Anticoagulant Drugs

Question 1

What parts of the coagulation cascade are acted upon by heparin and warfarin?

Answer 1

Heparin - helps anti-thrombin

Warfarin - interrupts clotting factor synthesis

Question 2

Heparin and Warfarin both have a narrow therapeutic window. What does this mean?

Answer 2

• small gap between effective dose and toxic dose

- same dose does not work for all patients (due to differing levels of Cytochrome P450 in the liver)

Question 3

When should warfarin tablets be taken each day?

Answer 3

• no time specified, as long as tablet is taken at the same time each day

Question 4

When are anticoagulants normally used?

Answer 4

• venous thrombosis

- AF stroke prophylaxis

Question 5

How do doctors differentiate which stroke patients need anticoagulation and which need antiplatelets

Answer 5

• stroke in situ = atheroma rupture in vessel
  => antiplatelets req’d
• stroke from AF = venous stasis
  => anticoagulation

Question 6

Why can warfarin not be given immediately after a venous event and must be covered by heparin?

Answer 6

• initially drops protein C/S levels (as these are dependent on the vitamin K warfarin is antagonising)
• dropping these levels puts patients in a PROTHROMBOTIC state (i.e. more likely to clot)

=> need to cover with heparin whilst this occurs

Question 7

What are the aims of Heparin?

Answer 7

• prevent clot extending in vessel (getting larger)

- prevent embolus breaking off of clot and travelling in body

Question 8

How can Heparin be given?

Answer 8

IV (usually unfractioned heparin)

S/C (usually LMWH)

Question 9

Explain how heparin works with antithrombin to prevent clotting

Answer 9

• Antithrombin usually attaches to thrombin (or Factor Xa) to do its job
• Heparin binds to the antithrombin part of this complex to keep it stable

Question 10

What is the difference between unfractioned and LMWH?

Answer 10

LMWH - works when antithrombin bound to Factor Xa

=> requires less monitoring than Unfractioned

Question 11

Why is unfractioned heparin still used?

Answer 11

some patients may be prone to bleeding and to clotting

=> need to be on unfractionated heparin as the IV infusion can be stopped quickly if patient starts bleeding

The effects of the unfractionated heparin disappear within 30 mins (whereas LMWH would be much longer)

Question 12

How is treatment with heparin usually monitored?

Answer 12

Unfractionated = APTT
- as thrombin is responsible for activating FVIII/IX
=> APTT more sensitive than PT

Anti-Xa assay for LMWH
- only used in pregnancy as this can increase renal heparin clearance

Question 13

What are the main complications of Heparin use?

Answer 13

• Bleeding
• Heparin induced thrombocytopenia (HITT)
  => Ab to platelets so they aggregate and can cause clots!
• Osteoporosis with long term use

Question 14

How can the effects of Heparin tx be reversed?

Answer 14

Stop the heparin

In severe bleeding -
Antidote = Protamine sulphate
=> Reverses antithrombin effect (only partial reversal in LMWH)

Question 15

What is meant by a Coumarin Anticoagulant drug and how does it work?

Answer 15

Drug e.g. warfarin

Mechanism of action => inhibition of vitamin K

Question 16

How is Vitamin K usually absorbed?

Answer 16

• Fat soluble vitamin (can be found in diet or made in gut)
• Absorbed upper intestine
• Requires bile salts for absorption

Question 17

What is the main role of vitamin K in clotting?

Answer 17

• Final carboxylation of clotting factors II, VII, IX and X

=> makes the negative charged carboxyl groups that will eventually be attracted to the Ca2+ outer layer of the clot

Question 18

For how long should a patient be anticoagulated if they have experienced their first VTE?

Answer 18

3-6 months

- long term if recurrent

Question 19

HOw is warfarin therapy monitored?

Answer 19

INR (International Normalised Ratio)

INR = Patient’s PT in Seconds/ Mean Normal PT in Seconds

(also then standardised with ISI)

Question 20

What factors can increase the risk of a patient bleeding on warfarin?

Answer 20

• Intensity of anticoagulation
• Other clinical disorders or medications
• BEWARE DRUG INTERACTIONS
  => less cytochrome p450 left behind after metabolising other drugs means less metabolism of warfarin => increased bleeding risk

Question 21

What bleeding complications can occur in warfarin use?

Answer 21

MILD:
bruising
epistaxis
haematuria

SEVERE
GI
Intracerebral
Drop in Hb

Question 22

How can the effects of warfarin be reversed?

Answer 22

If INR is HIGH (i.e. increased bleeding risk)
=> omit warfarin doses
=> takes 2-3 days for clotting factors to increase and INR to decrease

Give oral vitamin K to reverse antagonising warfarin effect
=> takes around 6 hours to reverse effect

Administer clotting factor concentrates
=> immediate effect but should only be used in emergencies

Question 23

What are the new oral anticoagulants directed at in the coagulation cascade

Answer 23

• Oral direct thrombin inhibitors (less commonly used)

- Oral Xa inhibitors

Question 24

What problems can occur with the Oral direct thrombin inhibitors?

Answer 24

• may cause deranged LFTs

- not suitable in patients with poor renal function as the drugs are renally metabolised and excreted

Question 25

What is the main advantage of the Direct Factor Xa inhibitors and give examples of these drugs

Answer 25

• No monitoring is required

- Rivaroxaban, Apixaban, Edoxaban

Question 26

What are Factor Xa inhibitors now being used for?

Answer 26

• prophylaxis before elective hip/knee replacement surgery
• Tx of DVT/PE as can be used immediately (no heparin cover)
• 1st line for AF stroke prevention

Question 27

When is warfarin still used?

Answer 27

• patients with metal heart valves

- antiphospholipid Ab syndrome (due to slight arterial effect)