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Thrombosis In The Pediatric Patient: Unique Risk Factors, Diagnosis & Management Issues

Surgeon General's Workshop on Deep Vein Thrombosis

1 | 2 | 3 | 4 | 5 | 6 | 7 | 8 | 9 | 10 | 11 | 12 | 13 | 14 | 15 | 16 | 17 | 18 19 | 20

SLIDE 1:

Thrombosis In The Pediatric Patient: Unique Risk Factors, Diagnosis & Management Issues. Surgeon General’s Workshop on DVT May 8-9, 2006 Bethesda, Maryland

Marilyn J. Manco-Johnson, MD & Neil A. Goldenberg, MD Departments of Pediatrics and Medicine, Mountain States Regional Hemophilia & Thrombosis Center University of Colorado at Denver & Health Sciences Center & The Children's Hospital, Denver, CO, US

SLIDE 2: DVT is the Most Common Blood Clot in Children (n=84)

Pie chart showing the following percentages:

DVT=63%
CSVT=18%
Isol PE=5%
RVT=6%
IAS=10%

SLIDE 3: Although Rare, DVT is a Health Risk During Childhood, Especially for Newborn Infants & Adolescents

Newborn 5.1/100,000
Childhood VT 0.7/100,000
Childhood Stroke 2/100,000
Adolescent 10/100,000
Elderly 5-15,000/100,000

SLIDE 4:

DVT is an Important Cause of Death in Children

2.2% (9/405) Monagle et al. Pediatr Res 2000;47:763-6
3.8% (3/79) Nowak-Göttl et al. Arch Dis Child 1997;76:F163-7
1% (1/100) Van Ommen et al. J Thromb Haemost 2003;1:2516-23
2.2% (13/584) Composite

DVT Has a High Risk of Pulmonary Embolism in Children

18% (11/61) Nuss et al. Pediatrics 1995;96:291-4.
17% (69/405) Monagle et al. Pediatri Res 2000;47:763-6.
17% (80/466) Composite

SLIDE 5: DVT in Children Can Be Recurrent

Monagle P, et al Pediatr Res 2000;47:763-6

8.1% (33/405) median 2.8 yrs

Van Ommen, et al J Thromb Haemost 2003;1:2516-22

8% (8/100) after 1 year

18% (18/100) after 7yrs

10% (51/505) Composite

SLIDE 6: Children with DVT are More Likely to Have Multiple Thrombophilia Traits

Mountain States Regional Hemophilia & Thrombosis Center

Number of Children Seen 2001-2003 293

Thrombosis 131

Family Study 162

Thrombophilia testing:

No abnormality: 19%
Single trait: 27%
Two traits: 27% Multiple traits in 54% evaluated
Three traits: 5%
Four traits: 22%

DVT recurrence is more likely with multiple thrombophilia traits!

SLIDE 7: LMWH Dosing Is More Variable in Children & Requires More Monitoring

Theraputic Dose of Enoxaparin (mg/kg Q12h by age cohort)	1.00	1.25	1.375	1.5	1.625	1.75-2.0
Birth to < 1 month N=11	0%	9%	9 %	36%	28%	18%
1 month to < 1 year N=12	8%	8%	0%	59%	8%	17%
1 year to < 6 years N=16	0%	31%	25%	44%	0%	7%
6 years to < 12 years N=12	0%	75%	17%	8%	0%	0%
12 years to < 21 years N=43	5%	88%	5%	0%	2%	0%

SLIDE 8: Post Thrombotic Syndrome (PTS) Causes Disability in Children & Adolescents

Stage1: Swelling: DVT age 16 years; FVL, OCP

Stage 2: Visible Collaterals DVT age 14 yrs; APA, prolonged bus ride

Stage 3: Induration, hyperpigmentation DVT age 13 years; FVL, APA

Stage 4: Stasis ulcers; DVT age 10 yrs; PC, tibial fracture

12.4% (50/405) median 2.8 yrs Monagle P, et al Pediatr Res 2000;47:763-6

59% (10/17) pain 41% (7/17) abn PE IVC Hausler M, Arch Dis Child 2001;85:228-33.

63% (96/153) Kuhle S, et al. Thromb Res 2003;111:227-33.

70% (23/33) Van Ommen, et al J Thromb Haemost 2003;1:2516-22

29% (179/608) Composite

SLIDE 9: DVT Therapy is Frequently Delayed in Children Due to Under-Recognition.

Two charts showing Treatment Delay Results in Poor DVT Resolution and Long-Term Pain.

Results of 81 DVT in Children treated with Anticoagulation

SLIDE 10: Teen Age is a Risk Factor for PTS

Line chart showing Teen Age is a Risk Factor for PTS

SLIDE 11: Overweight Predisposes to PTS in Children & Teens

Photos showing how Overweight Predisposes to PTS in Children & Teens (January 2004 and October 2004)

Stage 3: Skin induration, venous eczema

Overweight Predisposes to PTS in Children & Teens

88% rate of overweight in children with PTS

Overweight children have RR of 7 for PTS

SLIDE 12: Inflammation is the Most Common Risk Factor; DVT without a Risk Factor is Rare in Children

Pie chart showing

Lupus anticoag=40%
Central venous catheter=24%
Acute infection=13%
Chronic inflamm=10%
Other=8%
Idiopathic=5%

SLIDE 13: Inflammatory Markers* at Diagnosis Predicts a Poor Outcome of Thrombosis in Children

Probability of a Poor DVT Outcome: Positive Likelihood Ratio 6.1

All children

51%

Children with inflammation

90%

* FVIII, DD, Goldenberg, et al NEJM, 2004;351:1081-8

SLIDE 14: The Newborn Infant Has a Unique Hemostatic Balance:

BLEEDING

lower Thrombin Generation
lower Fibrin Tensile Strength
lower Platelet Aggregation

THROMBOSIS

higher Rate of Thrombin Generation & Thrombin Regulation
higherTF Expression, Whole Blood Clotting & Hematocrit
higher Platelet Adhesion

SLIDE 15: Thrombosis May Be Devastating in Neonates

Photos of thrombosis in Neonates

SLIDE 16: Children Have an Excellent Chance for Recovery From Severe DVT

Now 18 years old, this "Gifted & Talented" HS Senior with severe protein C deficiency (compound heterozygous, <1%) is going to college.

SLIDE 17: Outcome of In Utero Thrombosis with Severe Thrombophilia is Good with Treatment

[Photo]

CXR on Infant with Respiratory Infection

PMH: normal pregnancy, labor and delivery; well until acute respiratory illness

FH: negative for bleeding, thrombosis

Left: Organized IVC clot, left adrenal hemorrhage
Right: Organized right atrial clot
Thrombophilia eval: Homozygous Factor V Leiden, Heterozygous Protein C Deficiency; D-dimer, F 1+2, TAT persistently elevated

SLIDE 18: Critical Issues in DVT in Children

DVT is an important and increasing problem in infancy, childhood and adolescence.
Health and cost burdens of DVT and its long-term complications are disproportionately higher in children:
- Children will live 60 - 80 years following DVT.
- PTS limits aerobic activities that are necessary for normal childhood development.
DVT trials specific for children are urgently needed.

SLIDE 19: DVT is the Most Common Blood Clot in Children (n=84)

Time-Limited Risk Factors: Trauma, surgery, immobility Indwelling Catheters Infection, Post infectious APA Surgically Correctible Congenital Heart Disease Leukemia, Cancer, Chemotherap Steroids On-Going Risk Factors: Genetic Thrombophilia Primary or Secondary APAS Inflammatory Diseases Prosthetic Cardiac Valves Sickle Cell Anemia

Pie chart showing

DVT=63%
CSVT=18%
Isol PE=5%
RVT=6%
IAS=10%

SLIDE 20: Clot Formation is Accelerated in the Newborn

Picture of CloFAL Assay

Picture of newborn and adultCloFAL Assay