Childhood Thrombosis

(1)

Childhood

Thrombosis

Rachelle Nuss, MD; Tarn Hays, MD; and Marilyn Manco-Johnson, MD

ABSTRACT. Objective. The objective of our study

was to evaluate the age, sex, clinical conditions, family

history, site, catheter association, means of radiologic evaluation, development of pulmonary involvement, prevalence of antithrombin III, protein C and protein S

deficiencies, and lupus anticoagulants in children who

suffered a thrombotic event.

Methods. Data were collected on children over 1

month of age who had or developed a thrombotic event from 1987 through 1993 at two pediatric centers.

Results. Sixty-one children (mean age, 10 years)

suf-fered a thrombotic event. Males and females were equally affected. A variety of clinical prothrombotic conditions sim-ilar to those described in adults could be identified for two

thirds of the children. Family history was positive in seven children. The primary thrombotic site for two thirds of the children was the central nervous system and other centrally located blood vessels. Diagnosis of the primary thrombotic site was primarily by ultrasound. A central vascular access device was associated with 25% of thromboses. Lung in-volvement occurred in 20%. Two thirds of the children were evaluated for a lupus anticoagulant and a deficiency of protein C and protein 5; two thirds had one of these diag-nosed. For further analyses, children without an underlying prothrombotic systemic illness or precipitant at the time of thrombosis (n = 20) were compared to those with these conditions (n = 41). Central nervous system thromboses

were significantly increased in the children without

pro-thrombotic conditions. The prevalence of a deficiency of protein C or protein S or the presence of a lupus anticoag-ulant approached 90% in the group without prothrombotic conditions as compared with 50% in the other group.

Conclusion. We conclude that prospective

multi-center pediatric thrombosis studies are warranted to con-firm our preliminary findings of a high incidence of

lupus anticoagulants and protein C and protein S

defi-ciency in children with thromboses. Pediatrics 1995;96: 291-294; thrombosis, children, protein C, protein S, lupus anticoagulant.

ABBREVIATIONS. APTT, activated partial thromboplastin time; AT III, antithrombin III; PNP, platelet neutralization procedure; RVVT, Russell viper venom time; ACA, anticardiolipin antibodies; LA, lupus anticoagulant.

Thrombotic events, although relatively rare in

chil-dren, are increasingly being recognized. The

associ-ated clinical conditions and precipitating events,

ge-netic and acquired plasma coagulation protein

From the Department of Pediatrics, University of Colorado School of

Med-icine and The Children’s Hospital, Denver.

Received for publication Oct 5, 1993; accepted Nov 14, 1994.

Reprint request to (RN.) Box C-220, University of Colorado Health Sciences Center, Denver, CO 80262.

deficiencies, therapy, short- and long-term outcome,

and recurrence risk have been well studied in

adults.’6 In contrast, there is only one large

prospec-tive study of thrombosis in children that is limited to

venous thromboembolism7 and published data are

otherwise in the format of case reports primarily

focused on response to therapy.8

Here, we present the results of our retrospective

study investigating the age, sex, clinical conditions,

family history, site, catheter association, means of

radiologic evaluation, and development of

pulmo-nary involvement, found in 61 children who suffered

a thrombotic event. To better understand the

etiol-ogy of thrombosis in children, we characterized

chil-dmen as having a preexisting systemic illness known

to predispose to thrombosis (prothrombotic) or being

apparently well at the time of their thrombotic event.

We comparatively analyzed the children based on

this classification system.

Given that individuals with deficiencies of the

physiologic anticoagulant proteins, protein C,

pro-tein 5, or antithrombin III, are predisposed to

throm-boses,124 assay results for these proteins are

me-ported when available. Recognition of a coagulation

protein deficiency could impact acute management

of children with thromboses given that antithmombin

III concentrate is currently commercially available

and protein C concentrate is soon to be available in

the United States. Also, given the association

be-tween a lupus anticoagulant and thromboses

me-ported in adults,17 findings supportive of a lupus

anticoagulant are reported when available.

General

METHODS

All children over I month of age at University Hospital,

Den-ver, CO or The Children’s Hospital, Denver, CO diagnosed with

symptomatic thromboses from 1987 through 1993 are reported.

Neonates were excluded because the underlying etiologies and

pathophysiology associated with their thromboses may be differ-ent from older children. Children with thromboses secondary to solid organ transplant were excluded because the authors are

rarely involved in their care.

History, physical exam, and laboratory results were reviewed.

Data were entered onto a form designed specifically for this study. Data collected included age at time of clotting episode, sex,

pro-thrombotic conditions, family history, clot site, clot association with a venous access device, imaging technique for confirmation,

and pulmonary involvement. Hematologic evaluation of the

chil-dren was ordered by the primary caregivers, who included pedi-atricians, surgeons, and hematologists. Laboratory results re-ported here include the following assays: activated partial

thromboplastin time (AP’IT), protein C, protein S, antithrombin III (ATIII), platelet neutralization procedure (PNP), dilute Russell

viper venom time (RVVT), and anticardiolipin antibodies (ACA).

Given that there has been no standardized evaluation for a child with hypercoagulability, not every assay was performed on every

at Viet Nam:AAP Sponsored on September 1, 2020

www.aappublications.org/news

(2)

292 CHILDHOOD THROMBOSIS

child. Available test results were compared with normal values

derived in our laboratory. Evaluation for and confirmation of a lupus anticoagulant (LA) became more extensive over the 7-year time period as an association between a LA and thrombosis was increasingly being reported in adults. Treatment and outcome are not reported as treatment was random and thus relevant outcome data can not be extracted. Family history was obtained by one or more of the authors for the 57 children whose care they provided. For the other four children family history was obtained from the hospital chart. Family history was considered positive if siblings, parents, aunts, uncles, or grandparents had suffered thrombotic events at a relatively young age.

Laboratory Investigation

Two laboratories using comparable methods performed all the studies. Studies were obtained at the time of thrombosis and abnormal results were repeated after the course of therapy was completed.

PT and AlIT were performed by standard technique and served as screening tests for a LA.’8 If the AP1T was prolonged and did not correct with 3:1 or 1:1 mixing with standard pooled plasma, a PNP or a RVVT was performed by standard technique’9 to confirm the presence of a LA. Anticardiolipin antibodies were performed by ELISA.2#{176}ATTIII was quantified by a chromogenic

assay, which measures neutralization of thrombin in the presence

of heparin.2’ Protein C activity was dependent on the prolongation of the APTT after activation of plasma by the snake venom

Agkis-troden contortrix contortrix. Total protein S was assayed using

Laurell rocket immunoelectrophoresis as previously described.u Free protein S was determined by Laurel! technique with

adsorp-tion of the plasma with PEG 8000 at 10#{176}C.’

Statistical Analysis

Following completion of data collection, children were divided into two groups for analyses. We separated children with known acquired hypercoagulable conditions from those who were appar-ently well at the time of presentation with a thrombosis. Group I

is thus comprised of children for whom prothrombotic conditions,

similar to those reported in adults, could be identified. Group II children are without prothrombotic conditions. To determine whether there were statistically significant differences between Group I and II children, a test was used for comparative analysis.

Clinical

RESULTS

Children were diagnosed with a thrombosis at

either University Hospital or The Children’s

Hospi-tal, Denver, CO. At least one of the authors was

directly involved in the care of 57 of the children. An

additional four children with thromboses were

iden-tified by medical record search. The mean age for all

children was 10.2 years with a mange of 6 weeks to I 7

years. The group was comprised of 33 males and 28

females.

Underlying contributory medical conditions or

precipitating events were present in 41 children.

These included: malignancy (nine), serious infection

(six), major trauma (six), vasculitis (five), renal

dis-ease (four), systemic lupus emythematosus (three),

sickle cell anemia (three), oral contraceptives (three),

cardiac disease (one), inflammatory pulmonary

dis-ease (one), and immobilization (one). Of those with

malignancies, four had acute lymphoblastic

lym-phoma, two had brain tumors, one had Ewing’s

sam-coma, one had non-Hodgkins lymphoma, and one

had an osteoblastoma. Infections included gram

neg-ative sepsis (two), pneumonia (one), mastoiditis

(one), cellulitis following varicella (one), and a

yen-triculoperitoneal shunt infection (one). Trauma was

by automobile accidents, a fall from three stories,

wrestling, and child abuse. Five of the children had

also had recent brain or back surgery. Family history

was positive for seven children.

Sixteen thromboses involved the central nervous

system (1 1 cerebral arteries, two superior sagittal

sinus, one dural sinus, one transverse venous sinus,

and one vertebral artery). Twenty-five were

other-wise centrally located (13 iliac veins, five pulmonary

vessels, three vena cava, two cardiac graft and artery,

one renal vein, and one mesenteric artery). Thirteen

were proximal (eleven femoral and two subclavian

veins) and seven were distal (five popliteal veins and

two radial arteries). Fifteen clots were associated

with a venous access device including central and

peripheral venous catheters, arterial catheters, and

dialysis shunts.

All of the thromboses were radiologically and/or

surgically confirmed. Confirmation of the

thrombo-ses in the children was by one or more of the

follow-ing: ultrasound (29), ventilation/perfusion scan (6),

CAT scan (10), magnetic resonance imaging (11),

venogram/artemiogram (10), and surgery (4). Eleven

children had or developed pulmonary involvement

including four children without another documented

site, three with a documented primary site at

presen-tation and four who developed pulmonary emboli

during therapy. All pulmonary emboli were

con-firmed by ventilation perfusion scan.

Laboratory

All but three children had an APTT performed at

presentation; 18 were prolonged (two of the children

had DIC) and the APTT did not correct with normal

plasma. Seventeen of the eighteen children with a

prolonged APTT had one or more positive

confirma-tory tests for an antiphospholipid antibody including

PNP (12), ACA (five), and/or RVVT (two).

Fifty-three children were evaluated for a

defi-ciency of ATIII; two had transiently low levels that

on repeat testing became normal. One child had

inflammatory lung disease and the other DIC.

Forty-six children were evaluated for protein C

deficiency; nine were found deficient. Their sites of

thromboses were: central nervous system (two),

cen-tral vessels (six), and distal vein (one). Two were

proven genetic by family studies and two had

par-ents with levels in the normal range. These two

chil-dren had persistently low levels on repeat testing

suggesting they were protein C heterozygotes. DNA

studies have not yet been performed on the parents

to determine whether one of them is a genetic

het-erozygote with normal plasma protein C activity.24

Three children had presumptive acquired protein C

deficiency; two had low protein C activity in

associ-ation with a lupus anticoagulant, one child had

sep-sis and DIC and another had vasculitis. One child

with a vertebral artery thrombosis after head trauma

from wrestling was studied only acutely and refused

repeat testing or family studies so it is undetermined

whether his deficiency was genetic or acquired.

Forty-three children were evaluated for protein S

deficiency. Three were found deficient and each had

iliofemoral thromboses. Two deficiencies were

(3)

TABLE 1. Results by Group

Group I (N = 41) Group II (N = 20) Pvalue

(Prothrombotic) (Nonprothrombotic)

Age (y) 9.6 (6t) 10.9 (4.3) NS*

Females:males 19:22 9:11 NS

Family history 3 4 NS

Positive

Primary Location of Thrombosis:

Central nervous system 7 9 .02

Central (non-central nervous system) 17 8 NS

Proximal 11 2 NS

Distal 6 1 NS

Line-associated thrombosis 15 0 .007

Pulmonary involvement 7 4 NS

t Standard deviation.

*NS, not significant.

presumably genetically inherited; the mother of one

had a history of recurrent thromboses and had died

of a pulmonary embolism and the other had multiple

family members who proved deficient. The cause in

the third is unclear but his low protein S activity has

persisted. His parents have protein S levels in the

normal range. He was also found to be activated

protein C cofactor deficient and family studies for

this are pending.25

Of the 61 children, 40 had a complete evaluation

for a deficiency of protein C, protein S and ATIII, and

assessment for a LA. Of these, 26 were found to

either have a LA or protein C or protein S deficiency.

Twenty of the 61 children did not have an

under-lying disorder or obvious precipitant for their

throm-bosis. Data comparing them with the 41 children

with underlying disorders or obvious precipitants

are shown in Tables I and 2. Except for the

labora-tory test results, they differed only in that those

children without prothrombotic conditions had a

sig-nificantly increased prevalence of central nervous

system thromboses.

DISCUSSION

Eighty percent of adults with thromboses have

acquired hypercoagulable conditions or precipitating

events.26 These include: collagen vascular disease,

infection, malignancy, renal disease, hemolytic

ane-mias, indwelling catheters, surgery, and trauma.

There are no large series about hypercoagulable

con-ditions and precipitating events in children with a

broad spectrum of thromboses. In the only large

series of children, Andrew et al reviewed all

litema-ture from 1975 through 1991 specifically relevant to

venous thromboembolism in children and reported

that 98% of those children with deep vein thrombosis

or pulmonary embolism had a serious underlying

disorder or precipitating factor, similar to those

found in adults.7 We studied children with a broader

spectrum of thrombotic sites and found similar

un-derlying conditions and precipitants in 70% of the

children.

It has historically been reported that 4 to 8% of

adults with a thrombosis have a hemostatic disorder

that predisposes to thrombosis.2’4’24 In the series by

Andrew et al, 45 of 137 children were evaluated for

deficiencies of protein S and protein C; six (13%)

were found to be genetically deficient for protein S

and six (13%) were found to be genetically deficient

for protein C. We found, in our series of children

with a broader spectrum of thromboses, that

appmox-imately 7% and 20% of those tested were found to

have an acquired or genetic deficiency of protein S or

protein C, respectively. We detected LAs much more

frequently. Overall, of forty children studied, a LA or

deficiency of protein C, or protein S was present in

two thirds. ATIII deficiency was infrequently seen.

To better understand the cause of thrombosis in

children, we analyzed findings in those children

without underlying systemic prothrombotic illnesses

or obvious precipitants of thrombosis and compared

them with findings in children with hypemcoagulable

conditions. Approximately one third of the children

did not have underlying pmothrombotic conditions

and were apparently well at the time of their

thmom-botic event. The children without a hypercoagulable

condition had a significantly increased prevalence of

central nervous system thromboses. A deficiency of

TABLE 2. Results by Group-Laboratory

Group I Group II P value

(Prothrombotic) (Nonprothrombotic)

Plasma protein deficiency

Protein C 5/28* 4/18 NSt

Protein S 0/26 3/17 NS

Antithrombin III 2/35 0/18 NS

Lupus anticoagulant 9/39 8/19 NS

Either plasma protein deficiency or 13/25 13/15 .02

lupus anticoagulant

*Number positive/number tested.

t Not significant.

(4)

294 CHILDHOOD THROMBOSIS

either protein C or protein S or the presence of a LA

could be identified in almost 90% of these children as

compared with 50% of those with prothrombotic

conditions. Whether these children without obvious

prothmombotic clinical conditions are at a

signifi-cantly increased risk for one of these abnormalities is

unclear given that the 95% confidence interval was

quite large suggesting a larger sample would be

needed to be conclusive. Also proportionately more

children without an obvious prothmombotic clinical

condition were studied.

Although our study is retrospective, with just

two thirds of children in each group completely

evaluated for a LA and deficiency of ATIII, protein

C and protein 5, the findings suggest there is a

high prevalence of LAs and deficiencies of protein

C and protein S in children with thromboses.

Larger, prospective multicenter studies are

neces-sary for confirmation of our findings. These

stud-ies should also include investigations for the

me-cently described defect in Factor V, termed

activated protein C resistance, which may prove to

be the most common cause of familial venous

thrombosis.25 Appropriate guidelines for

evalua-tion of children with thromboses can not be

estab-lished in the absence of such studies. Until then,

we suggest evaluation of children with thromboses

minimally include assessment for a LA and a

de-ficiency of protein C and protein S.

ACKNOWLEDGMENTS

Supported by General Clinical Research Centers Program

(Grant number MOl RR00069), the National Center for Research Resources, and the National Institutes Health.

The authors wish to express their appreciation to Drs Urmish

Chudgar and William Hathaway.

REFERENCES

I. Bick R, Ucar K. Hypercoagulability and thrombosis. Hematol Oncol Cliii North Am. 1992;6:1421-1429

2. Tabernero M, Tomas J, Alberca I, Orfao A, Borrasca A, Vicente V. Incidence and clinical characteristics of hereditary disorders associated with venous thrombosis. A,?: JHe,natol. 1991;36:249-254

3. Heijboer H, Brandjes D, Buller H, Sturk A, Wouten the Cate.

Deficien-cies of coagulation inhibiting and fibrinolytic proteins in outpatients with deep-vein thrombosis. N Engl IMed. 1990;323:1512-1516

4. MaIm J, Laurell M, Nilsson I, Dahiback B. Thromboembolic disease-critical evaluation of laboratory investigation. Thromb Haemost. 1992;8:

7-13

5. Hirsh J. Oral anticoagulant drugs. N EngI JMed. 1991;324:1865-1875

6. Rogers L, Lutcher C. Streptokinase therapy for deep vein thrombosis: a comprehensive review of the English literature. Am JMed. 1990;88:

389-395

7. Andrew M, David M, Adams M, et al. Venous thromboembolic complications in children. I Pediatr. 1993;123:337-346

8. Whitlock J, Janco R, Phillips J. Inherited hypercoagulable states in children. Am IPediatr Hematol Oncol. 1989;l1;170-173

9. Rosenbaum T, Rammos 5, Kniemeyer H-W, Gobel U. Extended deep

vein and inferior vena cava thrombosis in a 15-year-old boy: successful

lysis with recombinant tissue-type plasminogen activator 2 weeks after onset of symptoms. Eur IPediatr. 1993;152:978-980

10. Levy M, Benson L, Burrows P. et al. Tissue plasminogen activator for the treatment of thromboembolism in infants and children. I Pediatr.

1991;1 18:467-482

ii. Ryan CA, Andrew M. Failure of thrombolytic therapy in four children

with extensive thromboses. Am JDis Child. 1992;146:187-193

12. Marlar RA, Montgomery R, Broeckmans AW. Diagnosis and treatment

of homozygous protein C deficiency. IPediatr. 1989;114:528-534

13. Engesser L, Broekmans, Briet E, et al. Hereditary protein S deficiency:

clinical manifestations. Ann Intern Med. 1978;106:677-682

14. Demers D, Ginsberg J,Hirsh J. Thrombosis in ATIII deficient persons. Report of a large kindred and literature review. Ann Inter,, Med. 1992;

16:754-761

15. Ginsburg K, Liang M, Newcomer L, et al. Anticardiolipin antibodies and the risk for ischemic stroke and venous thrombosis. Ann Intern Mcd.

1992;1 17:997-1002

16. Bernstein M, Salusinsky-Sternbach M, Bellefleur M, Esseltine D. Throm-botic and hemorrhagic complications in children with the lupus

anticoagulant. Am IDis Child. 1984;138:1132-1135

17. Mayumi T, Nagasawa K, Inoguchi T, et al. Haemostatic factors associ-ated with vascular thrombosis in patients with systemic lupus

erythem-atosus and the lupus anticoagulant. Ann Rheum Dis. 1991;50:543-547 18. Cameron J, Frampton G. The “antiphospholipid syndrome” and the

“lupus anticoagulant.” Pediatr Nephrol. 1990;4:663-678

19. Exner T, Triplett D, Tabemer D, Machin S. Guidelines for testing and revised criteria for lupus anticoagulants. Thromb Haemost. 1991;65: 320-322

20. Hughes GRV, Harris EN, Gharavi AE. The anticardiolipin syndrome.

IRheumatol. 1986;133:486-489

21. SambranoJ, Jacobson L, Reeve E, Hathaway W. Abnormal antithrombin

III with defective serine protease binding (antithrombin III “Denver”). I

Cli,, Invest. 1986;77:887-893

22. Manco-Johnson M, Marlar R, Jacobson L, Hays T, Warady B. Severe

protein C deficiency in newborn infants. IPediatr. 1986;109:843-845

23. Manco-Johnson M, Abshire T, Jacobson L, Marlar R. Severe neonatal

protein C deficiency: prevalence and thrombotic risk. IPediatr. 1991;119: 793-798

24. Allaart CF. Poort 5, Rosendal F, Reitsma P. Bertina R. Increased risk of venous thrombosis in carriers of hereditary protein C deficiency defect. Lancet. 1993;341 :134-138

25. Dahlback B, Hildebrand B. Inherited resistance to activated protein C is corrected by anticoagulant cofactor activity found to be a property of factor V. Proc NatI Aca Sci LiSA. 1994;91 :1396-1400

26. Bick R, Jackway J, Baker W. Deep vein thrombosis: prevalence of etiologic factors and results of management in 100 consecutive patients.

Senin Thromb Hemost. 1992;18:267-274

(5)

1995;96;291

Pediatrics

Rachelle Nuss, Taru Hays and Marilyn Manco-Johnson