6.2 anti-platelets/ anticoagulants/ thrombolytics

Question 1

Give 2 types of arterial thromboembolic events

Answer 1

Stroke (CVA) and MI

Question 2

Give 2 types of venous thrombo-embolic events

Answer 2

DVT and PE

Question 3

What is Virchow’s Triad and give the 3 factors involved

Answer 3

3 factors that are critically important in the development of venous thrombosis:

1) Hypercoagulability
2) Endothelial damage
3) Stasis

Question 4

Give the MoA of Warfarin

Answer 4

Inhibits production of Vitamin K dependent clotting factors (factor II (prothrombin), VII, IX, X)

Question 5

What is the t1/2 of Warfarin and what is the implication of this for starting and stopping treatment

Answer 5

Long t1/2 = 48 hrs (but variable), hence it has slow onset and offset of action

This means:

• Initial anti-coagulation requires Heparin cover alongside warfarin
• If patient requires surgery we must stop warfarin 5 days prior

Question 6

Is the anticoagulant effect of Warfarin reversible?

Answer 6

Yes

Question 7

How is Warfarin administered and what is its protein binding?

Answer 7

Usually orally as it is has good GI absorption and is heavily protein bound (increased potential for DDis)

Question 8

How is warfarin metabolised and therfore why must care be taken?

Answer 8

Hepatic metabolism by CYP450

Caution with liver disease or drugs that affect p450 system

Question 9

Does Warfarin cross the placenta and what is the implication of this during pregnancy?

Answer 9

Crosses Placenta:

• do not give in 1st trimester: Teratogenic
• do not give in 3rd Trimester: risk of bleeding at delivery

Question 10

How do we monitor Warfarin and how can we assess these results?

Answer 10

Prothrombin Time: measures how long it takes blood to clot (extrinsic pathway)

Use INR (international normalized ratio) to assess the standard value between labs (while the PT may vary from lab-lab, INR should be the same)

Question 11

If a drug which increases anticoagulant effects is given alongside Warfarin what is the risk?

Answer 11

Increase risk bleeding

Question 12

If a drug which decreases the anticoagulant effect is given alongside Warfarin what is the risk?

Answer 12

risk of thrombosis

Question 13

Give 2 types of drugs which may increase the effect of Warfarin? (Incl examples)

Answer 13

1. Drugs which Inhibit hepatic metabolism
   * Eg. Amiodarone, Quinolone, Metronidazole, Cimetidine, ingesting alcohol
2. Drugs which reduce Vit K from gut bacteria
   * Eg. Cephalosporin, Antibiotics

Question 14

Give 2 drugs/classes which may decrease the effect of Warfarin

Answer 14

Anti-epileptics (except Na valproate)

Rifampicin

Question 15

How do drugs which decrease effect of Warfarin work?

What would be seen in the INR?

Answer 15

Most work by inducing hepatic enzymes thereby increasing metabolism of warfarin: INR ↓

Question 16

Give 4 main Indications for Warfarin use

Answer 16

1. DVT/PE
2. atrial fibrillation
3. dilated cardiomyopathy
4. mechanical prosthetic valves

Question 17

What is the ONLY anti-coagulant which can be used on patients with mechanic valves?

Answer 17

Warfarin

Question 18

Give 4 limitations of warfarin therapy

Answer 18

1. Narrow therapeutic window (INR range 2-3)
2. Slow onset/offset of action
3. Frequent dose adjustments
4. Routine coagulation monitoring

+ others on image below

Question 19

What is the INR range we aim to achieve?

Compare the risks of an INR which is too LOW vs too HIGH

Answer 19

Normal ➞ 2-3

LOW ➞ risk of stroke

HIGH ➞ risk of hemorrhage

Question 20

Give 3 adverse effects of Warfarin

Answer 20

1) Bleeding/ bruising
2) Teratogenic (if pregnant)
3) Reversal of Therapy

Question 21

If a patient on Warfarin presents with bleeding and a high INR what must we do?

Answer 21

Warfarin Reversal!

1) stop Warfarin!
2) consider bleeding, INR, Indication
3) If they have a mechanical valve - call cardiologist/ caematologist
4) administer reversal agents
5) find source of bleeding, potential surgery

Question 22

Give 3 agents which can be used for Warfarin Reversal

Answer 22

1) IV Vit K (pro-coagulant effects for 6 weeks)
2) Prothrombin Complex Concentrate
3) Fresh Frozen Plasma

Question 23

How is Heparin administered and why?

Answer 23

Parenteral - due to poor GI absorption

Question 24

Give the onset and bioavailability of Heparin

Answer 24

Rapid onset, variable bioavailability

Question 25

Heparin is produced by ________ and binds to _________ via unique Pentasaccharide sequence

Binding leads to activation of ________ and inactivation of Factor _____, _____, _____

Answer 25

Mast cells, Anti-Thrombin III, Anti-Thrombin III

IIa (thrombin) , IXa, Xa,

Question 26

Describe the structure of Heparin

Answer 26

Heparin is a Glycosaminoglycan meaning it has a glucose backbone

Question 27

What are the 2 main types of Heparin and how does their administration differ?

Answer 27

Unfractionated Heparin (UFH): continuous IV infusion

LMWH: Administered subcutaneously

Question 28

Revise Coag cascade

Question 29

UFH has ______ length heparin chains which inhibit activation of _________ and factor _____.

Its effect can be monitored via _______blood test

Answer 29

long, Prothrombin (IIa), Xa, activated partial thromboplastin time (APTT)

Question 30

In what instance may the administration of UFH change?

Answer 30

Occasionally used subcutaneously for prophylaxis in patients with renal failure unsuitable for LMWH

Question 31

Compare chain length of UFH and LMWH + the implication of this is on their actions

Answer 31

As UFH has long chain its can inhibit activation of Prothrombin (IIa) and factor Xa (by binding simultaneously)

As LMWH has small chains it only inhibits factor Xa not IIa (it is not long enough to catalyse inhibition of IIa by AT III)

Question 32

Give 3 benfits of LMWH over UFH?

Answer 32

It has predictable pharmacokinetics, a high bioavailability >90% and a long half life (cleared by kidneys)

Therefore can be given at a fixed one dose daily and monitoring is not usually required

Question 33

If monitoring of LMWH is required what can we use?

Answer 33

Anti Xa level

(Not APTT because it does not impact directly on thrombin)

Question 34

Give 4 comparisons between UFH and LMWH

(Hint: AM PM)

Answer 34

1) Administration ➞ UFH = IV, LMWH =subcutaneous
2) MoA ➞ UFH = long chains so inhibits IIa and Xa, LMWH = short chains so only inhibits Xa
3) PK ➞ UFH = unpredictable, LMWH = predictable
4) Monitoring ➞ UFH = APTT, LMWH = anti-Xa

Question 35

Study comparison of UFH and LMWH

Answer 35

Question 36

Give 4 uses of Heparin

Answer 36

1) Cover for risk of thrombosis ➞ given if patient, who is usually on Warfarin requires surgery (quick offset time allows its cessation if bleeding)
2) Prophylaxis in patients at high risk of thrombosis ➞ eg. medical Inpatients, post- op patients, Immobility
3) LMWH given prior to warfarin as quick onset covers patient whilst warfarin loading is achieved
4) Pregnancy ➞ can be used in place of warfarin

Question 37

Give 3 adverse effects of Heparin

Answer 37

1) Bruising/bleeding
2) Osteoporosis ➞ a/w long term use (UFH>LMWH)
3) Thrombocytopenia (HIT)

Question 38

What is Heparin Induced Thrombocytopenia, how is it diagnosed and how would you treat?

Answer 38

RARE Autoimmune phenomenon (usually after 4-14 days after starting Heparin). Tends to present with thrombosis not bleeding

Diagnosed by Lab assay and clinical probability

Treatment ➞ Stop heparin and give Fondaparinux

Question 39

How do we do reversal of therapy for Heparin?

Answer 39

1) Stop Heparin
2) If UFH and actively bleeding, give Protamine
3) Monitor APTT if unfractionated
4) Protamine sulphate: dissociates heparin from anti-thrombin III

Question 40

Give 4 anti-platelet drugs and the target of each

Answer 40

1) Aspirin (COX inhibition affecting platelet activation)
2) Dipyridamole (phosphodiesterase inhibition)
3) Clopidogrel (inhibits ADP dependant platelet aggregation)
4) Glycoprotein IIb / IIIa Inhibitors (inhibits platelet crosslinking and activation)

Question 41

What is the purpose of Thrombolytics and how do they work?

Answer 41

Used to lyse already formed clots

Work by promoting Fibrinolysis by converting inactive plasminogen to active plasmin (plasmin degrades fibrin clot)

Question 42

Give 3 uses of Thrombolytics

Answer 42

1) STEMI
2) Massive PE with haemodynamic compromise
3) Strokes (as long as haemorrhage is excluded by CT)

Question 43

What are the 2 main types of Thrombolytics?

Answer 43

1) Recombinant tissue plasminogen activator e.g. rt-PA
2) Streptokinase

Question 44

What are ‘novel oral anticoagulants’ (NOAC)

Give 2 targets and examples of each

Answer 44

NOAC: new anticoagulants

1) Direct Thrombin Inhibitor ➞ Dabigatran
2) Direct Factor Xa Inhibitors ➞ Apixaban, Rivaroxaban, Edoxaban

Question 45

Give 4 advantages of NOAC over Warfarin

Answer 45

1) Rapid onset/offset of action
2) Few drug interactions
3) Predictable pharmacokinetics
4) Wide therapeutic window
5) eliminated need for regular coagulation monitoring and allowed fixed dosing in adults

Question 46

Give 4 uses/Indications for NOAC

Answer 46

1) Atrial Fibrillation
2) Treatment of DVT/PE
3) Prevention of Recurrent DVT/PE
4) Prevention of DVT/PE post Hip/Knee surgery