Author: Danielle Cassidy, PharmD, BCPS
Audience: Third year pharmacy students at University of Colorado School of Pharmacy & Oregon State University College of Pharmacy.
Background: Provides overview of common causes of pediatric venous thromboembolism & treatment management.
2. Objectives
Define common risk factors and adverse
outcomes of venous thromboembolism (VTE).
Identify appropriate anticoagulation therapy for
VTE.
Recommend appropriate dosing and monitoring
parameters for anticoagulation therapy.
Appropriately counsel families on LMWH and
warfarin therapies.
4. VTE Pathophysiology
Thrombi form in venous
valve pockets and/or
other areas of stasis
within the venous
vasculature.
Clots can embolize and
travel through the
vasculature to the heart
or lungs.
Clots that originate
proximal to the knee are
at higher risk for
emobolizing.
Image available at:
www.childrenshospital.org/az/Site2850/mainpageS2850P0.html
5. Coagulation Cascade
From Ferri F [ed]: Practical Guide to the Care of the Medical Patient, 7th ed. St. Louis, Mosby, 2007
6. Incidence of VTE in Children
~2 million cases annually.
Estimated incidence of VTE
Adults: 1 per 1000 patients per year
Pediatrics (per 10,000 patients per year)
Overall=0.49
Neonates=14.5
Adolescents=1.1 (15-17 years)
Mortality rate due to VTE
Adults: 18%
Pediatrics: 0-2%
9. PTS
A condition of chronic venous insufficiency
following DVT.
Occurrence rate: 33-70% of children vs. ~29% of
adults.
Signs & symptoms
pain, chronic edema, visible superficial collateral
vein formation.
skin abnormalities: hyperpigmentation, dermatitis,
or skin ulceration.
10. Examples of PTS
(A) Dilated collaterals in a 14-year- (B) stasis dermatitis in a 13-year-
old boy who had ileofemoral old boy who had iliofemoral to
DVT. IVC DVT.
Goldenberg N and Bernard T. Venous Thromboembolism in Children. Pediatr Clin N Am 2008;55:317.
11. Quiz Question #1
Which of the following is not a clinical risk
factor for VTE?
a) indwelling catheter
b) oral contraceptives
c) smoking
d) chemotherapy
13. Unfractionated Heparin (UFH)
First line agent in clinically unstable
patients or patients with significant/liable
renal function.
MOA: UFH binds to anti-thrombin (AT)
resulting in inhibition of thrombin (factor
IIa), factors IXa, Xa, XIa, XIIa.
Elimination: Heaptic and renal
14. UFH: Contraindications
Pork allergy or history of heparin induced
thrombocytopenia (HIT).
Loading doses are contraindicated in:
Cerebrovascular accident
Active bleeding
Severe thrombocytopenia
Mechanical cardiac prosthesis
Patient’s at high risk for bleeding
DVT prophylaxis
15. UFH: Dosing
Loading dose: 50-100 units/kg IV over 10
minutes
Initial maintenance dosing:
preterm infants: 15 units/kg/hour
term infants: 25 units/kg/hour
greater than 1 month: 15-20 units/kg/hour
Dose adjustment: dependent upon anti-Xa
levels.
16. UFH: Goals and Monitoring
Standard treatment anti-Xa goals: 0.35-0.7
units/mL
Monitoring:
6 hours after initiating the infusion, 6 hours with
every infusion rate change, and every 24 hours
once a stable infusion rate is obtained.
Exception: 8 hours if no bolus was given.
More frequent with significant renal (CrCl <30
mL/min) or hepatic impairment.
17. Low-Molecular Weight Heparin (LMWH)
Enoxaparin (Lovenox), dalteparin (Fragmin),
tinzaparin (Innohep)
First line agent in clinically stable patients for
acute or long-term treatment.
MOA: binds to AT resulting in inhibition of factor
Xa.
Contraindications: HIT, invasive procedures in
previous 24 hours, allergy to UFH/LMWH.
18. Enoxaparin Dosing
Based on actual body weight.
Initiating therapy
Route: subcutaneous
Frequency: q12 hours
Initial dosing
Preterm infant: 1.375-1.625 units/kg/dose
0 to <1 month: 1.625 units/kg/dose
1 month to <1 year: 1.5 units/kg/dose
1 year to < 6 years: 1.375 units/kg/dose
6 years to <21 years: 1.25 units/kg/dose
19. Dalteparin Dosing
Based on actual body weight.
Initiating therapy:
Route: subcutaneous
Frequency: q 24 or 12 hours
Initial dosing: 100–150 international units/kg
Further studies are needed to better define
dosing parameters.
20. Tinzaparin Dosing
Based on actual body weight.
Initiating therapy
Route: subcutaneously
Frequency: q12 hours
Dosing
Preterm infant: no information available
0-2 months: 275 units/kg/dose
2-12 months: 250 units/kg/dose
1-5 years: 240 units/kg/dose
5-10 years: 200 units/kg/dose
Greater than 10 years: 175 units/kg/dose
Further studies are needed to better define dosing
parameters.
21. LMWH: Goals & Monitoring
Standard treatment anti-Xa goal: 0.5-1 units/mL.
Dose adjustments are dependent upon anti-Xa
levels.
Monitoring
Level ~4 hours after the 1st or 2nd dose and with
every dose change.
Once therapeutic, levels necessary only if there
are significant changes in weight (>10%), renal
function, or serious bleeding side effects.
Levels usually obtained weekly in infants.
23. Commonly Used Direct Thrombin Inhibitors
IV: bivalirudin and argatroban
Common uses: HIT diagnosis or continued
progression on therapeutic UFH.
MOA: reversibly binding to the active site of
thrombin
24. IV Direct Thrombin Inhibitors
Dosing and Monitoring
Argatroban
Initial: 0.75 mcg/kg/min continuous IV infusion
Adjustment: increments of 0.1 to 0.25 mcg/kg/min to
achieve aPTT of 1.5 to 3 times the initial baseline
value (not to exceed 100 seconds).
Bivalirudin
Bolus dose: 0.125 mg/kg
Initial infusion rate: 0.125 mg/kg/hour
Adjustments: as needed to achieve aPTT 1.2 to 2.5
times the initial baseline value.
25. Alternative Thrombin Inhibitors
Not established in pediatrics:
Antithrombin dependent factor Xa inhibitor:
fondaparinux (Arixtra)
Direct thrombin inhibitor: dabigatran (Pradaxa)
Direct factor Xa inhibitor: rivaroxaban (Xarelto),
apixaban (Eliquis)
26. Warfarin
Treatment in patients requiring long-term therapy.
MOA:
Inhibits Vitamin K epoxide reductase, blocking the
oxidation of vitamin K and depleting vitamin K
stores, thus reducing the production of clotting
factors II, VII, IX, and X, and proteins C and S.
Does not inhibit the activity of existing clotting
factors; depletion occurs via normal catabolism .
27. Warfarin: Pharmacology
LMWH or UFH bridge for a minimum of 5 days
and/or two INR’s at/or above goal.
Steady state: ~5-7 days
Hepatic CYP450 metabolism:
Primary: 2C9
Minor: 2C8, 2C18, 2C19, 1A2, and 3A4
28. Warfarin: Dosing, INR Goals, & Monitoring
Initial dose: 0.1-0.2mg/kg once daily; dosing
based on actual body weight.
Standard INR goals: 2.0-3.0 or 2.5-3.0
Monitoring:
INR should be ordered 5-7 days after initiation or dose
change.
More frequent monitoring should be considered in
patients with significant hepatic impairment or serious
bleeding side effects.
Dose adjustments: INR, compliance, diet,
interactions.
29. Warfarin: What Can Affect INR Levels?
Factors that can Factors that can
increase the INR decrease the INR
Drug interactions Drug interactions
Acute alcohol Increased vitamin K
ingestion intake
Reduced oral intake Poor compliance
Fever Chronic alcohol intake
Vomiting or diarrhea Growth
Increased activity
30. Anticoagulation Duration
Duration of
Etiology anticoagulation therapy by
episode
Resolved risk factors First: 3-6 months
Recurrent: 6-12 months
Idopathic First: 6-12 months
Recurrent: 12 months
Chronic risk factors First and recurrent: life long
Congenital First and recurrent: life long
thrombophilia
32. Aspirin
MOA: irreversible inhibition of platelet
cyclooxygenase 2.
Uses: thrombophilia, addition to warfarin therapy
in high risk patients, CSVT, or cardiac anomalies.
Dose: 1-5 mg/kg po qd (max dose 325mg; round
to the nearest ¼, ½, or whole tab).
Side effects: low dose well tolerated (alone).
Treatment duration: determined by risk factors;
standard duration is 1-2 years.
33. Clopidogrel (Plavix)
MOA: irreversible inhibition of adenosine
diphosphate.
Uses: aspirin allergy, thrombophilia, addition to
warfarin therapy in high risk patients, CSVT, or
cardiac anomalies.
Dose: 1 mg/kg qd (max dose 75 mg; round to the
nearest ¼, ½, or whole tab).
Side effects: well tolerated (alone).
Treatment Duration: determined by risk factors;
standard duration is 1-2 years.
34. Quiz Question #2
Which of the following is considered first line
therapy for a clinically unstable patient with
VTE?
a) dalteparin
b) warfarin
c) heparin
d) bivalirudin
36. Common/Minor Side Effects
Irritation at the injection site
Hematomas under skin or around injections sites
Bruising more easily or around injection sites
Gum bleeding
Epistaxis
Bleeding after a minor cut
Women: heavier menstrual bleeding
37. Serious Side Effects
Excessive/unusual Chest pain
bleeding Weakness on one side of
Dark brown/red urine the body
Red/black (tar-colored) Sudden difficulty
stools speaking
Hematemesis Sudden changes in
Excessive bruising vision
Severe stomach pain Unusually severe or
Painful swelling of an prolonged headache
arm or leg Yellowing of the skin or
Dizziness eyes
38. LMWH
Apply 5 minutes of pressure to minimize/prevent
bruises and hematomas.
Prior to injection can apply ice or numbing topical
(e.g. Emla) to minimize injection pain.
Injections should be given at the same time
every day.
Rotate injection sites to prevent scaring and
minimize bruising/bleeding.
39. Warfarin
Take doses at the same time every day.
All tablets (brand or generic) are color coded by
strength.
Double check the dose prior to administration (i.e.
check the number and strength of tablets).
Double check the bottle before leaving the
pharmacy.
40. LMWH and Warfarin
Avoid medications that contain aspirin (if not
medically necessary), ibuprofen, or naproxen.
Never double or take extra doses to make up for
a missed dose.
Inform all health care providers about any
anticoagulation medications you are taking.
42. Case Study #1
RM is a 16 year old obese male (120kg) with type 2
diabetes who was diagnosed with a right femoral
DVT three months prior to admission.
RM presents today with severe leg pain and swelling
making it difficult to walk.
RM reports that his insurance lapsed and he stopped
using Lovenox two months prior to admission due to
cost.
Ultrasound was positive and CT showed clot
progression in the R femoral vein.
43. Case Study #1
The doctors would like to restart Lovenox
therapy for RM. Is this an appropriate choice for
first line therapy? Why?
Yes first line therapy for all clinically stable
patients and RM has no direct contraindications.
44. Case Study #1
The doctors start Lovenox therapy at your
recommendation. They would like to know what
anti-Xa goal to achieve and when they should
check a level. What would you recommend?
• Goal anti-Xa: 0.5-1 units/mL
•Check level ~4 hours after the 1st or 2nd dose
and with every dose change.
45. Case#2
EB is a 6 year old female (32 kg) with a distal left
lower extremity DVT. The doctor would like to
transition EB from Lovenox to warfarin therapy (INR
goal 2.0-3.0).
What starting dose would you recommend?
0.1-0.2 mg/kg once daily (3-6mg)
What are some common bleeding side effects the
family should be counseled about?
Bruising more easily, gum bleeding, epistaxis,
bleeding after a minor cut.
46. Case#2
EB is started on warfarin 3mg po qd as
recommended by pharmacy. Upon filling the
prescription at an outside pharmacy the family
notices the tablets are green.
The family would like to know if the if the prescription
was filled with the correct warfarin strength.
No green = 2.5mg tablet. Brown=3mg tablet.
47. References
Monagle P, Chan A, Goldenberg N, et al. Antithrombotic therapy in neonates
and children: College of Chest Physicians Evidence-Based Clinical Practice
Guidelines (9th Edition). Chest 2012;133;737-801.
Manco-Jonson, MJ. How I treat venous thrombosis in children. Blood.
2006:107;21-29.
Ronghe MD, Halsey C, Goulden NJ. Anticoagulation Therapy in Children.
Pediatr Drugs 2003;5(12):803-820.
Goldenberg NA, Bernard TJ. Venous Thromboembolism in Children. Pediatr
Clin N Am 2008;55;305-322.
Jilma B, Kamath S, Lip GYH. ABC of antithrombotic therapy: Antithrombotic
therapy in special circumstance. II-In children, thrombophilia, and
miscellaneous conditions. Br J Haematol 2001;114:512-528.
Albisetti M, Chan AKC, Mahoney DH, Kim MS. Diagnosis and treatment of
venous thromboembolism in infants and children. UptoDate® Accessed
September 17, 2008. Last updated October 29, 2007.
Coutre S. Heparin Induced Thrombocytopenia. UptoDate® Accessed
September 17, 2008. Last updated May29, 2008.
Hirsh J, Hoak J. Management of deep vein thrombosis
and pulmonary embolism.Circulation 1996; 93:2212-45.
48. References
Tapson VF. Acute pulmonary embolism. N Engl J Med 2008;
358:1037-52.
Nohe N, Flemmer A, Rumler R, et al. The low molecular weight
heparin dalteparin for prophylaxis and therapy of thrombosis in
childhood: a report on 48 cases. Eur J Pediatr 1999;158:S134–9.
Phillips, KW, Dobesh P, Haines ST. Considerations in using
anticoagulant therapy in special patient populations. Am J Health-
Syst Pharm August 1, 2008 Vol.65; Suppl. 7. pS14-S21.
Valentine KA, Hull RD. Therapeutic use of heparin and low molecular
weight heparin. UptoDate® Accessed September 9, 2008. Last
updated June 3, 2008.
Spandorfer J. The management of anticoagulation before and after
procedures. Med Clin North AM 2001;85(5):1109-16,v.
American Heart Association. AHA Statistical update: 2012. Accessed
May 1, 2012. Available at:
http://circ.ahajournals.org/content/125/1/e2.full
Kerlin BA. Current and future management of pediatric venous
thromboembolism. Am J Hematol 2012;87:S68–S74.
Notes de l'éditeur
American Heart Association estimates that ~2 million cases of VTE will be diagnosed annually.Neonates- postulated to be due to immature coagulation pathway, Adolescents-postulated to be due to hormonal changes highest among teenage boys
The pathogenesis of VTE (Virchow triad) consist of venous stasis, endothelial damage, and the hypercoagulable state. risk factors often from more than one component of the triad.most common clinical prothrombotic risk factors in childhood is an indwelling central venous catheter. More than 50% of cases of DVT in children and more than 80% of cases in newborns
First choice due shorter half-life than LMWH {Half-life of UFH is dose dependent (~90 minutes),longer half-life is usually seen at high doses.}UFH can only prevent clot propagation and growth.Rate of elimination is reduced in patients with hepatic or renal dysfunction; dose adjustments may be necessary.
Studies suggests clearance is faster in newborns due to a larger volume of distribution than older children. Also, it is thought that heparin protein binding in newborns also different from that in older children and adults.
UFH requires frequent monitoring due to intra- and inter-patient variability. ApTT not good indicator as this extrapolated from adults
Preferred agent d/t ease of administration, the decreased need for monitoring, decreased risk for the development of HIT.LMWH-AT complex can not inactivate clot-bound factor Xa and can only prevent clot propagation and growth.{Factor Xa and thrombin inhibition ratio 4:1 (UFH ratio 1:1), LMWH’s contain a lesser quantity of 18-unit chain lengths as compared to UFH and therefore cannot bind simultaneously to AT and thrombin}.
Preferred agent d/t greatest amount of clinical data in kids
Therapeutic range of anti-Xa activity for LMWH is higher than that for UH because UH inhibits antithrombin as well as anti-Xa activity.Peak anticoagulant effect: 3-5 hours
Dosing, safety, and efficacy have not been established in the pediatric population.
A short term hypercoaguable state is produced due to rapid depletion of protein C and S and delayed depletion of factors II and X; response to warfarin is dependent upon degradation half-life of VK dependent clotting factors; complete depletion of factors II (~120 hrs) and X (~70 hrs)
Maximum starting dose=discuss
Drug interactions: Increase: bactrim, marijuana, amiodarone, azole antifungals Decrease: Rifampin,
Duration is derived from adult data
Most common antiplatelet used in kidsLow dose well tolerated as compared with higher doses used for inflammation.Reye syndrome appears to dose dependent effect and usually associated with doses >40 mg/kg. Usually recommend child stop med when febrile.