SPECIAL ISSUES OF INFANTS, CHILDREN AND ADOLESCENTS REGARDING DEEP VEIN
THROMBOSIS

Marilyn J. Manco-Johnson, MD

Professor of Pediatrics

Director, Mountain States Regional Hemophilia & Thrombosis Center

University of Colorado at Denver and Health Sciences Center

& The Children's Hospital

Denver, Colorado

May 8, 2006

Address: MSRHTC

US Mail: MailStop F-416, PO Box 6507

Aurora, CO 80045-0507

FedEX: Fitzsimons, Bldg 500, Rm WG109

13001 E. 17^th^ Place

Aurora, CO 80010

Phone: 303-724-0365

FAX: 303-724-0947

Infants, children and adolescents also develop deep vein thrombosis
(DVT), although recognition of DVT in children has received attention
only recently (1). DVT in pediatrics is most common during the neonatal
period and adolescence (2,3). DVT carries a mortality rate of
approximately 2% in children and the rate of pulmonary emboli has been
reported at about 20% (1). In contrast to adults, the majority of
children with DVT are found to carry multiple thrombophilic traits, and
DVT recurrence rates are higher in children with multiple trait
thrombophilia (4). The recurrence rate of DVT in children is
approximately 10% (1,5). Many of the risk factors for DVT in children
are known (Table 1). Most DVT occur in hospitalized children who are
receiving care for significant underlying medical conditions. DVT arises
in children following trauma or surgery, with significant infections or
inflammation, during chemotherapy for cancer, or in relationship to the
use of indwelling venous catheters placed to aid delivery of medicines.
The most frequent risk factor for DVT in children is inflammation.
Recently published reviews indicate that children with DVT are at risk
for thrombus recurrence as well as long-term complications of DVT (5,6).
While the risk of DVT is lower in children, the number of children
suffering DVT is increasing because, with improved intensive supportive
care, 80% of children survive who develop DVT during treatment for
conditions like leukemia and severe prematurity that previously were
fatal. DVT is an important and increasing problem in infancy, childhood
and adolescence.

Most adults develop DVT in middle to later age. Unlike older adults with
DVT, children are expected to survive for six or more decades following
an episode of DVT. The post thrombotic syndrome or PTS is a condition
marked by limb swelling and pain that develops following DVT and is
aggravated by activity. PTS is likely to incur more disability and
health care costs in children compared with adults (5,6). Running and
active sports are important for normal growth and development in
children. The disability of severe PTS profoundly lowers quality of life
for young children. Health and cost burdens of DVT and its long-term
complications are disproportionately higher in pediatric patients.

Because the actual rate of DVT in all children who undergo surgery or
infection is still very low, prevention of DVT using a universal
prophylaxis strategy, for example with blood thinners, is not practical
in children as it is in adults and would result in more complications
caused than the number prevented. Therefore, it is critical to determine
predictors of which children will benefit from targeted DVT
prevention.** **

A major barrier to achieving the best outcomes in children with DVT is a
lack of knowledge regarding the effect of different drugs, drug dosages
and treatment schedules in children. Dosing of antithrombotic therapies
specific for children is necessary because developmental differences in
children affect how blood clots are formed and dissolved as well as how
young bodies use and clear drugs. For example dosing of the low
molecular weight heparin, enoxaparin, is age-related in children, with
younger children requiring higher doses and a broader range of doses in
order to be within the targeted therapeutic range (7). In addition,
infants and children may be able to tolerate intensive drug regimens
better than adults with fewer bleeding complications because they have
generally better health and organ function.

Using a validated, structured examination for PTS, we found that
approximately 50% of children show signs of PTS one year following an
episode of DVT, and the rate of PTS is similar at 2 years (7-9).
Furthermore, the risk of PTS could be predicted by characteristics of
the child, characteristics of the DVT and characteristics of the
treatment.

Child factors:

Adolescents are at higher risk for pain and limb dysfunction following
DVT as compared with infants and children under the age of 12 years
(10).

Overweight pediatric patients with BMI \> 29 are at greater risk for PTS
compared with children who have a BMI of 29 or less (MSRHTC, unpublished
data, 2006).

Blood markers measured at the time of presentation with DVT predict poor
outcomes including DVT progression, recurrence and the PTS (11). Blood
markers of clotting activation such as the D-Dimer and markers of
inflammation like factor VIII activity can be used to identify children
at risk for poor DVT outcomes.

There are a number of traits that convey an increased tendency to form
DVT. Traits promoting DVT are shown on Table 2. The state of carrying
one or more of these traits is termed thrombophilia. DVT in children
with thrombophilia usually develops during a triggering event, such as
the ones described above. Certain thrombophilia traits, particularly
factor V Leiden, interact with estrogens and precipitate DVT in
teenagers in association with oral contraceptive agents. Because the
risk of DVT in children and adolescents with a single thrombophilic
trait is low, there is no benefit from mass screening of asymptomatic
children. However certain children, including children with highly
positive family history who are undergoing high-risk surgery or other
interventions may benefit from screening. There is emerging evidence
that children with multiple trait thrombophilia have an increased risk
for DVT recurrence (4).

DVT factors:

Persistent venous blockage by blood clot appears to be a major cause of
DVT recurrence in children and adolescence (7,8). Failure to resolve
venous obstruction by DVT by one year predicts physical abnormalities
and pain.

Treatment factors:

The lag time before starting treatment for DVT in children has been a
problem because physicians were not used to thinking of DVT as a
possible cause of painful swollen limbs or organ malfunction in young
children and teens. Delayed diagnosis and start of therapy results in a
lower rate of DVT resolution and a higher rate of pain following DVT
(12).

Conclusions:

-   DVT is an important and increasing problem in pediatrics as more
    children are surviving serious medical conditions that previously
    were fatal and DVT often occurs as complications of intensive care.

-   Health and cost burdens of DVT and its long-term complications are
    disproportionately higher in children because most children will
    live 60 to 80 years following an episode of DVT and the post
    thrombotic syndrome limits aerobic activities that are necessary for
    normal childhood development.

-   DVT trials specific for children are urgently needed.

References:

1\) Journeycake J, Manco-Johnson MJ. Thrombosis during infancy: what we
know and what we do not know. Hematol Oncol Clin North Am.
2004;18:1315-38.

2\) Nowak-Gottl U, et al Arch Dis Child Fetal Neonatal Ed 1998;78:F163

3\) Andrew M et al. Blood 1994;83:1251-7.

4\) Mathew P, Manco-Johnson M, Hutter JJ, Hanrahan J, Knapp-Clevenger R,
Miller B, Schwartz M, Bleak S, Goldenberg N, Hays T. Early clot
recurrence or progression is not increased in children with genetic
thrombophilia---preliminary results from the Regional Thrombophilia
Registry Eight and Ten (the ReTREAT Study). Blood 2003;102:548a.

5\) Goldenberg NA. Long-term outcomes of venous thrombosis in children.
Curr Opin Hematol 2005;12:370-6.

6\) Manco-Johnson MJ. Postthrombotic syndrome in children. Acta Hematol
2006;115:207-13.

7\) Manco-Johnson MJ. How I treat venous thrombosis in children. Blood
2006;107:1-9.

8\) Manco-Johnson MJ, Knapp-Clevenger R, Miller B, Hays T.
Post-thrombotic syndrome (PTS) in children: validation of a new
pediatric outcome instrument and results in a comprehensive cohort of
children with extremity deep vein thrombosis (DVT). Blood 2003;102:553a.

9\) Manco-Johnson MJ, Hays T, Knapp-Clevenger R, Riske B, Miller B.
Outcome of thrombosis in children: Results of a pilot thrombophilia
program. Blood 2002:100:282a.

10\) Manco-Johnson MJ, Knapp-Clevenger R, Miller B, Hays T.
Post-thrombotic syndrome (PTS) in children: validation of a new
pediatric outcome instrument and results in a comprehensive cohort of
children with extremity deep vein thrombosis (DVT). Blood 2003;102:553a.

11\) Goldenberg N, Knapp-Clevenger R, Manco-Johnson MJ. Elevated plasma
factor VIII and D-dimer levels predict poor thrombotic outcomes in
children. New Eng J Med 2004;351:1081-8.

12\) Manco-Johnson M, Graham D, Valentino L, Knapp-Clevenger R. Low
molecular weight heparin dose requirements are age-related through
childhood. Pediatr Res 2003;53:284a.

Table 1: Risk Factors Predisposing to DVT in Children

**Time-Limited Risk Factors:**

Indwelling Catheters

Infection

Post-infectious Antiphospholipid Antibodies

Surgery

Surgically Correctable Congenital Heart Disease

**On-Going Risk Factors:**

Genetic Thrombophilia

Primary or Secondary Antiphospholipid Antibody Syndromes

Leukemia, Cancer and Chemotherapy

Inflammatory Diseases

Systemic Lupus Erythematosus, Inflammatory Bowel Disease, Rheumatoid
Arthritis

Prosthetic Cardiac Valves

Sickle Cell Anemia

Table 2: Thrombophilic Traits Predisposing to DVT in Children

*Genetic Traits:*

Decreased or Dysfunction: Antithrombin, Protein C, Protein S

Founder Mutations: Factor V Leiden, Prothrombin 20210

Elevated: Homocysteine, Lp(a)

*Acquired Traits:*

Antiphospholipid Antibodies (APA):

Lupus Anticoagulant

Anticardiolipin Antibodies

Anti-β2GP1-antibodies

Acquired abnormalities in Antithrombin, Protein C, Protein S