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Flashcards in Anticoagulant Drugs (Dawes) Deck (33):

Are the the indications for anticoagulants? (when do we use anti-coagulants?)

1) Arterial disease (anti-platelets + anticoagulants) include:

  • Coronary artery disease
    • Acute coronary syndrome (STEMI, NSTEMI, acute chest pain etc.)
      • Blood supplying the heart
  • Cerebrovascular disease
    • (e.g. stroke)
  • Peripheral vascular disease


2) Thrombo-embolic disease (anticoagulants) include:

  • Atrial fibrillation
    • (arrhythmia that’s associated with high risk of developing systemic emboli)
  • Venous thromboembolism
    • (DVT, PE) (acutely give someone an anticoagulant and also over the next few months)
  • Prosthetic cardiac valves
    • (Metal heart valves are very thrombogenic, activates the coagulation cascade causing thrombi to form on the unnatural metal heart valves, requires a lifetime of concurrent anticoagulant)


Describe the Virchow's Triad and its indications for anticoagulant use

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Describe the uses of Unfractionated Heparin

Its uses include:

  • Acute coronary syndromes
  • Thromboembolism (prophylaxis and treatment)
    • Venous: DVT, PE (although LMWH used much more commonly)
    • Arterial: AF
  • Temporary "warfarin replacement",
    • e.g. pregnancy (you can't use warfarin as anticoagulant during pregnancy)


Describe The Molecular design of UH

Unfractionated heparin consists of linear mucopolysaccharide chains (highly negatively charged, very heterogeneous, vary greatly in molecular weight 3,000-40,000).


It is mix of variable length heparin chains (pig intestinal mucosa, bovine lung)

  • Sulphated GAGs (glycoaminoglycans)
  • Alternating glucuronic acid and N-acetyl-D-glucosamine residues

It can be used as intravenous or continuous infusion. (Cannot cross the mucosal barrier so cannot be given orally)


Describe the UH Mechanism of Action

Unfractionated heparin binds to and increases activity of antithrombin III.


Antithrombin III inactivates:

  • Thrombin (IIa) and factor Xa
  • And also IXa, XIa, XIIa

It requires constant APTT monitoring (blood test) (tells you whether you have achieved the desired anticoagulant effect, underdosed or overdosed)

  • Therapeutic range: 50-80 secs

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Describe the UH Pharmacokinetics

Unfractionated heparin must be given parenterally (IV, SC). This is because it has negative charge, so no GI absorption


It has rapid onset and offset of action (IV)

  • Short half-life (<60 min)
  • Reticulo-endothelial uptake
    • Cleared by reticulo-endothelial system, as compared to LMWH which is cleared renally
    • Therefore, one of UH's biggest advantage is that you can rapidly turn it on and off

It has variable bioavailability

  • Unpredictable binding to cells and plasma proteins
    • Platelets (heparin neutralizing protein); endothelial cells
    • Albumin

Therefore, it needs monitoring with APTT (activated partial thromboplastin time)

  • APTT in normal adult is 25-37s
  • Therapeutic range is 50-80s

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Describe how you would administer the UH (UH Infusion)

Loading dose is 60 units/kg (max 5000 units).

  • Give bolus dose IV over 5 minutes.


Maintenance infusion commences at 12 units/kg/hr IV (max 1000 units/hr)

  • Use heparin solution 100 units/mL (2500 units in 250mL saline)
  • Rate of infusion varies with bodyweight
  • Titrate heparin dose appropriately vs APTT
    • Monitor APTT 6 hours after starting the infusion and then adjust the infusion rate according to the table.
    • If already therapeutic, check next morning


Also the patient was 50kg, you'd give them 600 units per hour.  About 4 hours later, you'd check the patient's APTT. If the result was 50-80s, then you'd keep giving them the same dose. 

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What are some disadvantages of UH?

UH Disadvantages

It is 1) difficult, 2) complicated, 3) time consuming. 4) It requires multiple blood tests and 5) variable APTT control.


It has 6) multiple adverse effects

  • Bruising/bleeding sites (can be reversed), i.e. intracranial, injection sites, GI loss, epistaxis.
  • Thrombocytopenia (Heparin Induced Thrombocytopenia - HIT)
    • Check platelets every 2 days
    • Autoimmune phenomenon (usually 1-2 weeks of Rx); lab assay for these antibodies
    • May bleed or get serious thromboses
    • Stop heparin
  • Osteoporosis (long term use)


If someone on UF Heparin Therapy starts bleeding, what should you do?

Reversal of UH Therapy

  • Stop heparin
  • If actively bleeding, give protamine sulphate
    • Dissociates heparin from antithrombin III
    • Irreversibly bind to heparin
    • Little effect on LMWH
  • Monitor APTT


Describe the Mechanism of Action of Low Molecular Weight Heparin

LMWH has smaller chains (usually 4-5 kDaltons). Generated by chemical or enzymatic depolymerisation of UH.


  • LMWH have unique sequence to bind to antithrombin III
  • But Do not inactivate thrombin (IIa)
  • Affects factor Xa specifically


It has reliable dose-effect relationship (bioavailability much more predictable; weight-dependent dose; given subcutaneously)

No monitoring is required (can measure Xa activity, but mostly unnecessary)


What are some advantages of LMWH?

  • LMWH is better absorbed so higher bioavailability.
  • It does not bind to plasma proteins, macrophages or endothelial cells
    • Longer biological half-life
    • More predictable dose-response
    • No monitoring required
  • It is given subcutaneously (done in hospital or at home)
  • Lower risks of thrombocytopenia, bleeding, osteoporosis
  • Safety and use during pregnancy is not evaluated



What are some disadvantages of LMWH?

  1. LMWH cannot be monitored by APTT
  2. It is not fully reversed by protamine
  3. Use with caution in renal failure
  • Dose reduction if eGFR <30
  • LMWH is cleared renally, whereas UH is cleared by reticulo-endothelial system


What are the uses of UH vs LMWH?

Unfractionated Heparin

  • Initial DVT/PE Rx
  • Short term warfarin alternative


Low Molecular Weight Heparin

  • Non STEMI; STEMI (fibrinolysis)
  • Initial DVT/PE Rx diagnosis
  • Warfarin alternative
  • Most commonly used heparin


Describe the Administration of LMWH

It is usually subcutaneous (sc) administration (o.d./b.d.), usually use enoxaparin

  • Prophylaxis: 20-40mg od sc (for people at high risk of DVT/PE)
    • Don't need to memorise the doses. 
  • Treatment: 1mg/kg bd sc (DVT/PE)


Name the type of LMWH we usually use in NZ?



How do we usually treat Deep Vein Thrombosis and Pulmonary embolism?

  • Initially LMWH (~5 days)
  • Also give warfarin
  • Continue with LMWH until INR therapeutic


What is Wafarin (oral)?

Coumarin Derivatives

Warfarin (oral) is vitamin K antagonist.

Used in pro-thrombotic diseases


It is racemic mixture (S-warfarin much more effective than R-warfarin).

Other coumarin derivatives include nicoumalone and phenindione.


Describe the Mechanism of Action of Wafarin(oral)

Vitamin K is required by the liver when synthesizing clotting factors II, VII, IX and X (vitamin K dependent proteins)

  • Warfarin antagonises this process by inhibiting the oscillation between oxidized and reduced vitamin K.
  • Therefore, warfarin inhibit synthesis of coagulation factors.


Warfarin has slow onset of anticoagulation action

  • Because even if the liver is inhibited from synthesizing more factors, there are already some circulating
  • Time taken for anticoagulant effect is dependent on the half-life of the clotting factors (which is a few days)
  • That's why when someone presents with DVT or PE you don't give them warfarin first but instead LMWH because of its fast onset of action (maintain heparin infusion until you know the warfarin is taking full anticoagulant effect)


*Note that the anticoagulants don't dissolve the blood clot. It just prevents its propogation. (gives time for our own plasmins etc. to dissolve it) 

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Vitamin K is required by the liver when synthesizing clotting factors________

Vitamin K is required by the liver when synthesizing clotting factors II, VII, IX and X


If someone comes in presenting with DVT or PE, why do you not give them Wafarin straight away?

Warfarin has slow onset of anticoagulation action

  • Because even if the liver is inhibited from synthesizing more factors, there are already some circulating
  • Time taken for anticoagulant effect is dependent on the half-life of the clotting factors (which is a few days)
  • That's why when someone presents with DVT or PE you don't give them warfarin first but instead LMWH because of its fast onset of action (maintain heparin infusion until you know the warfarin is taking full anticoagulant effect)


What are the Uses of Wafarin?

Treatment of venous or arterial thromboses

  1. Deep vein thrombosis (DVT) and pulmonary embolism (PE)
  2. Mural thrombus (post anterior MI) (reduce risk of embolization)

Prevention of venous or arterial thromboembolism (don’t want to inject heparin every day, easier to take warfarin orally)

  1. Mechanical heart valves
  2. Atrial fibrillation (decreases risk of systemic emboli) (reduce lifetime risk)


Describe the Duration of Anticoagulation use. 

Anticoagulants mentioned so far don’t actually dissolve the blood clot, they prevent existing clots from extending and breaking off to form an embolus. It is the body's own plasmin and proteases that break down the clots over time.


Therefore, duration of anticoagulation depends on how long proteases and plasmin take to break down the clot


*See pic

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Describe the Metabolism of Wafarin

It is administered orally (R and S enantiomers) once daily (99% bound to plasma protein, high bioavailability, rapid absorption)

  • Pharmacological activity takes days (long effective half life)
  • Awaiting degradation of active factors (e.g. factor II half-life is 60 hours)


It is completely absorbed

  • (crosses placenta, therefore contraindicated in pregnancy)

It is metabolized by the liver

  • S enantiomer (cytochrome P450-2C9) and R enantiomer (cytochrome 1A2, 3A4) (t1/2 = R>S)
    • Subject to drug interactions because many other drugs are also metabolized by cytochrome P450 system
  • Glucuronidation/oxidation
  • Enterohepatic cycling


What are some adverse effects of Wafarin Therapy?

  • Haemorrhage
    • Intracranial or GI
      • Risk group include older age group, high target INR, cerebrovascular disease, previous GI ulcer/bleed, liver/renal disease, CCF, hypertension, malignancy
  • Teratogenic
    • First trimester include
      • bone and CNS problems,
      • osteodysplasia,
      • optic atrophy,
      • microcephaly
    • Last 4 weeks include
      • intracerebral haemorrhage





How do you monitor Wafarin?

IND = Patient's Prothrombin time/Mean normal PT time


Usually you're aiming for INR of 2-3

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What are some relative contraindications ot wafarin therapy (who shouldn't have it)

  • Situations where the risk of hemorrhage is greater than the potential clinical benefits of therapy
    • e.g. uncontrolled alcohol/drug abuse, unsupervised dementia/psychosis, falls, poor concordance/insight
  • Pregnancy


Why might individuals vary greatly in dose requirements for wafarin?

  • Absorption (affected by diarrhoea/vomiting)
  • Metabolism (affected by liver disease)
  • Nutrition/dietary (affected by vitamin K)
  • Co-existing illness (liver, malignancy, fever, thyroid)
  • Drugs



What are some drug interactions with wafarin?

  • Majority of drugs increase anticoagulant effect (increase INR), hence cytochrome P450 inhibitors (slower metabolism)
  • But some drugs decrease effect (decrease INR), hence cytochrome P450 inducers (faster metabolism)

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What are some general advice you'd give to patients on wafarin

  • Bruising and bleeding
  • Other medication (starting or stopping!)
  • Stopping before surgery (?heparin cover)
  • INR Monitoring (1-4 weeks)



If someone on wafarin starts bleeding, what would you do? (Management of increased INR)

It depends on severity of bleeding:

  • Vitamin K has long action on reducing warfarin effect but slow onset
    • Vitamin K (IV) 1-10mg
    • Vitamin K (oral)
  • Prothrombinex (IV) brings INR down in minutes
    • Prothrombin complex concentrate
    • Contains factor II, VII, IX, X
  • In less life threatening cases, withhold warfarin and recheck INR daily; or lower dosage.


Describe Factor Xa inhibitors

  • Rivaroxaban
    • Licenced VTE and AF
    • Once daily
  • Available in NZ from august
  • Selective
  • Direct inhibitors
  • Orally active/no monitoring


Describe Dabigatran mechanism of action

Wafarin alternative


Dabigatran Mechanism of Action

Dabigatran etexilate is prodrug. Dabigatran is a competitive, reversible inhibitor of thrombin.

  • It is marketed as a capsule with tartaric acid.
  • Gut, plasma, liver esterases cleave etexilate chain to activate drug

It is not cytochrome P450 dependent. It is P-glycoprotein substrate.

It has half-life of 12-14 hours after multiple dosing.

It has renal excretion. Since eGFR <30mL/h has increased half-life, do not use if eGFR <30mL/h!!!


Describe uses/indications of Dabigatran

Uses/Indications of Dabigatran

Dabigatran is used in:

  • Atrial fibrillation (150mg bd; (110mgbd))
  • Started to be used in VTE (prevention and treatment)

Do not use dabigatran for mechanical valves, have to use warfarin!