Page 2461 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 150 Disorders of Coagulation in the Neonate 2199

of stroke is embolism of placental thrombi via the umbilical vein Principles of Therapy
and through the patent foramen ovale of the fetus or neonate.
Evaluation of placental pathologic conditions is important because
demonstration of placental thrombi or abruption may be indicative Supportive Therapy
of maternal prothrombotic state. Furthermore, if placental thrombi
are seen histologically, the risk for recurrent events is especially As with other age groups, therapeutic modalities available to neonates
low. Long-term developmental outcomes depend on the extent of include supportive care, anticoagulation, thrombolytic agents, and
the stroke and location of the lesion; strokes involving Broca and surgical thrombectomy. The British Haemostasis and Thrombosis
Wernicke areas, the internal capsule, or the basal ganglia have a poor Task Force and the American College of Chest Physicians have
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outcome. proposed guidelines for the management of neonatal TE. Sup-
Treatment depends on whether the stroke is embolic or nonem- portive therapy is recommended for clinically silent thrombi, includ-
bolic in origin. For nonembolic AIS, current guidelines recommend ing catheter-associated events. As soon as practical, clotted catheters
against anticoagulation or aspirin for neonates with first AIS, espe- should be removed, and all documented thrombi should be followed
cially if the infarct is large or there is evidence of hemorrhage. by serial imaging. If venous access is required, one can either monitor
Anticoagulant or aspirin therapy is recommended for neonates with the clot closely or provide anticoagulation therapy.
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recurrent AIS. In a patient with a documented cardioembolic stroke,
anticoagulant therapy is suggested.
Vitamin K Antagonist Therapy
Cerebral Sinovenous Thrombosis Vitamin K antagonists, such as warfarin, are not recommended for
neonates, because liquid preparations are not available, monitoring is
Based on data from the Canadian Pediatric Ischemic Stroke Registry, complicated, and doses are variable owing to alterations in the dietary
the prevalence of cerebral sinovenous thrombosis (CSVT) is 0.67 intake of vitamin K.
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per 100,000 children, with 43% occurring in the neonatal period.
The clinical presentation may be relatively silent, or patients may
manifest with diffuse neurologic changes, seizures, and IVH. The Heparin (UFH or LMWH)
most frequently involved vessels are the superior and lateral sinuses,
and up to one-third of cases have associated venous infarction and UFH or LMWH is the mainstay of anticoagulant therapy in neo-
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subsequent hemorrhage. Up to 31% of full-term neonates with nates. The UFH and LMWH dosing regimen is outlined in the
IVH have associated CSVT, suggesting that the pathophysiology box on Treatment of Neonatal TE. Neonates require higher doses
of IVH in full-term neonates is different from that in premature of heparin than adults, owing to lower native AT levels, increased
infants. volume of distribution, and faster clearance. 3,38–40 Additionally, they
Risk factors for neonatal CSVT include perinatal asphyxia, diffuse may require supplementation with AT concentrate or FFP in cases
hypoxic injury, dehydration, infection, congenital heart disease, of heparin resistance. Anticoagulation is monitored using anti-FXa
and severe illness, with ECMO now recognized as a specific risk assays. Therapeutic anti-FXa levels are 0.3 to 0.7 units/mL for UFH
factor. The frequency of hereditary thrombophilia in neonates with and 0.5 to 1 units/mL for LMWH. There are two types of anti-FXa
CSVT ranges from 20% to 40%, with FV Leiden and MTHFR assays: (1) with exogenous AT added and (2) without exogenous
C677T occurring most often. In contrast to purpura fulminans, AT. The addition of exogenous AT allows measurement of the UFH
no cases of congenital deficiencies of protein C, protein S, or effect without the influence of AT deficiency (if present), whereas
AT have been reported in association with CSVT. Multiple risk the anti-FXa assay without exogenous AT allows measurement of the
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factors (maternal, neonatal, perinatal, or prothrombotic) are found in vivo UFH effect. Studies comparing the two types of anti-FXa
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in over half of neonates with CSVT. Although the diagnosis of assays found a lack of correlation. Hence, it is necessary to know the
CSVT in neonates is often made by transcranial ultrasonography, type of anti-FXa assay conducted in a particular laboratory when
magnetic resonance venography is the most sensitive diagnostic interpreting results. In neonates, the discrepancy between assays may
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test. On the basis of data from the Canadian Pediatric Ischemic also be increased owing to lower baseline AT levels. The aPTT
Stroke Registry, neonatal CSVT is associated with cerebral paren- level can also be used to monitor UFH; aPTT values that cor-
chymal infarcts in 42% of cases, and 83% of these are hemorrhagic relate with anti-FXa levels of 0.3 to 0.7 units/mL are considered
infarcts. 35 therapeutic.
Aside from treatment of the underlying conditions, when rel- Prophylactic UFH is recommended to maintain patency of
evant, there are no standard treatment guidelines. Nonetheless, good umbilical arterial lines (0.25–1 units/mL, 25–200 units/kg/day, the
results have been obtained with anticoagulant therapy, and UFH or lowest dose possible) and for cardiac catheterization (bolus dose of
LMWH is given, provided that there is no significant ICH. Extended 100–150 units/kg with catheter insertion, repeat for prolonged
treatment with LMWH or a vitamin K antagonist is recommended procedures). In most other cases, LMWH has emerged as the anti-
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for a minimum of 6 weeks and no longer than 3 months. The coagulant of choice in the neonatal setting, both for prophylaxis and
goal of anticoagulation is not to prevent recurrence; rather, it is to for treatment. The advantages of LMWH include better bioavail-
prevent progression and minimize neurologic sequelae. In a study by ability, longer half-life allowing twice-daily administration, dose-
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Kenet et al, none of the 75 neonates with CSVT had a recurrence dependent clearance, predictable anticoagulant response, and a lower
after a median follow-up of 36 months. For those with significant risk of heparin-induced thrombocytopenia (HIT) and osteoporosis
hemorrhage, radiologic monitoring at 5 to 7 days is recommended, than with UFH. Although the current American College for Chest
and anticoagulation should be initiated if there is evidence of Physicians guidelines recommend a dose of 1.5 mg/kg of LMWH for
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thrombus propagation. Anticoagulation is associated with a high treatment of neonatal TE, there is growing evidence to suggest that
rate of hemorrhage, so treatment plans should be individualized. neonates may, in fact, require higher doses up to 1.7 mg/kg and
In older patients, punctate hemorrhage behind a cerebral venous 2.0 mg/kg for term and preterm neonates, respectively, to obtain a
infarct is not an absolute contraindication to anticoagulation, but therapeutic anti-FXa level. 42
studies in neonates are lacking. Nevertheless, in the Canadian reg- HIT antibodies are found in up to 1.5% of neonates, particularly
istry, 36% of neonates were treated with UFH or LMWH, mostly in those who have undergone cardiac surgery. Overt HIT with TE,
for 3 months, and no cases of death or neurologic compromise however, is rare, but it can occur. Mothers with HIT can passively
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from hemorrhage were reported. Overall, neurologic impairment immunize their fetuses. Diagnostic criteria for HIT are described
was reported in up to two-thirds of cases, and approximately in detail in Chapter 133. Treatment includes cessation of heparin
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2% died. and anticoagulation with argatroban, danaparoid, or lepirudin.