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.

1. Pediatric Venous Thromboembolism &
Anticoagulation
Danielle Cassidy, Pharm.D.
May 2012

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.

3. Background

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%

7. Clinical Risk Factors
 ~90% of pediatric VTE is risk associated as
compared to ~60% in adults.
 Risk factors
 Transient: indwelling catheter, oral contraceptives,
cast/splint, surgery, trauma, surgically correctable
congenital heart disease.
 Chronic: genetic/acquired thrombophilia, cancer,
infection, chemotherapy, inflammatory diseases,
prosthetic cardiac valves, sickle cell anemia,
hyperhomocysteinemia.

8. Adverse Outcomes
 Clot progression
 Recurrent VTE
 Pulmonary embolism (PE)
 Cerebral sinovenous thrombosis (CSVT)
 Post-thrombotic syndrome (PTS)
 Death

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

12. VTE Treatment Options:
Anticoagulants

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.

22. Reducing pain with injections

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

31. VTE Treatment Options: Antiplatelet
Agents

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

35. LMWH & Warfarin: Patient
Counseling Points

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.

41. Real Life Case Studies

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.

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