Download Thrombosis in Pediatrics

Venous Thromboembolism
in Pediatrics
Shalu Narang, M.D.
Pediatric Hematology
Newark Beth Israel Medical Center
Objectives
• Epidemiology and pathophysiology of pediatric
thrombotic disorders
• Signs, symptoms and diagnosis of deep venous
thrombosis (DVT)
• Acquired vs. inherited thrombophilia
• Diagnostic screening tests for thrombotic
disorders
• Role of anticoagulation in children with
thrombotic disorders
• Long-term sequelae of thrombosis
Epidemiology
DVT is the Most Common Blood Clot in
Children (n=84)
DVT=63%
CSVT=18%
Isol PE=5%
RVT=6%
IAS=10%
Goldenberg et al.
NEJM 2004;351:1081-8.
Highest incidence of DVT in
neonates and adolescents
40
Cases / 10,000 general population
35
30
25
20
15
10
5
0
0
5
10
15
20
25
Age (Y)
30
35
40
45
50
Pathophysiology
Pathophysiology
• Virchow’s Triad
• Endothelial Injury
– Indwelling catheters
• Abnormal Blood Flow
–
–
–
–
–
–
Immobilization
Dehydration
Inflammation
Nephrosis
Cancer therapy
Hyperviscosity
• Hypercoagulability
Conceptual Model of
Hemostasis
Reprinted with permission from Sidney Harris.
Coagulation Cascade
Pathophysiology
Fibrinolysis
Coagulation
Hemostasis
Pathophysiology
Coagulation
↓
Thrombosis
Hemostasis
Fibrinolysis
Signs, Symptoms and Diagnosis
Signs & Symptoms
• DVT:
– Poorly Functioning
Catheters
– Edematous extremity
– Plethoric extremity
– Warm extremity
– Painful extremity
• PE:
– Cough, SOB, Hemoptysis
– Tachycardia
Risk Factors
•
•
•
•
•
•
•
•
•
Indwelling catheters
Thrombophilia
Malignancy
Chemotherapy
Prosthetic cardiac valves
Diabetes mellitus
Sickle cell anemia
Infection
Surgery
Thrombophilia
Thrombophilia
• Inherited:
–
–
–
–
–
–
Protein C deficiency
Protein S deficiency
Antithrombin deficiency
Factor V leiden
Prothrombin gene mutation
Elevated Lipoprotein a, homocysteine
• Acuired:
– Antiphospholipid Syndrome
– Nephrotic syndrome
Prevalence of inherited
thrombophilia in children with DVT
Test
Affected/tested
Prevalence
Study
Population
Factor V Leiden
8/171
4.7 %
4%
Prothrombin G20210A
4/171
2.3 %
2%
Protein S deficiency
2/171
1.2 %
0.3 %
Protein C deficiency
1/171
0.6 %
0.3 %
Antithrombin deficiency
0/171
0.0 %
0.02 %
Lipoprotein (a) >30mg/dl
8/107
7.5 %
7%
Revel-Vilk. J Thromb Haemost 1 (2003), 915-921
Revel-Vilk. J Thromb Haemost 1 (2003), 915-921
Length of therapy remains the
same regardless of thrombophilia
First episode of DVT
Length of anticoagulation
Transient risk factor
3 months
Idiopathic TE
6-12 months
Thrombophilia
6-12 months
7th ACCP evidence based guidelines
Why Screen?
Single Defect: OR 4.6, p<.0001
Combined Defect: OR 24.0, p<.0001
Nowak-Gottl et al. Blood 2001;97:858-862.
Laboratory Studies
• DIC Screen:
– CBC, PT, aPTT, Thrombin Time, Fibrinogen, D-dimer
•
•
•
•
•
•
•
Protein C Activity
Protein S Activity
Antithrombin III Activity
Lupus Anticoagulant
Anticardiolipin antibody
Prothrombin gene mutation
Factor V leiden
Healthy Children w/
Family History of DVT or
Thrombophilia
• Screening is rarely indicated:
– Risk assessment limited by heterogeneity of
genotype and phenotype
– No guidelines for management
– Potential risk of anticoagulation outweighs benefit
– May inhibit ability to obtain life/disability insurance
– Ethical concerns: autonomy, assent, consent
– Appropriate age for screening unknown
– Unnecessary anxiety
Courtesy: Bryce A. Kerlin, M.D.
Anticoagulation Therapy
Therapeutic Goals
• Prevent thrombus propagation and/or
embolization
• Restore blood flow (rapidly, when
necessary)
• Minimize long-term sequelae
Anticoagulants
• Heparin
– Un-fractionated vs. low
molecular weight
– IV or SQ
– Monitoring with PTT or
anti-Factor Xa
– Reversible with
protamine
• Warfarin
– Vitamin K antagonist
– Only oral
anticoagulant
– Monitor with PT
– Reversible with
vitamin K
– Very long T½
Risk Stratification*
(for persistence or recurrence)
• Low Risk
– Thrombus post surgery, trauma, CVL
– Resolves within 6 weeks
• Standard Risk
–
–
–
–
FVIII <150U/dL
D-dimer <500ng/mL
< 3 thrombophilic factors
Non-occlusive thrombus
• High Risk
–
–
–
–
FVIII >150u/dL
D-dimer >500ng/mL
>3 thrombophilic factors
Occlusive thrombus
Manco-Johnson, Blood 2006
*Studies in progress
Anticoagulant Duration
• Ongoing Studies: no guidelines!
– Low/Standard Risk:
• 6 wks (Thrombus Resolution and no thrombophilia)
• 3 months (Residual Thrombus or thrombophilia)
– High Risk:
• Early thrombolysis AND
• 6 months vs.12 months
Multi-institutional studies in progress.
Long-term Sequelae
• Post-thrombotic
Syndrome (PTS)
– Pain, swelling, visible
collateral vain
formation, skin
abnormalities
– 10-60% children
• Recurrent TE
– Life-Threatening
Embolic Disease
– 7-8% children
Summary
• Pediatric thrombosis is most common in infants
and adolescents
• DVT is most common form of VTE
• The upper extremity circulation is most
commonly affected
• Diagnosis should be confirmed with:
– D-dimer
– Venous Doppler Ultrasonography
– CT Angiogram
Summary
• Initial treatment should be standard or low
molecular weight heparinization
• Short courses may be completed with heparin,
longer courses may benefit from transition to
Warfarin
• Duration of anticoagulant therapy is
individualized based on underlying comorbidities
• Patients should be followed closely for recurrent
disease and/or post-phlebitic syndrome
Summary
• All thrombosis patients should be screened for
treatable molecular thrombophilias
• Some patients may benefit from additional
screening
• Asymptomatic patients and family members not
at increased risk for thrombosis should not
routinely be screened
Thanks!