Anticoagulants Flashcards
What is an anticoagulant?
Reduces the tendency of blood to coagulate
Usually considered distinct from antiplatelet agents
All anticoagulants reduce thrombin generation
Why anticoagulate?
To reduce risk of thrmobosis in people suseptible/after suseptible events
In some cases, risk of thrombosis outweighs risk of anticoagulation
Ways to use anticoagulant therapy
Prophylactic - low dose
Therapeutic - high dose
Effect of surgery on VTE
in-patient surgery – risk increased by 100% and this lasts for weeks
Increases for outpatient too but much less
VT recurrence
After people have a thrombosis - define themselves as prone to thrmobosis
Why are we interested in venous thombosis
Common
Significant sequelae
PE is the cause of 5-10% of hospital deaths
25000 deaths pa from hospital related VTE
Difficult to reverse and leads to morbidity
Preventable
Natural procoagulant factors
V VIII XI IX X II Fibrinogen Platelets
Natural anticoagulant factors
TFPI Protein C Protein S Thrombomodulin EPCR Antithrombin
Fibrinolysis
Approach to anticoagulation
Reduce procoagulant factors
Enhance natural anticoagulant pathways
Inhibit procoagulant factors
How to reduce procoagulant factors?
- Vitamin K antagonists (warfarin)
2. Inhibition of FXI synthesis
How does warfarin work
Pro coagulant factors need carboxylation - this requires vit K
Warfarin is vit k antagonist. Makes people a bit vit K deficient but it doesn’t do much else in body so it’s fine
Warfarin structure
Similar to vit K - blocks recycling of Vit K.
Vit K dependent factors
FVII
FIX
FX
FII
Protein C
Protein S
Protein Z
How long does warfarin action take
Days - because indirect effect on anticoagulation
Why is initial effect of warfarin procoagulant?
Rapid fall in protein C
How do avoid initial procoagulation effect of warfarin
Combination with immediate immediate acting acting
Warfarin effect between people
Therapeutic effect of warfarin is a balacne of how much you give them and how much vit k they are taking in.
The amount of warfarin needed to achieve desired effect can vary quite sgnificantly person to person
Consequence is that it needs monitoring.
Warfarin dose sensitive to…
diet (Fat and Vitamin K intake)
other drugs (+/-)
ethnicity (polymorphisms)
age
Measure of warfarin
INR
Action of warfarin
Reduces thrombin generation
When INR goes up, means…
more anticoagulant with warfarin
Downside of warfarin
major bleeding rate of 3.8%
Why is there a therapeutic window of warfarin
Ischaemic stroke risk decreases significantly with warfarin
Intracranial bleeding risk increases with warfarin
SO you need to be in the therapeutic range INR: 2-3
Risk of poor INR control
Increases stroke risk
Why do we need warfarin reversal
- Active bleeding (esp ICH): Therapeutic INR, Elevated INR
2. Likelihood of bleeding: High INR ± other factors, Surgery, Trauma
Underlying thrombotic risk of warfarin reversal
Atrial Fibrillation
VTE
Prosthetic valve
How to do warfarin reversal
Stop warfarin
Give vit K
Why can’t you just stop warfarin in warfarin reversal
Will take several days to resynthesises the coagulation factors
If correction in <12-24 hrs required for warfarin reversal
Replace factors:
- FFP
- Prothrombin complex concentrate (PCC) contains Factors II, VII, IX, X
What is FXI-ASO
a factor XI targeted second-generation antisense oligonucleotide
Outcomes of FXI suppresion
High dose is better and don’t bleed more
but takes weeks
Augmenting natural anticoagulants
- Unfractionated heparin (UFH)
- Low molecular weight heparin (LMWH)
- Fondaparinux (pentasaccharide)
Action of heparin suplhate
enhances inhibitory activity of Antithrombin
- causes AT to adopt active conformation
Where is heparin synthesised
Synthesised in mast cells. Not found in vasculature physiologiclaly (collected from gut mucosa)
Related to heparin sulphate
What is heparin sulphate
on proteoglycans present on the vascular endothelium.
The essential pentasaccharide can be synthesised for therapeutic use (fondaparinux)
2 effects of heparin on antithrombin
- The pentasaccharide “activates” AT. This is all that is required for the enhancement of anti-FXa activity. This only marginally enhances anti-thrombin activity
- Longer heparins (>18 saccharide units) stimulates
anti-thrombin activity by ~2000 fold by bridging antithrombin
Mechanism of action of heparin
1) The pentasccharide sequence is necessary
for any anticoagulant activity
2) The length of the heparin chain is important
For anticoagulant activity:
-for inhibition of factor Xa, a pentasaccharide
is minimum sequence (MW ~1500) required
- for thrombin inhibition, there must be 18 saccharides (MW ~5000) at least – and possibly more
- LMWH is made by degradation of UFH (mean MW~7000
LMWH effect vs UFH effect
More effect on Xa than IIa
Monitoring of UFH vs LMWH
UFH necessary.
Not for LMWHN
What reverses UFH and LMWH
Protaimine
Complete reversal of UFH
Incomplete reversal of LMWH
Biggest benefit of LMWH over FH
No complex dose response
What is protamine
Protamine is positively charged. Binds and neutralises heparin
Less effective for LMWH
Coagulation inhibitors
Direct acting oral anticoagulants (DOACs)
anti – IIa
anti - Xa
DOAC for IIa
Dabigatran
DOAC for Xa
Rivaroxaban
Apaxiban
Edoxaban
Pros of DOACs
Oral Immediate acting Direct action No monitoring Fewer drug/lifestyle interactions Short half life of effect
Cons of DOACs
Lack of experience side effects, safety Adherence less certain Single therapeutic range Unable to tailor intensity No antidote/reversal Some renal dependence Cost
