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

Abstract Objectives To 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/results Clinical 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). Conclusions We 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.