Anti-Coagulant and Antiplatelet Therapy Flashcards
What are some disorders of haemostasis?
Normal is haemostasis
Abnormal = thrombosis, embolism
Arterial: white clot: CVA, MI
Venous: Red clot: DVT, PE
What is Virchow’s triad?
The three factors that contribute to thrombosis
Hypercoagulability (Thick)
- Genetic (Factor V leiden…)
- Acquired (OCP, smoking, prosthetic heart valves)
Endothelial damage
- Atheroma (MI, CVA)
- Hypertension
- Toxins (cigarettes, homocysteine)
Stasis
- Immobility (ill health, post op, economy class) (venous)
- Cardiac abnormality (AF, CCF, mitral valve disease)
(arterial)
Tell me about warfarin.
It is an anticoagulant
Inhibits production of vitamin K dependant clotting factors
Stops conversion of Vit K to active reduced form
So stops production of Prothrombin and factors VII, IX, X
Onset takes days due to turnover of clotting factors
Tell me about the PKs of warfarin and the clinical consequences of this.
Good GI absorption: give PO (orally)
- Preferred choice for long term AC
Slow onset of action (Can cover that with heparin)
Slow offset: t1/2 48 hrs but variable!
- Need to stop three days before surgery
Heavily protein bound
- Caution with drugs that displace it
Hepatic metabolism : CYP450
- Caution with liver disease
- Caution if used with drugs that affect p450 system
Crosses placenta
- DO NOT GIVE in 1st trimester: teratogenic
- DO NOT GIVE in 3rd trimester: Brain Haem
How do we monitor warfarin?
Extrinsic pathway factors
Prothrombin time
- Citrated plasma clotting time after adding calcium and
thromboplastins
I.N.R. International Normalised Ratio
- Allows a standard value between labs
- Corrected for different lab thromboplastins reagents
What is the significance of warfarin and drug
interactions?
Warfarin has many drug interactions
Very important
Effects on anticoagulation:
- Majority increase anticoagulant effect
- But some decrease effect
What are some drugs that potentiate warfarin?
3 ways:
1. Inhibit hepatic metabolism
Amiodarone, Quinolone, Metronidazole, ingesting alcohol
- Inhibit platelet function
Aspirin - Reduce vitamin K from gut bacteria
Broad spec. antibiotics - Cephalosporin antibiotic
Albumin displacement (NSAIDs) and drugs that decrease GI absorption of Vit K have lesser effect
INR will increase in these cases
What are some drugs that inhibit warfarin?
Antiepileptics (except Na valproate)
Rifampicin
St Johns Wort
Most work by inducing hepatic enzymes thereby increasing metabolism of warfarin
What are the uses of warfarin?
With INR range of 2-3
DVT
PE
Atrial fibrillation (until risk>benefit)
INR range of 2.5-4.5
Mechanical prosthetic valves (high risk)
Patients with recurrent thromboses on warfarin
Thrombosis associated with inherited thrombophilia conditions
Other uses:
Cardiac thrombus
CVA esp. with AF
Cardiomyopathy
What are the ADRs of warfarin?
Bleeding/bruising
- Intercranial (serious)
- Epistaxis
- Injection
- GI loss
Teratogenic
How can you reverse warfarin therapy?
STOP treatment
Consider
- Bleeding, INR, Indication
- Mechanical valve, call cardiologist
Agents
Parenteral vitamin K (slow)
Prothrombin Complex Concentrate
Fresh frozen plasma (fast)
Source of bleeding (OGD, surgery)
Elective surgery
What are some things to consider when starting someone on warfarin?
Indication
Past med history (PMH) Bleeding disorder, PUD, SAH
Medications (interactions)
Age, mobility (blood tests and clinics), falls risk score
Review blood tests (LFTs, INR….)
Consider loading dose and heparin cover
Prescribe (when to start)
What are the different heparin molecules you can give?
Unfractionated heparin
Intravenous, continuous
20kDa (big)
Low Molecular Weight heparins (LMWH)
subcutaneous
3-4kDa
What is the mechanism of action of unfractionated heparin?
Unique pentasaccharide sequence which binds to anti-thrombin III
This causes a conformational change and increased AT III activity
AT III inactivates thrombin (IIa) and factor Xa: but also V, VII, IX, XI
What is the mechanism of action of LMW heparin?
what is the difference from unfractionated heparin
Same mechanism as unfractionated, binding to AT II
BUT:
Xa inhibition by AT III only needs heparin to bind to AT II, so LMWH can do it
But to be able to inhibit IIa heparin needs to bond to IIa and AT III which LMWH can’t do
Tell me about LMW heparin.
Smaller chains
Absorbed more uniformly, high bioavailability >90%
Long biological half life
More predictable dose response
Only affects factor Xa and so no monitoring needed usually
Cleared by kidney, care in renal failure
Less likely to cause thrombocytopenia
Tell me about the PKs of Heparin.
Factor: UF heparin \/ LMW heparin
Dose-response: Non-linearity \/ Predictable
Bio-availability: Variable \/ Predictable
Action: Variable (Monitor) \/ No monitoring
Administration: IV \/ SC
Initiation: Bolus then IVI \/ OD/BD
What are the uses of heparin?
Peri-operative: LMWH low dose
Covers risk of thrombosis around times of operation in those normally on warfarin but have stopped it for surgery as quick offset time allows cessation if bleeding
Immobility: CCF, frail or unwell patient
DVT/PE and AF
- Administered prior to warfarin - quick onset to cover
patient whilst warfarin loading is achieved
- LMWH often used
Acute coronary syndromes
- Reduces recurrence/extension of coronary artery
thrombosis
- MI, unstable angina
Pregnancy
- Can be used cautiously in pregnancy
What are the ADRs of heparin?
Bruising/bleeding (intracranial, injection sites, GI loss)
Thrombocytopenia
Autoimmune phenomenon
May bleed or get serious thromboses
Heparin and PF4 on platelet surface are immunogenic
Immune complexes activate more platelets
Leads to depletion of platelets, thrombosis
STOP heparin, add hirudin
Long term
Osteoporosis
How can you reverse heparin therapy?
Stop heparin
If actively bleeding, give protamine
Protamine sulphate
- Dissociates heparin from anti-thrombin II
- Irreversible binding to heparin
- Allergy/anaphylaxis
Monitor APTT if unfractionated
Name some anti-platelet drugs.
Aspirin - COX-1 inhibition Dipyridamole - Phosphodiesterase inhibitors Clopidogrel - ADP antagonists Glycoprotein IIb/IIIa inhibitors
What are some different mechanisms of antiplatelet drugs?
Inhibition of COX-1
G IIb / IIIa Inhibitors
Abciximab, tirofiban, eptifibatide
Decreases platelet crosslinking by fibrinogen
Blockade of P2Y12
Clopidogrel, prasugrel, ticagrelor
P2Y12 receptor decreases cAMP via Gi
An increased cAMP reduces aggregation
Dipyridamole inhibits PDE
Tell me about Clopidogrel and Prasugrel
Inhibit ADP dependant aggregation Cardiac indications: - ACS, PCI Used with aspirin - More serious bleeds but same rate of life threatening - Not for long term use of possible
Tell me about Dipyridamole.
Probably phosphodiesterase inhibitor
Positive Ionotrope and vasodilatory (flushes and headaches)
Secondary prevention of stroke (with aspirin)
