Antithrombotic therapy in children

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Antithrombotic therapy in children

• Dr.K.Mahesh

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Introduction

• Rising use of Anticoagulant / Antithrombotic
  drugs among pediatric patients
• Thromboembolic Disease The new Epidemic of
  Pediatric Tertiary Care Hospitals.
• Nowhere more evident than in pediatric
  cardiac/cardiac surgery patients.
• In the last decade vast improvements in
  surgical techniques,new drugs, new
  applications,critical and supportive care-
  resulted in improved survivals.
• TE Disease is one the most frequent complications
  in these survivors.

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• Majority of children on primary anticoagulant
  prophylaxis have underlying CHD/acquired heart
  disease
• Venous thromboembolic disease in children has a
  mortality of 7
• Morbidity in the form of post-phlebitic syndrome
  and recurrent venous thrombosis occurs in 20

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Arterial Thromboembolic Disease
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Points of discussion

• Antithrombotic / Anticoagulant therapy in context
  of Pediatric Cardiac morbidities.
• Biochemical basis of coagulation and factors that
  influence / modify it.
• Specific drugs that regulate coagulation
• Recommendations for anticoagulant therapy in
  specific clinical situations

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Indications for Anticoagulant / Antithrombotic
therapy in Pediatric Cardiology

• Native structural cardiovascular disease
• Vavular heart disease
• Cardiomyopathies
• Surgically altered cardiovascular architecture
• BT Shunt, Glenn, Fontan, Norwood
• Valve replacements
• Post-op / intensive care related issues
• Central line, sepsis
• Cardiac catheterization and interventions
• Prophylaxis
• Interventional procedures

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How are things different in children compared to
adults?
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Epidemiolgical differences

• High proportion of secondary thrombosis in
  children with major underlying HD
• Role of central venous access devices
• Biphasic age difference highest risk in
  neonates and Adolescents
• Age distribution of major illnesses that require
  CVA.
• Small physical size of blood vessels related to
  CVA in neonates
• Maturation of coagulation system in adolescents

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• Frequency and type of intercurrent illnesses
  makes administration and regulation of oral
  anticoagulant therapy difficult
• Vascular access impacts ability to deliver and
  monitor AC
• GA used in procedures more commonly in children,
  affecting ability to confirm and monitor
  thromboembolic disease and therefore therapeutic
  decisions

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The coagulation cascade
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Thrombogenesis

• Vasospasm
• Platelet adhesion
• Platelet aggregation
• Viscous metamorphosis
• Platelet plug
• Fibrin reinforcement
• Local production of thrombin
• Platelet ADP
• Thromboxane A2, Prostacyclin (PGI2).
• Serotonin
• White thrombus, Red thrombus

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Drugs that affect coagulation
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Indirect Thrombin Inhbitors
Heparin Fondaparinux
Vitamin K Antagonists Warfarin
Coumarinsl
Antithrombotics
Direct Thrombin inhibitors Hirudin,
Bivaluridin Argatroban, Melagatran
Ximelagatran
Antiplatelet agents
Aspirin Dipyridamole , Clopidogrel
Ticlopidine
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Indirect Thrombin Inhbitors Act
on ANTITHROMBIN
Vitamin K Antagonists Act via Vit K
dependent factors II, VII, IX, X
Direct Thrombin inhibitors Directly bind to
Thrombin
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Adults Vs Children / Infants
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Developmental Haemostasis

• Affects frequency, natural history, and response
  to agents
• Global functioning of the haemostatic system is
  different from adults
• Plasma values of many coagulation proteins are
  different
• Qualitative differences in many of the
  coagulation proteins, especially in neonates
• Significant differences in the antithrombotic
  properties of the vessel wall

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Developmental Haemostasis

• Antithrombin (AT) levels are physiologically low
  at birth (0.50 U/ml)
• Adult values are reached only after 3 months
• Sick preterms have levels less than 0.30 U/ml
• Fetal range 0.20-0.37 at 19-38 weeks
• Significance Profound effect on the action of
  Heparin
• Following infancy, thrombin generating capacity
  increases but remains 25 less than adult
  capacity throughout childhood
• In-vitro tests show both increased sensitivity
  and resistance to Unfractionated Heparin (UFH) in
  neonates

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Developmental Haemostasis

• Infants have physiologically low levels of Vit K
  dependent factors and contact factors which
  gradually rise to adult values nearing 6 months
• Levels of Protein C and Protein S are very low at
  birth
• Interaction of Protein C with Protein S in
  newborn plasma may be regulated by increased
  concentration of alpha-2 macroglobulin
• Plasma concentration of thrombomodulin is
  increased in early childhood, decreasing to adult
  values by teenage
• Free tissue factor pathway inhibitor (TFPI)
  concentrations are significantly lower in
  neonates

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Pharmacokinetic differences

• Distribution, binding and clearance of AC agents
  is age-dependent
• Larger volume of distribution, faster clearance
  of UFH, LMWH in newborns
• Altered heparin binding (unproved)
• Low levels AT
• Result Higher initial dose of Heparin needed to
  attain therapeutic levels
• Maintenance doses required are highest in infants
  lt 2 months
• Higher patient-patient variability
• Warfarin doses are also age dependent reasons
  not known

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Drug formulations

• No specific pediatric formulations available

Dietary differences

• Vit K concentrations in breast milk and infant
  formulae differ
• Breast fed babies are very sensitive to VKA
• Formula-fed babies need high doses, increasing
  the risk of bleeding in case of intercurrent
  illnesses etc

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• There are numerous studies defining appropriate
  strategies in adults with a range of TEs
• Anticoagulation strategies are controversial and
  unproven in children
• Attempt to formulate a consensus 7th ACCP
  Conference on Antithrombotic and Thrombolytic
  Therapy Evidence based Guidelines

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Specific DrugsHeparins
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Heparin

• A heterogenous mixture of glycosaminoglycans
  ranging from 3000 to 30000 daltons in MW
• Non-branching, negatively charged pentasachharide
  chain
• Pentasachharide sub-unit structure is
  instrumental in its ability to bind to
  Antithrombin

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Heparin Mechanism of Action

• Indirect thrombin inhibitor
• Catalysis the action of Antithrombin by over
  1000-fold.
• (AT inhibits Thrombin i.e IIa, IXa,and Xa)
• Active Heparin molecules bind tightly to AT,
  causing conformational changes, exposure of its
  active site for more rapid interaction with the
  activated clotting factors).
• Once AT-protease complex is formed, Heparin is
  released intact for binding to more AT.
• Prevents additional thrombus accretion
• Does not lyse a thrombus already formed

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• HMW fraction of Heparin inhibits all three
  thrombin (Factor IIa), IXa and Xa, esplly
  thrombin and Xa.
• LMWH inhibits activated factor X but has less
  effect on thrombin than HMW species.
• Commercial heparin consists of a family of
  molecules of different MW.
• Commercial heparin is extracted from porcine
  intestinal mucosa and bovine lung.
• Usually sodium or calcium salts. Lithium salt for
  in-vitro anticoagulation.
• UFH dosing in in USP units/mg

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Therapeutic range of UFH

• That reflects a heparin level by protamine
  titration of 0.2 0.4 U/ml or an Anti Factor Xa
  level of 0.35 0.7 U/ml
• aPTT therapeutic ranges are universally
  calculated using adult plasma and are
  extrapolated onto the pediatric population as
  well. Validity yet unknown.
• In pediatric patients, aPTT values correctly
  predict therapeutic concentrations approx 70 of
  the time

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Pharmacokinetics and Dose

• Volume of distribution is more and clearance
  rapid in neonates and young infants heparin
  binding may also be different.
• So higher dose required to achieve adult
  therapeutic range
• Bolus dose of 75 100 U/Kg results in
  therapeutic aPTT value in nearly 90.
• Maintenance is age-dependent
• Infants lt 2 mo 28U/kg/Hr
• Children gt 1 yr 20U/kg/Hr
• Older children 18U/kg/Hr

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Heparin Dosing Nomogram
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Adverse effects of Heparin

• Bleeding Andrew M et al reported 1.5 incidence
  in their prospective cohort study in children
  treated for DVT/pulmonary embolism
• Thrombocytopenia
• Non-immune HAT (HIT Type I)
• Immune mediated (HIT Type II)
• Osteoporosis and spontaneous fractures
• Allergic reactions
• Reversible alopecia
• Long-term usage mineralocorticoid deficiency

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Frequency of HIT
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Treatment of adverse affects

• Bleeding Cessation of heparin and IV Protamine
  if needed

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Treatment of thrombocytopenia

• Non-Immune HAT Promptly discontinue Heparin
• Suspected HIT
• Discontinue all Heparin
• Confirm diagnosis with alternate tests
• Alternative anticoagulants
• Monitor for thrombosis and platelet counts
• Avoid prophylactic platelet transfusion

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Treatment of HIT

• Stop Heparin
• Alternative anticoagulants
• Warfarin disadvantage- takes 4-5 days for full
  therapeutic effect associated with venous limb
  gangrene when used alone
• LMWH
• Recombinant Hirudin,
• Danaparoid sodium
• Ancrod (isolated from Malayan Viper)
• Prostacyclin analogues
• IVIG
• Plasmapharesis

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Low Molecular Weight Heparins(LMWH)

• Principally inhibit Factor X, less effect on
  Thrombin
• Enoxaparin same source as regular heparin, but
  doses specified in mg
• Dalteparin , Tinzaparin, Danaparoid (a mixture of
  heparan sulfate, dermatan sulfate and chondroitin
  sufate)doses specified in Anti Factor Xa units

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• Low Molecular Weight Heparins
• Have rapidly become AC of choice in many
  pediatric patients both for primary prophylaxis,
  and treatment of TE, despite unproven efficacy
• Advantages
• Need for minimal monitoring
• Lack of interference by other drugs or diet (as
  for VKAs)
• Reduced risk of HIT
• Reduced risk of Osteoprosis
• Disadvantages
• High in-vitro cross-reactivity with Heparin
  dependent antibodies
• Significant risk of recurrent or progressive
  thrombocytopenia and/or thrombosis
• Reduced predictability of anticoagulant effect
  compared to adults

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LMWH Therapeutic range and dosage

• Extrapolated from adult data, based on Anti
  Factor Xa levels 0.50 1.0 U/ml in a sample
  taken 4-6 hours following a subcutaneous inj
• Peak occurs 2-6 hours after s/c inj
• lt 2-3 months or lt5 Kg have higher requirement due
  to increased volume of distribution, lower levels
  of AT and or altered heparin pharmacokinetics

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L M W H D O S A G E
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Adverse effects of LMWH

• Dix D et al reported 10.8 major bleeding
  complication in infants in a prospective cohort
  study
• Same authors reported bleeding complication in
  4.8 patients with enoxaparin
• Massicotte P et al reported major bleeding
  complications in 8.1 patients in a randomized
  trial, with Reviparin
• No data on frequency of osteoporosis, HIT,
  hypersensitivity reactions in children
• TREATMENT Protamine Sulfate

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Contra-indications to Heparin

• Hypersensitivity
• Active bleeding
• Hemophillia
• Significant thrombocytopenia/purpura
• Severe hypertension
• ICH
• IE
• Active TB
• Ulcerations of GI tract
• Threatened abortion
• Visceral Ca
• Advanced hepatic or renal disease
• AVOID IN Recent neuro/ophthalmic surgery, or
  undergoing lumbar puncture / regional anaesthetic
  block, pregnancy

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Vitamin K Antagonists
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Vitamin K Antagonists Warfarin and coumarin
anticoagulants

• Discovery of an anticoagulant substance (
  bishydroxycoumarin ) formed in spoiled sweet
  clover silage which resulted in hemorrhagic
  disease in cattle.
• Warfarin is the most reliable member of this
  group, which also comprises Dicumarol,Phenprocoumo
  n,Phenindione, Diphenindione

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• Warfarin generally administered as a Sodium salt
• 100 bio-availability
• 99 bound to albumin, small volume of
  distribution
• Long plasma half life 36 hours
• Racemic mixture of levorotatory S-warfarin (4
  times more potent) and dextrorotatory R-warfarin

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MOA of Warfarin

• Blocks gamma carboxylation of several glutamate
  residues in Prothrombin and factors VII, IX, X
  and endogenous anticoagulant proteins C and S
  results in biologically inactive molecules
• Oxidative deactivation of Vit K. Prevents
  reductive metabolism of inactive Vit K epoxide
  back to its active hydroxyquinolone form

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• AC effect results from a balance between
  partially inhibited synthesis and unaltered
  degradation of the 4 Vit K dependent factors
• The effect therefore depends on their degradation
  rates in circulation. Therefore there is an 8-12
  hour delay in onset of anticoagulant action
• Larger initial doses of upto 0.75 mg/Kg can
  hasten the onset of action but there is no
  benefit beyond this dose

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VKA use in neonates and children

• Vit K dependent factors are physiologically low
  in newborns ( equivalent to an adult getting VKA
  with target INR of 2 3)
• Multiple issues
• Formula feeds are fortified with Vit K, so
  formula fed babies are resistant to VKAs
• Breast milk is deficient in Vit K, so breast fed
  babies are very sensitive to VKAs
• Only oral formulations are available
• Require frequent monitoring in newborns because
  of rapidly changing physiological values of
  Vitamin K-dependent proteins, changes in
  medications and dietary changes
• No data on their efficacy or safety in newborns

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VKA Therapeutic Range

• Current therapeutic INR ranges for children are
  directly extra-polated from adults there are no
  clinical trials for optimal INR range for
  children based on clinical outcomes
• Andrew M et al proposed initial dose of 0.2 mg/Kg
  with dose adjustments according to nomogram
• Streif W et al in the largest cohort study (319
  patients) found that infants required 0.33 mg/Kg
  and teenagers required 0.09 mg/kg warfarin to
  maintain a target INR of 2-3

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• Monitoring of Efficacy -- the INR or
  International Normalised Ratio.  This represents
  a standardised prothrombin time (PT) which is
  specific for the extrinsic pathway of coagulation
  (sensitive to factors I, II, V, VII, and X). 
• INR (PT pt / PT
  ref)ISI
• where PTpt patient prothrombin time, PTref
  specific laboratory reference PT, and ISI
  international sensitivity index. 
• This normalisation is approximately equal to a PT
  of 1.6 for most American laboratories. 
• Effective warfarin therapy should produce an INR
  that is 2.5-3.5 times the normal

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Monitoring and Adverse Effects

• Monitoring in children is difficult and requires
  close supervision and frequent dose adjustments
• In contrast to adults, only 10-20 can be
  monitored safely monthly
• Bleeding is the main adverse effect
• Monagle P et al reported serious bleeding in
  lt3,2 per patient year in children receiving VKA
  for mechanical prosthetic valve
• Streif W et al reported bleeding rate of 0.5 per
  patient year
• Massicotte P et al reported bleeding in 12.2 of
  patients in a randomized control trial (41
  patients, target INR 2-3, for 3 months)
• Non-hemorrhaegic complications tracheal
  calcification, hair loss, loss of bone density -
  rare

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Drug interactions of warfarin

• Drugs that increase PT/INR by pharmacokinetic
  mechanisms
• Amiodarone, Cimetidine, Disulfiram,
  Metronidazole, Fluconazole, Phenylbutazone,
  Sulfinpyrazone, Cotrimoxazole
• Drugs that increase PT by pharmacodynamic
  mechanisms
• Aspirin (high dose),third generation
  Cephalosporins, Heparin
• Body factors causing increase in PT
• Hepatic disease, hyperthyroidism

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Drug interactions of warfarin

• Drugs that cause fall in PT/INR by
  pharmacokinetic mechanisms
• Barbiturates, Rifamicin, Cholestyramine
• Drugs that cause fall in PT/INR by
  pharmacodynamic mechanisms
• Diuretics, Vit K
• Body factors resulting in fall in PT/INR
• Heriditary resistance, hypothyroidism

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Direct Thrombin Inhibitors
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• Relatively new class of drugs
• Directly binding to the active site of thrombin
• Hirudin
• Specific irreversible thrombin inhibitor from
  leech.Bivalent DTI, ie., binds at both the active
  site AND at the substrate recognition site of
  thrombin
• Recomb form Lepuridin Parenteral drug,
  monitored by aPTT, FDA approved for HIT, short
  halflife but accumulates in renal insufficiency,
  has no antidote.No effect on platelets.

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• Bivaluridin also bivalent DTI, I/V administered,
  rapid onset and offset of action, short
  halflife.Inhibits platelet activation,
  FDA-approved for use in PTCA.
• Argatroban I/V infusion, short half life,
  monitored by aPTT, FDA-approved for HIT. Requires
  dose adjustment in liver disease
• Melagatran and oral pro-drug Ximelagatran
  predictable pharmacokinetics and
  bio-availability, no need for routine monitoring,
  lack of drug interaction, rapid onset and offset
• No data in children on DTI

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Platelet function and Antiplatelet Drugs
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• Neonatal platelets have an intrinsic defect that
  makes them hyporeactive to thrombin,
  ADP/epinephrine, and thromboxane A2.But
  paradoxically, BT is short due to increased RBC
  size, high hematocrit and increased level of vW
  Factor
• BT is prolonged throughout childhood, compared to
  adults Andrew M et al, Sanders J et al

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Aspirin

• Most common agent
• Pediatric doses not based on studies of effect on
  platelets in pediatric patients
• Empirical dose 1 5 mg/kg/day
• Adverse effects
• Risk for bleeding in neonates exposed to maternal
  aspirin ingestion
• Significant bleeding rare except with underlying
  bleeding disorder, or anticoagulant/thromboltyic
  therapy
• TREATMENT platelet transfusion / plasma products
  with vW factor or des-amino-D-arginine

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Other anti-platelet drugs

• Dipyridamole 2-5mg/kg/d
• Ticlopidine and clopidogrel Thienopyridines.Selec
  tively inhibit ADP-induced platelet
  aggregation.Effect additive to that of Aspirin.
  No reported use in children
• (GP)IIb-IIIa antagonists abciximab,
  eptifabitide (Integrilin), tirofiban (Aggrastat)
  Powerful antiplatelet agents as they block the
  final common pathway of fibrinogen-mediated
  platelet aggregation by binding to platelet
  surface GPIIb-IIIa
• Williams RV et all reported the use of abciximab
  in addition to standard therapy in Kawasaki
  Disease, resulting in greater regression in
  coronary aneurysm at earlier follow-up

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Surgical therapy

• Venous interruption devices
• Sugical thrombectomy Rare
• Acute thrombosis of BT shunt
• Life threatening intra-cardiac thrombosis
  immediately after complex cardiac surgery
• prosthetic valve thrombosis
• Peripheral artery thrombosis following vascular
  access in neonates
• No specific guidelines

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THROMBOLYTIC DRUGS
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Streptokinase

• Synthesized from streptococcus
• Binds circulating plasminogen, catalysing its
  conversion to plasmin
• Non-specific, generalized action

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Urokinase

• Synthesized from urine
• Actually converts plasminogen to plasmin
• Non-specific, generalized action

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Tissue plasminogen Activator

• Preferentially activates fibrin-bound plasminogen

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Specific Indications for Antithrombotic Therapy
in Children
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1).Systemic Venous Thrombosis in neonates

• gt80 of venous TE in neonates are secondary to
  central venous lines
• Mechanism damage to vessel walls, disrupted
  blood flow, TPN, thrombogenic catheter material
• An international registry of symptomatic VTE in
  neonates reports an incidence of 2.4/1000
  admissions to NICUs

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• Acute problems loss of CVL patency, swelling,
  pain, discoloration, SVC syndrome, respiratory
  compromise, pulmonary embolism
• Chronic problems development of collateral
  circulations, requirement for local thrombolytic
  therapy, repeated requirement for CVL
  replacement,sepsis, chylothorax,
  chylopericardium, recurrent VTE requiring
  long-term AC therapy.
• Long term sequelae portal HTN, variceal bleeds,
  hypertension

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Systemic Venous Thrombosis in neonates -
Recommendations

1. UFH or LMWH, or radiographic monitoring and AC
   therapy if extension occurs
2. If AC (UFH/LMWH) is administered, subsequently
   give LMWH for 10d to 3 months
3. Adjust the dose of UFH to prolong the aPTT
   corresponding to an anti-FXa level of 0.35 - 0.7
   U/ml
4. Adjust the dose of LMWH to achieve an Anti FXa
   level of 0.5-1 U/ml
5. If thrombus extends following discontinuation of
   heparin therapy, administer VKAs or extend LMWH
   therapy

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• DO NOT use thrombolysis unless there is a major
  vessel occlusion causing critical compromise of
  organ or limb. In that case, supplement with FFP
  immediately prior to thrombolysis
• Remove the CVL / UVL in situ or give prophylactic
  LMWH therapy till its removed

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2).Systemic venous thromboembolic disease

• Estimated incidence of symptomatic VTE in
  children 5.3/10000 hospital admissions
• 95 secondary to serious conditions like CHD /
  cancer / trauma / surgery / SLE
• lt1 year, teenagers at max risk
• Most common risk factor CVL
• Asymptomatic, radiologically detected CVL-related
  VTE important because of association with
  CVL-related sepsis, and pul embolism
• 2 major trials Reviparin in Thromboembolism
  (REVIVE) and Prophylaxis of Thromboembolism in
  Kids Trial (PROTEKT) both closed early,
  underpowering them

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Systemic venous thromboembolic diseaseRecommendat
ions

• Based on adult data
• IV Heparin to prolong aPTT corresponding to Anti
  FXa level of 0.35-0.7 U/ml, or LMWH to achieve
  anti FXa level of 0.5-1 U/ml after 4 hours of inj
  (G 1C)
• Initial t/t with UFH/LMWH for 5-10 d.If
  subsequent VKAs to be used, then begin oral
  therapy as early as D1 and discontinue Heparin on
  D6 if INR in therapeutic range on 2 consecutive
  days.For massive PEs or extensive DVTs, longer
  period of UFH/LMWH therapy (G1C)
• Continue AC for idiopathic TE for at least 6
  months using VKA to achieve target INR of 2.5
  (2.0 3.0), or LMWH to maintain anti FXa level
  of 0.5 1.0 U/ml (G 2C)
• 6 mo rather than life long, placing relatively
  high value on avoidance of known bleeding
  complication, and less value on unknown risk of
  recurrence

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• 4.For secondary TEs, continue ACs for at least 3
  months using VKAs to achieve a target INR of 2.5
  (2 -3), or LMWH to maintain anti FXa level of
  0.5-1.0 U/ml
• 5.In presence of continuing risk factor, eg
  nephrotic syndrome, ongoing asparaginase therapy,
  AC therapy in either therapeutic or prophylactic
  doses to continue till risk factor resolved
• 6.Do not use thrombolysis routinely.If used,
  supplement with FFP
• 7.Recurrent idiopathic TEs need indefinite
  therapy with therapeutic/prophylactic doses of
  VKA (G1C). LMWH if VKA too difficult
• 8.Recurrent secondary TE, following intial 3
  months, AC therapy to continue for another 3
  months or till removal of precipitating factors
• 9.If no longer required, CVL be removed give 3-5
  days of AC therapy prior to removal.If CVL
  required and functioning, retain it and give AC
  therapy
• 10.First CVL-related DVT after initial 3 months
  of therapy, prophylactic dose of VKA ( INR 1.5-8)
  or LMWH (anti FXa 0.1-0.3) till CVL removed
• 11.Recurrent CVL related TEs after initial 3
  months of therapy, prophylactic VKA (INR 1.5-1.8)
  or LMWH (anti FXa 0.1-0.3) till removal of CVL.
  If there is recurrence during prophylactic
  therapy, continue therapeutic doses until CVL
  removed OR minimum of 3 months

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CVL ProphylaxisRecommendations

• 1.No routine primary prophylaxis
• 2.In long term TPN, continuous VKA therapy
  (target INR 2-2.5), or alternately, for the first
  three months after each CVL is inserted (G2C)

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Primary prophylaxis for neonatal BT
ShuntRecommendations

• Incidence of thrombotic complications in BT shunt
  1 17
• Intra-operative heparin followed by either
  Aspirin (5mg/Kg/day) or no further anticoagulant
  therapy

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Glenn Shunt

• Thrombotic complications are infrequently
  reported.
• 30 year follow-up GS Kopf et al, JACC 1990
  reported no long term thrombotic complications.
• 2 reported cases of RV thrombosis
• No evidence to support need for routine
  thromboprophylaxis

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Fontan Surgery

• TE is a major cause for early and late
  morbidity/mortality
• Venous TE 3-16
• Stroke 3-19
• May occur anytime, often present months or years
  later
• High mortality. Response to therapy in lt 50
  cases.

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Primary prophylaxis for Fontan Surgery in
childrenRecommendations

• 1.Aspirin (5mg/kg/day) or therapeutic heparin
  followed by VKAs with target INR of 2.5 (2-3)
  (G2C)
• Optimal duration unknown.Whether fenestrated
  fontans need more intensive therapy till
  fenestration closure, is unknown

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Primary prophylaxis for Stage 1
NorwoodRecommendations

• Heparin therapy immediately after the procedure

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Primary prophylaxis for endovascular
stentsRecommendations

• Heparin perioperatively

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Primary prophylaxis for DCMRecommendations

• VKA to achieve INR of 2.5 ( 2-3) (G2C)
• (awaiting transplant)

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Thromboprophylaxis for cardiac cath in neonates
and children

• For arterial punctures, IV Heparin (G1A)
• 100 150 U/Kg bolus dose. Further doses may be
  required in prolonged procedures (G2B)
• Do NOT give aspirin (G1B)

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Femoral artery thrombosis following cardiac
cathRecommendations

1. Therapeutic dose of IV Heparin (G1C)
2. Treatment for at least 5-7 days
3. In limb-threatening or organ-threatening
   thrombosis who fail to respond to initial heparin
   therapy,and who have no contraindications,
   thrombolytic therapy is recommended (G1C)
4. When thrombolysis is contraindicated or
   organ/limb death is imminent, Surgical
   intervention is recommended (G2C)

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Peripheral artery thrombosisRecommendations

1. Administration of low-dose heparin through the
   peripheral arterial catheters in-situ, preferably
   by cont infusion
2. For children with peripheral arterial
   catheter-related TE, immediate removal.
   Subsequent AC therapy with/without thrombolysis

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Kawasaki Disease in childrenRecommendations

• Aspirin in high dose (80 100mg/kg/d) during
  acute phase for upto 14 days, then 3-5 mg/kg/d
  for gt7weeks
• IVIG (2g/kg as a single dose) within 10 days of
  onset
• In GIANT CORONARY ANEURYSMS, Warfarin therapy is
  recommended ( target INR 2.5 range 2.0-3.0) in
  addition to low dose aspirin

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Spontaneous aortic thrombosis in
neonatesRecommendations

• In aortic thrombosis with e/o renal ischemia,
  urgent, aggressive thrombolytic or surgical
  therapy, supported by AC therapy with heparin /
  LMWH

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Antithrombotic therapy in Valvular Heart Diseases
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Valvular Heart Disease

• Native valves
• Prosthetic Valves
• Mechanical Valves
• Bioprosthetic Valves
• Endocarditis
• Infective
• Non-Bacterial Thrombotic

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Native cardiac valvular disease

• Rheumatic valvular disease
• Thromboembolic complications maximum with Mitral
  Valve disease
• Wood (1961) 9-14 prevalence in large early
  series with MS
• Ellis and Harkin 27 in 1500 mitral
  valvuloplasty patients
• Szekely et al 1.5 /patient year
• At least 1in 5 chance of clinically detectable
  emboli during course of MV Disease

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Risk factors of TE in MV Disease

• MS vs MR
• Wood 1.5 times more common in MS
• AF vs Sinus Rhythm
• Szekely 7 times higher risk in AF
• Hinton et al 41 in autopsy studies of MS/AF
• Coulshed et al 31.5 in MS/AF vs 8 in MS/NSR
• 22 in MR/AF
• Age
• LA thrombus / LA size
• Significant AR
• Chiang et al MV area, LA size
• H/o previous embolism 30-65 60-65 of these
  occur within 1 year

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Mitral Valve disease with AF/ Previous Systemic
emboli
Long term OAC Non Anticoagulated
Szekely et al 3.4 per pt yr 9.4 per pt yr
Fleming et al 0.8per pt yr 25per pt yr
Roy D et al 0.75.46 per pt yr 5.46per pt yr
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• Evidence strongly tilted in favour of offering
  anticoagulant therapy for all patients with
  Rheumatic Mitral Valve Disease and AF, or with
  h/o previous embolism
• Mitral Valve Disease with sinus rhythm also
  carries substantial risk
• Prior AF
• Antiarrhythmics
• Large LA

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RECOMMENDATIONS FOR MITRAL VALVE DISEASE
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MVD WITH AF / PREVIOUS SE

• Long term OAC therapy target INR 2.5 ( 2 3)
• Do not use concomitant therapy with OAC and
  antiplatelet agent
• Systemic embolism while on OAC with therapeutic
  INR
• Add Aspirin
• Add Dipyridamole or Clopidogrel- If unable to
  take aspirin

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MVD IN SINUS RHYTHM

• With LA diameter gt 55mm
• Long term OAC target INR 2.5 ( 2 3 )
• With LA diameter lt 55mm
• No anticoagulant therapy

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Mitral Valvuloplasty

• OAC with VKA for three weeks prior to and four
  weeks after the procedure target INR 2.5 ( 2 3
  )

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Mitral Valve Prolapse

• No systemic embolism / unexplained TIAs / AF no
  anticoagulant therpay
• Documented but unexplained TIAs long term
  Aspirin therapy
• Documented systemic embolism or recurrent TIAs
  despite Aspirin VKA with target INR of 2.5 ( 2
  3 )

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Native Aortic Valve Disease
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• Isolated Aortic valve disease causing
  thromboembolic complications is rare among all
  age groups, especially in children except if
  associated with MVD or AF
• Microthrombi, usually clinically undetected are
  known to occur

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Recommendation for AV disease

• Do not use long term VKAs unless for some other
  indication
• Use VKA if
• Aortic plaques gt 4mm
• Mobile aortic atheromas

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PROSTHETIC CARDIAC VALVES
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MECHANICAL VALVES

• All types of mechanical valves need anticoagulant
  therapy
• Permanent therapy with VKAs

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RECOMMENDATIONS FOR MECHANICAL VALVES
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• All patients to get permanent VKA therapy. UFH or
  LMWH until INR is stable and at therapeutic level
  for two consecutive days.
• St.Jude Medical Bileaflet valve in Aortic
  position, target INR 2.5 ( 2 3 )
• Tilting disc valves and bileaflet mechanical
  valves in Mitral position, target INR 3.0 ( 2.5
  3.5 ).
• CarbosMedics bileaflet valves or Medtronic Hall
  tilting disk valves in aortic position with
  normal LA size and SR, target INR 2.5 ( 2 3 )

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• Additional risk factors such as AF, LAE,
  endocardial damage, low EF, target INR 3.0 ( 2.5
  3.5 ), combined with low dose aspirin.
• Caged ball or caged disk valves, target INR 3.0 (
  2.5 3.5 ) with aspirin.
• Systemic embolism despite therapeutic INR, add
  aspirin maintain INR at target 3.0 ( 2.5 3.5
  ).
• If VKA must be discontinued, LMWH.

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RECOMMENDATIONS FOR BIOPROSTHETIC VALVES
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BIOPROSTHETIC VALVES

• First three months high propensity for TE.
• Higher incidence in Mitral position.
• Ionescu et al 5.9 in 1st 3 months after
  operation, without anti-coagulant therapy.
• Orszulak et al Strokes during 1st month after
  opreation _at_ 40 per patient year.

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RECOMMENDATIONS

• In the Mitral position VKA with a targt INR of
  2.5 ( 2 3 ) for the first 3 months.
• In Aortic position VKA with a target INR of 2.5
  ( 2 3 ) for the first 3 months OR aspirin.
• Heparin until INR is stable at therapeutic
  levels for 2 consecutive days.
• With h/o systemic embolism, VKA for 3-12 months.
• With evidence of LA thrombus at surgery, VKA with
  a target INR of 2.5 ( 2 3 ).

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Long term risks with Bioprosthetic valve

• Thromboembolism 0.2 3.3 per patient year.
• Aortic position, with sinus rhythm risk of
  stroke is 0.2 per year.
• Risk factors low EF, Large LA , permanent
  pacemaker.

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Long term antocoagulation in BP valves -
Recommendations

• Bioprosthetic valve in patients with AF
  long-term treatment with VKA with target INR of
  2.5 ( 2 3 ).
• In sinus rhythm Aspirin.

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Anticoagulation in presence of Endocarditis

• With mechanical prosthetic valve and endocarditis
  continue long-term VKAs.
• In NBTE and systemic or pulmonary emboli, full
  dose UFH I/V or S/C.
• Debilitating disease with aseptic vegetations
  full dose UFH.