6.2- Anti-coagulants Flashcards
What can disorders of haemostats be divided into?
Arterial Thrombo-embolic events
Venous Thrombo-embolic events
Name 2 types of arterial thromboembolic events?
Stroke ( CVA)
MI
Name 2 types of venous thromboembolic events?
DVT
PE
Name the components of Virchow’s Triad
Hypercoagulability
Endothelial damage
Vascular stasis
What does Warfarin do?
inhibits production of Vitamin K dependent clotting factors ie factor II ( Prothrombin), VII, IX and X
Briefly describe warfarin
long half life
slow onset and offset of action
anticoagulant effect is potentially reversible
only ORAL anti-coagulant which can be measured therefore safe
Describe the PK of warfarin
good GI absorption therefore give orally/ PO
slow onset of action so give Heparin as a cover
Slow OFFSET; half life is 48 hrs but varies–> so you need to stop it 5 days before surgery
Describe a consequence of Warfarin’s hepatic metabolism
CYP450 system
- CAUTION w alcoholics/ liver disease bc their INR fluctuates
- caution w drugs that affect P450 system bc they can affect the metabolism of Warfarin ( induce/ inhibit)
Is Warfarin given in pregnancy?
NO bc it crosses the placenta
in first trimester it is TERATOGENIC
in third trimester, there is a risk of bleeding at delivery
Why would you be at risk of clotting in pregnancy?
Immobility
Oestrogen is dominant during pregnancy –> increases all the pro-coagulant factors and reduces the anti-coagulant factors therefore you are at HIGH risk of clots
How do you monitor Warfarin?
Prothrombin Time
using citrated plasma and light blue tube
PT is standardised into INR, which allows a STANDARD VALUE between labs
but PT varies ( INR will be the same
Which drugs POTENTIATE Warfarin ie increase its affect and HOW
1) INHIBIT hepatic metabolism; AMIODARONE, QUINOLONE, CIMETIDINE, ingesting alcohol
2) REDUCE VIT K from GUT BACTERIA
Cephalosporin antibiotics
How do drugs INHIBIT warfarin
give 2 examples
INDUCE hepatic enzymes thereby increasing metabolism of Warfarin; therefore DECREASING INR ie HIGHER risk of clot
e.g. Rifampicin
Anti-epileptics EXCEPT Na Valproate
Which conditions does Warfarin treat to raise INR range to 2-3?
DVT/PE
AF
Dilated cardiomyopathy
Which conditions does Warfarin need to raise INR event higher in, to 3-4?
Mechanical prosthetic valves; need an even higher INR than 2-3, bc HIGH risk of thrombotic event
Thrombosis associated w ANTI-Phospholipid syndrome
What is ANTI-PHOSPHOLIPID SYNDROME?
autoimmune, acquired
type of thrombophilia, INCREASED risk of clotting
young patients<45 yrs presenting w stroke/ MI
What are women w anti-phospholipid syndrome at risk of?
How is this treated?
RECURRENT MISCARRIAGE
treat with aspirin and heparin
Name 8 LIMITATIONS of Warfarin Therapy
1) Unpredictable response; bc of its high protein binding and lots of ADR’s
2) Narrow therapeutic window; INR range 2-3
3) Requires ROUTINE coagulation monitoring
4) SLOW onset and offset of action
5) Requires FREQUENT DOSE ADJUSTMENTS
6) Drug-drug interactions
7) Drug-food interactions
8) Warfarin resistance
What is the trouble with warfarin’s narrow therapeutic range?
INR 2-3
If a patient’s INR is sub-therapeutic
If INR<2, their stroke risk is HIGH bc increased clotting
If INR>3 ie too high, THEN there is a risk of an intracranial bleed
Name 2 adverse effects of Warfarin
TERATOGENIC ( in 1st trimester and at 3RD trimester there is a high risk of bleeds)
BLEEDING/BRUISING; epistaxis, intracranial, GI loss
How do you reverse warfarin therapy?
stop warfarin
PARENTERAL VITAMIN K( Slow)
FRESH FROZEN PLASMA(Fast)
What do you consider during warfarin reversal?
Bleeding, INR, Indication
Mechanical valve ; ask consult
Name agents for Warfarin reversal?
IV Vitamin K; pro-coagulant effects for 6 weeks
Prothrombin Complex Concentrate (PCC)
Fresh Frozen Plasma
Which is better for Warfarin reversal, FFP or PCC
PROTHROMBIN COMPLEX CONCENTRATE ( completely reverses Warfarin , unlike FFP)
Why is PCC preferred to FFP?
FFP is given in a large volume, so if you give an elderly patient a large volume of FFP, they could get a volume overload–> therefore RISK of heart failure
Whereas in PCC, it is given in a SMALL VOLUME, so no risk of heart failure
How does Heparin’s route of admin differ from Warfarin’s?
1) Heparin is given via SUBCUTANEOUS INJECTION ( if low molecular weight) whereas Warfarin is given orally
2) If in un-fractionated form, it is given IV or SC
What is Heparin?
glycosaminoglycan; glucose backbone
Produced by MAST CELLS
Give the general action of Heparin
- binds to Anti-Thrombin III; ATIII via a unique pentasaccharide sequence
- leads to activation fo ATIII and inactivation of Factor Xa, IIa( prothrombin), IXa
How does UFH become LMWH
UFH can be fractionated to produce molecules with LMWH
LMWH has more PREDICTABLE PHARMACODYNAMICS
How does Heparin work on the clotting cascade?
Heparin stimulates ATIII, which then inactivates Thrombin and factor IIa therefore no clotting
Warfarin inhibits the production of Prothrombin from Factor X–> therefore no Thrombin produced-> no clot
Describe the structure of UFH
long length heparin chains
usually given by continuous IV infusion
Occasionally given via SC for prophylaxis in patients w renal failure who are unsuitable for LMWH
long enough length to inhibit activation of PROTHROMBIN ( IIa) and factor XA
How can UFH be monitored
via APTT but cannot measure LMWH by this
done every 2-3 hours to check the effect and level of unfractionated heparin in blood of patient
What is LMWH
smaller chains
given SUBCUTANEOUSLY
Describe the PK of LMWH
PREDICTABLE
high bioavailability
long half life–> cleared by kidneys
THEREFORE given at a fixed once daily dose, monitoring is not usually required
What are the 3 instances for which you DO have to monitor LMWH?
Monitored by Anti Xa level not APTT if monitoring required
1) Pregnancy
2) MODERATE renal failure
3) Patients with very high or low body weight
Describe the mechanism of LMWH
to catalyse the inhibition of IIa by AT-III, heparin needs to bind SIMULTANEOUSLY to IIa and AT III
LMWH is not large enough for this therefore it can only inhibit Factors Xa but NOT IIa
Why can’t LMWH be measured with APTT, unlike UFH?
un-fractionated heparin can bind to both thrombin and factor Xa
WHEREAS
LMWH can only bind to factor Xa NOT thrombin ie IIa
THIS IS WHY you cannot check LMWH with APTT bc the APTT blood test depends on this point of thrombin activation
Describe the route of administration of heparin
MUST be given parenterally as poor GI absorption
RAPID onset and offset of action
UFH: IV
LMWH: SC
Which anti-coagulant do you give before surgery?
HEPARIN
i.e. it has a much smaller half life than Warfarin therefore once you stop a patient on Warfarin when they come in for surgery (5 days before), you replace it with Heparin
because you can stop the Heparin on the morning of the procedure and still provide the patient with an anti-co-agulatory effect all the way up to the procedure AND
Reducing the risk of them clotting in the TIME BETWEEN the surgical procedure and stopping the Warfarin
QUICK OFFSET TIME of Heparin allows its cessation if bleeding
How is heparin is used for prevention of VTE?
Used prophylactically in hospital bc all admitted patients are at HIGH risk of clotting, therefore all in-patients should be on anti-coagulant
in patients
Post-op patients
Immobility
What instances is heparin given in?
Administered prior to warfarin; quick onset to cover patient whilst warfarin loading is achieved
LMWH is often used
in PREGNANCY, it can be used in place of Warfarin
What are the side effects of heparin?
Bruising/ bleeding
Osteoporosis; for long term use, UFH is preferred> to LMWH
Thrombocytopenia ( HIT)
What is HIT?
Heparin Induced Thrombocytopenia
autoimmune phenomenon ( 4-14 days Rx)
tend to present w thrombosis not bleeding
diagnosed by Lab assay and clinical probability
What action do you take if a patient has HIT?
STOP HEPARIN
Treat with Fondaparinux ( synthetic form of Heparin) or Lepirudin
How is heparin therapy reversed?
Stop Heparin
If on UFH and actively bleeding–> give PROTAMINE
Monitor APTT if unfractionated
What is Protamine and what is it used for?
Protamine sulphate
dissociates heparin from AT-III ( anti-thrombin III)
Are anti-platelet drugs used for arterial or venous drugs?
Arterial clots
Differentiate between arterial and venous clots
Arterial clots are more related to Virchow’s triad—> related to ATHEROSCLEROSIS ie vessel wall integrity
WHEREAS
venous clots are more related to the STASIS of blood
Therefore drugs treating arterial clots aim to have a greater effect on PLATELETS
and venous clot drugs focus on ANTI-COAGULATION specifically
Name 4 anti-platelet drugs used to treat arterial clots
ASPIRIN; COX inhibition affecting Plt activation
DIPYRIDAMOLE; phosphodiesterase inhibition
CLOPIDOGREL; inhibits ADP dependent Platelet aggregation
GLYCOPROTEIN IIb/ IIIa inhibitors ( inhibits platelet crosslinking and activation
What are thrombolytics used for?
to lyse already formed clots
STEMI
Massive PE w haemodynamic compromise
Stroke; AS LONG AS haemorrhage is EXCLUDED by CT scan
How do thrombolytics work?
- promote fibrinolysis by converting inactive plasminogen to active plasmin
- Plasmin DEGRADES fibrin clot
How can a massive PE cause haemodynamic compromise?
a SADDDLE EMBOLUS–» thromboembolus at the bifurcation of the pulmonary artery —> causing acute haemodynamic compromise
Why are thrombolytics given in ADDITION to Warfarin and Heparin?
Warfarin and Heparin do not actually break down clots, they just prevent them from enlarging ie prevent clot propagation
But they are still relying on the body’s inherent fibrinolytic system to break them down
BUT there are certain situations where there is not enough time to wait for the fibrinolytic system to breakdown the clot THEREFORE you administer thrombolytics
What is an instance of when you HAVE to give a thrombolytic? ( and not wait for fibrinolytic system to take action)
1) MI; collateral damage occurs during the period of time when there is a major obstruction to the vessel
IF you don’t thrombolyse a patient with STEMI, the will have a NON-FUNCTIONING LEFT VENTRICLE—> will go into cardiac failure–> will die
2) STROKE; window to reduce clot or neurological symptoms will occur
3) MASSIVE PE–> patient will die of hypoxia
Name the 2 types of thrombolytics
Recombinant tissue plasminogen activator e.g. rt-PA
Streptokinase
What are NOAC’s?
Novel Oral Anticoagulants
Direct thrombin Inhibitor- DABIGATRAN
Direct factor Xa inhibitors- APIXABAN
Name 5 advantages of NOACs over Warfarin
- rapid onset/offset of action
- few drugs interactions
- predictable pharmacokinetics
- wide therapeutic window
- eliminated the need for regular coagulation monitoring and allowed fixed dosing in adults
Give 4 indications for the use of NOAC’s?
AF
Treatment of PE/DVT
Prevention of recurrent PE/DVT
Prevention of DVT/PE post hip/knee surgery
