The Use of Anticoagulants in Paediatric Patients

1
The Use of Anticoagulants in Paediatric Patients
Soheir Adam, MD, MSc, MRCPath
2
TED in Children

• Infrequent but causes morbidity mortality
• Peak incidence lt 1 yr adolescence
• Prospective Canadian study DVT / PE in 5.3
  /10,000 hospital admissions and 0.07 / 10,000
  children lt 18 yrs

3
Hemostasis in Childhood

• 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

4

• Increasing numbers of paediatric patients are
  developing VTE
• VTE develops as complications to the successful
  treatment of prematurity, congenital heart
  disease and cancer

5
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)

6

• Children comprise 25 of the population
• gt 70 of drugs currently prescribed for
  paediatric outpatients are for unlicensed and
  off-label use
• For inpatients 67 of infants and children and
  90 of newborns receive off-label prescriptions
  in acute care setting
• In case of chemotherapy, lt50 of drugs used in
  the US include paediatric-specific information
  in their labeling.

7

• Clinical trials are the corner stone of
  evidence-based medicine
• Many obstacles have prevented the condition of
  properly designed prospective randomized studies
  in the paediatric age group

8
Standard of care for treatment of VTE in children
consists of unfractionated heparin for 7-10 days
followed by oral anticoagulation.
9
Risk Assessment for Persistence or Recurrence of
Venous Thrombosis in Children
Characteristic Low risk Standard risk High risk
Patient Trigger resolved/removed Transient underlying medical condition FVIII lt 150 U/dL D-dimer lt 500 ng/mL lt 3 Trait Thrombophilia FVIII gt 150 U/dL D-dimer gt 500 ng/mL gt 3 Trait Thrombophilia Persistent Antiphospholipid Antibody
Thrombus Thrombus Resolved within 6 weeks Atrial Non-occlusive DVT Vena Cava Occlusive DVT
Thrombophilias include genetic and acquired
prothrombotic traits that can be determined in
blood.
10
Anticoagulants in Children

• 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

11
Anticoagulants in Children

• 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.

12
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 lt 24 hours CNS Ischemia/Hemorrhage/Surgery lt 10 days (includes birth asphyxia) Surgery lt 7 days Invasive procedure lt 3 days Seizures lt 48 hours Limitations size of involved vessels and experience of interventionalists
13
UFH Heparin in Pediatrics

• 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),
  childrengt 1 yr need lower doses (22U/kg/hr), and
  older children need doses similar to adults

14
UFH Heparin in Pediatrics

• UFH clearance is faster in newborns because of a
  larger volume of distribution
• Heparin binding may be different

15
LMWH in Children

• 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 lt 2-3 months have increased requirements
  per kg
• Altered pharmacokinetics , decreased
  anticoagulant activity due to decreased plasma
  concentration of AT

16
LMWH

• 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

17
Dosing for Antithrombotic Therapy in Children
Unfractionated Heparin Low Molecular Weight Heparin Tissue Plasminogen Activator
Continuous IV Lovenox , enoxaparin Subcutaneous, q12h Continuous IV or Bolus
Loading Dose Newborn lt 37 weeks 50 U/kg New born gt 37 weeks 100 U/kg Infant/Child gt 1 month 50 U/kg None None
Initial Newborn lt 37 weeks 15 U/kg/hr Newborn to lt 1 month 1.625 mg/kg Infants to lt 3 months 0.06 mg/kg/hr
Maintenance Dose Monitoring (may require gt 25 U/kg/hr to achieve therapuetic anti-Xa level) Newborn gt 37 weeks 28 U/kg/hr (may need gt 50 U/kg/hr to achieve therapeutic anti-Xa level) Infant/Child/Adolescent 20 U/kg/hr (may need gt 30 U/kg/hr to achieve therapeutic anti-Xa level) Anti-Xa activity 0.3-0.7 U/ml Infants to 1 month to lt 1 year 1.5 mg/kg 1 year to lt 6 years 1.375 mg/kg 6 years to lt 21 years 1.25 mg/kg Anti-Xa activity 0.5 1.0 U/ml 3 months to lt 21 years 0.03 mg/kg/hr, max 2 mg/hr Clot Lysis by imaging or decrease in extent Increase in D-dimer or FSP
Lower doses of TPA are used in interventional
catheter-directed procedures higher doses of TPA
are used by others. See text for dosing
schedules. Bolus dosing of TPA can be used for
massive PE.
18

• 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.

19
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.

20
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.

21
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.

22
Obstacles to Performing Trials

• 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

23
Obstacles

• Paediatric population is divided into 4 age
  groups.
• Birth to one month (Neonates)
• One month to 2 yrs (Infants)
• Two years to 12 yrs (Children)
• 12 yrs to 18 yrs (Adolescents)

24
Obstacles

• No paediatric formulations of antithrombotic
  drugs
• Accurate, reproducible age- adjusted dosing is
  difficult
• Cost issues leading to premature closing of
  several paediatric clinical trials

25
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

26
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)

27
REVIVE Trial

• 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.
• Terminated early due to slow accrual.
• Outcomes for enrolled patients by intention to
  treat analysis.
• Recurrent VTE occurred by 3 months in 6 of
  reviparin- treated patients and in 10 of
  patients who received UFH followed OAC.
• By 6 months 6 and 13

28
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.

29
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.

30
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

31
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.

32
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.

33
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.

34
Oral Anticoagulants

• 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

35
Oral Anticoagulants

• 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

36
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.

37

• 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.

38
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.

39

• 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 lt 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.

40

• 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.

41
Details of studies evaluation central venous
line-related thrombosis
Predisposing factors Occurrence of TE Occurrence of TE Occurrence of TE Patients with symptomatic TE Number of patients with TE () n Study
Predisposing factors Other malignancies Hematologic malignancies Hematologic malignancies Patients with symptomatic TE Number of patients with TE () n Study
Predisposing factors Other malignancies Non-ALL ALL Patients with symptomatic TE Number of patients with TE () n Study
CVL insertion technique and site of insertion - - 29 / 85 3 / 29 29 (34) 85 Male et al.
Prothrombotic defects, infection 3 / 28 4 / 24 4 / 25 9 / 11 11 (14) 77 Knoffler et al.
None evaluated 7 / 14 4 / 7 1 / 3 5 / 12 12 (50.0) 24 Glacer et al.
No correlation between thrombophilia or infection and development of TE UK / 6 UK / 10 UK / 27 0 / 18 18 (44) 41 Rudd et al.
Prothrombotic defects increase the risk of TE in children with ALL but not in children with other malignancies 2 / 41 2 / 23 6 / 73 UK 10 (7.3) 137 Wermes et al.
- 12 / 83 (14.45) 10 / 54 (18.51) 40 / 186 (21.50) - 80 (21.97) 364 Total
n total number of patients studied ALL acute
lymphoblastic leukemia CVL central venous
line TE thromboembolism UK unknown
42
Likely clinical features and preferred diagnostic
evaluation for TE according to anatomical site
Likely clinical signs and symptoms Preferred diagnostic method/s Site
Unexplained headahces, vomiting, visual problems, or neurological deficits, seizure, drowsiness or any unexplained change in status MRI with/without contrast MRA with/without contrast MRI with/without contrast MRV with/without contrast Arterial ischemic stroke Sinovenous thrombosis CNS
Swelling, pain tenderness, erythema or discoloration of affected limb, dilated vessels, CVL malfunction, headache, swelling of face ECHO, linogram venogram and/or Doppler USG depending upon the site of CVL CVL-related
Swelling, pain, tenderness, erythema or discoloration of affected limb, dilated vessels Bilateral venogram, especially for subclavian/brachial vessels Doppler USG sufficient for jugular area, MRV if possible Recommend ECHO to evaluate RA Doppler USG To evaluate all sites Upper venous system Lower venous system DVT
CVL malfunction, sepsis, congestive heart failure ECHO Right atrial Cardiac
Breathing problems like tachypnea, dyspnoea, shortness of breath, chest pain, hypoxia, cyanosis, syncope, unexplained pneumonia V/Q scan, spiral CT Pulmonary vasculature PE
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.
43
Guidelines for use of anticoagulant agents and
monitoring of anticoagulation parameters around
invasive procedures in children with cancer
Pre-procedure 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 lt1.2. Stop warfarin 3-5 days prior to procedure. One center stopped 1 day prior but reversed with Vitamin K and Protamine for target INR lt1.2.
Target INR Target INR for lumbar puncture lt 1.3 for most centers (up to 1.5 in some centers). Target INR Target INR for lumbar puncture lt 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. 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 didnt measure pre-procedure, in those that did, a target of 0.3 was preferred 0.1 for Neurosurgery. Target anti-Xa level. Most centeres didnt measure pre-procedure, in those that did, a target of 0.3 was preferred 0.1 for Neurosurgery.
For LP 30-50 x 109/L Surgery 40-100 x 109/L Neurosurgery gt100 x 109/L Platelet counts
Fibrinogen levels Only 2 centers reported routinely monitoring fibrinogen levels, and required them to be normal (or corrected) to proceed with the procedure. 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
44
Incidence of adverse outcomes ( per patient year)
Acenocoumarol (Bonduel et al, Argentina) Warfarin (Streif et al, Canada) Study
1.3 2.3 Minor bleeding
0 0.5 Major bleeding
1.3 1.3 Recurrent TEs
TEs Thromboembolic events
45
Recommendations for oral anticoagulation therapy
in children
Duration of therapy Target therapeutic range Indication for oral anticoagulation
Lifelong 2.5-3.5 Prosthetic mechanical heart valves
Lifelong 2.5-3.5 Recurrent thrombotic episodes
6 mo 2.0-3.0 First thrombotic episode without concurrent risk factors
3 mo, then until acquired risk factor resolves 2.3-3.0 then 1.4-1.8 First thrombotic episode with concurrent risk factors
6 mo 2.0-3.0 Pulmonary embolism
46
Reversal of oral anticoagulation therapy
Bleeding No bleeding
Life threatening and/or potential mobidity No life threatening, no potential morbidity Pre-surgery
Vit K (iv) 5 mg and FFP 20 cc/Kg or PCC 50 U/Kg Vit K (sc-iv) 0.5-2 mg and FFP 20 cc/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
47
Examples of Therapeutic Decision Making for 1st
Episode Venous Thrombosis in Infants, Children
Adolescents

• 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
• Occlusive DVT, or non-occlusive Central Thrombus,
  symptoms lt 14 days ? Anticoagulation or Systemic
  Low-Dose TPA ? Anticoagulation until clot
  resolves, 3 to 12 months
• Occlusive Superior or Inferior Vena Cava or
  Lliac, or Hemodynamically Significant Cardiac
  Clot, Symptoms present lt 14 days ? Systemic
  Thrombolysis ? If not resolved in 48-96 hours ?
  Interventional Radiology for Catheter-directed
  Thrombectomy/Thrombolysis
• Occlusive Superior or Inferior Vena Cava or
  Lliofemoral or Cardiac, Symptoms present gt 14
  days ? Intervention Radiology for
  Catheter-directed Thrombectomy/Thrombolysis
• Indefinite long-term anticoagulation for all
  persistent Lupus Anticoagulant or gt 3 trait
  Thrombophilia

Lower doses of TPA are used in interventional
catheter-directed procedures higher doses of TPA
are used by others. See text for dosing
schedules. Bolus dosing of TPA can be used for
massive PE.
48
Properties of GPIIb-IIIa antagonists
Tirofiban Eptifibatide Abciximab
Aggrastat Integrilin ReoPro Trade name
Nonpeptide tyrosine derivative Cyclic heptapeptide Chimeric antibody Fab fragment Structure
Fast Fast Slow Off rate
-4 h -4 h -2 days Return of 50 platelet aggregation after cessation of infusion
49
Antagonists Clopidogrel Ticlopidine
PGI2
ATP
ADP
ADP
P2Y1
P2Y12
Gq
Gi
Gs
Ca2
PLC
P13K
AC
Platelet aggregation