PATHOBIOLOGY OF HUMAN FACTOR IX: STRUCTURE AND FUNCTION

因子IX蛋白虽然在血浆中以非常低的浓度存在， 对止血至关重要。 先天性因子缺乏症患者 IX型血友病B，有出血性疾病，患病率为5%。 十万只雄性。 这些病人需要过量的献血 产品，以控制他们的出血，从而导致几乎正常的生活。 获得性因子IX缺陷本身并不常见，但伴随着 肝病中其他维生素K依赖性凝血因子的抑制 以及口服抗凝剂的患者。 出血的管理 后天性缺陷则困难得多。 为了在凝血中发挥作用，因子IX必须转化为活性物质， 形式，因子IXa。 这是如何发生的无论是正常的还是病理性的 人们对其了解甚少，限制其活动的手段也是如此。 以来 第九因子激活是一长系列的初始步骤之一， 生化反应，导致凝血，它提供了良好的 引发或控制常见疾病的可能性 血栓形成 更好地理解等离子体之间的相互作用 蛋白质，血小板（凝血细胞）和血管内壁。 需要血管。 提出阐明功能异常和结构异常 血友病（异常）因子IX蛋白的碱基将提供见解 这种凝血蛋白在正常血液凝固中的作用， 血栓形成 从大肠杆菌中纯化异常因子IX蛋白的抗体技术 病人的血浆正在研制中。 异常的因子IX蛋白 将被标记上微量放射性，并由敏感的 免疫化学方法。 表征将包括微筛选 测试：1）它们从非活性前体转化为 活性形式，2）它们被某些酶分解的能力，3） 它们作为酶的功能特性和4）它们与 辅因子 我们还将能够评估不稳定的变体， 比正常情况下更快地从循环中清除。 研究 血友病因子IX基因将用于确定什么是错的， 通过鉴定给定的血友病因子IX蛋白的结构， 遗传密码的异常

Factor IX protein, although present in a very low concentration in plasma, is essential for hemostasis. Patients with congenital deficiency of factor IX, hemophilia B, have a bleeding disorder with a prevalence of 5 per 100,000 males. These patients require an inordinate supply of donor blood products to control their bleeding and thus lead nearly normal lives. Acquired factor IX defects are uncommon by themselves but accompany the depression of other vitamin K-dependent clotting factors in liver disease and in patients on oral anticoagulants. Management of bleeding in the acquired defects is much more difficult. In order to function in clotting, factor IX must be converted to an active form, factor IXa. Just how this occurs either normally or pathologically is poorly understood as are the means of limiting its activity. Since factor IX activation is one of the initial steps of a long series of biochemical reactions which lead to clotting, it provides excellent potential for either setting off or controlling the very common disorders of thrombosis. A greater understanding of interactions between this plasma protein, blood platelets (the clotting cells) and the innner walls of the blood vessels is needed. It is proposed that elucidating the functional abnormalities and structural bases of hemophilic (abnormal) factor IX proteins will provide insights into the role of this clotting protein in normal blood clotting and thrombosis. Antibody techniques to purify abnormal factor IX proteins from patients' plasmas are being developed. The abnormal factor IX proteins will be labeled with a trace of radioactivity and studied by sensitive immunochemical methods. Characterization will include micro-screening tests for: 1) their ability to be converted from an inactive precursor to the active form, 2) their ability to be broken down by certain enzymes, 3) their functional properties as enzymes and 4) their interactions with cofactors. We will also be able to assess for unstable variants which are cleared more rapidly than normal from the circulation. Studies of hemophilic factor IX genes will be used to determine what is wrong with the structure of a given hemophilic factor IX protein by identifying the abnormality in the genetic code.