Drugs affecting coagulation

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Drugs affecting coagulation
Applied Clinical Sciences Lecture Programme
Dr Cathy Armstrong Anaesthetic SpR Clinical
Fellow in Undergraduate Medical Education May
2010
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Aims and objectives

• To understand the principles of haemostasis
  clotting
• To classify anticoagulants antiplatelets into
  groups
• Describe mechanisms of action
• Describe relevant pharmacokinetic aspects
• Discuss common clinical uses

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Why do we need to know about them?
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Haemostasis

• Vasoconstriction secondary to endothelial
  mediators
• Platelet activation aggregation
• Formation of fibrin mesh (enhanced by clotting
  factors)
• Opposing effects of fibrinolysis

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Main drug categories

• Drugs that inhibit the clotting cascade
• Drugs that inhibit platelet activity
• Drugs that augment fibrinolysis

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The coagulation cascade
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The intrinsic pathway

• Activated when blood comes into contact with
  subendothelial tissues
• Quantitatively most important of 2 pathways
• slower

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The Extrinsic pathway

• Rapid response to tissue injury
• Main function to augment intrinsic pathway
• Factor VII factor III (Tissue factor) unique to
  extrinsic pathway
• Factor VIIa/TF/Ca complex rapidly activates
  factor x

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The Final Common pathway

• Results in production of thrombin which converts
  fibrinogen to fibrin

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Tests of Coagulation

• Activated partial thromboplastin time (APTT)
• Normal range 25-45s
• Prothrombin time (PT)
• Normal range 11-15s
• International normalised ratio (INR)

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The APTT tests the

• Intrinsic final common pathway
• The extrinsic and final common pathway
• The final common pathway only

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The PT tests the

• Intrinsic final common pathway
• The extrinsic and final common pathway
• The final common pathway only

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Cell-based Theory of coagulation

• Focuses on the central role of specific cell
  surfaces in controlling and directing the
  haemostatic process
• 3 phases
• Initiation
• Amplification
• propagation

http//www.frca.co.uk/article.aspx?articleid10009
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Drugs that inhibit the clotting cascade

• Vitamin K Antagonists
• Warfarin
• Indirect thrombin inhibitors
• Heparin
• LMWH
• Factor Xa inhibitors
• Fondaparinux
• Danaparoid
• Direct thrombin inhibitors
• E.g Levirudin, Bivalirudin, Argatroban,
  Dabigatran

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Warfarin
Inactive precursor
Active Clotting Factor

• Vitamin K antagonist
• Inhibits Vit k reductase which catalyses the
  reduction of vit k
• Racemic mixture of 2 optically active isomers
• S more potent than R
• Inhibits synthesis of vit k dependent clotting
  factors II, VII, IX X protein C S

Reduced Vitamin K
Oxidised Vitamin K
Vitamin K oxide reductase
S-Warfarin
R-Warfarin
CYP1A2 CYP3A4
CYP2C9
WARFARIN
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Warfarin primarily affects the

• Intrinsic final common pathway
• Extrinsic final common pathway
• Final common pathway only

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Warfarin

• Uses
• Treatment of VTE
• Prevention of systemic embolism in patients with
  prosthetic heart valves AF
• Therapeutic effects take 48-72hrs to develop
• Highly water soluble
• High bioavailability rapid GI absorption
• Half life 36-48 hrs
• Circulates bound to plasma proteins
• Accumulates in liver
• Potent S enantiomer metabolised by CYP2C9

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Warfarin challenges

• Narrow therapeutic window
• Exhibits variability in dose response among
  patients
• Subject to interactions with drugs diet
• Laboratory tests difficult to standardise

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Warfarin drug interactions
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Warfarin adverse effects

• Haemhorrhage
• Hypersensitivity
• Skin rashes
• Alopecia
• Pupura
• Congenital malformations / IUD

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Treatment of high INR no significant bleeding
(ACCP guidelines)

• INR lt5
• ? / omit dose regular INR monitoring
• INR gt5 lt 9
• Omit 1 2 doses regular INR monitoring
• OR
• Omit 1 dose administer Vit k 1-2mg PO

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Treatment of high INR- reduction for urgent
surgery

• No significant bleeding 24 hrs
• Omit warfarin Vitamin K 5mg PO
• Further 1-2mg Vit K if required
• Serious bleeding or emergency surgery
• Omit warfarin
• Vit K 10mg slow IV
• FFP or prothrombin complex concentrate
  (octaplex) or recombinant factor VIIa

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Prothrombin Complex Concentrate (PCC)

• Octaplex
• Combination of clotting factors II, VII, IX X
  protein C S
• Reverses warfarin
• Expensive, only given at advice of senior
  haematologist
• Contraindicated in patients with known HIT
• Caution in IHD
• Max dose 3,000IU (120ml) slow iv infusion
• INR recheck 20 min post administration
• Can cause hypersensitivity reactions
• Ideally given via separate, fresh, cannula

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Indirect thrombin inhibitors
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Heparin

• Anionic, highly sulphated mucopolysaccharide
• MW 3,000 ? 30,000 Da
• Enhances activity of endogenous antithrombin
• Arginine reactive centre on AT binds covalently
  to serine active centre of thrombin other
  coagulation factors irreversibly inhibits their
  procoagulant activity
• Heparin binds to AT via specific pentasaccharide
  sequence (present in ? molecules)

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Heparin

• Thrombin inhibition requires heparin to bind to
  AT via pentasaccharide sequence but also relies
  on non-specific charge related effects
  dependent on mw
• Factor Xa inhibition only requires heparin to
  bind via pentasaccharide sequence (explains
  effects of LMWH)
• Heparin AT complex inactivates Thrombin, factors
  Xa, IXa, XIa, XIIa
• Inhibition of thrombin by heparin prevents
  fibrin formation but also thrombin induced
  activation of platelets factors V, VIII XI
• Other effects
• Attenuates proliferation of vascular smooth
  muscle cells
• Inhibits osteoblast formation activates
  osteoclasts ? promotes bone loss

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Heparin

• Uses
• Anticoagulation during vascular cardiac surgery
• Anticoagulation priming for RRT and CPB circuits
• Bridging anticoagulation
• Not absorbed orally requires parenteral
  administration
• Binds to various plasma proteins accounts for
  variability of response
• Monitoring
• APTT ACT

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Heparin adverse effects

• Haemorrhage
• Hypotension (rapid iv administration)
• Osteoporosis
• Alopecia
• Hyperkalaemia (due to aldosterone inhibtion)
• Thrombocytopenia
• Non- immune
• Immune mediated (HIT)

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Reversal of Heparin

• Protamine
• Basic protein derived from fish sperm
• Positive charge
• Binds to heparin to form stable salt
• 1mg iv neutralises approx 100 IU of heparin
• Adverse reactions
• Hypotension (due to histamine release)
• Bradycardia
• Pulmonary hypertension
• Flushing
• Allergic reactions

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LMWH

• Derived from UFH by chemical / enzymatic
  depolymerisation
• Reduced activity against thrombin relative to
  factor Xa
• Mw approx 5,000 Da
• Longer plasma half life - due to ? binding to
  endothelial cells macrophages
• Lower incidence of HIT (less binding to
  platelets)
• Less bone loss

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LMWH

• More predictable anticoagulant response than UFH
• Elimination half life 3-6 hours
• Anti-Xa levels peak at 3-5 hrs after dosing
• Cleared by kidneys prolonged action in renal
  failure
• Monitoring
• Not regularly monitored
• Some advice that anti-Xa levels should be
  measured in obese patients, renal failure
  pregnancy
• No antidote
• Complications
• 3 fold lower incidence of HIT
• Less risk osteoporosis

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Fondaparinux

• Synthetic analogue of AT binding pentasaccharide
• Specific anti-Xa activity gt LMWH
• Longer half life than LMWH (17 vs 4 hrs)
• Predictable anticoag response linear
  pharmacokinetics in sc doses 2-8mg
• Lab monitoring not required (anti Xa levels can
  be used)
• Excreted unchanged in urine
• Contraindicated in renal failure
• Fixed dose
• Thromboprophylaxis 2.5mg
• Treatment dose (50-100kg) 7.5mg
• Complications
• Not known to cause HIT
• No effect on bone
• Contraindicated in pregnancy (due to lack of
  safety data)

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Direct Thrombin Inhibitors

• Have their own intrinsic activity bind to
  thrombin and blocks its enzymatic activity
• Hirudins
• Lepirudin
• licensed for thrombosis complicating HIT
• Bivalirudin
• Hirudin analogue
• Licensed as alternative to heparin in patients
  undergoing PCI (e.g previous HIT)
• Dabigatran (Pradaxa)
• Licensed for DVT prophylaxis following hip knee
  replacement surgery
• British Heart Foundation campaigning for drug to
  be used in place of warfarin
• Oral preparation
• No monitoring required
• Predictable anticoagulant effect little
  variation between individuals

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Antiplatelet therapy
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Platelet adhesion Activation
Damage to vascular endothelium collagen exposure
Platelet Adhesion (via GPIa GPIb)
Platelet Activation
Platelet Aggregation Platelets become more
spherical GPIIa/IIIb bind with fibrinogen (with
aid of vwf) to build bridge between platelets
Platelet release reaction (degranulation) Release
of 5-HT ? vasoconstriction Release of ADP Release
of arachidonic acid ? thromboxane A2
?
cycloxygenase 1
Release of ADP thromboxane A2 stimulate further
platelet activation, aggregation and release ?
formation of platelet plug
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What is the average lifespan of a platelet?

• 1 - 2 days
• 7 - 10 days
• 20 - 40 days
• 100 - 120 days

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Drugs affecting platelets

• Cyclooxygenase Inhibitors
• Inhibitors of ADP-mediated platelet activation
• Phosphodiesterase Inhibitors
• Glycoprotein IIb/IIIa Inhibitors

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Cyclooxygenase Inhibitors

• Aspirin
• Irreversibly blocks the activity of COX-1
• Platelet function impaired for 7 -10 days until
  new platelets are formed
• COX-1 is responsible for the production of
  thromboxane A2, a potent vasoconstrictor and
  stimulator of platelet aggregation
• Rapidly orally absorbed
• Aspirin has been found to reduce vascular death
  by 15 non-fatal vascular events by 30 in
  high risk patients

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Damage to vascular endothelium collagen exposure
Platelet Adhesion (via GPIa GPIb)
Platelet Activation
Platelet Aggregation Platelets become more
spherical GPIIa/IIIb bind with fibrinogen (with
aid of vwf) to build bridge between platelets
Platelet release reaction (degranulation) Release
of 5-HT ? vasoconstriction Release of ADP Release
of arachidonic acid ? thromboxane A2
?
cycloxygenase 1
Release of ADP thromboxane A2 stimulate further
platelet activation, aggregation and release ?
formation of platelet plug
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Inhibitors of ADP-mediated platelet activation

• Thienopyridines ticlopidine clopidogrel
• Reduce platelet aggregation by the selective
  irreversible inhibition of the P2Y12ADP receptor
  on the platelet surface
• Both pro-drugs requiring metabolism by liver
• Side effects
• Thrombocytopenia
• Aplastic anaemia severe neutropenia
  (ticlopidine only)
• Clopidogrel
• Rapid oral absorption
• Irreversible blockade for life of platelet

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Damage to vascular endothelium collagen exposure
Platelet Adhesion (via GPIa GPIb)
Platelet Activation
Platelet Aggregation Platelets become more
spherical GPIIa/IIIb bind with fibrinogen (with
aid of vwf) to build bridge between platelets
Platelet release reaction (degranulation) Release
of 5-HT ? vasoconstriction Release of ADP Release
of arachidonic acid ? thromboxane A2
?
cycloxygenase 1
Release of ADP thromboxane A2 stimulate further
platelet activation, aggregation and release ?
formation of platelet plug
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Phosphodiesterase Inhibitors

• Dipyridamole
• Predominantly inhibits platelet adhesion to
  damaged vessel walls
• Usually used in combination with aspirin in
  management of cerebrovascular disease
• Biliary excretion

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Glycoprotein IIb/IIIa Inhibitors

• Block the final common pathway of platelet
  activation
• Used in management of acute coronary syndrome and
  PCI
• Examples
• Abciximab
• Eptifibatide
• Tirofibran

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Damage to vascular endothelium collagen exposure
Platelet Adhesion (via GPIa GPIb)
Platelet Activation
Platelet Aggregation Platelets become more
spherical GPIIa/IIIb bind with fibrinogen (with
aid of vwf) to build bridge between platelets
Platelet release reaction (degranulation) Release
of 5-HT ? vasoconstriction Release of ADP Release
of arachidonic acid ? thromboxane A2
?
cycloxygenase 1
Release of ADP thromboxane A2 stimulate further
platelet activation, aggregation and release ?
formation of platelet plug
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Summary

• Discussed the principles of haemostasis
  clotting
• Briefly discussed tests of coagulation
• Categorised anticoagulants antiplatelets
• Described mechanisms of action
• Described relevant pharmacokinetic aspects
• Discuss common clinical uses

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