Keywords
ductus arteriosus aneurysm - thrombophilia - protein S deficiency - K196E
Ductus arteriosus aneurysm (DAA) occurs in 8.8% of full-term newborn infants as a
secondary event to altered intimal cushion formation or delayed aortic segment closure
of the ductus.[1]
[2] It usually develops asymptomatically and resolves spontaneously but can present
with murmur, cyanosis, respiratory distress, and feeble cry, along with a ductal bump
on chest X-ray.[3] Urgent surgical repair is performed in cases at a high risk of compression or rupture.
Another lethal complication is occlusive thrombosis of DAA involving the pulmonary
artery and systemic organs. Because intra-arterial thrombus formation affects approximately
30% of symptomatic cases of DAA,[4] the early detection of high-risk DAA is mandatory for curative intervention. However,
little information is available concerning the genetic risk of progressive thrombosis
in DAA.
Protein S deficiency is the leading cause of heritable thrombophilia in Japanese adults
with thromboembolism.[5] The most prevalent allele is protein S-Tokushima (K196E), which is found in approximately
2% of the Japanese population as a type II phenotype of natural anticoagulant deficiency
with almost normal total and free protein S antigen levels to decrease activated protein
C cofactor activity.[6]
[7] The prothrombotic risk of the variant has been considered to increase with age and
to also be augmented by the accompanied factors for the development of thrombosis.
The risk of thrombosis in pediatric patients is highest in the early neonatal period.
There have been only two reported cases of thrombosed DAA in association with a genetic
predisposition toward thrombosis.
We herein report the first case of neonatal thromboses of DAA and the pulmonary artery
associated with congenital protein S deficiency. Furthermore, based on a literature
review on DAA thrombus and thrombophilia, we also discuss about the prothrombotic
effect on the development of high-risk DAA thrombosis in newborns.
Case Presentation
A male infant who weighed 3,060 g at 40 weeks' gestation was born through vaginal
delivery after an uneventful pregnancy. He was the first child of a family with no
history of miscarriage, bleeding, or thromboembolism. There was no asphyxia at birth.
Breastfeeding was started for the active newborn infant. Two days after birth, the
infant's percutaneous oxygen saturation (SpO2) levels at right upper extremity decreased to 93% without changes in the vital signs.
Echocardiography showed a closed ductus arteriosus and a secundum atrial septal defect
with a right-to-left shunt that did not require monitoring of central venous catheterization.
Because follow-up echocardiography 7 days after birth revealed a massive lesion occupying
the bifurcation of the left pulmonary artery (LPA), this infant was immediately transferred
to the neonatal and pediatric intensive care unit of Fukuoka Children's Hospital.
On admission, the afebrile and nondysmorphic infant showed no cyanosis, tachycardia,
or respiratory distress. Resting SpO2 was 99% at the right upper extremity, 98% at the left upper extremity, 98% at the
right lower extremity, and 94% at the left lower extremity, with no significant differences
among the extremities. SpO2 at the right upper extremity dropped to the 70 to 80% range during crying, but measurements
were not taken at the extremities at this time. Cardiorespiratory sounds were unremarkable.
There was no hepatosplenomegaly. Chest radiography showed a cardiothoracic ratio of
51% and normal lung vascularity. Echocardiography showed a high-intensity mass of
6.5 mm × 4.3 mm diameter in the LPA bifurcation on short-axis imaging ([Fig. 1A]), with a mild acceleration of 2.3 m/s at the same site. A sagittal view of the aortic
arch showed a mass attached to the DAA ([Fig. 1B]). There was no narrowing of the aortic arch due to thrombus protrusion to the aortic
side. Contrast-enhanced computed tomography indicated a 4.6 mm × 13.2 mm thrombus
within the DAA protruding into the LPA bifurcation ([Fig. 1C]). No other thromboembolic lesions were identified in the brain or whole body. Peripheral
blood counts showed a leukocyte count of 17.109/L, hemoglobin level of 15.2 g/dL, and platelet count of 408 × 109/L. Coagulation studies showed a normal prothrombin time (12.4 seconds, reference
range [rr]: 10.0–15.0), activated partial thromboplastin time (33.6 seconds, rr: 24.0–39.0),
fibrinogen concentration (291 mg/dL, rr: 200–400), and fibrinogen degradation product
level (3.7 µg/mL, rr: 0.0–5.0). The D-dimer level was slightly elevated to 1.6 µg/mL
(rr < 1.0). The plasma activity levels of total protein C and protein S were each
38%. These were subnormal levels according to the lower limits of age-dependent standards
(age < 90 days: protein C 45%, protein S 42%),[8] no antigen or free level of protein S was measured.
Fig. 1 Echocardiography and contrast-enhanced computed tomography (CT) findings on admission
and results of a histological examination of the resected specimen. (A) An echocardiographic short-axis view shows a hyperintense mass ∼ 6.5 mm × 4.3 mm
in diameter in the left pulmonary artery (LPA) bifurcation upon short-axis imaging,
with a mild acceleration of 2.3 m/s at the same site. (B) In the sagittal view of the aortic arch, the mass occupies the ductus arteriosus,
indicating a thrombus. Ao, aorta; LPA, left pulmonary artery; RPA, right pulmonary
artery; PA, pulmonary artery. (C) Sagittal reconstruction of contrast-enhanced computed tomography shows a 4.6 mm × 13.2 mm
thrombus within the ductus arteriosus aneurysm (DAA) continuously protruding into
the LPA bifurcation. Ao, aorta; PA, pulmonary artery. (D1) A histological examination shows that the vascular lumen is filled with blood clots
with focal organization and calcification. (D2) A histological examination of the thrombus shows fibrinous materials with inflammatory
cells and a few fibroblasts, accompanied by calcification.
Considering the complications of thrombolytic therapy and recurrent thromboembolism
with residual DAA, the infant underwent thrombectomy and ductus resection 8 days after
birth. A thrombus occupied the LPA bifurcation. The ductus showed a closed aortic
side and dilated pulmonary artery side. A histological examination showed an organized
thrombus and fibrous materials with few inflammatory cells, calcification, and blood
clots within the vascular vessels in the ductus ([Fig. 1D]). The patient received unfractionated heparin to keep around 40 seconds of activated
partial thromboplastin time. Oral aspirin was administered at 5 mg/kg/day for 6 months
postoperatively. He was discharged without complications.
The plasma activity levels of protein C, protein S, and antithrombin were then followed.
At 1 year old, the protein C level had increased to 119%, but the protein S level
had increased to 47% of the lower limit for age (the lower limits of each activity:
age 90 days–2 years: protein C 64%, protein S 51%). The dissociation between the protein
S and protein C levels prompted us to complete the genetic analysis of PROS1, which identified a heterozygous single-nucleotide substitution in exon 6 of PROS1 (c.586A > G, p.K196E, protein S-Tokushima) in this infant. A family study after obtaining
informed consent revealed a healthy mother, but the father had 45% of the borderline
plasma protein S activity and the same heterozygous variant.
Discussion
This is the first case report of DAA and pulmonary artery thromboses in association
with protein S deficiency. There have been eight cases of newborn-onset DAA complicated
with pulmonary artery thromboses, including the present patient ([Table 1]).[9]
[10]
[11]
[12]
[13] One prenatally diagnosed case resulted in stillbirth.[14] All eight diagnosed cases after birth survived without recurrence or complications.
Three infants underwent surgical interventions and anticoagulant therapy for a median
of 4.5 months, ranging from 3 to 6 months. Two received anticoagulant therapy alone
for 5 weeks. Six infants presented with clinical signs or symptoms within the first
72 hours of life, reportedly defined as the high-risk period for neonatal thrombosis.[15] Two newborn infants had a heterozygous methylenetetrahydrofolate reductase (MTHFR) variant, C677T, one of whom had a trigger for thrombosis (central venous catheterization).
No prothrombotic factors were described in the remaining cases. Considering the existence
of two previous cases with a similar low-risk genetic predisposition toward thrombosis,
the monoallelic variant of protein S might have augmented the progressive thrombus
formation during the high-risk neonatal period. Because plasma activity levels of
natural anticoagulants are unable to be used to diagnose newborn thrombophilia, follow-up
studies and genetic testing are needed during and after anticoagulation therapy.
Table 1
Reported cases of neonatal-onset thrombosis of ductus arteriosus aneurysm involving
pulmonary artery
|
Case
|
Age at diagnosis
|
Signs and/or symptoms
|
Management/Outcome
|
Thromboprophylaxis on anticoagulants
|
Associated conditions
|
Genetic predisposition
|
Reference
|
|
1
|
0 day
|
Heart murmur, cyanosis
|
Surgery/alive
|
3 months after surgery
|
Maternal GDM
|
Heterozygote of MTHFR C677T
|
Nyp et al, 2011[9]
|
|
2
|
0 day
|
Respiratory distress
|
Aspirin/alive
|
Aspirin for 5 weeks
|
Not described
|
Not described
|
Masood et al, 2015[10]
|
|
3
|
1 day
|
vomit, collapse, hepatomegaly
|
Surgery/alive
|
None
|
Prolonged PT and APTT
|
Not described
|
Fripp et al, 1985[11]
|
|
4
|
1 day
|
Respiratory distress, PH
|
Enoxaparin/alive
|
Not described about period
|
Umbilical line
|
Heterozygote of MTHFR
|
Ciliberti et al, 2016[12]
|
|
5
|
1 day
|
Differential cyanosis
|
Heparin, surgery/alive
|
Not described about postoperative anticoagulants
|
Not described
|
Not described
|
Aly et al, 2020[13]
|
|
6
|
2 days
|
Cyanosis
|
Surgery/alive
|
6 months after surgery
|
Protein S deficiency
|
Heterozygote of PROS1 A586G
|
Present case
|
|
7
|
5 days
|
Heart murmur, cyanosis
|
Surgery/alive
|
Not described
|
Not described
|
Not described
|
McArdle et al, 2017[1]
|
|
8
|
11 days
|
Heart murmur, cyanosis
|
Surgery/alive
|
Not described
|
Not described
|
Not described
|
Dyamenahalli et al, 2000[3]
|
Abbreviations: APTT, activated partial thromboplastin time; GDM, gestational diabetes
mellitus; MTHFR, methylenetetrahydrofolate reductase; PH, pulmonary hypertension; PT, prothrombin
time.
More than 60% of symptomatic DAA cases have aneurysms filled with thrombi that disappear
with organization and fibrosis.[2] During the closure of aneurysm, initial changes begin on the pulmonary artery side
because thrombogenesis is related to turbulent flow or endothelial injury within the
narrowing pulmonary ductus segment.[16] Delayed closure of the pulmonary side can thus be a trigger for developing thrombosis.
The histopathological findings in the present patient suggested the delayed closure
of DAA followed by the progression to pulmonary artery thrombosis.
The major concern is the impact of protein S-Tokushima on thrombus formation in this
patient with DAA. Among seven reported neonatal cases of symptomatic DAA and pulmonary
artery thromboses ([Table 1]), thrombotic predisposition factors were found in two: maternal diabetes, catheter
insertion, and MTHFR variants. Maternal diabetes has been reported as a nongenetic risk factor of DAA
as well as umbilical artery thrombosis.[17] Although the effect size of MTHFR variants (C677T, A1298C) is weak, a recent integrative study demonstrated the significant
risk of heterozygous MTHFR C677T (odds ratio: 1.33).[18] We did not conduct a genetic study for MTHFR variants in the present patient because (1) approximately half of healthy Japanese
individuals have an allele of MTHFR C677T (AV genotype), and (2) the VV but not the AV genotype is a significant risk
factor for adult Japanese patients with deep vein thrombosis.[19] Both previous patients with a MTHFR variant had other nongenetic prothrombotic factors including maternal diabetes and
umbilical line. However, the present patient with protein S-Tokushima did not have
other nongenetic prothrombotic factors. Three heterozygotes of PROS1 or MTHFR variants presented within the first 3 days of life, the period during which the majority
of cases of neonatal thrombosis reportedly occur, regardless of heritable thrombophilia.
Protein S-Tokushima is the most frequent allele, being present in approximately 2%
of the Japanese population. The risk of deep vein thromboembolism in Japanese adults
with PROS1 A586G has been estimated to have an odds ratio of 2.15 (95% confidence interval,
1.16–3.99).[20] In this context, the rapid progression to massive thrombosis in the pulmonary artery
of this patient may be attributable to the significant effect of the protein S variant
during the critical prothrombotic period of the first 3 days of life. Hypercoagulability
is associated with the circulating amount of free protein S, not total protein S.
At present, plasma activity levels of free protein S are not measured as the clinical
laboratory testing. Because of low complement C4-binding protein (C4BP) in the fetal
and neonatal blood, protein S circulates as the free form during the perinatal period.[21] The relatively high levels of free protein S were reported in fetal blood but not
always neonatal blood.[22] The balanced effect between the increasing C4BP and relatively decreasing free protein
S on the hypercoagulability after birth may contribute to the progression of neonatal
thrombosis. In this setting, we emphasize that the borderline levels of total plasma
protein S activity need to be followed until a sufficient rise to age-dependent standard
ranges. There is no consensus concerning appropriate thromboprophylaxis in patients
with DAA. Future screening on thrombophilia may be required to reduce the developing
risk of neonatal thrombosis in the era of genomic medicine.
