Transcript Anticoagulants in Children

The Use of Anticoagulants
in Paediatric Patients
Soheir Adam, MD, MSc, MRCPath
TED in Children
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Infrequent but causes morbidity &
mortality
Peak incidence < 1 yr & adolescence
Prospective Canadian study; DVT / PE in
5.3 /10,000 hospital admissions and
0.07 / 10,000 children < 18 yrs
Hemostasis in Childhood
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Vit K procoagulant proteins are reduced
at birth and increase in 6 months
Natural anticoagulants like AT, PC, PS
and heparin cofactor II are also reduced
Alpha 2 macroglobuin : thrombin
inhibitor is increased & remains high
Despite the above, a hypofibrinolytic
state is observed in neonates and
adolescents
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Increasing numbers of paediatric
patients are developing VTE
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VTE develops as complications to the
successful treatment of prematurity,
congenital heart disease and cancer
Risk Factors for Thrombosis in Children
Time-Limited Risk Factors
 Indwelling catheters
 Infection
 Post-infectious antiphospholipid antibodies
 Surgery
 Surgically correctable congenital heart disease
On-Going Risk Factors
Thrombophilia:
Genetic Thrombophilia
 Factor V Leiden, Prothrombin 20210 mutation
 Deficient/dysfunctional antithrombin, protein C, protein S
 Elevations in lipoprotein (a), homocysteine
 Other less common genetic disorders of coagulation regulation or
fibrinolysis
Acquired thrombophilia (genetic contributions are variable)
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Children comprise 25% of the population
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> 70% of drugs currently prescribed for paediatric
outpatients are for unlicensed and off-label use
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For inpatients: 67% of infants andchildren and
90% of newborns receive off-label prescriptions
in acute care setting
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In case of chemotherapy, <50% of drugs used in
the US include paediatric-specific information in
their labeling.
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Clinical trials are the corner stone
of evidence-based medicine
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Many obstacles have prevented the
condition of properly designed
prospective randomized studies in
the paediatric age group
Standard of care for treatment of VTE
in children consists of unfractionated
heparin for 7-10 days followed by oral
anticoagulation.
Risk Assessment for Persistence or Recurrence of
Venous Thrombosis in Children
Characteristic
Low risk
Standard risk
High risk
Patient
Trigger
FVIII < 150 U/dL
FVIII > 150 U/dL
resolved/removed
D-dimer < 500 ng/mL
D-dimer > 500 ng/mL
Transient underlying
< 3 Trait Thrombophilia*
> 3 Trait Thrombophilia*
medical condition
Thrombus
Persistent Antiphospholipid Antibody
Thrombus Resolved
Atrial
Vena Cava
within 6 weeks
Non-occlusive DVT
Occlusive DVT
* Thrombophilias include genetic and acquired prothrombotic traits that can be determined in blood.
Anticoagulants in Children
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In most countries all anticoagulants remain
unlicensed in children and used off-label
Frequently, the choice of anticoagulant is
dictated by practical ability to administer it
Vascular access used for drug delivery and
not for monitoring
Anticoagulants in Children
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Compliance issues : lack of understanding
in infants, emotional issues in adolescents,
dysfunctional families and inadequate
parenting.
The need for GA to perform diagnostic
studies impacts monitoring and
management of TED.
Contraindications to Specific Antithrombotic
Therapies in Infants and Children
Unfractionated
Heparin
Low Molecular Weight
Heparin
Systemic TPA
Thrombolysis by
Interventional
Radiology
Known allergy
Known allergy
Known allergy
Known allergy
History of HIT (T) s
History of HIT (T) s
Active bleeding
In cases where needed,
inability to place vena cava
Invasive procedure < 24
CNS
Limitations: size of involved
hours
Ischemia/Hemorrhage/Surgery
vessels and experience of
< 10 days (includes birth
interventionalists
asphyxia)
Surgery < 7 days
Invasive procedure < 3 days
Seizures < 48 hours
UFH Heparin in Pediatrics
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Bolus dose of 75-100 U/kg results in
therapeutic values in 90% of children,
maintenance doses are age-dependant
Infants have highest requirements
(28U/kg/hr), children> 1 yr need lower
doses (22U/kg/hr), and older children
need doses similar to adults
UFH Heparin in Pediatrics
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UFH clearance is faster in newborns
because of a larger volume of distribution
Heparin binding may be different
LMWH in Children
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Approximately 25% of children complete a course of
anticoagulation using LMWH.
The remainder transition to warfarin to complete the
prescribed anticoagulation course.
More patient to patient variability in doses in children than
in adults
Infants < 2-3 months have increased requirements per kg
Altered pharmacokinetics , decreased anticoagulant activity
due to decreased plasma concentration of AT
LMWH
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Many adult patients are treated as outpatients using LMWH.
Most venous thrombosis in children is treated in the hospital, at least initially
LMWH has the advantage of subcutaneous administration and reduced
requirement for monitoring ( venous access is often limited in infants )
Insufficient dosing data regarding LMWH
Small pharmacokinetic studies of enoxaparin and dalteparin in pediatric
patients demonstrate wide ranges of dose requirements with neonates
requiring the highest doses
The recommendations of Hirsch et al. call for a therapeutic anti- Xa activity
range of 0.6 to 1.2 U/mL in adults
Published pediatric series have typically achieved anti-Xa activity levels at or
below the lower end of this published therapeutic range.
Based upon a recent analysis of enoxaparin dose-response in children, more
specific age-related doses for enoxaparin can be recommended as shown on
Table
Dosing for Antithrombotic Therapy in Children
Unfractionated Heparin
Low Molecular Weight Heparin
Tissue Plasminogen* Activator
Continuous IV
Lovenox ®, enoxaparin
Continuous IV or Bolus*
Subcutaneous, q12h
Loading Dose
Newborn < 37 weeks: 50 U/kg
None
None
Newborn to < 1 month: 1.625 mg/kg
Infants to < 3 months:
New born > 37 weeks: 100 U/kg
Infant/Child > 1 month: 50 U/kg
Initial
Newborn < 37 weeks: 15 U/kg/hr
0.06 mg/kg/hr
Maintenance
(may require > 25 U/kg/hr to achieve
Dose
therapuetic anti-Xa level)
Newborn > 37 weeks: 28 U/kg/hr
Infants to 1 month to < 1 year: 1.5 mg/kg
(may need > 50 U/kg/hr to achieve
therapeutic anti-Xa level)
1 year to < 6 years: 1.375 mg/kg
3 months to < 21 years: 0.03
mg/kg/hr, max 2 mg/hr
Infant/Child/Adolescent: 20 U/kg/hr
6 years to < 21 years: 1.25 mg/kg
(may need > 30 U/kg/hr to achieve
therapeutic anti-Xa level)
Monitoring
Anti-Xa activity 0.3-0.7 U/ml
Anti-Xa activity 0.5 – 1.0 U/ml
Clot Lysis by imaging or decrease in
extent
Increase in D-dimer or FSP
Although children are notoriously reluctant to receive medications by
injection, enoxaparin has been successfully administered for up to six
months using the Insuflon® catheter (Insuflon, Maersk Medical,
Lynge, Denmark; distributed by Chronimed).
The Insuflon® is a soft plastic infusion device placed under the skin
via a small diameter metal cannula and covered with an adhesive
plastic dressing.
Doses of LMWH are administered through a small plastic hub. The
Insuflon® catheter is replaced weekly.
Local hematomas are common but can be reduced by applying
pressure following injection.
LMWH
 Because of the unique pharmacokinetics of enoxaparin,
this agent can be given IV
 Its plasma elimination is equal to the subcutaneous route.
 In a rare situation where subcutaneous administration
was contraindicated in a very small preterm infant with
an infected atrial thrombus, intravenous enoxaparin was
used successfully .
 LMWH must be with-held for twenty-four hours prior to
invasive procedures, especially lumbar puncture.
 Thus LMWH is not first-line therapy for certain pediatric
patients.
Heparin Induced Thrombocytopenia
 Heparin-induced thrombocytopenia is recognized
in approximately 1% of at-risk pediatric patients
 No clinical trials of therapy for HIT in children
have been reported; however,
 Therapy with alternative anticoagulants, including
argatroban and lepirudin, has been extrapolated
from adult recommendations.
Obstacles to Performing Trials
Recommendations in children extrapolated
from adult studies
 Previously thought that its unethical to
conduct research in children
 Children cannot report all drug toxicities
reliably
 The need for painful , repeated phlebotomies.
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Obstacles to Performing Trials
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Outcomes used in adult studies may not be
applicable
 Outcome scales used for different age groups,
may pass thru different developmental stages
during study.
 QOL added to outcome
 Parents filling outcome forms may not be
reliable
Obstacles:
Paediatric population is divided into 4 age groups.
1.Birth
to one month (Neonates)
2.One
month to 2 yrs (Infants)
3.Two
years to 12 yrs (Children)
4.12 yrs
to 18 yrs (Adolescents)
Obstacles
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No paediatric formulations of antithrombotic drugs
Accurate, reproducible age- adjusted dosing is
difficult
Cost issues leading to premature closing of several
paediatric clinical trials
Clinical trials
First international multicenter trials of
anticoagulation therapy in children
1. To determine the safety and efficacy of
LMWH compared to UFH/warfarin for the
treatment of deep venous thrombosis (DVT)
in children (secondary thromboprophylaxis),
the REVIVE Study
Clinical trials
2. To determine the safety and efficacy of LMWH
prophylaxis in children with central venous
lines (CVL) (primary thromboprophylaxis),
the PROTEKT Study (PROphylaxis of
ThromboEmbolism in Kids Trial)
REVIVE Trial
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Initiated in 1997 as a multicenter randomized controlled
trial to evaluate the safety and efficacy of 3 months of
LMWH “Revirparin” versus UFH followed by oral
anticoagulation.
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Terminated early due to slow accrual.
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Outcomes for enrolled patients by intention to treat
analysis.
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Recurrent VTE occurred by 3 months in 6% of reviparintreated patients and in 10% of patients who received UFH
followed OAC.
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By 6 months 6% and 13%
Thrombolytic Therapy
 Systemic thrombolytic therapy should be strongly considered in
children with high risk clots which present within two weeks of
symptomatic onset. Both TPA and UK have been used successfully
in children .
 Thrombolytic agents can be administered systemically or locally.
 Systemic thrombolysis avoids the requirement for interventional
radiologic procedures
 Requirement for anesthesia and the delay to therapy potentially
encumbered during the organization of local invasive
thrombolysis.
 Higher dose TPA (0.1 to 0.5 mg/kg/hr) in short courses of 6 to 48
hours are generally chosen for arterial clots and can also be used
for venous thrombi.
Thrombolytic Therapy
 Low dose (0.03 to 0.06 mg/kg/hr) longer duration systemic
infusions of TPA for 12 to 96 hours is effective for lysis of venous
thrombi
 TPA is primarily cleared during the first pass through the liver.
 Most TPA will bypass a completely obstructed venous segment.
 A longer infusion of TPA at a lower concentration theoretically
increases the probability of drug contact with the clot.
 Systemic infusions of both TPA and UK are highly effective in lysis
of most pediatric clots when administered within two weeks of
symptomatic clot onset, but partially effective beyond two weeks
 An initial infusion of TPA for twenty-four hours has improved its
success
 Interventional thrombectomy can be used in refractory cases.
Thrombolytic Therapy
 Objective monitoring is determined by objective imaging.
 Clots should be imaged prior to and at the conclusion of
thrombolytic therapy
 If complete clot lysis is determined on Doppler US, no marker of
biochemical thrombolytic effect is necessary.
 Using low dose TPA, repeat imaging at 24 hours, and may double
the hourly rate of TPA to 0.06 mg/kg/hr (0.12 mg/kg/hr for
neonates) if there is no evidence of improvement in blood flow.
 Coagulation screening tests including PT, aPTT, fibrinogen,
plasminogen and D-dimer or FDP, obtained at baseline and every
24 hours while on therapy
Thrombolytic Therapy
 If no clot lysis is determined at 24 hours, substantial elevation in
D-dimer or FDP and/or fall in fibrinogen and plasminogen
suggest a systemic fibrinolytic effect in which case higher doses of
TPA are unlikely to be more efficacious.
 If markers do not indicate systemic fibrinolysis, the dose can be
increased.
 Fresh frozen plasma at a dose of 10 mL/kg may be infused daily
 to replenish plasminogen for plasma concentrations less than
50%.
 Infusions of thrombolytic agents should be discontinued as soon
as clot lysis has been achieved as there is no potential for further
improvement and bleeding complications increase with
increasing dose and duration of thrombolytic therapy.
Thrombolytic Therapy
 More recently local delivery of TPA by pulse spray into clots
has been used in combination with mechanical clot
disruption and thrombectomy, based on encouraging results
in adults
 Increasingly, adolescents and larger children with high risk
 clots are being referred to interventional radiology for
endovascular thrombectomy using Angiojet system (Possis)
or the Amplantz Clot Buster system (EV3) and/or
localthrombolysis as primary therapy.
 Smaller children with high risk clots, particularly SVC
obstructions, can be treated with catheter-directed
thrombolysis by pediatric cardiologists or radiologists
skilled in interventional procedures.
Interventional Techniques
 Venous stents have been placed in pediatric patients to
prevent recurrent PE, similar to adults .
 Temporary Greenfield or Tulip filters placed most
commonly in children with large vena cava thrombi who
have unstable cardiopulmonary function from recent
massive PE, in order to prevent further showering the
lungs with emboli during interventional thrombectomy.
 Surgical thrombectomy currently is reserved for
children with life or limb-threatening thrombi that have
failed or are not amenable to interventional approach, e.g.
SVC occlusion resulting in a hemodynamically unstable
decrease in cardiac venous return.
Oral Anticoagulants
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No suspension / liquid form
No stability data or critical assessment of
tablets dissolved in water
Infant formula contains vit.K, makes them
resistant to vit K antagonists
May require up to 15mg/ day
Considerable risk of bleeding, if formula intake
is reduced transiently
Oral Anticoagulants
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Breast- fed infants are more sensitive to
vit K antagonists
Milk contains low concentrations of vit K
This can be compensated by
supplementing with 30- 60 ml / kg
formula each day
Adjuvant Therapies for Children with Limb DVT
 All children and adolescents are referred for fitted
compression stockings (Jobst) (compliance with use of
compression stockings has been exceedingly problematic
and fewer than 50% of adolescents exhibit consistent use).
Stasis ulcersdeveloping in adolescent patients with lower
extremity DVT have been very difficult to manage.
 Pre-existing obesity has been present in adolescents who
developed venous stasis ulcers, similar to reports in adults .
 Nutritional and exercise counseling are part of standard
care for children and adolescents with DVT.
 Oral anticoagulation with warfarin is routinely started
using a maintenance dose of 0.1 mg/kg.
 The INR is first measured after 3 to 5 days of therapy.
 Heparin is not discontinued until the INR is greater
than the target for two consecutive readings.
 Dose adjustments are made by small increments,
usually of 0.5 mg/dose.
Oral Anticoagulants
Frequency of INR determinations
 For an average child, the INR is determined twice weekly
until the target range is achieved, then weekly for two
readings, biweekly for two determinations, and then
monthly.
 The target INR is 2 to 3 for standard courses of
anticoagulation in children;.
 A higher INR target of 2.5 to 3.5 is maintained for children
on anticoagulation for valvular cardiac disease or for
antiphospholipid antibody syndrome.
 An unusual pediatric patient, such as a teenager with severe
protein C deficiency, may require a target INR of 3 to 4.
 A small number of patients, approximately 10%, are treated
with “mini dose” warfarin with a target INR of < 2,usually
1.5 to 2.0.
 This unproven dose-range is used for the occasional young
child with multiple trait thrombophilia who manifests a
persistently elevated D-dimer but no thrombosis in a steady
state, without evidence of infection or inflammation, or a
rare child with a high risk for bleeding on standard intensity
warfarin.
 Most children require 0.1 to 0.15 mg/kg/day of warfarin
therapy.
 Infants less than a year require higher doses of warfarin, up
to 0.5 mg/kg/day and an older child or teenager may require
as little as 0.05 mg/kg/day.
 Using this approach, a retrospective review of the data base
 indicates that the INR is in the target range 60% of the time,
low 25%, and high 15%.
 In the average children for whom target INR is 2 to 3,
extreme values, less than 1.5 or greater than 4.0 each are
found on approximately 3% of determinations.
Details of studies evaluation central venous line-related thrombosis
Study
n
Occurrence of TE
Number of
patients with
TE (%)
Patients with
symptomatic TE
Hematologic malignancies
ALL
Non-ALL
Other
malignancies
Predisposing factors
Male et al.
85
29 (34%)
3 / 29
29 / 85
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-
CVL insertion technique and site of
insertion
Knoffler et al.
77
11 (14%)
9 / 11
4 / 25
4 / 24
3 / 28
Prothrombotic defects, infection
Glacer et al.
24
12 (50.0%)
5 / 12
1/3
4/7
7 / 14
None evaluated
Rudd et al.
41
18 (44%)
0 / 18
UK / 27
UK / 10
UK / 6
No correlation between
thrombophilia or infection and
development of TE
Wermes et al.
137
10 (7.3%)
UK
6 / 73
2 / 23
2 / 41
Prothrombotic defects increase the
risk of TE in children with ALL but
not in children with other
malignancies
Total
364
80 (21.97%)
-
40 / 186
(21.50%)
10 / 54
(18.51%)
12 / 83
(14.45%)
-
n = total number of patients studied; ALL = acute lymphoblastic leukemia;
CVL = central venous line; TE = thromboembolism; UK = unknown
Likely clinical features and preferred diagnostic evaluation for TE according to anatomical site
Site
Preferred diagnostic method/s
Likely clinical signs and symptoms
MRI with/without contrast
MRA with/without contrast
MRI with/without contrast
MRV with/without contrast
Unexplained headahces, vomiting, visual
problems, or neurological deficits, seizure,
drowsiness or any unexplained change in
status
ECHO, linogram + venogram and/or
*Doppler USG depending upon the site of
CVL
Swelling, pain tenderness, erythema or
discoloration of affected limb, dilated
vessels, CVL malfunction, headache,
swelling of face
Upper venous system
Bilateral venogram, especially for
subclavian/brachial vessels
*Doppler USG sufficient for jugular area,
MRV if possible
Recommend ECHO to evaluate RA
Swelling, pain, tenderness, erythema or
discoloration of affected limb, dilated
vessels
Lower venous system
*Doppler USG
To evaluate all sites
Cardiac
Right atrial
ECHO
CVL malfunction, sepsis, congestive heart
failure
PE
Pulmonary vasculature
V/Q scan, spiral CT
Breathing problems like tachypnea,
dyspnoea, shortness of breath, chest pain,
hypoxia, cyanosis, syncope, “unexplained
pneumonia”
CNS
Arterial ischemic stroke
Sinovenous thrombosis
CVL-related
DVT
* = detection of echogenic material within the lumen of a vein on a gray scale and presence of partial or complete absence of flow by pulse wave or color Doppler
ultrasonography.
In the presence of TE at one site recommend evaluating other sites (especially if anatomically related e.g. jugular vessels in presence of SVT) for associate
asymptomatic TE, if possible.
CNS = central nervous system, MRI = Magnetic resonance imaging; MRV = magnetic resonance venogram; MRA = magnetic resonance arteriogram; PE =
pulmonary embolism; V/Q scan = ventilation/perfusion scan; CT = computerized tomogram; DVT = deep venous thrombosis; USG = ultrasonogram; CVL =
central venous line; ECHO = echocardiography; RA = right atrial.
Guidelines for use of anticoagulant agents and monitoring of anticoagulation
parameters around invasive procedures in children with cancer
Pre-procedure:
Stop warfarin 3-5 days prior to procedure. One center stopped 1 day prior but reversed with Vitamin K and Protamine for target INR <1.2.
Target INR: Target INR for lumbar puncture < 1.3 for most centers (up to 1.5 in some centers).
For LMWH: Stop 2 doses prior to procedure. One center ‘bridge’ anticoagulated with UFH in high risk patients until 4 h prior to procedure.
Target anti-Xa level. Most centeres didn’t measure pre-procedure, in those that did, a target of 0.3 was preferred; 0.1 for Neurosurgery.
Platelet counts:
For LP: 30-50 x 109/L
Surgery: 40-100 x 109/L
Neurosurgery: >100 x 109/L
Fibrinogen levels: Only 2 centers reported routinely monitoring fibrinogen levels, and required them to be normal (or corrected) to proceed
with the procedure.
Post-procedure:
UFH start 4-6 h post-procedure, unless patient had bleeding complications intra-operatively, or currently showing signs of bleeding.
LMWH start 12 h post-procedure, some centers wait 24 h to restart after neurosurgery
INR = international ratio; LMWH = low molecular weight heparin; UFH = unfractionated heparin; LP = lumbar puncture
Incidence of adverse outcomes (% per patient year)
Study
Warfarin
(Streif et al, Canada)
Acenocoumarol
(Bonduel et al, Argentina)
Minor bleeding
2.3
1.3
Major bleeding
0.5
0
Recurrent TEs
1.3
1.3
TEs: Thromboembolic events
Recommendations for oral anticoagulation therapy in children
Indication for oral anticoagulation
Target therapeutic range
Duration of therapy
Prosthetic mechanical heart valves
2.5-3.5
Lifelong
Recurrent thrombotic episodes
2.5-3.5
Lifelong
First thrombotic episode without
concurrent risk factors
2.0-3.0
6 mo
2.3-3.0 then
1.4-1.8
3 mo, then until
acquired risk
factor resolves
2.0-3.0
6 mo
First thrombotic episode with
concurrent risk factors
Pulmonary embolism
Reversal of oral anticoagulation therapy
No bleeding
Bleeding
Pre-surgery
No life threatening, no
potential morbidity
Life threatening and/or
potential mobidity
Vit K (sc-iv)
0.5-2 mg and
FFP 20 cc/Kg
Vit K (iv) 5 mg and FFP
20 cc/Kg or PCC 50 U/Kg
Vit K (sc-iv) 0.5-2 mg need to
continue in OA therapy
Vit K (sc-iv) 2-5 mg
discontinuation of OA therapy
Examples of Therapeutic Decision Making for 1st Episode
Venous Thrombosis in Infants, Children & Adolescents
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Non-occlusive DVT, no on-going trigger (e.g. catheter is removed) or prothrombotic
conditions  Anticoagulation  Thrombus resolved within 6 weeks
- Newborn: Anticoagulation for 10 days or until clot resolves
- Infant, child, adolescent: Anticoagulation for 6 weeks to 3 months
Thrombus not resolved within 6 weeks  Anticoagulation until clot resolves, 3 to 12 months*
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Occlusive DVT, or non-occlusive Central Thrombus, symptoms < 14 days  Anticoagulation or
Systemic Low-Dose TPA  Anticoagulation until clot resolves, 3 to 12 months*
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Occlusive Superior or Inferior Vena Cava or Lliac, or Hemodynamically Significant Cardiac
Clot, Symptoms present < 14 days  Systemic Thrombolysis  If not resolved in 48-96 hours
 Interventional Radiology for Catheter-directed Thrombectomy/Thrombolysis
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Occlusive Superior or Inferior Vena Cava or Lliofemoral or Cardiac, Symptoms present > 14
days  Intervention Radiology for Catheter-directed Thrombectomy/Thrombolysis
* Indefinite long-term anticoagulation for all persistent Lupus Anticoagulant or > 3 trait Thrombophilia
Properties of GPIIb-IIIa antagonists
Abciximab
Eptifibatide
Tirofiban
Trade name
ReoPro
Integrilin
Aggrastat
Structure
Chimeric antibody
Fab fragment
Cyclic heptapeptide
Nonpeptide tyrosine
derivative
Off rate
Slow
Fast
Fast
Return of 50% platelet
aggregation after cessation
of infusion
-2 days
-4 h
-4 h
Antagonists | Clopidogrel
Ticlopidine
ATP
P2X1
Ca2+
ADP
ADP
P2Y1
P2Y12
PGI2
IP
Gq
Gi
Gs
PLC
P13K
AC
Platelet aggregation