Eur J Pediatr (2000) 159: 239±242

Ó Springer-Verlag 2000

ORIGINAL PAPER

Friedrich A. M. Baumeister á Karin Auberger á Karl Schneider

Thrombosis of the deep cerebral veins
with excessive bilateral infarction in a premature infant
with the thrombogenic 4G/4G genotype
of the plasminogen activator inhibitor-1
Received: 25 March 1999 and in revised form: 22 June 1999 / Accepted: 15 September 1999

Abstract We report on a preterm infant with deep cerebral venous thrombosis, a rare
condition in this age group. This premature infant had a gestational age of 33 weeks and
normal development until day 18, when he presented with tonic seizures and a tense
fontanelle. Ultrasound and computed tomography revealed bilateral haemorrhagic infarction of the whole region drained by the deep cerebral veins, including the periventricular white matter, thalamus and choroid plexus. The child was homozygous for
the 4G allele of the plasminogen activator inhibitor-1 (PAI-1) 4G/5G promoter polymorphism.
Conclusion In patients with bilateral cerebral infarction, thrombosis of the deep cerebral
veins should be considered. In addition the role of prothrombotic risk factors, including
PAI-1 4G/5G promoter polymorphism, in cerebral vein thrombosis should be clari®ed
in a multicentre study.
Key words Thrombosis á Deep cerebral veins á Preterm á Newborn á Plasminogen
activator inhibitor-1
Abbreviations PAI-1 plasminogen activator inhibitor-1 á CT computed tomography

Introduction

Thrombosis of the deep venous drainage of the brain has
been characterised by clinical and radiographic ®ndings
in adults [2]. Reports of thrombosis of the deep cerebral
veins in term newborns are rare [1, 11] and the condition
has been reported in only two premature infants [11, 19].
We describe deep cerebral venous infarction in a
preterm infant homozygous for plasminogen activator
inhibitor-1 (PAI-1) 4G/4G promoter polymorphism,
Co-investigators with Karin Auberger in the childhood thrombophilia study group were Marion Hofer, Georg MuÈnch, Georg
Simbruner (Kinderklinik und Kinderpoliklinik im Dr v. Haunerschen Kinderspital der UniversitaÈt MuÈnchen), Ralf Junker
(Institut fuÈr Klinische Chemie und Laboratoriumsmedizin, WestfaÈlische Wilhelms-UniversitaÈt, MuÈnster), Ulrike Nowak-GoÈttl
(PaÈdiatrische HaÈmatologie und Onkologie, Klinik und Poliklinik
fuÈr PaÈdiatrie, WestfaÈlische Wilhelms-UniversitaÈt, MuÈnster)
Friedrich A. M. Baumeister (&)
Kinderklinik und Poliklinik

which may constitute an additional prothrombotic
factor initiating the clinical manifestation of cerebral
venous thrombosis in carriers of prothrombotic risk
factors [15].
Case report
A male infant at 33 weeks of gestation was delivered by Caesarean
section because of the HELLP-syndrome of the mother. The
mother had abdominal pain, hypertension (150/100 mmHg), lightly
der Technischen UniversitaÈt MuÈnchen,
Kinderklinik Schwabing, KoÈlner Platz 1,
80804 MuÈnchen, Germany
e-mail: u7r11cf@mail.lrz-muenchen.de
Tel.: +49-89-30682591
Karin Auberger á Karl Schneider
Kinderklinik und Kinderpoliklinik im Dr v. Haunerschen
Kinderspital der UniversitaÈt MuÈnchen,
Lindwurmstraûe 4, 80337 MuÈnchen, Germany

240
increased alanine aminotransferase (61 U/l, normal <23 U/l),
thrombocytopenia (75,000/ll) and oedema. The Apgar scores were
7 at 1 and 8 at 5 and 10 min. The infant had a birthweight of 1560 g
and was in a clinically stable condition requiring ventilatory support for 3 days because of a mild respiratory distress syndrome.
Polycythaemia with a venous haematocrit of 69% was treated with
a partial plasma exchange transfusion on the 2nd day of life. The
further postnatal course was uneventful until the 18th day of life,
when unexpected sudden generalised opisthotonic seizures with
extensor rigidity of the limbs occurred, together with a tense
fontanelle. The haematocrit decreased from 48% to 36% within
two days. The infant was lethargic and hypotonic. His pupils were
equal and reactive. The sucking re¯ex was weak, and grasp and
tendon re¯exes were absent. The intermittent seizures were controlled with midazolam and later with phenobarbital. The infant
gradually improved over the following 3 weeks; sucking, grasp and
tendon re¯exes reappeared, hypotonia decreased and he became
more active. At the age of 8 months he was su€ering from spastic
quadriplegia, mental retardation and epileptic seizures.
The initial ultrasound scan performed on day 3 was completely
normal. An ultrasound scan immediately after the seizure on day
18 and computed tomography (CT) 12 h later revealed 1) bilateral
infarction of the thalami, 2) bilateral haemorrhagic infarction of
the white matter, extending from frontal to occipital, with a sharp
delimitation against an una€ected subcortical area 0.5 to 1 cm
below the cortex, 3) haemorrhagic infarction of the plexus in both
lateral ventricles and intraventricular haemorrhage (Fig. 1), and 4)
while the ¯ow in the superior sagittal sinus was normal, duplexscanning demonstrated no ¯ow in the great vein of Galen, indicating venous occlusion. Thrombosis was visualised in the
non-contrast enhanced CT by the abnormally hyperdense appearance of the internal cerebral veins, the vein of Galen (Fig. 2) and
the straight sinus. The diagnosis of thrombosis was also supported
by an increase in D-dimers up to 8 mg/l (normal <1.0 mg/l) (Nyco
Card) 4 days after the ®rst seizure.
Subsequent sonographic observations demonstrated recanalization after 8 days and the development of bilateral multicystic
regression in the following weeks.
The child was homozygous (4G/4G) for the deleted allele of the
PAI-1 gene. PAI-1 4G/5G polymorphism was determined using a
modi®ed method of Falk et al. [8].

Fig. 2 Non-contrast enhanced CT revealed the thrombus in the
internal cerebral veins (1) and the vein of Galen (2) through its
abnormally dense appearance

The clinical evaluation and laboratory investigations excluded
septicaemia, asphyxia and any abnormalities in PT (77%, normal
45±85), PTT (52.6 s, normal: 35±65) antithrombin (95%, normal
30±50), protein S (71%, normal 30±50), protein C activity (30%,
normal 30±50; 8 months 75%), ®brinogen (193 mg/dl, normal 150±
350), plasminogen (77%; normal 50±100), activated protein C resistance (2,27), lipoprotein (a) (5 mg/dl, normal <30), platelet
count and platelet size. Mutations of factor V (G1691 A) and
prothrombin (G20210 A) were excluded and maternal anticardiolipin antibodies were negative. Metabolic screening revealed
normal values for lactate and homocysteine (3.7 lmol/l, normal
<10). The patient was heterozygous for a mutation of the
methylenetetrahydrofolate reductase gene (C677 > T transition).
Aminoacidopathias and organoacidurias, especially 3-hydroxyacyl
coenzyme A dehydrogenase de®ciency and carbohydrate-de®cient
glycoprotein syndrome, could be excluded. No malformation of the
vena cerebri magna was demonstrated by magnetic resonance
imaging.

Discussion

Fig. 1 Cerebral spiral CT 12 h after the seizure showed di€use
hypodensity throughout both cerebral hemispheres, with haemorrhaging into the cortical white matter and into the plexus of both
lateral ventricles. Blood was seen in the posterior horn of the left
lateral ventricle (arrow)

This case report describes thrombotic infarction of the
whole region drained by deep cerebral veins. Deep cerebral venous thrombosis during the neonatal period
had already been observed in 1875, as mentioned by
Ehlers [3]. However only a few reports of this condition
in newborns at term and only two in premature infants
have been published so far [1, 11, 19]. Compared to
dural sinus thrombosis, thrombosis of the deep cerebral
veins is rare [19, 20].
Thrombosis of the great vein of Galen and/or the
deep cerebral veins leads to venous infarction with
haemorrhagic necrotic zones in the drained regions, especially in the thalamus and the periventricular white
matter [11, 12]. Because the venous drainage of the
choroid plexus of the lateral ventricles occurs by way of
the deep cerebral veins, thrombosis of these veins is

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nearly always associated with intraventricular haemorrhage [11, 12].
Consequently a pattern of bilateral cerebral lesions
a€ecting the thalamus, white matter and choroid plexus
suggests occlusion of the vena cerebri magna and/or the
deep cerebral veins.
In the premature infant described here, the diagnosis
of deep cerebral venous thrombosis was con®rmed by
Doppler sonography and CT. The duplex scan demonstrated the absence of ¯ow in the great vein of Galen,
indicating venous occlusion, while non-contrast enhanced CT visualised the thrombus. The description
di€ers from previous reports by the maximal extension
of deep cerebral venous infarction, with bilateral lesions
of the thalamus, white matter and choroid plexus associated with intraventricular haemorrhage.
The pathogenesis of cerebral venous infarction often
remains unclear. It has been reported in association with
coagulopathy, hyperviscosity, asphyxia, sepsis, meningitis and compression of the jugular veins [1, 11, 15, 18, 20].
A greater prevalence of prothrombotic mutations
than in full-term infants has been demonstrated in preterm infants of very low birth weight (<1500 g) [10],
indicating an increased risk of thrombosis in the latter
group. In the patient reported here, apart from the
polycythaemia which was treated with blood-plasma
exchange transfusion, the PAI-1 polymorphism (4G/4G)
might be a possible risk factor for the thrombotic event.
The ®brinolytic potential of the vasculature is
modulated primarily by the activity of plasminogen
activators, which convert plasminogen into the ®brindegrading enzyme plasmin. PAI-1 is a major physiological inhibitor of ®brinolysis [4, 14, 21]. The
regulation of PAI-1 transcription by endothelial cells
is incompletely understood. However the 4G/5G
polymorphism in the PAI-1 promoter is of functional
importance in regulating the expression of the PAI-1
gene under stimulation [14]. Cell culture experiments
have demonstrated that the 4G allele of the PAI-1
promoter results in increased mRNA transcription in
response to cytokine stimulation compared to the 5G
allele, while there is little or no di€erence under basal
conditions [14].
Patients who are homozygous for the 4G allele have
higher PAI-1 levels than patients who are either heterozygous or homozygous for the 5G-allele [13, 14, 16,
21] and there is considerable evidence for the relevance
of increased PAI-1 activity in thrombotic disorders [14].
In an animal model with transgenic mice, elevated levels
of PAI-1 were closely associated with the development
of venous occlusions [4]. In patients with familial autosomal dominantly transmitted hypo®brinolysis, high
PAI-1 concentrations are associated with idiopathic
osteonecrosis, which is thought to be caused by inadequate lysis of thrombin in the bone venous circulation
[9]. An up-regulation of PAI-1 has been demonstrated in
thrombotic microangiopathy of the kidney [22] and the
4G/4G genotype is associated with increased PAI-1
activity and myocardial infarction [5, 16].

From the available clinical data there is no certainty
that an increased PAI-1 level causing poor ®brinolytic
function is an independent risk factor for venous
thrombosis [17, 21, 23]. However there is evidence that
increased PAI-1 levels may be a particular risk for
thrombotic events in association with other prothrombotic factors. Postoperative venous thrombosis is
associated with impaired ®brinolysis caused by increased levels of PAI-1 [17]. Further the PAI-1 4G/4Ggenotype is associated with pulmonary embolism in
patients with hereditary protein S de®ciency [23] and
with cerebral sinus thrombosis in factor V-Leiden
carriers [15].
The HELLP-syndrome of the mother is probably an
additional exogenous prothrombotic factor. In patients
with pre-eclampsia high levels of PAI-1 result in
depressed ®brinolysis, positively correlated with the
severity of placental damage [6, 7].
Further investigations should focus on the interaction
of the HELLP-syndrome or pre-eclampsia with PAI-1
promoter 4G/5G polymorphism or further prothrombotic risk factors in neonatal thrombosis of the cerebral
veins.
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