# Low-Molecular-Weight Heparin Use in a Case of  Noncardiogenic Multifocal Perinatal Thromboembolic Stroke

Authors: Matthew A. Saxonhouse; Dan Tarquinio; Paul R. Carney; Jeff Bennett; Amy Smith; Stephen P. Hunger; James D. Geyer
Journal: Advances in Hematology
 (2009)

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## Abstract

A full-term neonate suffered multifocal cerebral infarctions due to multiple large vessel thrombi. Thrombophilia and cardiovascular assessments were negative, but due to the severity of the lesions and the concern for expansion of the thrombi or future embolic events, treatment with low-molecular-weight heparin (LMWH) was initiated. No complications from treatment were experienced. We present this severe case in order to highlight difficult management decisions for newborns with multifocal perinatal thromboembolic stroke and to stress the need for further practice guidelines and research in this area.


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## Body

## 1. Introduction

Perinatal
stroke,  occurring between 20 weeks' gestation through the 28th postnatal day [1–3], has a
prevalence ranging from 17.0 to 43.4 per 100 000 live births [4–6]. The
majority (80%) of these events is ischemic in nature and most abnormalities
occur in the left hemisphere within the distribution of the middle cerebral
artery (MCA). Rarely, multifocal
cerebral infarctions can occur and these tend to be embolic in origin [7, 8].Despite the prevalence of perinatal
stroke, no randomized clinical trials exist to address acute management or
prevention [1, 8, 9]. Current
guidelines from the American College of Chest Physicians (ACCP) suggest
anticoagulation or aspirin therapy only for neonates with a first perinatal
stroke with a documented ongoing cardioembolic source (Grade IB) or recurrent arterial
ischemic stroke (AIS; Grade 2C) [9]. However, recent recommendations
from the American Heart Association (AHA) suggest that anticoagulation may be
selected in neonates with multiple cerebral emboli (Class IIb, Level of
Evidence C) [1].We present a neonate who suffered
multifocal cerebral infarctions due to thrombosis of five vessels. No evidence
suggested cardiac disease or a prothrombotic disorder. Due to the severity,
size, and locations of the thrombi, plus the multifocal presentation of the
cerebral infarctions, we decided to anticoagulate the patient with low-molecular-weight
heparin (LMWH) in an attempt to decrease the risk of extension of the thrombi
and/or secondary emboli. This case of multifocal thromboembolic perinatal
stroke represents the most severe end of the spectrum and highlights the
difficulties inherent in management of these types of patients.


## 2. Case Report

A 40-week, 2884 g, female infant was delivered via
cesarean section to a 41-year-old primigravida after arrest of descent and
failed vacuum extraction. Complications of the pregnancy included a history of
infertility, gestational diabetes (glyburide controlled), prolonged rupture of
membranes, and chorioamnionitis. Apgar scores were 1, 7, and 8. Umbilical
artery and venous pH were 6.94 and 7.06, respectively. Initial blood testing
was nonspecific. Physical examination was significant for a large left caput
succedaneum with a soft and flat anterior fontanel. Neurological examination
demonstrated mild hypotonia. At approximately 36 hours of age, the patient had
seizure activity consisting of eye fluttering, bilateral clonic movements of
the upper extremities, and tongue thrusting. Two separate events occurred, each
lasting less than three minutes.Repeat blood testing revealed a normal
glucose level, no significant electrolyte abnormalities, a white blood count of9.8×103/mm3, and hematocrit of 46.8%. The platelet count had
decreased from 155 (initial) to 119×103/mm3 with subsequent drop to 109×103/mm3 twenty four hours later. Cerebrospinal fluid evaluation revealed
(traumatic lumbar puncture) 115000/mm3 red blood cells, 50/mm3 white blood cells with 87% polys and 12% lymphs.
The patient was given a loading dose of phenobarbital, and ampicillin and gentamicin
had been started shortly after birth.Magnetic resonance imaging (MRI) of the
brain (Figure1) demonstrated bilateral multifocal regions of increased signal
on diffusion-weighted imaging in the left pons, left occipital lobe, left
thalamus, left and right frontal lobes, and left and right frontoparietal
regions. No evidence indicated hemorrhage, and all of the lesions were dark on apparent
diffusion coefficient of water (ADC) mapping indicating that they were acute in
nature (within 1 week). A transthoracic echocardiogram demonstrated normal
cardiac anatomy with no intracardiac thrombus or vegetation. Magnetic resonance
angiography (MRA) of the head and neck without contrast (Figure 2) demonstrated
occlusion of the right internal carotid artery (ICA) at its origin without distal
reconstitution. Collateral flow directed blood through the anterior
communicating artery to the right anterior cerebral artery (ACA) and right
middle cerebral artery (MCA). The vertebral arteries were diminutive and the
basilar artery was occluded. The posterior communicating arteries and PCAs were
not visualized. With this extent of vessel occlusion, even more widespread
brain infarction might be expected. However, the complex distribution of the
infarcts demonstrated on diffusion-weighted images can be explained by the
relative robustness of the patient’s leptomeningeal collateral vessels. EEG
evaluation demonstrated left parieto-occipital spike wave discharges with
associated slowing, excessive subtransients for age, and mild slowing and
suppression of background activity.(a)–(c): Axial
diffusion-weighted images,b=1000, demonstrate multiple areas of high signal in
bilateral frontal and parietal lobes, left occipital lobe, left thalamus, and
left pons.
(a)(b)(c)Figure 2
3D maximum-intensity
projection (MIP) image from a 3D time of flight MRA demonstrates occlusion of
the right internal carotid artery at its origin (arrow). The vertebral arteries
are diminutive (arrowheads) and the basilar artery is not visualized.Bacterial
and viral studies were negative. Placental pathology demonstrated a third
trimester placenta with acute necrotizing chorioamnionitis and a three-vessel
cord with acute funisitis (inflammation of the umbilical cord). Extensive thrombophilia
evaluation performed on day of life four (Table1) failed to identify any
inherited or acquired prothrombotic risk factors. However, other than negative
DNA mutation analysis, definitive protein abnormalities could not be ruled out
until repeat evaluation performed at 3–6 month of life [10]. State metabolic screening through the State of
Florida was negative.Table 1
Thrombophilia Evaluation Performed [10, 11].
TestPerformedTestPerformedPT1* and
2*Anti-B2
glycoprotein IgG1 and
2INR1 and
2Anti-B2
glycoprotein IgM1 and
2aPTT1 and
2Anti-phosphatidylserine
IgG1 and
2Fibrinogen1 and
2Anti-phosphatidylserine
IgM1 and
2Factor
V Leiden1Heparin
cofactor 21 and
2Prothrombin
202101Homocysteine1 and
2MTHFR1Lipoprotein
(A)1 and
2Protein
C activity1 and
2Antithrombin1 and
2Protein
S activity1 and
2Factor
VIII activity2Anticardiolipin
IgG1 and
2Lupus anticoagulant2Anticardiolipin
IgM1 and
2Factor
XII activity2Plasminogen2PT: prothrombin time; aPTT: activated partial thromboplastin time; INR: international normalized ratio; MTHFR: methylenetetrahydrofolate reductase.1* Test performed
at day of life no. 4; 2* Test performed
at four months of age.Prior
to the results of the thrombophilia evaluation, we decided to anticoagulate the
patient with LMWH. We based this decision on the occlusion of multiple large
blood vessels with evidence of multifocal cerebral infarctions, a pattern
indicative of an embolic process. Our rationale for choosing LMWH was to
decrease the risk of clot extension, which was suggested by the progressive
thrombocytopenia. LMWH was initiated, using a therapeutic antifactor Xa level
of 0.5–1.0 IU/mL.The patient had no further seizure
activity, and gradually improved during her admission. The platelet count
increased after starting therapy to156×103/mm3 and then 253×103/mm3, at 48 hours
and 96 hours, respectively. She was discharged home on day of life 13 from the
neonatal intensive care unit taking full oral feedings, and her family was
instructed to continue phenobarbital and LMWH with scheduled follow-up.MRI evaluation at four months of age
demonstrated bilateral encephalomalacia in areas of prior infarction with no
evidence of current or prior hemorrhage. Mild encephalomalacia was also seen in
the right PCA territory, which was not ischemic on the initial MRI. This likely
reflected an additional infarct which most likely occurred during or soon after
the initial scan, possibly before the initiation of LMWH. MRA evaluation
(Figure3) revealed resolution of the right ICA thrombus with overall decreased
caliber of the vessel compared to the left, and residual irregularity and
narrowing at the superior cervical segment. The intracranial vessels were all
patent, although the right PCA was diminutive. Repeat thrombophilia assessment at four months of life was negative (Table 1).3D MIP
images from a noncontrast 2D time of flight MRA demonstrate restoration of flow
in the right internal carotid artery and posterior circulation. Residual
occlusion of the distal right PCA persists (arrow).
(a)(b)We
discontinued LMWH treatment after obtaining the results of the repeat MRI, MRA,
and thrombophilia evaluations. Neurological evaluation at 4.5 months of age
demonstrated asymmetric tracking and blinking to confrontation which was worse
on the left, mildly increased flexor tone of the left upper extremity, normal
lower extremity tone and reflexes bilaterally, and age appropriate milestones
for gross motor, fine motor, and social interaction. No seizure activity has
been observed or suggested on EEG evaluation, and phenobarbital has been
weaned. Neuro-ophthalmological examination at 6 months of age demonstrated
normal visual acuity for age and normal blinking to confrontation. The patient continues to thrive and develop
at home.


## 3. Discussion

Multifocal
cerebral infarction is a rare type of perinatal stroke that tends to be embolic
in origin [8]. Despite the multiple risk factors
ascribed to perinatal stroke, little evidence exists to inform management of
these infants after initial stabilization [1, 9].
Previous studies of perinatal stroke have been limited due to small sample size
or lack of adequate control groups [6, 8].Current ACCP guidelines suggest that
only neonates with proven cardioembolic arterial ischemic stroke or those with
recurrent arterial ischemic stroke should receive treatment with
anticoagulation or aspirin therapy [9]. Recommendations from a special
writing group of the AHA stroke council and the council on cardiovascular
disease in the young [1] suggest that anticoagulation may
be considered in neonates with multiple cerebral emboli. Both of these
recommendations are based on expert opinion and case series/reports. However,
they leave the clinician with difficult treatment decisions to make when faced
with a neonate with severe multifocal perinatal thromboembolic stroke (such as
our case report).Recent research has demonstrated
increasing evidence that LMWH may play a pivotal role in perinatal stroke [12]. Studies in pediatric patients
have shown efficacy and safety of LMWH similar to that observed in adults, and
they have demonstrated that LMWH prevents progression of stroke, development of
new symptomatic thrombi, and extensions of existing thrombi [12–14]. Punzalan et al. present two children with
internal carotid artery thrombi who had either complete or partial resolution
of thrombi while being treated with LMWH [13]. One of the largest neonatal
studies involving LMWH demonstrated that with careful monitoring and laboratory
evidence of therapeutic LMWH effect, complete or partial resolution of
thromboembolism was achieved in the majority of cases [15]. Significant bleeding occurred in
four of the 62 infants, but none of the events resulted in severe sequelae or
death. Other studies and case reports have not only demonstrated similar
efficacy, but also decreased clot extension and prevention of embolic
phenomenon [16]. One limitation with applying
these reports to perinatal stroke is that only four patients in these studies
had clots in the central nervous system [15]. Although LMWH does appear to be a
safe medication for treatment and prophylaxis of neonates with perinatal stroke,
individual judgment (for now) should be applied to specific cases.This
case is characteristic of the severe end of the spectrum of perinatal stroke and
emphasizes the difficult acute management decisions regarding such
neonates. The comprehensive ACCP
guidelines provide recommendations that facilitate the standardized use of
antithrombotic and thrombolytic therapy in neonates and children. We appreciate
that extreme cases, such as the one presented, are not routinely encompassed by
such guidelines, and in these situations optimal treatment may fall outside the
recommendations provided. Other sources (such as those of the AHA) can be
referred to in order to provide some guidance but the physician may ultimately
have to make a balanced decision.We
decided to treat the neonate described above with LMWH based on the severity of
the thrombus in the right internal carotid artery and the multifocal nature of
the arterial ischemic stroke. Although the probable source of the initial
thrombus was the placenta, we believed that there was a high risk for extension
of the internal carotid thrombus and/or further embolic complications. We felt
that the potential risk associated with bleeding was significantly less than
the devastating ramifications of further central nervous system insult. Our
patient suffered no complications from the treatment and had resolution of the
thrombi, thus supporting the safety and efficacy of LMHW in neonates.We
cannot prove definitively that LMWH resulted in clot resolution without a
similar control patient and a timeline involving serial imaging studies. Serial
MRA/MRI was not performed due to the extreme cost and the potential morbidity
associated with repeated sedation. The patient's thrombocytopenia and clinical
condition improved after initiation of LMWH, suggesting that LMWH halted clot
extension. Moreover, the follow-up MRI/MRA after four months of LMWH treatment
demonstrated almost complete recanalization of the cerebral vessels. This MRI
did demonstrate encephalomalacia in the right PCA territory which was not
predicted from the original infarct pattern. However, based on consistent
clinical improvement, we strongly feel that this infarct occurred in close
proximity to the initial MRI, most likely before the initiation of LMWH. In
addition, it suggests that LMWH may have prevented further infarcts. Therefore,
we feel that this case supports the recommendations provided by the AHA for LMWH
treatment in complex cases of multiple cerebral emboli. While we recognize that
one case study does not represent strong evidence, we propose that when the ACCP
guidelines are again updated, the authors consider review and inclusion of a
subset of patients with severe multifocal noncardioembolic stroke who may
benefit from anticoagulation. This case also highlights the need for controlled
clinical trials to address the management of the broad spectrum of perinatal
stroke [2].



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*Source: 153643-2009-02-16.xml*