Week 1: Anticoagulants Flashcards
What is the mode of action of warfarin
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Vit K antagonist
- Redcues the biological activity if factors 2, 7, 9, 10
- Vitamin K epoxide reductase is blocked by warfarin (and other coumarin agents)
- There is no carboxylation of glutamic acid residues - coagulation proteins are biologically inactive
What are the vit k dependent factors?
What happens if a pt is given a high dose of warfarin?
Factors: 2, 7, 9, 10 and protein C and S
Due to T1/2 of these factors, you need to cover the patients with heparin whilst waiting for it to take effect. It takes 48-72 hours for anticoagulant effect to develop fully (the half life of factor ii).
What causes variation in the effect of warfarin metabolism?
Genetics
Medicine
Diet
Adherence
How can genetics cause a difference in warfarin sensitivity amongst patients?
- Single nucleotide polymorphisms in CYP enzymes and VKORC (vitamin K epoxide reductase), causing variability in response.
- Tested on finger prick test, caused by genetic variation in CYP enzymes.
- Cytochrome p450 (CYP2C9) metabolises S warfarin and is considered to be the most important.
- CYP2C9 variations 2 and 3 associated wtih lower warfarin dose and increased bleeding risk during induction
- Some patients are warfarin resistant:
- Vitamin K epoxide reductase VKORC1 - required to reduce vitamin K into its active form.
- Some patients have a single nucleotide polymorphism- produce less VKORC1 than normal and therefore already produce less clotting factors
- increase risk of haemorrhage, require lower dose of warfarin.
What vitamins can interact with warfarin?
How do they alter coagulation?
Increase anticoagulation: Vitamin E
Reduce anticoagulation: Vitamin K, C, coenzyme q10
Describe the coagulation cascade (both intrinsic and extrinsic PW)
What is APTT/ PTT?
What is PT/INR?
-
Extrinsic p/w:
- TF = extrinsic, blood not normally exposed
- activates factor 7 –> factor 7a
- Factor 7a, TF and Ca2+ forms a complex –> activates factor 10 –> common pathway –> prothrombin converts to thrombin –> fibrinogen to fibrin
-
PT/ INR = Prothrombin time, international normalised ratio (standardised prothrombin time test)
- patients on anticoagulants have a target of INR 2.0-3.0
- measures the extrinsic pathway factors
- a normal aPTT with abnormal PT suggests defect in extrinsic pathway, suggests possible factor 7 deficiency.
- PT/INR monitors response to warfarin.
-
Intrinsic p/w:
- Factor 12 —> 12 a
- converts factor 11, converts factor 9
- factor 9 with factor 8 converts factor 10 –> common p/w –> thrombin produces fibrin from fibrinogen
- Partial thromboplastin time (PTT) and activated partial thromboplastin time (aPTT) test the same functions, but in aPTT an activator is added (calcium and phospholipid) that speeds clotting time and has narrower reference range.
- aPTT more sensitive version of PTT monitors response to heparin therapy.
- measures all clotting factors of intrinsic pathway and common pathways (factors 1 (fibrinogen), 2(prothrombin), 5,8,9,10,11,12.
- A normal PT and abnormal aPTT suggests defect in intrinsic p/q (factor viii, ix, x, xiii).
What is INR?
Comes from prothrombin time test (PT)
Blood sample taken, take plasma and add thromboplastin (mixture of phospholipids and tissue factor) and add calcium.
Source of error –> The type of thromboplastin used in the assay (human or animal) induces different results. Plus human error in PTT. The difference in sensitivities of which thromboplastin used is known as the sensitivity index.
Then introduced INR = international normalised ratio
INR = PT ratio raised to international sensitivity index (PT ratio ISI)
Prothrombin time ratio = Patient PT (S) / GMN PT(s) where GMN = geometric mean normal
What is ISI?
International sensitivity index
The prothrombin time (PT) of an invididual with deficiency in clotting factor will vary with the type of thromboplastin used in the assay. Difference sensitivites is known as the sensitivity index. Different thromboplastins are calibrated against the international WHO refernce.
Used plasma from health normal individuals and oral anticoagulant patients
compared the PT for each candidate with the international reference preparation, used regression to allow ISI to be worked out.
Contraindications ot warfarin?
- Pregnancy –> most switched to LMWH as can cause damage to fetus in 1/20, also dose dependent
- Active peptic ulcer
- uncontrolled HTN
- Infective endocarditis
What precautions or what should you be aware in warfarin pts?
- Hx of GI bleed
- severe HF
- Liver disease
- Renal failure
- Alcoholism
- Mental impairment
- Thrombocytopenia -> already have low platelets
- Coagulation disorder
- Interacting drugs (e.g. NSAIDS that increase risk of bleeding).
What are some of the non haemorrhagic side effects of warfarin?
Rash
Alopecia -> often in younger women with replacement heart valves
Sx. of association common
What is the main risk of warfarin?
Bleeding
Risk of intracranial bleed around 1/ 400 pts
Risk of major extracranial bleed on OAC therapy 0.4-2% per year
additional risk of major bleed if hx of GI bleed/ concurrent use NSAID, genetic differences in warfarin metabolism, iNR variability comorbidity, duration of OAC therapy
Risk of GI bleed around 1% per yr, 1 in 100 pts every yr
Risk of minor bleed (nose bleed/ heavy period) 6-21%
What are the alternatives to warfarin?
What does an alt to warfarin need to be?
- Alt needs to be as good, low risk of bleeding, few SE’s, taken 1/2 a day with oral availability, few interactions (drugs and food), broad therapeutic window at standard dosing, good patient acceptability and long term tolerance
- 4 drugs available:
- Dabigatran –> Prothrombin inhibitor (Factor 2)
- Rivaroxaban –> FX a inhib
- Apixaban –> Fxa inhib
- Edoxaban –> Fxa inhib
- All work within a few hours compared with warfarin where it takes several days/ week to have effect
Atrial fibrillation and stroke prevention affects which age group?
How has disease prevalence changed?
Mostly elderly patients, if detected when younger due to underlying structural problem.
Becoming more common, 3 fold increase from 1960’s - 1980’s
More common in men than women, many with underlying cardiac disease.
25% of AF is paroxysmal
What is the impact of AF?
- Increased risk of death
- Increased risk of stroke
- Ass. with higher mortality from CHD and HF
- Impaired cognition and dementia strongly correlated
How can herbs alter warfarin action?
How do they alter anticoagulation?
- Increase anticoagulation: Garlic, Devil’s caw, dong quia, danshen
- Reduce anticoagulation: Korean ginseng, green tea
What are the 4 main new oral anticoagulants?
What is their MOA?
Bioavailability?
half life
dose
time to max effect?
- Dabigatran
- selective direct F2a inhibitor
- oral prodrug poor oral bioavailability
- 12-17 hours half life
- taken twice daily
- 1-4 hrs for max effect
- Rivaroxaban
- selective Fxa inhibitor
- good oral bioavailability
- 6-9 half life
- once a day
- 1-4 hrs
- Apixaban
- selective direct Fxa inhibitor
- good oral bioavailability
- 12 hours half life
- twice a day
- 1-4 hrs
- Edoxaban
- competitive inhibitor Fxa
- good oral bioavailability
- T1/2 9011 hours
- once a day
- 1-4 hrs
What score is used to determine the risk of stroke in atrial fibrillation?
CHA2DS2VASc
How would you assess bleeding risk on oral anticoagulation for AF?
HAS-BLED score for bleeding risk when placing patient w AF on oral anticoagulants.
HTN
Abnormal renal/ liver function
Stroke in past
Bleeding tendency
Labile INR
Elderly (> 65 yrs)
Drugs & alcohol (NSAID)
Outline the steps you would take for stroke prevention in patients with non valvular AF?
- Assess risk of stroke using CHADVASC
- Assess risk of bleeding on oral anticoagulants using HASBLED
- discuss risks a benefits of oral anticoagulation
- Low risk patients could have no antithrombotic therapy, increased risk patients need to consider oral anticoagulation for CHADBASC score of 1. Scores greater than 2 need to offer oral anticoagulation.
- If oral anticoagulation contraindicated —> left atrial appendage occlusion.
- If patient wants to go ahead with oral anticoagulation –> dicuss warfarin, new oral anticoagulants.
- Monitor INR/ coagulation if warfarin –> poor control need to offer non vitamin K dependent oral anticoagulation.
- annual review of all patients
What is optimal anticoagulation control?
Aim for target INR 2.5
acceptable range 2-3
Note with higher INR value increase the risk of intracranial haemorrhage
With lower INR increase the risk of stroke
