Genetic predisposition and clinical expression of early onset thrombophilia

Abstract

The number of reports on the importance of genetic predisposition in pediatric thrombosis is increasing. We defined early-onset thrombophilia (EOT) as thrombosis occurring at ≤20 years of age associated with a genetic predisposition. An EOT registry, comprising cases diagnosed by genetic testing and obtained from a literature review, was established to identify the genetic and clinical characteristics of EOT. Anticoagulant activity levels can detect EOT with high sensitivity using an age-dependent reference range. However, the specificity is low, and genetic testing is necessary for the diagnosis of EOT. In neonates and infants, protein C (PC) deficiency, which causes purpura fulminans and/or intracranial thrombosis/hemorrhage, is common, and protein S/antithrombin (AT) deficiency increases with age. These results indicate the need for the prophylaxis and treatment of thrombosis based on age and genetic predisposition. Neonatal PC-deficient patients with PROC biallelic variants experience severe neurological sequelae, including visual impairment. Novel management strategies from early diagnosis and fetal treatment to postnatal treatment are required to reduce neurological sequelae. Genetic testing of the parents of patients with EOT (32 families) revealed a de novo variant in only one family with PC deficiency. In three families (two with PC deficiency and one with AT deficiency), the mother and neonate developed thrombosis concurrently, indicating the possibility of screening for genetic predisposition to protect them from thrombosis.