RECENT ADVANCE COAGULATION PROPHYLAXIS

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RECENT ADVANCE COAGULATION PROPHYLAXIS

• Speaker Dr Tanuja Mallik
• Moderator Dr Chitra Chatterjee

www.anaesthesia.co.in anaesthesia.co.in_at_gmail.c
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• PHYSIOLOGY

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PRIMARY HAEMOSTASIS
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SECONDARY HAEMOSTASIS
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COAGULATION STEPS (NEW ASPECT)

• INITIATION
• In vivo coagulation initiated mainly by VIIa
  bound to TF
• which then activate both X , IX
• AMPLIFICATION
• To increase thrombin generation further ,
  thrombin activates V, VIII, XI , in a feedback
  loop

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COAGULATION STEPS (NEW ASPECT)

• PROPAGATON
• Continuation of thrombin generation results
  mainly from ongoing generation of Xa by IXa
  VIIIa
• STABILISATION
• Maximum thrombin generation occur only after
  formation of fibrin ,
• leading to formation of XIIIa ,
• which then crosslink , fibrin monomer

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FIBRINOLYTIC PATHWAY

• ACTIVATED ALONG WITH COAGULATION CASCADE
• ( to maintain fluidity of blood).
• FDP, D- dimer assay

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WHAT PREVENT COAGULATION IN NORMAL TISSUE ?????

• PGI2 /PROSTACYCLIN
• (vasodilator - platelet aggregation)
• NORMAL BLOOD FLOW
• ANTITHROMBIN III (- all factor except VII)
• PROTEIN C S (- factor V VIII)
• TISSUE FACTOR PATHWAY INHIBITOR/TFI
• (- factor VII)

• Virchow's triad
• (thrombogenesis)

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LABORATORY ASSESMENT

• Platelet count
• Platelet function analyser
• by MA of TEG ,
• Dade platelet function analyser
• Medtronic Hemostatus
• Array Medical Ichor Platework system ( both
  platelet count index of platelet function )
• Bleeding time
• Clotting time

• PT/ INR
• PTT
• TT
• FDP
• D- Dimer
• ACT
• TEG

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THROMBELASTOGRAPHY

• by Hartert in 1948
• TEG monitors hemostasis as a whole dynamic
  process.
• determine kinetics , growth as well as the
  strength and stability of the formed clot.
• Examine interaction platelet protein together
  with great no. of dynamic activator inhibitor

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strength of clot graphically represented over
time as characteristic cigar shape figure.

• R start of fibrin formation.
• k coagulation time (until trace amplitude 20mm)
• represent speed of clot growth.

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• ALPHA ANGLE represents the acceleration
  (kinetics) of fibrin build up and cross-linking.
• MA represent number and function of platelets
  and its interaction with fibrin.
• MA60 represents stability of the clot.

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MODIFICATION WITH TEG

• Heparinase to TEG
• useful during long pump runs
• deep hypothermia
• ventricular assist devices
• complicated major vascular cases i.e. repair of
  thoracoabdominal aneurysm.
• The test will also detect if more protamine is
  needed to fully reverse heparin.
• antifibrinolytic agents such as
  Epsilon-Aminocaproic Acid, Tranexamic acid and
  Aprotinin CAN BE ADDED
• This will test their effectiveness in treatment
  of fibrinolysis.
• Adding c7E3 Fab (REOPRO), a recently FDA approved
  monoclonal antibody which binds to the platelet
  GPIIb/IIIa receptors, to the TEG will eliminate
  platelet function from the TEG
• The MA will become a function of fibrinogen
  activity (MAR).
• MAP MAW- MAR

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PHARMACOLOGY
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ANTICOAGULANT CLASSIFICATION

• HEPARINOID
• HEPARAN SULPHATE
• DANAPAROID
• LEPIRUDIN
• ANCROD

• HEPARIN
• LMWH
• Dalteparin (Fragmin)
• Enoxaoparin (Clexane)
• Nadroparin (Fraxiparin)
• Tinzaparin (Lovenox)

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• ORAL ANTICOAGULAT
• COUMARIN DERIV
• (DICUMAROL/ WARFARRIN /ACENOCOUMANOL/ETHYL
  BISCOUMACETOL)
• INDANDIONE DERIVATIVE
• NEWER ANTICOAGULANT
• FONDAPARINUX
• DIRECT THROMBIN INHIBITORS (DTIS)
•   ARGATROBAN, LEPIRUDIN,
  BIVALIRUDIN,
• DABIGATRAN. MELAGATRAN ,
  XIMELAGATRAN

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ANTIPLATELET AGENT

• ACETYLSALICYLIC ACID (Aspirin)
• THIENOPYRIDINE( Clopidogrel /Prasugrel)
• GLYCOPROTEIN II b / III a INHIBITOR
• ( Abciximab / tirofiban /eptifibatide)
• STATINS

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ANTIFIBRINOLYTIC /for hemostasis

• Epsilon amino - caproic acid (EACA)
• Tranexamic acid
• Aprotinin
• Desmopressin

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HEPARIN

• sulfated glycosaminoglycan , present in mast
  cell
• forms catalytic template for antithrombin III
  thrombin
• MW 10000- 20000 Dalton
• half-life 90 minutes
• Doesnt cross BBB/ placenta
• Follow saturation kinetics with ivi
• iv / s/c
• Use Treatment of arterial and venous thrombosis
• To prevent clot propagation
• ( DVT/ PE /CABG / hemodialysis)
• Dosage Start 50- 100u/kg/hr , then 15- 25 U/kg/hr
  ivi
• Target PTT 1.5 2 times
• s/e hge / HIT / osteoporosis /
  hypersensitivity
• Overdose of UFH
  protamine sulfate (1 mg / 100 units heparin)

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LMWH

• MW 3000- 7000 dalton
• Longer duration action (s/c) , OD dose
• Better bioavailability (70-90) UFH 20- 30 )
• Factor Xa inhibitor
• Follow first order kinetics
• Assay factor X level
• Gold standard for surgical thromboprophylaxis
• several studies proved LMWH for 4-6 Wk after
  major orthopaedic surgery shown that rate of
  venographic thrombosis can be reduced by gt 50

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3 PROPHYLACTIC LMWH REGIMEN IN HIGH RISK GROUP

• EUROPE PROPHYLAXIS STARTED 12 HR
  BEFORE SURGERY
• NORTH AMERICA START 12-48 HR AFTER SURGERY
• THIRD REGIMEN START EITHER MORETHAN 12 HR
  BEFORE / 12 HR AFTER SURGERY

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WARFARIN

• Indications T/t arterial venous thrombosis
• Prevention thromboembolic disease
• ( thrombophilia, atrial fibrillation,
  mechanical heart valves, and high-risk
  surgery)
• Prevents vitamin K dependent  gamma-carboxylation
  of factors II, VII, IX, and X, proteins C S
• slowing thrombin production

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• Dosage 5-10 mg/day loading dose.Affected by
  many drugs and dietary variation .Requires 2-7
  days to reach therapeutic levels. For immediate
  anticoagulation, begin with heparin
• Target INR
• 2.5 VTE/PE/AF
• 3.5 Prosthetic heart valves
• Warfarrin teratogenic not to be given in first
  trimester pregnancy.But recent literature review
  suggest , lowest risk of valve thrombosis was the
  use of oral anticoagulant thrrough out pregnancy.
• This is assosciated with warfarrin embryopathy in
  6.4 of live birth , this was less than 9.2 risk
  of valve thrombosis using heparin only between 6
  12 wk gestation.

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HEPARINOID

• Heparin like natural substance
• Eg .Heparan sulphate .used - in pt with HIT/
  Hypersensitivity to heparin
• Danaparoid from pig gut mucosa , used in HIT
• Lepirudin from leech salivary gland ,in pt with
  HIT
• Ancrod - from pit viper venom

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ARGATROBAN

• Direct thrombin inhibitor( binds irreversibly to
  thrombin active site)
• 100mg/ ml inj
• For prophylaxis treatment of thrombosis in HIT

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• Dosage
• coadministered with warfarin
• Upto 2 mcg/kg/min , till INR 4-6 , repeat INR 4-
  6 hr after stopping argatroban.
• In thrombosis in HIT
• 2 mcg/kg/min ivi initial dose , (max 10
  mcg/kg/min ) , then adjust dose according to PTT
  of 1.5 3 times (not gt100 sec)
• s/e hypotension , cardiac arrest , arrhythmia,
  bleeding , headache , hypersensitivity etc.

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FONDAPARINUX (Arixtra)

• Synthetic, pentasaccaride
• Binds activate antithrombin
• inhibit only FXa (not thrombin)
• anti-Xa heparin assay
• overll incidence venous thromboembolism upto
  day 11 reduced from 13.7 (371 of 2703 pt) in
  enoxaparin to 6.8 in fondaparinux (182 of 2682
  pt) Ref BjA june 2004

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• Uses
• DVT prophylaxis following ortho surgery (Hip/
  Knee) or abdominal surgery
• 2.5 mg sc OD , 6-8 hr after surgery , for 5- 9
  days
• DVT PE T/T
• 5mg (lt50kg)
• 7.5mg (50 -100 kg)
• 10mg (gt100kg) , for atleast 5 days until INR
  With oral anticoagulant 2-3 (Oral anticoagulant
  started within 72 hr of starting Arixtra)

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BIVALIRUDIN

• synthetic analogue of hirudin
• Direct thrombin inhibitor (Reversible)
• Linear pharmacokinetics with i.v administration
• Assay ACT, PTT,PT,TT
• Indication Decreases acute ischaemic
  complication of MI / PCI
• Dose .75 mg/kg loading
• Then 1.75 mg/kg/hr ivi till 4 hr after PCI,
• Then .2 mg/kg/hr for 20hr
• 2 hr after withdrawl drug sheath can be removed.
• s/e bleeding, anaphylaxis , thrombocytopenia

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MELAGATRAN (Exanta) / (XIMELAGATRAN)

• Synthetic , direct thrombin inhibitor .
• Oral Ximelagatran , as replacement for warfarin
• Prodrug converted into active melagatran
• Rapid onset , lack of drug food interaction ,
• No antidote
• No requirement routine monitoring
• s/e - hepatotoxic
• T ½ 4hr, BD dose oral
• Studies concluded that both regimen
  subcutaneous melagatran followed by oral
  ximelagatran oral xemelagatran alone were safe
  , well tolerated as effective as other regimen
• Approved in several european country for short
  term ortho prophylaxis.Under regulatory review
  in USA

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ASPIRIN

• complete irreversible block of platelet cox-1
• (50 -150mg/d)
• Ability to aggregate restore in 4-5 days of
  stopping aspirin
• Primary prevention (when 10 yr risk of vascular
  event gt10)
• secondary prevention ( decreases recurrence MI
  30 stroke by 25 )
• Given life long after coronary or cerebrovascular
  event
• Up to 300mg / day alone not c/I for regional
  anesthesia

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CLOPIDOGREL

• Platelet ADP receptor antagonist
• loading 300mg then 75 mg OD
• Decreases risk
• MI in unstable angina 18
• coronary stent thrombosis ,stroke recurrence 30
  
• T1/2 4hr . Recovery from drug effect takes 7
  days (irreversible platelet inhibition )
• ABSOLUTE C/I TO REGIONAL / NEURA AXIAL BLOCK
• Resistance to antiplatelet might be cause of
  recurrence of thrombosis ( related to gene
  polymorphism )

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Gp IIb /IIIa antagonist

• For prevention of IMMEDIATE thrombosis of
  coronary stent
• Use for 24 48 hr PCI
• Effective platelet aggregability restored
• in 48 hr , residual receptor blockade
  observed up to 7 days

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STATINS

• decrease LDL
• anti inflammatory
• increase nitric oxide production, decrease
  vascular smooth muscle proliferation, decrease
• re stenosis after PCI
• RECENT META ANALYSIS of 15 publication
  (223010 pt ), mortality reduced from 3.1 to 1.9
  in cardiac surgery 6.1 to 1.7 in vascular
  surgery
• Pt on statin should continue drug peri
  operatively

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AMINOCAPROIC ACID

• lysine analogue,
• binds reversibly to plasminogen.
• Clinical use to treat excessive postoperative
  bleeding
• Prostate surgery with primary fibrinolysis (
  Not in secondary fibrinolysis as in DIC , risk of
  indiscriminate thrombus formation )
• Oral surgery in hemophiliac (factor VIII
  replacement EACA , prevent ongoing
  fibrinolysis)
• A meta-analysis found that lysine analogs like
  aminocaproic acid significantly reduced blood
  loss in patients undergoing coronary artery
  bypass grafting
• In liver transplant , in final stage of excision
  of failing liver during anhepatic period (
  not to be given after new hepatic graft is
  perfused , risk hepatic artery thrombosis

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TRANEXAMIC ACID(CYKLOKAPRON)

• competitively inhibits plasminogen to plasmin
• 8 times the antifibrinolytic than
• e-aminoacaproic acid.
• Loading dose 10 mg/kg
• Maintenance 1mg/kg/hr ivi
• Therapeutic uses
• Mennorhagia, Hemophilia
• coronary artery bypass surgery to
  prevent excessive blood loss.
• in liver transplant decreases blood
  transfusion
• in orthopedic surgery proven reducing pre and
  postoperative blood loss. Drain and number of
  transfusion is reduced. However the hidden blood
  loss is not reduced.. It is commonly used in
  joint replacement surgery.

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APROTININ (BOVINE PANCREATIC TRYPSIN INHIBITOR,
BPTI (TRASYLOL)

• inhibits serine proteases, specifically
  trypsin, chymotrypsin and plasmin and kallikrein.
• Its action on kallikrein leads to the inhibition
  of the formation of factor XIIa.
• Intrinsic pathway of coagulation and
  fibrinolysis are inhibited.
• Its action on plasmin, slows fibrinolysis
• to reduce bleeding during heart and liver
  surgery.
• as well as end-organ damage due to hypotension
  (low blood pressure) as a result of marked blood
  loss
• .

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• Side effects
• gastrointestinal tract intolerance,
• myalgia
• Thrombosis
• Two studies published in early 2008, both
  comparing aprotinin with aminocaproic acid, found
  that mortality was increased by 32 and 64 ,
  respectively. One study found an increased risk
  in need for dialysis and revascularisation.
• Trasylol entirely withdrawn in May 2008, except
  at least for the time being - for very restricted
  research use.

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DESMOPRESSIN

• Vasopressin analogue
• Pressor effect
• Antidiuretic
• Mobilise factor VIII , VWF , t-pA from
  endothelium
• Used in factor VIII VWF deficiency
• S/e decrease urine output, water intoxication,
  severe hyponatremia, grandmal seizure esp lt2yr
  age
• T/t with 0.3 mcg / kg may experience improvement
  of cardiopulmonary bypass platelet dysfunction
• Can be used as rescue therapy in pt with
  excessive post op bleeding

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REPLACEMENT THERAPIES

• FFP (200- 250 ml)
• to antagonise the effect of warfarrin
  immediately .
• antithrombin III deficiency
• But risk of infection
• Cryoprecipitate (20 25 ml)
• Contain thawed plasma protein at 4 deg
• 30- 60 factor VIII
• 25 fibrinogen
• Also contain XIII, vWF , fibronectin
• Platelet transfusion
• If high risk surgery site ( intracranial /
  intraspinal/ ocular)
• with major surgery lt 1 lakh count or
• minor surgery with lt 50,000 count

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• Antihaemophilic factor Concentrate
• In haemophiliac pt in t/t active bleeding or
  prior to major surgery
• Prothrombin Complex Concentrates (PCC)
• Contain factor Ix , used in christmas disease
• Recombinant activator factor VII a( Novoseven)
• As rescue therapy in
• pt with penetrating trauma ,
• poorly controlled intra abdominal bleeding ,
• prior massive transfusion ,
• ongoing uncontrolled coagulopathy
• Antithrombin III concentrates
• In congenital antithrombin III deficiency , with
  increased risk of thrombosis
• eg . Pregnancy, surgery , sepsis

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UPDATE IN PERIOPERATIVE COAGULATION
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INCIDENCE DVT without prophylaxis

• 14 Gynaecological surgery
• 22 Neurosurgery
• 26 Abdominal surgery
• 45 - 60 orthopaedic surgery
• Markedly higher with malignancy

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PERIOPERATIVE ANTIPLATELET THERAPY IN
PATIENT with PCI (BJA JULY 2007)

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• Recent data suggest , risk of coronary thrombosis
  after antiplatelet drug withdrawl much higher
  than that of surgical bleeding if they are
  continued.
• Clopidogrel is mandatory until coronary stent are
  fully endothelialised ,
• takes 3mth for bare metal stent
• 1 yr for drug eluting stent
• In late 2006 found increased rate of late
  thrombosis with DES
• Early re stenosis common with BMS

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BJA july 2007

• It is proposed that , a part from low coronary
  risk situation ,patient on antiplatelet drug
  should continue their treatment throughout
  surgery , except when bleeding might occur in a
  closed space
• A therapeutic bridge with short acting
  antiplatelet drug may be considered..

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• HIGH RISK STENT
• long(36mm) proximal stent ,
• multiple stent implant,
• overlapping stent,
• stent in chronic total occlusion ,
• small vessel ,
• bifurcated lesion.

• LOW RISK STENT -
• gt 3mth after
• BMS/
• stroke/
• uncomplicated MI /
• PCI without stenting

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DURATION OF ANTIPLATELET THERAPY AND RECOMMENDED
DELAY FOR NON CARDIAC SURGERY AFTER PCI

• DILATATION WITHOUT STENTING 2-4 WKS
• SURGERY POSTPONED FOR 2-4 WKS (VITAL SURGERY
  ONLY)
• PCI AND BMS 4-6 WKS
• VITAL SURGERY POSTPONED FOR gt6WKS
• ELECTIVE SURGERY POSTED FOR gt 3MTH
• PCI DES 12MTH
• ELECTIVE SURGERY POSTPONED FOR gt 12MTH
• ASPIRIN LIFELONG THERAPY , WHICHEVER IS THE
  REVASCULARISATION TECHNIQUE

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ALGORITHM FOR PREOPRATIVE MANAGEMNT OF PT ON
ANTIPLATELET DRUG
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• THANKS
• GOOD DAY

www.anaesthesia.co.in anaesthesia.co.in_at_gmail.c
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