Anti-Coagulants

Question 1

Describe Virchows Triad and potential factors causing abnormalities

Answer 1

• Abnormality of blood constituents - hypercoagulability
  
  • Genetic - protein C & S deficiency, factor V Leiden
  • Acquired - smoking, malignancy, OCP, prosthetic heart valves
• Abnormality of vessel wall - endothelial damage
  
  • Atheroma - MI
  • Hypertension
  • Toxins - cigarette, homocysteine
• Abnormality of blood flow - stasis
  
  • Immobility - DVT
    
    • Cardiac abnormality - AF, mitral valve disease, post MI

Question 2

Recognize the sites at which anticlotting agents act

Answer 2

• Warfarin reduces factor II, VII, IV, X
• Heparin converted to heparin antithrombin complex and inhibits multiple clotting factors including factor Xa and IIa
  
  • Low molecular weight heparin inhibits factor Xa
• Antiplatelet drugs such as aspirin prevent platelet plug formation by affecting thromboxane A2 and GP IIb/IIIa

Question 3

Describe the mechanism of warfarin

Answer 3

• Warfarin inhibits production of vitamin K dependent clotting factors - factor II, VII, IX, X
• Vitamin K needed to carboxylate these clotting factors
  
  • Warfarin blocks recycling of vitamin K by acting as competitive inhibitors (coumarins)
• Clotting factors which have already been activated are unaffected and will decay

Question 4

Describe the main therapeutic uses of warfarin

Answer 4

• DVT, PE, AF
• Heart valve replacement
• Prophylaxis in heart attack, stroke

Question 5

Describe the route of administration and onset/offset of action of warfarin

Answer 5

• Good GI absorption - give orally
• Slow onset of action - need heparin to cover initially
• Slow offset - half life ~ 48 hours but variable - need to monitor INR to measure effect
  - Need to stop 3 days before surgery - give time for liver to synthesize new clotting factors

Question 6

Describe the distribution and metabolism of warfarin

Answer 6

• Heavily protein bound - drug interactions

- Hepatic metabolism - cytochrome P450 system, caution with liver disease

Question 7

Describe the significance of warfarin in pregnancy

Answer 7

• Crosses placenta - do not give in first trimester - teratogenic
• Do not give in third trimester - deformity in head of baby leading to brain haemorrhage

Question 8

Define INR

Answer 8

• INR is a standardised prothrombin time

- Measures the time it takes for coagulation to occur for patients taking oral anticoagulant medication

Question 9

Describe the general dosing regime of warfarin

Answer 9

• Loading dose of 10mg given and further doses given depending on INR
• DVT, PE, AF patients INR ratio kept between 2.0-3.0
• Conditions likely to have increased clotting have INR kept between 2.5-4.5

Question 10

Describe the important effects of DDI on warfarin

Answer 10

• Majority of DDIs increase anticoagulant effect of warfarin - will increase INR
  
  • Inhibit hepatic metabolism - drugs that affect CYP450, increasing concentration of warfarin and enhancing its anticoagulant effect
  • Inhibit platelet function
    
    • Aspirin - block both platelets and clotting cascade
  • Reduce vitamin K from gut bacteria
    - Cephalosporin antibiotics - block vitamin K enhances warfarin effect
• Some drugs inhibit anticoagulant effect of warfarin
  
  • Antiepileptics, rifampicin, St Johns Wort
    
    • Induce hepatic enzymes therefore increasing metabolism of warfarin - decrease INR

Question 11

Describe the main ADRs of warfarin

Answer 11

• An INR above 4.5 has a high risk of bleeding - withhold warfarin for 1-2 days and review
• Bleeding/bruising
  
  • Intracranial (rare but serious), epistaxis, injection sites, GI loss (anaemia)
• Teratogenic - crosses placenta

Question 12

With reference to INR< explain the steps in reversing warfarin action

Answer 12

• If INR > 4,5, withhold warfarin for 1-2 days and review
• If INR > 8.0, give vitamin K by slow IV injection to reverse warfarin action
  
  • Also give larger dose vitamin K if haemorrhage occurs
• Parenteral vitamin K takes 2-3 days to synthesize clotting factors and reverse warfarin effect
  
  • If vitamin K given, then patient cannot be anticoagulated for a month
• Give fresh frozen plasma (clotting factors given directly) if fast reversal needed
• When stopping or reversing warfarin, consider effects on bleeding and INR

Question 13

Describe the mechanism of heparin

Answer 13

• Both groups activate anti-thrombin III complex
• Xa inhibition by AT III needs only heparin to bind to AT III, thus both groups inhibit it
• To catalyse inhibition of IIa by AT III, heparin needs to simultaneously bind to IIa and AT III
  
  • Unfractionated heparin is large enough for this, thus it inhibits factor Xa and IIa
  • LMWH not large enough, thus only inhibits factor Xa

Question 14

Describe the route of administration of initiation of UFH and LMWH

Answer 14

• UFH given IV through bolus and then IV infusion as 5 half lives needed to reach steady state
• LMWH given subcutaneous once/twice a day

Question 15

Describe the dose-response, bioavailability and monitoring of UFH vs LMWH

Answer 15

• UFH non-linear dose-response while LMWH predictable response
• UFH bioavailability variable due to unpredictable binding to cells and proteins while LMWH predictable due to less binding to macrophages and endothelium
• UFH needs monitoring with APTT while LMWH does not need monitoring

Question 16

Describe the uses of heparin

Answer 16

• Prevention of thrombo-embolism
  
  • Peri-operative - low molecular weight heparin low dose
  • Immobility - chronic heart disease, frail, unwell patient
  • Used to cover for risk of thrombosis around times of operation in those normally on warfarin but who have stopped it for the surgery
    
    • Quick offset time allows its cessation if bleeding
• DVT/PE and AF
  
  • Administered prior to warfarin
  • LMWH often used unless fine control required (LMWH does not need monitoring thus heparin levels difficult to control)
• Acute coronary syndromes
  
  • Reduces recurrence/extension of coronary artery thrombosis
  • MI, unstable angina - LMWH given
• Pregnancy - can be used cautiously in pregnancy to replace warfarin

Question 17

Describe the main ADRs of heparin

Answer 17

• Bruising/bleeding sites - intracranial, injection sites, GI loss, epistaxis
• Thrombocytopenia - leads to depletion of platelets and thus bleeding or serious thromboses can form
• Osteoporosis - long term

Question 18

Describe how heparin can be reversed

Answer 18

• Protamine sulphate given to neutralize negative charge on heparin
• Dissociates heparin from anti-thrombin III
• Irreversible binding to heparin
• Overdose causes increased bleeding - APTT needs to be monitored

Question 19

Other than heparin and warfarin, state the action of newer ACAs

Answer 19

• Selective factor Xa inhibitors

- Direct thrombin inhibitors

Question 20

List 4 antiplatelet drugs

Answer 20

• Aspirin
• Glycoprotein IIb/IIIa inihibitors
• Dipyridamole
• Clopidogrel

Question 21

Describe the mechanism of aspirin

Answer 21

• Aspirin - COX-1 inhibition prevents conversion of arachidonic acid to thromboxane A2
• Need to generate new platelets if coagulation needed as aspirin irreversible

Question 22

Describe the mechanism and uses of glycoprotein IIb/IIIa inhibitors

Answer 22

• Decreases platelet crosslinking by fibrinogen and causes platelet aggregates to break apart
• Used in high risk acute coronary syndrome and post PCI
  
  • Increases bleeding complications but decreases acute thrombosis and re-stenosis
• Lasts long time in body

Question 23

Describe the mechanism and uses of dipyridamole

Answer 23

• Phosphodiesterase inhibitors
• Prevent the inactivation of cAMP and thus reduces platelet aggregation
• Prostaglandin further increases cAMP
• Positive inotrope and vasodilatory (flushes and headaches)
• Secondary prevention of stroke

Question 24

Describe the mechanism and uses of clopidogrel

Answer 24

• ADP antagonists
• By blocking ADP receptor, leads to a build up of cAMP which reduces platelet aggregation
• Used with aspirin in acute coronary syndrome and PCI

Question 25

Give examples of thrombolytic drugs

Answer 25

• Clot busters used in MI, stroke and PE
• Tissue plasminogen activators - alteplase, retaplase
• Streptokinase - less preferred compared to tissue plasminogen activators as more side effects