Clinical Impact of Heritable Thrombophilia on Neonatal-Onset Thromboembolism: A Nationwide Study in Japan

Egami, Naoki; Ochiai, Masayuki; Ichiyama, Masako; Inoue, Hirosuke; Sonoda, Motoshi; Ishimura, Masataka; Suenobu, Souichi; Nishikubo, Toshiya; Ishiguro, Akira; Hotta, Taeko; Uchiumi, Takeshi; Kang, Dongchon; Ohga, Shouichi

doi:10.1016/j.jpeds.2021.07.001

Cited by 4 publications

(12 citation statements)

References 41 publications

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“…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.…”

Section: Discussionmentioning

confidence: 99%

Ductus Arteriosus Aneurysm and Pulmonary Artery Thromboses in a Protein S-Deficient Newborn

Shirozu

Ichiyama

Ishimura

et al. 2023

AJP Rep

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Ductus arteriosus aneurysm (DAA) asymptomatically occurs in newborn infants and resolves spontaneously. High-risk DAA with compression, rupture and thrombosis requires early surgical intervention. Newborn infants have the highest risk of thrombosis among pediatric patients, but the genetic predisposition is difficult to determine in infancy. We herein report a neonatal case of massive thromboses in DAA and pulmonary artery. Desaturation occurred in an active full-term infant two days after birth. Echocardiography and contrast-enhanced computed tomography indicated thrombotic occlusion of the DAA and pulmonary artery thrombus. Urgent thrombectomy and ductus resection were successfully performed. After six months of anticoagulant therapy, the dissociated low plasma activity levels of protein S from protein C suggested protein S deficiency. A genetic study of PROS1 identified a heterozygous variant of protein S K196E, a low-risk variant of thrombophilia in Japanese populations. There have been seven reported cases with neonatal-onset symptomatic thromboses of DAA involving the pulmonary artery. All survived without recurrence after surgical intervention in five and anticoagulant therapy alone in two. Two newborns had a heterozygous methylenetetrahydrofolate reductase variant, but information on thrombophilia was not available for any other cases. A genetic predisposition may raise the risk of DAA thrombosis, leading to rapid progression.

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Section: Discussionmentioning

confidence: 99%

Ductus Arteriosus Aneurysm and Pulmonary Artery Thromboses in a Protein S-Deficient Newborn

Shirozu

Ichiyama

Ishimura

et al. 2023

AJP Rep

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“…However, the accuracy and high-coverage rate of our genetic study have been validated by previous studies in Japan. 2,12 Another limitation is that we did not define the unaffected carriers of thrombophilia.…”

Section: Discussionmentioning

confidence: 99%

“…Genetic and clinical information was collected from the registry data. 12 This study was approved by the Institutional Review Board of Kyushu University (#448-02 and #2020-106).…”

Section: Subjects and Data Collectionmentioning

confidence: 99%

The clinical and genetic landscape of early‐onset thrombophilia in Japan

Egami,

Ishimura,

Ochiai

et al. 2023

Pediatric Blood & Cancer

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ObjectivesTo determine the optimal management for early‐onset thrombophilia (EOT), the genetic and clinical features of protein C (PC)‐, protein S (PS)‐, or antithrombin (AT)‐deficient patients of ≤20 years of age were studied in Japan.Methods/resultsClinical and genetic information of all genetically diagnosed cases was collected through the prospective, retrospective study, and literature review. One‐hundred‐one patients had PC (n = 55), PS (n = 29), or AT deficiency (n = 18). One overlapping case had PC‐ and PS‐monoallelic variant. Fifty‐five PC‐deficient patients (54%) had 26 monoallelic or 29 biallelic variant(s), and 29 (29%) PS‐deficient patients had 20 monoallelic or nine biallelic variant(s). None of the patients had AT‐biallelic variants. The frequent low‐risk allele p.K193del (PC‐Tottori) was found in five patients with monoallelic (19%) but not 29 with biallelic variant(s). The most common low‐risk allele p.K196E (PS‐Tokushima) was found in five with monoallelic (25%) and six with biallelic variant(s) (67%). One exceptional de novo PC variant was found in 32 families with EOT. Only five parents had a history of thromboembolism. Thrombosis concurrently developed in three mother–newborn pairs (two PC deficiency and one AT deficiency). The prospective cohort revealed the outcomes of 35 patients: three deaths with PC deficiency and 20 complication‐free survivors. Neurological complications were more frequently found in patients with PC‐biallelic variants than those with PC‐, PS‐, or AT‐monoallelic variants (73% vs. 24%, p = .019).ConclusionsWe demonstrate the need for elective screening for EOT targeting PC deficiency in Japan. Early prenatal diagnosis of PC deficiency in mother–infant pairs may prevent perinatal thrombosis in them.

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“…A growing number of reports described thromboses among pediatric carriers of heterozygous PROC, 8,12 especially in the early neonatal period. 4,[13][14][15] The accurate diagnosis of PC deficiency is challenging in pediatric patients, 4,7 because plasma PC activity levels widely vary in infancy and slowly reach 50% or higher after 6 months of age. 8 The genetic tests for PC deficiency are thus skipped in case of stroke even if no prothrombotic factors existed.…”

Section: E T T E R T O T H E E D I T O R Stroke In a Protein C-defici...mentioning

confidence: 99%

“…Protein C (PC) deficiency is more closely associated with venous and arterial thromboembolic events in infants and young children than the other known heritable thrombophilia. 4,5 Homozygous or compound heterozygotes for PROC gene variants present with severe and fatal thromboses during the neonatal period, including purpura fulminans, intracranial thrombosis, and ocular hemorrhage (OMIM #612304). [6][7][8] Heterozygous PC deficiency is estimated to occur in 0.2%-0.5% of general population, 7 contributing to the development of adult venous thromboembolism.…”

Section: E T T E R T O T H E E D I T O R Stroke In a Protein C-defici...mentioning

confidence: 99%

Stroke in a protein C‐deficient infant after stem cell transplant for CHARGE syndrome

Tanaka

Sakaguchi

Inoue

et al. 2022

Pediatric Blood & Cancer

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Clinical Impact of Heritable Thrombophilia on Neonatal-Onset Thromboembolism: A Nationwide Study in Japan

Cited by 4 publications

References 41 publications

Ductus Arteriosus Aneurysm and Pulmonary Artery Thromboses in a Protein S-Deficient Newborn

Ductus Arteriosus Aneurysm and Pulmonary Artery Thromboses in a Protein S-Deficient Newborn

The clinical and genetic landscape of early‐onset thrombophilia in Japan

Stroke in a protein C‐deficient infant after stem cell transplant for CHARGE syndrome

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