PERINATAL DEVELOPMENT OF VITAMIN K-DEPENDENT HEMOSTASIS

围产期维生素 K 依赖性止血的发展

• 批准号: 3324469
• 负责人: EDWIN Gladstone BOVILL
• 金额: $ 22.7万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-08-01 至 1994-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3324469
• 关键词: blood chemistry; carboxylation; decarboxylases; gel electrophoresis; hemostasis; human subject; newborn human (0-6 weeks); nutrition related tag; protein C; protein biosynthesis; protein structure function; prothrombin; questionnaires; statistics /biometry; vitamin K; vitamin K deficiency; vitamin metabolism

Although all neonates are severely Vitamin K deficient at birth by comparison with adults, some will have abnormalities of vitamin K-dependent hemostasis. Our previous work demonstrated the presence of significant concentrations of undercarboxylated and thus, dysfunctional protein C and prothrombin in 3-15% of otherwise healthy term and pre-term neonates at birth. The clinical significance of these findings, especially in pre-term infants, remains to be determined; however, investigation of the mechanisms underlying the production of undercarboxylated vitamin K dependent proteins will improve our understanding of neonatal hemostasis and create a foundation for improved treatment (e.g., possible antenatal maternal vitamin K supplementation). We hypothesize that the neonatal production of abnormal undercarboxylated vitamin K-dependent coagulation proteins is related to the functional activity of the hepatic vitamin K cycle and gamma-glutamyl carboxylase, as well as deficiency of vitamin K1. This proposed investigation is the first attempt to study the relationship between vitamin K metabolism and the production of undercarboxylated proteins. The presence of undercarboxylated vitamin K-dependent proteins (for this project: Protein C, Prothrombin, and Bone Gla Protein) will be determined in 200 paired healthy term neonatal blood samples obtained at birth and at 3 days of life following a 1 mg prophylactic dose of vitamin K1. Vitamin K1, vitamin K1 epoxide and total vitamin K-dependent protein levels will also be measured in these paired samples. Relationships between: 1) the distribution of vitamin K metabolites and the presence of undercarboxylated protein, and 2) the increasing amounts of total vitamin K-dependent protein produced (as a measure of substrate presented to the carboxylase) and the production of abnormal undercarboxylated protein, will be evaluated in the paired samples. Underlying mechanism(s) for the production of undercarboxylated proteins in the neonate can be evaluated by these types of analyses. This study will improve our understanding of the development of vitamin K-dependent hemostasis during a crucial period of rapid change in human development, and provide insight into both normal and impaired response to hemostatic challenges in the perinatal period. The results obtained from this investigation will be important in laying the foundation for improved therapeutic strategies in the future.

尽管所有新生儿在出生时都严重缺乏维生素K， 与成年人相比，有些人的维生素 K-依赖性止血。 我们之前的工作证明了 显著浓度的羧化不足，因此功能失调 蛋白C和凝血酶原在3-15%的其他健康足月和早产儿中 新生儿出生时。 这些发现的临床意义， 特别是在早产儿中的作用仍有待确定;然而， 调查的机制产生的 低羧化维生素K依赖蛋白将改善我们的 了解新生儿止血，为改善 治疗（例如，可能的产前母体维生素K补充剂）。 我们假设新生儿产生的异常低羧化 维生素K依赖性凝血蛋白与维生素K依赖性凝血蛋白的功能相关， 肝脏维生素K循环和γ-谷氨酰羧化酶的活性， 以及缺乏维生素K1。 这项拟议的调查是 首次尝试研究维生素K代谢与 产生低羧基化蛋白质。 的存在 低羧化维生素K依赖性蛋白质（本项目：蛋白质 C、凝血酶原和骨玻璃蛋白）将在200对 在出生时和出生后3天获得健康足月新生儿血液样品 预防性服用1毫克维生素K1后的寿命。 维生素K1， 维生素K1环氧化物和总维生素K依赖蛋白水平也将 在这些配对样本中进行测量。 关系：（1） 维生素K代谢物的分布和存在 羧化不足的蛋白质，和2）总维生素的增加量 产生的K-依赖性蛋白（作为呈递给细胞的底物的量度） 羧化酶）和异常羧化不足蛋白质的产生， 将在配对样本中进行评价。 （一个或多个）基本机制 可以评估新生儿中羧基化不足蛋白质的产生 这些类型的分析。 这项研究将提高我们对维生素C开发的认识， 在人类快速变化的关键时期，K依赖性止血 发展，并提供洞察正常和受损的反应， 在围产期止血的挑战。 获得的结果 从这次调查将是重要的奠定基础， 未来的治疗策略。