Anticoagulants Flashcards
what are the treatment options for thromboembolic disease?
antiplatelets
anticoagulants
thrombolytics/fibrinolytics
mechanical options
what do antiplatelets do?
prevent clots
arterial use
what do anticoagulants do?
prevent clots
arterial and venous use
what do thrombolytics/fibrinolytics do?
destroy clots
arterial and venous use
mechanical options for thromboembolic disease
PCI
stents and angioplasty
common antiplatelets
aspirin clopidogrel dipyridamole prasugrel ticagrelor abciximab tirofiban
common anticoagulants
warfarin heparins apixaban rivaroxaban dabigatran danaparoid fondaparinux argatroban epoprostenol
common thrombolytics and fibrinolytics
tissue plasminogen activator
streptokinase
urokinase
what is VTE?
PE and DVT
ACS
acute coronary syndrome
MI
haemostasis
balance between haemorrhage and thrombosis
virchow’s triad
causes of thrombus formation:
- blood stasis
- hypercoagulability
- endothelial injury
what is thrombophilia?
pro-thrombotic state
what determines thrombosis treatment?
where the thrombus is
capillaries, veins or arteries
what are the stages of haemostasis?
formation of platelet plug
propagation of clotting
termination of clotting
fibrinolysis and clot removal
formation of platelet plug
platelet adhesion, aggregation, activation and secretion
activation of thrombin
propagation of clotting
intrinsic and extrinsic pathway activation
clotting cascade
amplification of cascade
recruitment of platelets
termination of clotting
limitation of clot formation
muting clotting cascade
restoring anti-thrombotic state
fibrinolysis and clot removal
activation of plasmin
lysis of cross-linked fibrin
production of D-dimer and FDPs
end of clotting cascade/ common pathway
factor X to Xa
Xa causes Va to convert
prothrombin to thrombin
Thrombin causes fibrinogen to fibrin and XIII to XIIIa which converts fibrin to cross linked fibrin
what triggers the coagulation cascade?
intrinsic pathway = response to sepsis, toxins and hyperlipidaemia
extrinsic pathway = tissue factor caused by injury
lining of blood vessels
antithrombotic
deeper down in the vessel wall is more thrombotic
fibrinolysis
plasminogen is converted to plasmin by tissue plasminogen activator
plasmin breaks down cross linked fibrin into fibrinogen degradation products (FDPs) and D-dimer
what are the antithrombotic factors?
activated protein C
protein S
anti-thrombin
what do anti-thrombotic factors do?
block coagulation cascade
How do protein S and C work?
protein S activates protein C
Protein C inhibits factor Va to prevent prothrombin conversion to thrombin
how does anti-thrombin work?
directly inhibits thrombin
tombstone ST elevation
indicates full thickness acute large MI needs immediate treatment - stent thrombolytic given to open coronaries
best treatment for STEMI MI
PCI
more effective than drugs
MI
atheroma causes ischaemia and thrombotic occlusion causes the infarction
when to use anti-platelets vs anticoagulants
have similar effects
can be used in same setting but anti-platelets are used more in arterial disease
why are anti-platelets used in arterial disease over anti-coagulants?
in arterial disease platelet plug is already occluding the artery and is a more important factor in the occlusion
platelet rich clots form in arteries
in veins more fibrin than platelets cause occlusion
how to treat ischaemic stroke?
antiplatelet
anticoagulation if in AF
what antiplatelets are used in treating ischaemic stroke?
aspirin
clopidogrel
dipyridamole
AF
risk of clot formation in left atrial appendage and other parts of heart
clots are clotting factor and fibrin rich
can cause bowel ischaemia or stroke
AF treatment
need treatment with anticoagulation
don’t use aspirin
who needs AF treatment?
younger people with no other comorbidities = bleeding risk from treatment is greater than risk of thrombus so no anticoagulation indicated
older people and those with comorbidities = risk of thrombus exceeds bleeding risk so treatment required
what comorbidities indicate AF treatment?
hypertension
high cholesterol
etc.
assessment for AF stroke risk
CHA2DS2-VASc score
CHA2DS2-VASc scoring system
- 0 points = no anticoagulation needed
- 1 = needs anticoagulation but may opt out in some circumstances
- > 1 = ANTICOAGULATION!! (unless good reason not to)
what are the classes of anticoagulants?
DOACs
warfarin
heparins
fondaparinux
e.g. of heparin
dalteparin
DOACs
direct oral anticoagulants
what are the indications for anticoagulants?
treatment of thromboembolism
prevention of thromboembolism
high risk thrombophilias
treatment of thromboembolism
arterial = warfarin and DOACs venous = heparins, DOACs and warfarin
prevention of thromboembolism
in stroke and AF = warfarin and DOACs
VTE prophylaxis = low does LMWH
treatment for high risk thrombophilias
seek specialist advice
advantages of DOACs?
fewer interactions with other drugs
no INR monitoring required
simpler for patients and doctors
disadvantages of DOACs?
no easy way to reverse them - but there is for warfarin
less long-term data on efficacy and safety
use of DOACs
relatively new
most people are now started on these and not warfarin
examples of DOACs
apixaban
rivaroxaban
edoxaban
dabigatran
how do DOACs work?
rivaroxaban and apixaban directly inhibit factor Xa and prevent activation of thrombin from prothrombin
dabigatran directly inhibits thrombin so fibrin cannot be formed
rivaroxaban
- caution in renal disease
- no monitoring required
- used for VTE prevention
- used for AF
- cannot be used in people with mechanical heart valve
- apixaban is increasingly common in place of this
Dabigatran
- renally excreted – avoid in severe CKD
- careful in acute kidney injury
- no monitoring required
- coagulation tests can demonstrate activity but poorly relate to actual degree of action
- dyspepsia and hepatobiliary disease = common side effect
Interactions with dabigatran
drugs that are inhibitors or inducers of P-glycoprotein affect dabigatran levels
parenteral anticoagulants
= anticoagulants that cannot be given orally
examples of parenteral anticoagulants
LMWH
unfractionated heparin
fondaparinux
LMWH administration
subcutaneous injection
use of fondaparinux
ACS/ MI
how does heparin work?
alone antithrombin is relatively weak at inhibiting thrombin but heparin binds and induces a conformational change that increases the binding of thrombin and Xa and increases activity of anti-thrombin and further inhibits thrombin
LMWH
affects Xa inhibition more than thrombin
fondaparinux mechanism of action
similar to heparin mechanism of action
how is heparin administered?
LMWH = subcutaneous injection of dalteparin
unfractionated heparin = less commonly used, given by IV injection (can be reversed quickly and titrated up and down)
who is LMWH given to?
large number of immobile patients
pregnant women
post-op patients
side effects of heparin
- bleeding
- thrombocytopenia – long-term use (need to monitor platelets)
- hypokalaemia
- osteoporosis in long-term use
- can accumulate in renal failure – needs dose reduction depending of eGFR
fondaparinux
- similar mode of action to heparin
- given by subcutaneous injection
- causes less thrombocytopenia
- replaced LMWHs for treatment of acute coronary syndromes (MIs)
warfarin
- common
- prescription complications are common
- complicated
disadvantages of warfarin
- no one dose
- variable doses between individuals and difficult to predict
- lots of interactions with drugs and foods
- dangerous – teratogenic in pregnancy
- non-fatal effects
- initial high-dose therapy is pro-thrombotic
normal vitamin K activation of clotting factors
clotting factors = serine protease
Carboxylase requires reduced vitamin K (abundant for activation)
During the process vitamin K is oxidised and no longer able to be used
NADH and vitamin K reductase can then reduce vitamin K again to be recycled and used for activating clotting factors again
warfarin mechanism of action
- blocks vitamin K reductase
- once all vitamin K is oxidised
- no more reduced vitamin K is present to activate clotting factors
- new vitamin K needed to activate serine protease/clotting factors
- warfarin keeps vitamin K oxidised
diet and warfarin
dietary intake of vitamin K can affect warfarin because warfarin inhibits carboxylation of vitamin K dependent coagulation factors
INR
international normalised ratio
what is INR?
measure of prothrombin time
use of INR
measures anticoagulant effect of warfarin and its effect on the clotting cascade
how to calculate INR?
prothrombin time of patient/prothrombin calibrated normal
benefit of INR
eliminates assay variation between places
INR of 2
prothrombin time is twice that of a normal control using that assay
what is the target INR for people on warfarin?
2-3
how to prescribe warfarin?
dedicated chart own policies risk assessment - balance of risk factors for bleeding and indication for use baseline monitoring advice on interactions
warfarin and drug interactions
enzyme inducers increase warfarin metabolism and reduce INR and its effect
enzyme inhibitors decrease metabolism of warfarin and so increase INR and bleeding risk
what else can affect warfarin?
other anticoagulants
protein binding
high risk drugs for warfarin interactions
anticonvulsants antibiotics analgesics - NSAIDs anticoagulants antidepressants anti-platelets
what common drugs enhance the effect of warfarin?
anabolic steroids antidepressants antidiabetics allopurinol amiodarone antibiotics aspirin NSAIDs phenytoin statins
what other substances enhance the effect of warfarin?
cranberry juice
grapefruit juice
smoking cessation
alcohol
what common drugs reduce the effect of warfarin?
azathioprine carbamazepine rifampicin oral contraceptive pills st john's wort
what other substances reduce the effect of warfarin?
chronic alcohol use
broccoli
green leafed vegetables
Initial parenteral treatment
when instant anticoagulation is required
initial oral treatment
when slower anticoagulation is needed
how to reverse warfarin?
depends on urgency and severity vitamin K oral or IV IV = 5mg varied doses omit the warfarin dose FFP prothrombin complex concentrates
FFP
frozen fresh plasma
instant effect
variable effect
new clotting factors
dried prothrombin complex concentrates
instant effect
e.g. octaplex
pooled clotting factors from other patients
given with vitamin K
warfarin reversal with vitamin K
slow
reversal of DOACs
support measures/resuscitation
normal INR excludes significant dabigatran effect but doesn’t exclude therapeutic concentrations of the other DOACs
need to wash out DOACs
if severe = dried prothrombin complex
wash out for DOACs
12 hours for dabigatran and apixaban
24 hours for rivaroxaban
new antidote for dabigatran
idarucixumab
expensive
reversal of heparin
depends on severity and urgency
omit dose of LMWH or stop the infusion of unfractionated heparin
protamine sulphate
what are thrombolytics?
clot busters
uses of thrombolytics
acute ischaemic stroke PE with cardiovascular collapse massive DVT upper limb DVT other rare uses
how do thrombolytics work?
activates plasmin
breaks down clot
TPA - tissue plasminogen activator
consent for thrombolysis
get verbal consent for administration
risks can be severe
make sure risks are explained
what are the risks of thrombolytics?
intra-cerebral haemorrhage other haemorrhages all clots in the body are broken down haemorrhagic strokes massive GI bleed
Criteria for TP in ischaemic acute stroke
<4.5 hours since clear onset
>18 years old
diagnosis of ischaemic CVE
most common PE ECG finding
sinus tachycardia
when to consider thrombophilia?
when atypical thrombosis is present or there is recurrent unprovoked disease
antiplatelets
irreversible COX inhibitors
P2Y12 receptor antagonists/ ADP receptor inhibitors
glycoprotein inhibitors
aspirin
inhibition of thromboxane synthesis in platelets
inhibits platelet aggregation
P2Y12 receptor antagonists examples
clopidogrel
prasugrel
ticagrelor
ticlopidine
how do P2Y12 receptor antagonists
inhibits P2Y12 receptor on platelets
inhibits platelet aggregation
no activation of Gp IIb/IIIa receptors
glycoprotein inhibitors examples
abciximab
eptifibatide
tirofiban
how do glycoprotein inhibitors work?
bind and block glycoprotein IIb/IIIa receptors on platelet surface
prevents platelets binding to fibrinogen
inhibits platelet aggregation and thrombus formation
