infant Development of the human coagulation ...

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1988 72: 1651-1657

Development of the human coagulation system in the healthy premature infant M Andrew, B Paes, R Milner, M Johnston, L Mitchell, DM Tollefsen, V Castle and P Powers

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Development

of the

Human

Coagulation

System

in the

Healthy

Tollefsen,

V.

Premature

Infant By This

M.

Andrew,

study

was

development healthy

infants

to

The

problems

and

oxygen.

weeks

did

not

were

of

90,

and

studied

thrombin

II.

kininogen

day

V.

VII.

(vWF)J

during

the

healthy

and

VIII,

IX.

first

6 months

of

infant

was

evidence of the

tune infant identified

compared problems

lishing

reference

to the

premature

in the coagulation

tests: time,

factor

assays

high-mol-wt

von

reference in the A similar

study because

that differ

in the

infant. need

fullterm

These for data

the

beyond

the

apply need

first

for the infant of the of the prema-

equally

for a large week

of life,

and the use of plasma from the infant rather than the cord day 1 values. In addition, many premature infants are which should exclude them from a study directed determining reference system

normal values in the

postnatal determine infant

The purpose a reference

infant and

the

Thus,

there

are

no

for ill, at

complete

as yet for the components of the coagulation healthy premature infant throughout the

period. such

premature

values.

with

our

of the range

previous

following and to

data

for both

II and

X only;

for

shown

for

XII.

for

adults.

plasminogen.

postnatal

all

By

of age.

6 months in

premature

components

infants.

the with

infants age

II, V. VIII.

levels

was IX,

XI.

general,

was

the

components

the

accelerated

fullterm

of the

had

was

Next,

in 1 1 8 fullterm

with

infants

set

compared

In

a PC,

data

of gestational

adult

most

was

AT-Ill.

these

factors

as compared

there of

entire

inhibitors.

towards

infants

and

for

study effect

eight

maturation

in premature

weeks

were

fibrinogen,

and

(PC).

immunologic

levels

premature

An

C

and

the

infants

published

for

HMWK.

ranges

system

those

36 for

therefore,

premature

of a previously with

to

age

reference

the

protein

of biologic 30

Powers

infants.

coagulation

achieved

near

adult

1988

by

Grune

&

Stratton,

Inc.

study was to compare the

University Medical Centre, and informed consent was obtained for all infants. The information from the premature infants was compared with the previously published normal values for I 18 healthy fullterm infants and 29 healthy adults.’ Laboratory. The techniques for obtaining blood samples, handling blood samples, and measuring the factor assays have been described in detail for the fullterm infant.’ In brief, a 2-mb blood sample was collected in the postnatal period on days 1, 5, 30, 90, and I 80. Platelet-poor plasma (PPP) was fractionated and frozen for future coagulation studies. A combination of biologic and immunologic assays was performed using previously published micro techniques.#{176} The screening tests consisted of a prothrombin time (PT; Dade C rabbit thromboplastin with an international sensitivity index of 2.5), an activated partial thromboplastin time (APT’F; Dade Actin FS) and a 2-U thrombin clotting time (TCT). The measured components of the fibrinolytic and coagulation systems included plasminogen, fibrinogen, factors II, V, VII, VIII, IX, X, XI, XII, prekallikrein (PK), high-mol-wt kininogen (HMWK), XIIIa, XIIIb, and von Wiblebrand factor (vWF). The inhibitors measured included antithrombin III (AT-Ill), hepanin cofactor II (HCII), a,-antitryp-

the fullterm

adult. From

MATERIALS

AND

METHODS

infants (30 to 36 weeks of gestational age) born at St Joseph’s Hospital or McMaster University Medical Centre in Hamilton, between December 1, 1983 and February 1, 1987 were eligible for this study. The gestational age was based on a combination of maternal dates and the Dubowitz assessment, with the latter used in cases of disagreement. The premature population was carefully screened to exclude infants who had any of the following: peninatal asphyxia, respiratory distress syndrome, oxygen support, sepsis, ventilation, or any other significant postnatal problem. In addition, infants who were small for gestational age were not recruited for this study. All infants received 1 mg vitamin K intramuscularly (IM) at birth, and the Apgar score and mode of delivery were recorded. On each study day, information regarding head circumference, crown to heel length and weight, milk formula, and medications was recorded. This study was approved by the Ethics Committee both at St Joseph’s Hospital and at McMaster Subjects.

gestational

coagulation

results

S

of con-

levels in the

infant

include

Between

of

P.

a1-

ranges fulltenm

undertaken literature system

of the

inhibitor,

used.

generate

system

Ill (AT-Ill).

a2-macroglobulin.

life.’

to

and

values.

Willebrand

to the fullterm infant.229 All previously contributing to the difficulty of estabvalues

the

following

XIII.

1 . 5,

infants

[antithrombin

we published coagulation system

factors

used

and

esterase

Castle,

A combination

effect

and

those

(PK).

inhibitors

were

minimal

20-mi

13 XII.

assays

supplemental blood

Cl S (PS)].

a

thromboplastin

Xl.

health

on days

D.M.

protein

or

of the

a2-antiplasmin.

premature

size,

X.

the

major

premature

plasminogen;

eight II.

siderable components

sample

each partial

prekallikrein

cofactor

ECENTLY, human

96

were

entered

any

period

and

for

time.

(HMWK).

heparin

40

or

premature

and

postnatal

activated

clotting

[fibrinogen. factor

each

time.

of healthy

age) have

Mitchell, antitrypsin,

the

Hospital Hamilton

ventilation

in the

in

thirty-seven

did not

Between

on

in

L.

postnatal

Joseph’s

information

1 80.

prothrombin

St

gestational

require

obtained

the system

Centre

infants

Johnston,

mothers

either

hundred

Demographic

sample

R

36

M.

determine

Consecutive at

One

premature

Milner,

coagulation

Medical

consent.

(30

study.

to

born

University for

R.

human

infant.

infants

McMaster

were

the

premature

asked

Paes,

designed

of

premature

30.

B.

Healthy

premature

Blood, Vol 72, No 5 (November),

1988: pp 1651-1657

the

Biostatistics,

Departments

Ontario,

Hamilton. ington

of

and Pathology, Canada;

University,

and

St

Louis.

Submitted

February

23,

Supported

by

Services

Pediatrics,

St

W, Rm

charge payment. “advertisement” indicate this 1 988

the

requests

McMaster

The publication

©

of

reprint

accepted

84-25

D.M.

is a scholar

Clinical

Epidemiology,

University

Department

1988;

No.

Medical

Centre,

of Medicine,

Wash-

July

from

the

7, /988. Ontario

Tollefsen

is supported

Institutes

of Health,

the National

Address

Main

Grant

Incorporated.

HL-27589from MA.

Pediatrics, McMaster

Heart

Ontario to

M.

University

Physician by

Grant

No.

Bethesda,

MD.

Foundation.

Andrew, Health

MD, Sciences

Department

of I 200

Centre,

3N27, Hamilton, Ontario L8N 3Z5, Canada. costs ofthis article were defrayed in part by page This article must therefore be hereby marked in accordance

with

18 U.S.C.

section

1 734 solely

to

fact.

by Grune

& Stratton,

Inc.

0006-4971/88/7205-0016$3.00/o

1651


ANDREW

1652

Table

1 . Demo graphic

Data

of Study

No.

ion: Postnatal

Populat

Age

of Infants

Born

Weeks

at 34-36

of Gestation

1

5

30

90

70

49

27

28

ET AL

al Age (Days) 180 24

Weight(kg)

2.16

±

0.35

2.03

±

0.29

3.05

±

0.73

5.10

±

1.03

7.03

±

Headcircumference(cm)

32.6

±

1.4

31.4

±

1.4

34.5

±

2.1

39.5

±

42.5

±

1.0

Length(cm)

45.4

±

3.0

45.6

±

2.8

47.8

±

4.2

54.2

±

3.5 4.8

64.2

±

3.1

sin (a,-AT), a2-antiplasmin (a2-AP), a2-macroglobulin (a2-M), C1 esterase inhibitor (C,INH), protein C (PC), and protein S (PS). For each component measured, change due to gestational age between 30 and 36 weeks was assessed using both a linear analysis and a two-way analysis of variance (ANOVA) with repeated measures comparing mean values of infants from 30 to 33 weeks to those of 34 to 36 weeks at all postnatal time points. The premature data were then amalgamated into one data set, and each component measured in the premature infant was compared with previously published data for the fulbterm infant’ by measuring the change in mean values over time in the postnatal period using a two-way ANOVA with repeated measures. Specific differences between the premature and fublterm infant were then tested using Student’s test. For the latter, because of the use of up to five comparisons, P values