel is a pro-drug mean

A

It requires activation and takes a couple of days to kick in

39
Q

What is one of the main reasons why Clopidogrel response is so variable

A

Because it is a PK problem effected by genotype polymorphism meaning there is a wide pharmacodynamic response

40
Q

What do Prasugrel and Clopidogrel need to work

A

Conversion from an inactive to active metabolite

41
Q

Describe Prasugrel in comparision to Clopidogrel

A

Clopidogrel is a prodrug and relatively weak anti-platelet. Prasugrel is a second-generation thienopyridine like Clopidogrel. Prasugrel is rapidly and more wholly metabolised to its active components

42
Q

Describe Ticagrelor

A

Is a direct acting P2Y12 antagonist (adenosine (P2Y12) receptor inhibitor) which means that it isn;t a prodrug. Ticagrelor acts rapidly and has moer potent and consistent antiplatelet effects than Clopidogrel

43
Q

What are oral antiplatelets used during ACS and what do they act on

A

Aspirin-COX, Clopidogrel-ADP, Prasugrel-ADP, Ticagrelor- ADP.

44
Q

What are IV drugs used during ACS

A

GPIIb/IIIa inhibitors: Abciximab, Airofiban, Eptifibatide

45
Q

Describe the 6 points of oral antiplatelet therapy

A
  1. The first antiplatelet aspirin blocks the production of thromboxane A2. 2. The CURE trial established the benefits of addition of P2Y12 receptor blocker Clopidogrel. 3. Clopidogrel has a modest inhibition of platelet aggregation and a delayed onset and offset action. 4. Prasugrel is a second-generation thienopyridine and is rapidly and more wholly metabolised to its active components. 5. Ticagrelor is a direct-acting P2Y12 antagonist which acts rapidly and has more potent and consistent antiplatelet effects than Clopidogrel. 6. There is an increased risk of bleeding with Ticagrelor and they cost substantially higher
46
Q

What does the fact that Clopidogrel is now off patent mean

A

It is considerably cheaper

47
Q

Why is chosing the most effective treatment difficult

A

There is not a test to check if platelets are inhibited or not

48
Q

What did the PLATO study show in terms of treatment

A

Aspirin improves outlook by 40% + Clopidogrel is another 20% + Ticagrelor is another 16%

49
Q

Why are thrombin inhibitors also used

A

Tissue factor is released from atheroclerotic plaques, tissue factor activates thrombin

50
Q

What is the number one thrombin inhibitor

A

IV heparin

51
Q

What effect does inhibition of factor Xa have on thrombin

A

Inhibition of one molecule of factor Xa can inhibit the generation of 5 molecules of thrombin

52
Q

Why do we need to produce factor Xa drugs instead of heparin

A

Blocking Xa which is higher up in the cascade blocks more thrombin

53
Q

What is an IV drug administered during treatment of STEMI

A

Bivalirubin

54
Q

What are thrombic and ischaemic events mediated by

A

Platelets

55
Q

What is the main target in anti-platelet drugs

A

P2Y12 receptor blockage

56
Q

What anti-coagulant can be given subcutaneously

A

Enoxaparin (lower molecular weight than heparin)

57
Q

What are IV/ subcutaneous agents used for

A

Used acutely to block coagulation cascade and therefore the production of thrombin

58
Q

What is one of the major risks of anti-coagulation drigs

A

Major bleeding, and those who suffer a major bleed have on average a 15% higher incidence of mortalilty

59
Q

What anti-coalgulation treatment do you use for unstable angina

A

Antithrombins

60
Q

What anti-coagulation treatment do you use for NSTEMI

A

SC controllable antithrombins, anoxaparin, fondaparinux

61
Q

What anti-coagulation treatment do you use for STEMI

A

Needs quick treatment therefore you use IV heparin (at the right dose) or Bivalirudin

Case 4 (7 decks)

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