30. Anticoagulants Flashcards
What types of heparin do you
know?
- Naturally occurring heparin
- Unfractionated heparin (UFH
- Low molecular weight heparin (LMWH
- Naturally occurring heparin
> A highly sulphated glycosaminoglycan carbohydrate
weighing between 3000 and 50 000 Daltons.
> It is produced by basophils and mast cells.
- Unfractionated heparin (UFH
> Synthetic agent weighing between
5000 and 25 000 Daltons.
> It binds to and potentiates the action
of antithrombin III 1000-fold.
> Activated antithrombin III inhibits
thrombin and other serine proteases that
promote blood clotting.
- Low molecular weight heparin (LMWH
e.g. enoxaparin, dalteparin, tinzaparin
> Newer drugs weighing between
2000 and 8000 Daltons.
> LMWHs do not target antithrombin,
but instead directly inhibit factor Xa.
The dose of both LMWH and UFH are calculated in units of activity rather than weight.
One unit of activity is the amount of a preparation required to keep 1 mL of cat’s blood fluid for 24 hours at 0 °C.
CLOTTING CASCADE
Factor X ——-> Factor Xa
|
Prothrombin -------> Thrombin
|
Fibrinogen -------> Fibrin
= CLOT
What are the differences between the unfractionated (UFH) and low molecular weight heparins
(LMWH)?
In order to inactivate thrombin,
the heparin molecule must be able to
bind both the
antithrombin III molecule
and the thrombin molecule.
To do this, it must have a size greater than 18 saccharide ternary units.
Smaller molecules, therefore, are only able to inhibit the activity of other proteases
such as factor Xa.
What are difference between Heparin + LMWH
Heparin LMWH
Xa inhibition + +++
Protein binding 50% 10%
t½ 30–150 m (dose dep) 2–3× longer equiv
Monitoring APTT Anti-Xa. Not routinely monit.
Administration Monitored infusion Once daily (or BD).
Bioavailability (s.c. dose) 40% 90%
How is heparin used clinically?
UFH
> UFH:
• As an infusion to prevent
the propagation of deep vein thrombosis
(DVT) and pulmonary emboli (PE)
• During cardiopulmonary bypass to reduce
clotting of blood in contact with bypass circuit
• During extracorporeal membrane oxygenation (ECMO) to prevent clotting in the circuit
• During vascular surgery to prevent newly
inserted stent occlusion
• Twice daily subcutaneous dose
for thrombosis prophylaxis.
Its half-life is only around 1 hour and
so UFH must be given continuously by infusion.
It is common practice to give a bolus of
5000 IU followed by an infusion
based on the patient’s weight.
The patient’s activated partial thromboplastin time (APTT)
is measured 6 hours following the
start of the infusion,
and the dose is adjusted to keep the APTT
at 1.5–2× normal.
Because of its short half-life,
the anticoagulant effects of UFH are quickly lost
once the infusion is stopped.
This can prove useful, e.g.
if bleeding becomes a problem,
or if the patient needs to go to theatre.
How is heparin used clinically?
> LMWH:
> LMWH:
• As a twice-daily subcutaneous injection
to prevent the propagation of DVT and PE
• As a twice-daily subcutaneous injection to
prevent clot propagation in
acute coronary syndrome
• Once-daily subcutaneous dose for
thrombosis prophylaxis.
Because of its longer half-life,
LMWH can be given once or twice daily
depending on the indication.
How is heparin therapy
monitored?
How is heparin therapy monitored?
APTT measures the activity of the
intrinsic clotting cascade
(factors VIII, IX, XI and XII)
and the final common pathway
and is therefore prolonged by UFH.
Hence, we measure APTT
to monitor and alter heparin infusions
LMWH inhibits mainly factor Xa and
therefore does not affect the APTT.
Usually no monitoring is required but
anti-factor Xa levels can be measured as needed.
What are the side effects of
heparin therapy?
1
> Haemorrhage:
• Heparin is given subcutaneously
to avoid intramuscular haematoma.
It can cause fatal haemorrhage if
given in overdose. I
ts dose should be reduced in patients with renal failure, in whom it can accumulate.
UFH, but not LMWH, can be
reversed with protamine
(dose 1 mg reverses
100 IU heparin).
2
> Non-immune thrombocytopenia:
• Occurs after approximately 4 days of therapy.
• Platelets recover spontaneously
without cessation of heparin.
3
> Heparin-induced thrombocytopenia (HIT):
• This immune-mediated process usually
takes around 5 days to
develop, though prior exposure
to heparin can cause an accelerated course.
• IgG antibodies are made
against heparin after it binds to platelet
factor 4 (PF4).
• These antibodies attach themselves
to the heparin PF4 complex and
go on to bind and activate platelets.
Consequently, thrombi are formed
throughout the vascular tree and
the platelet count falls.
HIT can result in fatal PEs, limb ischaemia and stroke.
• In suspected HIT heparin should be
discontinued and blood sent to
the lab for a ‘HIT screen’.
Alternative anticoagulation should be used.
4
> Hypotension:
• Can follow rapid bolusing of a large dose.
5
> Other:
• Osteoporosis following long-term administration.
• Alopecia.
What are the advantages of LMWH?
1
> It only requires once or twice daily dosing.
2
>It does not need monitoring.
3 > It is less likely to cause HIT (though it can still do so) and non-immunemediated thrombocytopenia.
How does warfarin exert its
anticoagulant effect?
Warfarin, a coumarin-based anticoagulant,
is primarily indicated in the
treatment of deep vein thrombosis,
atrial fibrillation in patients at
risk of embolisation
and patients with mechanical
prosthetic heart valves.
It exerts its anticoagulant effect
by inhibiting the synthesis of the
vitamin K-dependent clotting factors
(II, VII, IX and X).
Anticoagulant effect is monitored
via the international normalised ratio (INR).
It takes at least 48 hours to achieve its
clinical effect, which is why a heparin-based anticoagulant is often started at
the same time if an immediate effect is needed.
Which drugs may potentiate the
action of warfarin?
Warfarin is extensively protein bound
(>95%).
Therefore any drug that competes
for the protein binding site,
or any condition that reduces protein binding, will potentiate the activity of Warfarin.
NSAIDs and simvastatin if administered concurrently with warfarin compete for the plasma protein binding sites, leading to warfarin displacement and increased warfarin anticoagulant effect.
There are also various drugs that
affect the metabolism of warfarin such as
metronidazole, macrolides and alcohol.
All of these reduce its metabolism,
raise the INR and
increase the risk of bleeding.
Antibiotics that affect the vitamin K-
producing gut flora will also increase the
effect of warfarin
What other factors can potentiate
the action of warfarin?
Diet –
food stuffs and supplements
can increase the effect of warfarin such
as St John’s wort, ginger and ginseng.
Thyroid status will also affect warfarin,
hypothyroidism reducing it effect.
Protein binding:
as well as other drugs competing for
binding sites, there are other factors
that will reduce the protein binding of warfarin.
Changes in plasma pH such as in
severe sepsis will alter the
tertiary structure of proteins
and reduce binding sites.
Reduced production of proteins such
as in severe liver disease or old age
will reduce binding.
Pregnancy – warfarin is contraindicated in pregnancy due to its teratogenic effects on the fetus (it can cause cleft lip and palate formation) and the risk of maternal bleeding.
This risk is increased by the
progressively reduced protein
binding of warfarin through the pregnancy.
Describe the treatment of
overdose of warfarin.
The main adverse effect of
warfarin overdose is bleeding.
Major bleeding should be managed
using an ‘ABC’ approach.
Specific treatment includes
stopping the warfarin,
administration of vitamin K (10 mg IV),
administration of prothrombin complex concentrate e.g. beriplex
(which contains factors II, VII, IX and X)
or alternatively administration of 15 mL/kg of fresh frozen plasma, although the latter is falling out of favour because of the attendant risks.
What other anticoagulants
do you know
Rivaroxaban
Rivaroxaban is a direct factor Xa inhibitor that can be taken orally as a once daily dose.
It has the advantage over warfarin
in that it has a
wide therapeutic window
with a rapid onset of action.
It therefore does not need
dose adjustment or
monitoring.
Dabigatran
Dabigatran is a
direct thrombin inhibitor that
can be given orally.
It has a similar clinical effectiveness
to warfarin but like rivaroxaban
it does not need
monitoring.
Its major drawback is that there is no
way to reverse its effect.
How can anticoagulants
be reversed?
Protamine sulphate
Heparin’s action can be reversed
using protamine sulphate
(as opposed to protamine).
It is a highly positive molecule so forms strong ionic complexes with the highly negative heparin molecules reducing the activity of heparin and markedly increasing its elimination.
Care must be taken with its administration,
as allergic reactions are common
particularly in those with
fish allergies,
diabetics
(insulin often contains protamine)
and vasectomised men
(sperm contains protamine).
Warfarin’s action can be reversed by giving intravenous vitamin K, fresh frozen plasma or a prothrombin complex concentrate (PCC), such as beriplex or octaplex.
PCCs are a combination of
factors II, VII, IX and X with
protein C and protein S,
all of which are harvested from blood.
HEPARIN
(Unfractionated: 3000–40 000 Da)
Glycosaminoglycan
- Clear colourless solution
- Variable dose and potency depending on preparation
MOA
• Binds to antithrombin III (ATIII) reversibly,
and increases the rate at which ATIII
binds to thrombin by 1000x
• Once thrombin is complexed with ATIII,
clot formation is inhibited
• At low doses factor Xa inhibited
• At higher dose factors
IXa, XIa, XIIa are inhibited
• At very high dose
platelet aggregation is inhibited
METABOLISM
AND EXCRETION
• Metabolised in liver, kidney and
reticuloendothelial
system
• Excreted in urine
ABSORPTION/
DISTRIBUTION
- Not given orally
- t½ 40–120 min
- Highly protein bound
- VD 0.04–0.1 L/kg
• Low lipid solubility, so does not cross
BBB or placenta
• t½ 40–120 min
USES
• Prophylaxis of DVT
• Prevention of clot
propagation in
DVT/PE/vessel occlusion
• To prevent clot formation on extra-corporeal membranes, e.g. cardiopulmonary bypass circuits/haemofilters
HEPARIN
EFFECTS
EFFECTS
HAEMATOLOGICAL
- ↑ APTT
- ↑ TT
- ↑ ACT
- No effect on bleeding time
•
Thrombocytopenia (type I).
Non-immune, not usually
significant. Platelet count
recovers quickly on
stopping drug
• Heparin-induced
thrombocytopenia
(Type II = ‘HIT’). Immune
mediated – heparin binds
to platelets and complex
removed by IgG
OTHER • Osteoporosis • Reverse with protamine • Low molecular weight heparin works by inhibiting factor Xa via ATIII. Only needs once daily dosing, does not require monitoring
WARFARIN
ADME
ABSORPTION/
DISTRIBUTION
• Well absorbed orally
- Protein binding 99%
- VD 0.1–0.16 L/kg
- t½ 35–45 hours
METABOLISM
AND EXCRETION
• Hepatic metabolism
• Excreted in urine and faeces
EFFECTS HAEMATOLOGICAL • PT • INR DRUG INTERACTIONS • Availability affected by drugs which induce/inhibit liver enzymes • Cholestyramine decreases absorption of fat soluble vitamins A, D, E, and K therefore potentiates effect of warfarin OTHER • Hypersensitivity reactions • Teratogenic in rst trimester • Crosses placenta and can cause fetal haemorrhage PRE-OP • Stop warfarin 1 week before elective surgery– replace with heparin if necessary. INR should be < 2 to operate • Rapid reversal: beryplex/FFP • Slow reversal (12 hours): Vit K
