St. Jude Leukemia/Lymphoma Conference: St.

Jude Leukemia/Lymphoma Conference:

17 June 2003 17 June 2003

Diagnosis and Treatment

of Pediatric Patients Case Presentation
with Thrombosis
Introduced by Najat C. Daw,
Daw, MD

Robert P. Sanders, MD
Robert P. Sanders, MD Hematology/Oncology
St. Jude Childrens Research Hospital

Case Presentation

17 year old WF with Cystic Fibrosis

Multiple admissions for IV antibiotics
Subcutaneous port placed October 2000
Facial swelling August 2002
SVC syndrome diagnosed Late 2002
Thrombus detected by CT

Case Presentation Case Presentation

Port removed February 2003

Treated with daily aspirin No previous episodes of thrombosis
SVC syndrome and thrombus resolved
Admitted June 6 for CF exacerbation No family history of thrombosis or pro-
thrombotic disorders
Requires new central line
Hematology consulted:
Should this patient receive prophylactic
anticoagulation?

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 Questions Diagnosis: Did This Patient
Did this patient have a thrombotic Have a Thrombotic Event?
event? Clinical features
Why did this patient develop Sites
thrombosis? Symptoms
What is the risk of recurrence?
Diagnostic Imaging
Is prophylactic anticoagulation
indicated? Ultrasound
Venography
For how long?
CT
What anticoagulation regimen would
be optimal? MR Venography

Detour - Treatment Newer Treatment Options

No large scale clinical trials

LMW heparin
Conventional Therapy
Anticoagulation with heparin for 5 days to 2
weeks to aPTT 1.5x normal Thrombolytics
Oral anticoagulation with warfarin to INR 2 to 3 Systemic
Duration at least 3 months Localized

Pathophysiology

Why Did This Patient Develop cell

Thrombosis? cell
cell

Pathophysiology, Epidemiology, and

Risk Factors cell

cell

2
 Pathophysiology Epidemiology
VTE very uncommon in children
Balance of pro-thrombotic and
Incidence 0.07 0.14 per 10,000 children
anticoagulant / fibrinolytic factors
<18 yo
Populations at increased risk:
Turbulence/stasis of blood flow
Neonates
2.4 per 1000 NICU admissions
Foreign bodies Central lines
3.5 per 10,000 hospital admissions

Age Distribution of Venous Thromboembolism

CVL-
CVL-Related Thrombosis

Canadian Childhood Thrombophilia

Registry Massicotte,et al. J Peds 1998
244 patients with CVL-related DVT
60% of DVT in larger registry
171 upper venous system
105 lower venous system

Andrew, M. et al. Blood 83:1251,1994

CVL-
CVL-Related CVL-
CVL-Related
Thrombosis in Hemophilia Thrombosis in Cancer
Journeycake,
Journeycake, et al. Blood 2001
Glaser, et al. J Pediatr 2001
15 boys with severe hemophilia, CVL present 31 ports removed from 24 cancer pts
>12 months
50% had DVT
8 had DVT by venogram
5 had clinical problems
Mitchell, et al. Cancer 2003
Mean duration of placement 57.5 months
60 children with all screened by ultrasound
No abnormal venogram with line in place <48
months 22 (36.7%) had TE

3
 CVL-
CVL-Related Thrombosis
in Cystic Fibrosis Why Did This Patient Develop
Aitken,
Aitken, et al. Chest 2000.

Thrombosis?
218 Adult CF patients 1989-1998
65 had CVL (30%) Answer 1: Central line
75,660 catheter-days Answer 2: ?
14 thromboses (0.185/1000 catheter-days)
2 SVC syndrome (0.026/1000 catheter-days)

Prothrombotic Risk Factors: Inherited Thrombophilia

Congenital and Acquired Common
Factor V Leiden
Prothrombin G20210A gene mutation
Hyperhomocysteinemia (MTHFR C677T)
lipoprotein (a)
Rare
PC, PS, AT deficiency
Very rare
Dysfibrinogenemia, dysplasminogenemia,
homocystinuria

Pathophysiology Factor V Leiden

90% of APC Resistance

cell
Heterozygous mutation occurs in 2-15% of
Caucasians
cell cell 20-50% of Adults with VTE
10 studies of FVL in children with VTE
Significant risk factor in 9/10
cell

cell
Chalmers EA, Blood Rev 2001

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 Prothrombin 20210 Mutation
Results in increased prothrombin levels
Much less data than FVL in children
Significant risk factor in only 1 of 4 case-control
studies
Present in ~4% of childhood VTE
Chalmers EA, Blood Rev 2001
Less Common Defects
<1% of Normal Population
Protein C deficiency 9% of VTE
Protein S deficiency 5.7% of VTE
ATIII deficiency 3.4% of VTE
Nowak-Gottl, et al. Thromb Haemost 2001
Back to Our Patient
Factor V Leiden negative
Protein C, S, ATIII normal
Homocysteine normal
Anti-cardiolipin negative
Fibrinogen 1030 (nl < 280)
Lipoprotein (a) 102 (nl<30)
Possible Common Risk Factors
Hyperhomocysteinemia
Due to mutation in MTHFR gene
Minimal data in children
Lipoprotein (a)
Significant risk factor for VTE in 2 studies by same
author
Not significant in one additional study
Acute Phase reactant
Other Possible Risk Factors
Anti-phospholipid antibodies
Hyperfibrinogenemia
Hypo/dysplasminogenemia
Elevated Factor VIII, IX, XI
What is the Risk of Recurrent VTE?
Canadian Childhood Thrombophilia Registry
244 pts with CVL-related VTE
Median follow-up 24 mo (range 3 mo to 7 yrs)
16 recurrences (6.5%)
Massicotte, et al. J Pediatr 1998
5
What is the Risk of Recurrent VTE? What is the Risk of Recurrent VTE?

German Study
301 patients age neonate to 18 yo with VTE
Median follow-up 7 years after stopping anticoagulation
Recurrent VTE in 21.3% at median 3.5 yrs off
anticoagulation
Significantly shorter thrombosis-free survival in children
with combined pro-thrombotic defects
RR 2.6 in pts with elevated Lp(a) (95%CI, 0.7-9.9)

Nowak-Gottl, et al. Blood 2001

Nowak-Gottl, et al. Blood 2001

What Kind of Prophylaxis is

Optimal?
Is Prophylactic
Anticoagulation Indicated? Low Molecular Weight Heparin

Warfarin

Low Molecular Weight Heparin Yeager, Amer Fam Phys 1999

Yeager, Amer Fam Phys 1999

6
Low Molecular Weight Heparin
Subcutaneous administration
Greater bioavailability than UF heparin
More specific mechanism of action
Lower risk of bleeding
Very expensive
Warfarin
Vitamin K antagonist affects factors II,
VII, IX, X, Proteins C,S
Activity dependent on:
Age
Diet
Underlying disease
Other medications
Requires frequent monitoring
Inexpensive
Very Low (Mini) Dose Warfarin
Heaton, Intern Med J 2002
Patients with CVL
Received 1mg/d warfarin or nothing
No difference in thrombosis
Masci, J Clin Oncol 2003
Patients with cancer and CVL
Received 1mg/d warfarin and 5-FU
33% had elevated INR
19% had INR >3.0
Administration of LMW Heparin
Dose 1-2 mg/kg/dose SC Q12
Target anti-Xa level 0.2-0.4 units/ml
Very Low Dose Warfarin
Open randomized trial
Adults with CVL
82 patients evaluated
42 received 1mg warfarin daily
At 90 days, 4 had thrombosis
40 received no warfarin
15 had thrombosis p<0.001
Bern, et al. Ann Int Med 1990
Low Intensity Warfarin
(INR 1.5 to 2.0)
508 adults with idiopathic DVT
After median 6.5 months full dose anticoagulation
randomized to placebo or low-intensity warfarin
Trial terminated early after mean f/u 2.1years
37 of 253 placebo pts had recurrent VTE
14 of 255 treatment pts had recurrence
Risk reduction 64% (HR 0.36, 95% CI 0.19-0.67,
p<0.001)
Major hemorrhage in 5 placebo and 2 treatment pts
8 placebo and 4 treatment pts died
Ridker, et al. NEJM 2003
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 What Did We Do?

Figure 2. Cumulative Risk of the Primary Study End Point of Recurrent Venous Thromboembolism
(Panel A) and of the Composite Study End Point of Recurrent Venous Thromboembolism, Major
Hemorrhage, or Death from Any Cause (Panel B).

Conclusions
?
Venous thromboembolic events are uncommon
in children
Much more is known about risk factors than

Questions and Answers

effective treatment or prophylaxis
Management decisions must balance risks of
recurrence and therapy Some questions were asked without a
Low dose warfarin may be a viable option for microphone nearby and may be difficult
prophylaxis to hear, but they are presented here.

? ?

Questions and Answers Questions and Answers

Some questions were asked without a Some questions were asked without a
microphone nearby and may be difficult microphone nearby and may be difficult
to hear, but they are presented here. to hear, but they are presented here.

8
 ? !

Questions and Answers Comments

Some questions were asked without a From Dr. Daw
microphone nearby and may be difficult
to hear, but they are presented here.

End

Robert P. Sanders, MD

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