Week 3 - E - Anticoagulant drugs - V.T.E/A.Fib - Heparin, Warfarin, New oral anticoagulants (Thrombin and Xa inhibitors)

Question 1

What are the indications for anticoagulant drugs?

Answer 1

Venous thrombosis ie DVT or PE or patients with atrial fibrillation

Question 2

What do anticoagulant drugs target the formation of?

Answer 2

Anticoagulant drugs target the formation of the fibrin clot

Question 3

In a venous thrombosis, why cant we target the platelets?

Answer 3

In venous thrombosis, this is a low pressure system and as there is no damage to the endothelium the platelets are not activated and instead the fibrin clot just forms - hence hwy we need to target the fibrin clot with anticoagulants

Question 4

Why are anti-coagulants used in atrial fibrillation? (basically asking why does afib increase clotting)

Answer 4

In AFib the atrium of the heart is beating abnormally (usually quickly) & not contracting enough causing blood to pool inside the atrium This blood can can form a fibrin clot due to stasis and may break off and enter the circulation and end up in the cerebral circulation causing a stroke

Question 5

What is the score that is used to calculate a patients risk of stroke if they are diagnosed with atrial fibrillation?

Answer 5

Use the CHA2DS2VASc score

Question 6

What are the different elements of the CHA2DS2VASc score? What is the score where we are advised to start the patient on an anti-coagulant?

Answer 6

* C - Congestive heart failure * H - Hypertension (>/= 140/90) * A - Age >/= 75 2 points * D - Diabetes * S - Previous stroke or TIA 2 points * V -Vascular disease * A - Age 65-74 * S - Sex (female) If a patients score is /=1 then anticoagulant therapy

Question 7

What is the score used to assess patients with atrial fibrillation who are starting or have started anticoagulation? It assesses their risk of bleeding What is a Labile INR?

Answer 7

This is the HAS-BLED score Labile INR means there is poor control of the international normalised ratio

Question 8

What are the different types of heparin? How are they both given? What is the mode of action of heparin? How long do they take to work?

Answer 8

Heparin comes as unfractioned or low molecular weight heparin Unfractioned heparin can be given IV or subcut LMWH is given subcutaneously They both have immediate effect by potentiating the action of anti-thrombin III (anti-thrombin)

Question 9

What are the two main factors that antithrombin exerts its effects on? How does heparin potentiate the action of anti-thombin?

Answer 9

The two main factors that antithrombin acts on is factors Xa and IIa (thrombin) Heparin stablises the bond between anti-thrombin and the coagulation factors which increases its effect

Question 10

Which coagulation factors do unfractioned and LMWH increases anti-thrombins ability for inhibiting? What is therefore used to monitor and adjust the dose of heparin?

Answer 10

UNfractioned heparin increases anti-thrombins ability for inhibiting factor Xa and IIa (thrombin) LMWH increases anti-thrombins abiity to inhibit factor Xa Unfractioned heparin is monitored and adjusted according to the APTT (activated partial tromboplastin time) LMWH is not usually monitored as its response is more predicatable. If need be, can measure anti-XA assay for monitoring LMWH

Question 11

Unfractioned - increases anti-thrombin ability to inactivate thrombin - APTT for monitoring LMWH - increases anti-thrombin ability to inactivate factor Xa - not usually monitored - can use anti-Xa assay If enough heparin is given, what can happen to coag tests?

Answer 11

If enough heparin is given the prothrombin time can increase as well as the APTT

Question 12

What are the main complications of heparin? Which two of these three main complications are more common when using unfractioned heparin over LMWH

Answer 12

Bleeding is the main complication Also Heparin induced thrombocytoepnia and osteoporosis with long term used Both of these are more commonly seen in patients taking unfractioned heparin rather than LMWH

Question 13

How does heparin induced thrombocytopenia occur? How is it treated?

Answer 13

It occurs in a small number of patients because heparin bounds to a protein known as platelet factor IV and this cause antibodies to bind to the complex resulting in platelet aggregation The resulting effect is that due to the platelet plug, thrombosis can occur and there is a thrombocytopenia Treat by stopping the heparin and starting on a new anti-coagulant drug

Question 14

If someone is bleeding – stop the drug A big advantage of heparin apart from the immediate onset of effect is that it has a quick offset as well if someone has a severe bleed and is taking heparin, what can be given?

Answer 14

Can give the patient protamine sulfate This drug provides complete reversal for unfractionated heparin in roughly half an hour and partially reverses the effects of LMWH (taking up to 12 hours)

Question 15

What is the broad category name for the anticoagulants which are vitamin K antagonists?

Answer 15

These are known as coumarin anticoagulants Coumarins (vitamin K antagonists) These oral anticoagulants are derived from coumarin, which is found in many plants

Question 16

What is the main type of coumarin anticoagulant?

Answer 16

This is warfarin

Question 17

Describe how vitamin K acts? (Ie what is it, where are its sources, how is it absorbed, and what factors is it required for)

Answer 17

Vitamin K is a fat soluble vitamin obtained from the diet (leafy green vegetables) & synthesised in the intestine It requires bile salts for its absorption- small intestine Vitamin K is required for the carboxylation of clotting factors II, VII, IX and X as well as required for protein C and S

Question 18

Why is it that when starting someone on warfarin they should also be started on heparin for 5 days or until INR reaches 2-3?

Answer 18

When starting someone on wafarin, it acts to prevent carboxylation of Factors II, VII, IX and X as well as protein C and S As protein C and S have the shortest half-lifes, initially warfarin will exhibit and procoagulant effect as it inhibits the natural anticoagulants Therefore heparin is given alongside warfarin for the first few days

Question 19

Vitamin K essential to add 1 of the 2 COOH groups essential for coagulation factors What do these carboxyl groups of the coagulation factors then bind to? What happens if vitK deficient and therefore cant carboxylate the factors

Answer 19

These bind to calcium which is present on the surface of the platelet plug if vitK deficiency (then only one carboxyl group), resulting in the synthesis of non-functional coagulation factors from the liver as the bond between factor and calcium would be too weak

Question 20

Will warfarin cause an increase in the PT or APTT time mainly and why?

Answer 20

Because Factor VII has the shortest half life of II,VII,IX and X - this will increase the PT time when patients are on warfarin - if high enough dose, the APTT will also be affected

Question 21

If a patient is starting on warfarin, what must you tell them? if you miss a dose what happens?

Answer 21

Initially they will have to come in for quite a few checks to make sure their INR is maintained in the proper region and then will require INR checks weekly-monthly dependent on how well controlled they are The warfarin dose should also be taken at the same time every single day - usually this time is 6pm if the miss a dose, it is important to just take the next dose at the normal time and inform the doctor during next check up

Question 22

Where is warfarin metabolised?

Answer 22

Warfarin is metabolised by cytochrome p450 in the liver - be aware of foods that interact with this

Question 23

Warfarin has its main effect on the prothrombin time as the factor VII is reduced quickest but if give in high doses the APTT will rise in crease also Rememeber to use the INR to monitor warfarin (Based on the PT – standardized PT test)) - not the APTT How is the INR calculated? What is the targey INR when on warfarin?

Answer 23

The INR is a mathematical correction that normalizes the PT ratio by adjusting for the variability in the sensitivity of the different thromboplastins reagents INR - international normalized ratio

Question 24

What is the major adverse effect of warfarin and what factors may influence it?

Answer 24

Haemorrhage is the major adverse effect of warfarin The intensity of the anticoagulaiton, the drug interactions and dietary interactions may influence it as well as liver disease

Question 25

Name three dietary substance that should not be taken with warfarin? WHich herbal remedy taken for depression can interact with warfarin?

Answer 25

Cranberry juice Grapefruit juice Alcohol St Johns Wort - a herbal remedy taken for depression should be avoided as it can interact with warfarin

Question 26

What are the bleeding complications that can occur in a patient on warfarin?

Answer 26

Mild - skin burising, epistaxis, haematuria Severe - GI, intracerebral, significant drop in BP

Question 27

It is important to understand the methods of warfarin reversal They methods depend on the severity of the bleeding and the INR What are the methods of choice of warfarin reversal?

Answer 27

Omit the warfarin dose Give vitamin K Give factor concentrates

Question 28

When would you omit the next warfarin dose? When would you give vitamin K? When would you give factor concentrates?

Answer 28

Target INR is 2-3 (phytomenadione = vit K1) INR high but less than 5 –> potentially omit dose INR 5-8 but no bleed –> omit warfarin dose, restart when less than 5 INR 5-8 with minor bleeding –> omit warfarin, probs give Vit K IV, restart when less than 5 INR >8 with no or minor bleeding –> omit warfarin, give vitamin K IV, restart when less than 5 Major bleeding - STOP AWARFARIN - give vit K + prothrombin complex concentrate (concentrate of factos II, VII, IX, X) (fresh frozen plasma if unavailable)

Question 29

So INR >4.5 - omit the warfarin dose INR >8 with no or minor bleeding, or there is epistaxis - then stop wafarin and give oral vitamin Severe bleeding - stop warfarin and give factor concentrates/vitK How long does Clotting factor concentrates (prothrombin complex concentrates) take to work? How long does vitamin K take to work?

Answer 29

Clotting factors concentrates has an immediate action Vitamin K takes roughly 6 hours to work

Question 30

New oral anticoagulants (NOAC) are coming in to use right now - approx 50% of patients now on warfarin and 50% on NOACs What do the NOACs work on? (two types of NOAC) Name on edrug of each type?

Answer 30

There are the NOACs which are: Direct thrombin inhibitors eg dabigatran and Factor Xa inhibitors eg rivaroxaban and apixaban

Question 31

What are the advantages of the new oral anticoagulants? What is the main disadvantage?

Answer 31

They are oral and do not require any monitoring They also do not have as many drug interactions However currently there is no specific antidote - overdose is rare/unheard The NOAC is more expensive however the patent is about to run out so companies will be able to produce this cheaper