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Abstract：
OBJECTIVE: To clarify the incidence and genetic risk of neonatal-thromboembolism, we conducted a nationwide study exploring the impact of thrombophilia on neonatal-thromboembolism in Japan.
METHODS: A questionnaire survey was conducted for perinatal centers in Japan, focusing on the clinical expression, genotype, treatment, and outcome of patients who developed thromboembolism within 28 days of birth from 2014 to 2018.
RESULTS: The estimated incidence of neonatal-thromboembolism was 0.39 cases per 10 000 live births. Intracranial lesions and purpura fulminans occurred in 66 and 5 of 77 patients, respectively. Fifty-eight (75.3%) infants presented within 3 days after birth. Four (5.2%) died, and 14 (18.2%) survived with disability. At the diagnosis, <20% plasma activity of protein C was noted in 16 infants, protein S (in 2), and antithrombin (in 1). Thirteen genetic tests identified 4 biallelic and 5 monoallelic protein C-variants but no protein S- or antithrombin-variants. Protein C-variants had purpura fulminans (P < .01), ocular bleeding (P < .01), positive-family history (P = .01), and death or disability (P = .03) more frequently than others. Protein C-variants were independently associated with disability (OR 5.74, 95% CI 1.16-28.4, P = .03) but not death. Four biallelic variants had serious thrombotic complications of neurologic disability, blindness, and/or amputation. Three monoallelic variants survived without complications. The only protein C-variant death was an extremely preterm heterozygote infant.
CONCLUSIONS: Monoallelic protein C-variants had a higher incidence of neonatal-thromboembolism than biallelic variants. Thrombophilia genetic testing should be performed in the setting of neonatal-thromboembolism and low protein C to identify the underlying genetic defect.
METHODS: A questionnaire survey was conducted for perinatal centers in Japan, focusing on the clinical expression, genotype, treatment, and outcome of patients who developed thromboembolism within 28 days of birth from 2014 to 2018.
RESULTS: The estimated incidence of neonatal-thromboembolism was 0.39 cases per 10 000 live births. Intracranial lesions and purpura fulminans occurred in 66 and 5 of 77 patients, respectively. Fifty-eight (75.3%) infants presented within 3 days after birth. Four (5.2%) died, and 14 (18.2%) survived with disability. At the diagnosis, <20% plasma activity of protein C was noted in 16 infants, protein S (in 2), and antithrombin (in 1). Thirteen genetic tests identified 4 biallelic and 5 monoallelic protein C-variants but no protein S- or antithrombin-variants. Protein C-variants had purpura fulminans (P < .01), ocular bleeding (P < .01), positive-family history (P = .01), and death or disability (P = .03) more frequently than others. Protein C-variants were independently associated with disability (OR 5.74, 95% CI 1.16-28.4, P = .03) but not death. Four biallelic variants had serious thrombotic complications of neurologic disability, blindness, and/or amputation. Three monoallelic variants survived without complications. The only protein C-variant death was an extremely preterm heterozygote infant.
CONCLUSIONS: Monoallelic protein C-variants had a higher incidence of neonatal-thromboembolism than biallelic variants. Thrombophilia genetic testing should be performed in the setting of neonatal-thromboembolism and low protein C to identify the underlying genetic defect.
摘要：
目的：明确新生儿血栓栓塞症的发病率和遗传风险。我们在日本进行了一项全国性研究,探讨血栓形成倾向对新生儿血栓栓塞的影响.
方法：对日本的围产期中心进行了问卷调查，专注于临床表现，基因型，治疗,以及2014年至2018年出生后28天内发生血栓栓塞的患者的结局.
结果：新生儿血栓栓塞的估计发生率为每10000例活产0.39例。77例患者中有66例和5例发生颅内病变和暴发性紫癜，分别。58名(75.3%)婴儿在出生后3天内出现。4人(5.2%)死亡，14人(18.2%)因残疾存活。在诊断时,16例婴儿血浆蛋白C活性<20%，蛋白质S（在2中），和抗凝血酶（在1）。13项遗传测试鉴定了4种双等位基因和5种单等位基因蛋白C变体，但没有蛋白质S或抗凝血酶变体。蛋白C变体有暴发性紫癜（P<0.01），眼出血（P<0.01），阳性家族史（P=0.01），死亡或残疾（P=0.03）比其他人更频繁。蛋白C变体与残疾独立相关（OR5.74，95％CI1.16-28.4，P=0.03），但与死亡无关。四个双等位基因变异有神经系统残疾的严重血栓性并发症，失明,和/或截肢。三个单等位基因变异体存活无并发症。唯一的蛋白C变体死亡是极度早产的杂合子婴儿。
结论：单等位基因蛋白C变异体的新生儿血栓栓塞发生率高于双等位基因变异体。应该在新生儿血栓栓塞和低蛋白C的情况下进行血栓形成的遗传检测，以确定潜在的遗传缺陷。
方法：对日本的围产期中心进行了问卷调查，专注于临床表现，基因型，治疗,以及2014年至2018年出生后28天内发生血栓栓塞的患者的结局.
结果：新生儿血栓栓塞的估计发生率为每10000例活产0.39例。77例患者中有66例和5例发生颅内病变和暴发性紫癜，分别。58名(75.3%)婴儿在出生后3天内出现。4人(5.2%)死亡，14人(18.2%)因残疾存活。在诊断时,16例婴儿血浆蛋白C活性<20%，蛋白质S（在2中），和抗凝血酶（在1）。13项遗传测试鉴定了4种双等位基因和5种单等位基因蛋白C变体，但没有蛋白质S或抗凝血酶变体。蛋白C变体有暴发性紫癜（P<0.01），眼出血（P<0.01），阳性家族史（P=0.01），死亡或残疾（P=0.03）比其他人更频繁。蛋白C变体与残疾独立相关（OR5.74，95％CI1.16-28.4，P=0.03），但与死亡无关。四个双等位基因变异有神经系统残疾的严重血栓性并发症，失明,和/或截肢。三个单等位基因变异体存活无并发症。唯一的蛋白C变体死亡是极度早产的杂合子婴儿。
结论：单等位基因蛋白C变异体的新生儿血栓栓塞发生率高于双等位基因变异体。应该在新生儿血栓栓塞和低蛋白C的情况下进行血栓形成的遗传检测，以确定潜在的遗传缺陷。
