Anticoagulants and Antiplatelets

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Anticoagulants and Antiplatelets

• Presenter Dr. Ashish Chakravarty
• MD student
• Moderator Dr. Kavita Sharma
• Professor
• Dept. of Anesthesiology and Intensive Care,
• MAMC, New Delhi

www.anaesthesia.co.in anaesthesia.co.in_at_gmail.co
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What ull be served for lunch today!!

• Appetizers
• Basic pathophysiology of hemostasis
• Basic pharmacology of antithrombotics,anticoagulan
  ts, and thrombolytics
• Whole course
• An intensivists perspective regarding usage of
  these drugs
• An anesthesiologists perspective for an elective
  case
• Dessert
• An anesthesiologists perspective for an emegency
  case
• Some food for thought !!

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Terminologies

• Antithrombotics Drugs which interfere with
  platelet functions
• Anticoagulants Drugs used to reduce the
  coagulability of blood
• Thrombolytics (Fibrinolytics) Drugs used to
  lyse thrombin clot (mainly therapeutic)

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Functions of Platelet

• Plug formation by passive agglutination and
  active aggregation later reinforced by fibrin
• Exposure of PF3 which is clotting factor III
• Mechanical clot retraction involving platelet
  actin and myosin - strengthens clot
• Active biochemicals from a granules, dense
  granules and cytoplasm

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contd

• a granules
• vWF
• Dense granules
• ADP
• Ca2
• Serotonin
• Adrenaline
• Cytoplasm
• TxA2
• Fibrinogen
• TFPI (tissue factor pathway inhibitor)
• Receptors associated with platelets
• GP Ib links vWF
• GP IIb/IIIa links fibrinogen

• Granules
• Release their contents
• Expose their inner phospholipid surface
• which is PF3

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Antiplatelet activity in the body

• Invivo blockers of platelet aggregation
• PGI2 through cAMP pathway
• NO through cGMP pathway

Produced in vascular endothelium
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Antiplatelet pharmaceuticals

• NSAIDS inhibit cyclooxygenase and decrease TxA2
  synthesis (irreversibly with Aspirin)
• Ticlopidine and Clopidogrel ADP induced
  platelet aggregation platelet-fibrinogen
  interaction irreversibly blocked
• Cilostazol PDIII inhibitor increases
  cytoplasmic cAMP
• GP IIb/IIIa blockers Abciximab,Eptifibatide,
  Tirofiban
• Dextran interferes with platelet aggregation

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Antiplatelet phamaceuticalscontd

• Dipyridamole
• Increases PGI2 release from the endothelium
• Inhibits platelet phosphodiesterase - builds
  up platelet cAMP and decreases cytoplasmic Ca2
• Inhibits RBC uptake of adenosine which is an
  inhibitor of platelet reactivity
• Inhibits the formation of TxA2 by blocking Tx
  synthetase

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The Coagulation Cascade

• XII Intrinsic TF Extrinsic
  
• HMWH
• PK XI VIIa VII
• XIIa Ca2 IX
• HMWK Ca2
• XIa VIIa/TF
• IXa
• Ca2 Ca2
  PF3
• VIII VIIIa
• X Xa
• Ca2
• PF3
• V
  Va
• IIa II
• Fibrinogen Fibrin monomer

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Coagulation Cascadecontd..

• Three steps
• Initiation Phase
• Starts with VIIa/TF
• Ends with formation of IIa
• Amplification Phase
• Activation of V, VIII, XIII, XI and Fibrinogen by
  IIa, if the IIa is not neutralised by ATIII or
  Thrombomodulin
• Propagation Phase
• Refers to the phase during which activated
  factors Va, VIIIa, and IXa attach to the
  platelets and the platelets release PF3

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Coagulation Cascadecontd..

• All clotting factors are serine proteases except
  V and VIII which are coenzymes, and labile
  factors
• The serine proteases ( but not co-enzymes) are
  activated by Ca2
• TF and PF3 activate the clotting factors by
  attaching to Ca2 which in turn attach to the
  clotting factors (serine proteases) by 2 ve
  charge on their carboxyl group.
• Vit K carboxylates factors II, VII, IX, X and
  Protein C S thereby providing the needed 2-ve
  charge for binding to Ca2

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In-vivo Antithrombotic Mechanisms

• Antithrombin III
• Inhibits IIa, IXa, Xa, XIa, XIIa, XIIIa and
  Plasmin by binding to their active site
• When heparin bind to AT III the active sites of
  the clotting factors are further compromised
• Acquired AT III deficiency DIC, OCP, sepsis,
  c/c heparin Rx
• Protein C S
• IIa Protein C Protein Ca Va
  VIIIa inactivation
• Protein S is a co-factor for activated Protein C
  (Protein Ca)
• Tissue factor pathway inhibitor (TFPI)
• Inhibits VIIa/TF complex and Xa
• Circulates in Plasma or contained in Platelets or
  on Endothelium
• Heparin may release it from the surface of
  endothelial cells
• Fibrinolysis

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The Fibrinolytic System

• Plasminogen
• tPA Urokinase (endothelium)
• PAI-1 PAI-2
• Thrombin
• (IIa)
• Plasmin
• (a2 antiplasmin) PI Cross-linked
  fibrin polymer
• Fibrinogen
• fibrin
• Polymer
• FDP D-Dimer

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Anticoagulant pharmaceuticals

• Standard Heparin (Unfractionated Heparin) (mol.wt
  5000- 30,000 Da av.15,000 Da)
• Derived from porcine intestinal mucosa or beef
  lung, prepared as Na or Ca2salts
• AT III inhibits IIa, IXa, Xa, XIa, XIIa, XIIIa
  and Plasmin by binding to their active site. When
  heparin binds to AT III the active sites of the
  clotting factors are further compromised
• Routes IV, SC, Intra nasal. Never IM or Oral
• Peak plasma levels after SC inj. 2-4 hrs.
• Strongly anionic, hence rapidly bound to
  proteins.t1/2 90 min

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Heparincontd

• Complications
• Hemorrhageesp. intracranial, intraspinal,
  intraocular
• Heparin resistanceseen in a/c thrombotic
  processes with consumption of AT III. Rx FFP !!
• Maternal osteoporosis on c/c use
• HIT Syndrome spectrum
• Thrombocytopenia without thrombosis
• Hypotension Transient reversible platelet
  aggregation
• Irreversible platelet aggregation White clot
  syndrome
• Heparin antibodies

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LMWH

• M.Wt 2000-8000 Da ( avg 4500 Da )- prepared from
  SH by fractionation, enzymatic degradation or
  chem modifn
• Commercial preprn Enoxaparin, Dalteparin,
  Ardeparin, Tinzaparin, Fondaparinux
• Routes SC (OD)
• High anti-Xa and low anti-IIa activity? greater
  antithrombotic and lower anticoag activity
• Low anti-IIa activity, hence, aPTT, TT, ACT not
  ideal for monitoring. Anti-Xa assay ideal
• Less complicated, dose independent clearance and
  more predictable anticoagulant response than SH.
  Hence lab monitoring not required
• Fondaparinux synthetic, specific inhibitor of
  Xa, used for Px in THR TKR. Long elimination t
  1/2 (20 hrs). Renal clearance

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Anticoagulation with SH LMWH

• Indication SH Target PTT LMWH
• venous thrombosis
• Rx 5000 U I.V bolus 2-2.5
  100 U/kg SC 1000 U/hr
  BD
• Px 5000 U SC BD-TDS lt 1.5
• AMI
• With TLT 5000 U I.V bolus
  1.5-2.5 100 U/kg SC 1000 U/hr
  BD
• With mural 8000 U SC TDS
  1.5-2
• thrombus Warfarin
• Unstable Angina 5000 U I.V bolus
  1.5-2.5 100 U/kg SC 1000 U/hr
  BD
• Prophylaxis
• General surgery 5000 U SC BD lt 1.5 100
  U/kg SC before and BD
• Ortho surgery 10000 U SC BD 1.5
• CHF/ MI 10000 U SC BD 1.5
  100 U/kg SC BD

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Targeting PTT

• Normal PTT (27- 35 s) 5000 U i.v bolus 1300 U
  / hr infusion. Monitor PTT
• Recheck PTT 35- 50 s rebolus 5000 U increase
  infusion by 100 U / hr
• Recheck PTT 50- 60 s increase infusion by 100
  U / hr
• Recheck PTT 60- 85 s NO CHANGE
• Recheck PTT 85- 100 s decrease infusion by 100
  U / hr
• Recheck PTT 100- 120 s stop infusion for 30
  min, and decrease infusion by 100 U / hr at
  restart
• Recheck PTT gt 120 s stop infusion for 1 hr,
  and decrease infusion by 200 U / hr at restart

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Heparin-free CPB

• WHY?
• Hemorrhage, HIT syndrome, Heparin allergy
• HOW?
• Heparin of different biological source
• Chlorocresol-free heparin
• Methylprednisolone Px, H1blockers
• Heparin with iloprost (PGI2analog)
• Ancrod protease removes fibrinopeptide A from
  fibrinogen prevents fibrin cross-linkage.
  Monitor with fibrinogen levels. Reverse with
  cryoppt.
• Danaparoid LMW heparinoid anti XaIIa ratio
  221. Minimal effect on platelets. Monitor anti
  Xa assay. Renal excretion. Difficult to eliminate
  as t ½ gt 24hr. Reverse with plasmapheresis
• Recombinant hirudin highly specific for
  thrombin. Monitor aPTT. Renal excretion. t ½
  30-60 min. no antagonists
• Argatroban synthetic direct thrombin inhibitor.
  Not available yet

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Anticoagulation with SH LMWH contd

• Other uses
• To prevent catheter thrombosis 2-5 U/ml
• If sample collected from indwelling catheter,
  blood to be discarded prior to collection of the
  sample 3 times the volume of catheter.
• For ABG 1000 U/ml. Dont exceed 1/10th the
  volume of blood, since heparin is itself acidic.
  may alter results
• Temporary vascular occlusion 100 U/kg
• For CPB ECMO 300 U/kg. Monitor ACT. Reverse
  with Protamine 1mg / 100 U Heparin

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Coumarin derivatives

• Dicumarol and Warfarin
• Indirect anticoagulants- interfere with hepatic
  synthesis of Vit K- dependent clotting factors
• Used for Px and Rx in thrombophlebitis, AF, PTE,
  AMI, mechanical prosthetic valves and valvular
  heart disease
• A typical regimen warfarin started at 5mg/day x
  7days, then maintenance dose 2.5 to 7.5 mg OD
  depending upon required INR
• Monitored using Prothrombin time INR

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INR

• INR (PTTest/ PTControl)ISI
• ISI (International Sensitivity Index) of the
  thromboplastin reagent used in a specific
  coagulometer is assigned by the manufacturer.
• INR should not vary by reagent or equipment
• Only 30 of the normal concentrations of clotting
  factors is adequate to maintain a normal INR
• Hypofibrinogenemia will influence INR when its
  concentration goes below 80 mg
• Therapeutic range of INR varies with different
  clinical condition. Thus hemorrhage may occur
  even within the therapeutic range.

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INRcontd..

• INR target ranges for oral anticoagulation
• Condition INR Duration Venous
  thrombosis
• Rx 2-3 3-6 month Px 1.5 c/c
• AF 1.5-2 c/c
• MI 2-3 2-3 month Heart valves
• Tissue valves 2-2.5 c/c
• Mechanical 3-4 c/c
• CMP 2-3 C/C

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Factors affecting coumarin potency

• INCREASE PT
• Reduced clearance
• Disulfiram
• Metronidazole
• cotrimoxazole
• Reduced albumin binding
• Phenylbutazone
• Additive hemostatic effect
• Aspirin, Heparin
• Liver disease,
• Vit. K deficiency
• Incresed turnover of Vit.K
• Clofibrate,
• Hypermetabolic state

• DECREASE PT
• Accelerated clearance
• Barbiturates
• Rifampin
• Reduced absorption
• Cholestyramin
• Coumarin resistance

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Fibrinolytics

• Plasminogen activators
• Preparations
• Anistreplase (t ½ 100 minutes)
• Streptokinase (t ½ 83 minutes)
• Urokinase (t ½ 20 minutes)
• Reteplase (t ½ 15 minutes)
• Alteplase (t ½ 3 minutes)
• Streptokinase
• bacterial enzyme
• indirect activator of plasminogen SK first forms
  a complex with Plasminogen. It is this complex
  which activates subsequent plasminogen.
• Dose in AMI 1.5 million units I.V over 1 hour
• Urokinase
• product of renal tubular cell
• direct activator of plasminogen.

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Fibrinolyticscontd..

• Major problem hemorrhage
• Causes
• NOT related to residual activity
• Defective fibrin polymerisation due to FDPs can
  be a problem upto 24 hrs despite t1/2 of 3 hrs
• Platelet aggregation inhibition by FDPs
• Decreased concentration of factors I,V VIII
• Rx of hemorrhage due to fibrinolytics
• Discontinue administration
• Antagonise residual effect Aprotinin or EACA
• After residual effect wanes FFP / Cryoppt

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Fibrinolyticscontd..

• Some basic facts to be remembered
• Heparin should be added in the post-thrombolytic
  pd. till hospitalised followed by warfarin
  therapy till 3 months, as Plasminogen is most
  effective if it lies within the fibrin matrix
  during clot formation. Clots formed during the
  period of thrombolysis are resistant to
  subsequent thrombolysis.
• Reperfusion arrhythmia so must repeat an ECG
  post-thrombolysis
• Avoid coughing, straining, HTN post-thrombolysis
• No IM inj.
• Sampling through indwelling catheters
• Lower limb BP cuffs risk of embolisation of
  dissolving clots
• Local infusions of thrombolytics may have major
  systemic effects Do Not Underestimate !

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Fibrinolyticscontd..

• Contraindications
• Absolute
• Cerebrovascular hmg at any time
• Non hmgic stroke or other CVA within past year
• SBP gt180mmHg DBP gt110 mmHg
• Suspicion of Aortic dissection
• Active internal bleeding (excluding menses)
• Relative
• INR 2 on current anticoagulant
• Recent (lt 2 wk.) history of surgery or invasive
  procedure
• Prolonged ( gt 10 min )CPCR
• Known bleeding diathesis
• Pregnancy
• Hmgic ophthalmic condition (eg. hmgic diabetic
  retinopathy)
• Active peptic ulcer
• history of severe HTN, now adequately controlled
• history of having received SK within 5 days to 2
  years

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Neuraxial block along with anticoagulants
Recommendations

• Antiplateles
• NSAIDs alone and NAB are compatible
• The effect of ticlopidin and clopidogrel should
  be allowed to dissipate (7 days) before NAB
• GPIIb/IIIa inhibitors NAB 8 hrs after tirofiban
  and eptifibatide, and 48 hrs after abciximab
• Concurrent use of SH, LMWH, or anticoagulants
  increase the risk of bleeding (holds true for all
  subsequent anticoagulants)
• Fibrinolytics
• NAB not recommended upto 10 days
• If NAB is undertaken, monitor neurologically
  atleast q2h
• Confirm adequate fibrinogen and low FDP levels
  before removing the catheters

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contd..

• Oral anticoagulants
• Stop anticoagulants and allow normalization of
  INR prior to performance of NAB
• Preop warfarin if initial dose gt24 hrs earlier
  or a second dose was given, check INR before NAB
• Warfarin _at_ 5mg/day for gt36 hrs and receiving
  epidural analgesia should have INR checked daily
  and before catheter removal
• If epidural catheter present, withold / reduce
  warfarin if INR gt 3
• Remove catheter if INR lt 1.5
• If INR gt 1.5 and catheter removed, monitor
  neurologically for at least 24 hrs.

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Contd..

• Standard heparin
• Minidose, SC
• No CI to performance of NAB
• Consider delaying initiation of heparin till
  after institution of the NAB
• After 4 days of SH confirm whether HIT has
  occurred
• I.V Heparin for intraop anticoagulation
• A gap of 4-6 hrs required between heparin and NAB
• Consider minimal concentrations of local
  anesthetics to permit early detection of
  neurological changes
• Delay initiating heparin till 1 hr after needle
  placement for NAB
• Remove epidural cath 1 hr before any subsequent
  i.v dose of heparin (assuming 12 hrly dosing ) or
  4 hr after the last dose of heparin
• Difficult needle placement / bloody tap not an
  indication for cancellation, but frequent postop
  monitoring of neurological status mandatory

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contd..

• LMWH
• A gap of 24 hrs required between Fondaparinux
  administration and NAB. For catheter removal same
  interval recommended
• A gap of 12 hrs required between LMWH and
  performance of NAB. In renal failure the interval
  should be longer (16-18 hrs)
• Remove epidural cath 24 hr after last dose of
  LMWH and do not administer subsequent dose for
  next 2 hr
• Difficult needle placement / bloody tap not an
  indication for cancellation, but important to
  delay subsequent dose of LMWH for 24 hrs
• Consider minimal concentrations of local
  anesthetics to permit early detection of
  neurological changes
• Consider single dose SAB
• Prompt recognition of epidural hematoma is
  confirmed by CT or MRI followed by emergency
  decompressive laminectomy within 8 hrs

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Anticoagulants and periop considerations

• Advantages of stopping an anticoagulant should
  outweigh the risks
• Postop bleeding due to warfarin administration is
  rarely fatal or associated with major morbidity
  whereas the consequences of venous or arterial
  embolism may be fatal
• Anticoagulation decreases the risk of VTE by 80,
  the risk of arterial TE in patients with
  mechanical heart valves by 75, and risk of ATE
  in patients with nonvalvular AF by 66
• Rebound hypercoagulation state may develop by
  discontinuing warfarin, super-added by the
  prothrombotic effect of surgery .
• Surgery increases risk of VTE but not ATE in
  patients with AF or mechanical heart valves

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Patients on warfarin periop

• In cases where change over to alternative
  anticoagulant not done before sx
• INR 2-3 4 scheduled doses of warfarin withheld
  to allow INR to fall to 1.5 before sx
• INR measured day before sx to see response
• If INR 1.8 at this time, inj. Vit. K SC (not
  IM)
• If INR 1.5 perform surgery
• After surgery
• Warfarin takes 3-4 days to reach INR to 2. So Rx
  started soon after surgery
• With the above regimen patients can have
  subtherapeutic levels for 2 days before and after
  surgery. Yet these levels can still provide
  partial protection against thromboembolism

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Patient on warfarin for VTE

• During first 30 days
• Elective surgery should be avoided
• If not possible, substitute with I.V Heparin
  before and after surgery while INR lt2
• If PTT within Rxic range, stop heparin 4-6 hrs
  prior to surgery
• Restart Heparin 4-6 hrs after surgery, but do not
  infuse _at_ greater than the maintenance rate for
  about 12 hrs. Should be delayed even longer if
  evidence of surgical bleed
• PTT rechecked 12 hrs after restarting heparin
• After 30 days
• Discontinue warfarin 4 days prior
• Need not start I.V Heparin preop
• I.V Heparin must be started postop and continued
  till warfarin takes effect and INR 2.0
• Mechanical Px should be combined

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Recommendations for periop anticoagulation in
patients on warfarin

• Indications Before sx After sx
• Acute VTE / ATE
• (first 30 days) I.V Heparin I.V Heparin
• VTE after 30 days no change I.V Heparin
• Recurrent VTE no change SC Heparin
• Mech. Heart valve no change SC Heparin
• Non-valvular AF no change SC Heparin

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Patients on other anticoagulants

• Clopidogrel should be stopped 7 days before
  surgery. Aspirin can be substituted safely
• GPIIb/IIIa inhibitors contraindicated upto 6 wks
  after major trauma or surgery
• Fondaparinux administered 6 hrs after surgery

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What if?

• Emergency surgery ?
• Aspirin- not much bleeding
• Clopidogrel- platelet concentrates.
• UFH poses not much problem- can be stopped 4 hrs
  prior. May be reversed with protamine. FFP may be
  administered
• LMWH needs to be stopped 12 hrs earlierwhat if
  accompanied by renal failure?
• Warfarin now u have a problem. Vit K starts to
  act within 8-12 hrswhat route will u give?
  Menadione sodium diphosphate i.v. Try FFP.

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What if?

• Dire emergency? (half-hour ot time)
• Platelet concentrates, protamine, FFP
• A lot of prayer !!

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THANKYOU
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