HEREDITARY AND ACQUIRED PROTEIN S DEFICIENCY

蛋白S是活化蛋白抗凝作用的辅助因子 C. 我们发现缺乏功能性蛋白S的人 活动容易发生血栓栓塞性疾病，可能是由于 不能调节血液凝固。 然而，虽然这些人 缺乏功能性蛋白S活性，蛋白S抗原水平正常 或轻度降低。 它们的全部或大部分蛋白S与 C4结合蛋白，补体系统的抑制剂， 功能活跃。 在正常人中，只有60%的总蛋白质S是 与C4结合蛋白复合。 我们希望确定为什么这种转变 蛋白S分布在家族性功能蛋白S中 缺陷 为了实现这一目标，我们将调查造成 首先，初步确定表明， C4结合蛋白在功能缺陷个体中升高 我们将确定患者体内的C4结合蛋白水平 等离子体足以解释质量作用的变化。 这将 需要对血浆中的C4结合蛋白水平进行充分验证的测定。 其次，我们发现体外补体激活导致了 从游离蛋白S到结合蛋白 我们将确定补体激活 也参与了在患者中观察到的体内变化， 观察到的变化是通过C4 b与C4结合蛋白的结合介导的。 如果补体激活不能证明是引起 在患者中观察到蛋白S状态，我们将分离患者蛋白S 和C4结合，并表征这些蛋白质的动力学和 从结构上确定这些蛋白质之一的异常是否 改变了蛋白S的分布 我们发现，获得性功能缺陷发生在两个主要的医疗 有血栓栓塞并发症的疾病-系统性狼疮 肾病综合征。 同样，蛋白质S被转移， 到绑定和不活动的形式。 我们将通过以下方式确定机制： 这种转变的发生。 我们将调查其他医疗条件 已知有血栓栓塞并发症，以确定是否获得性蛋白质 S缺乏症。 这些患者研究是 追求我们的长期目标，这是决定是否 监测蛋白S状态可以作为一种合理的方式来决定 患者将从预防措施中受益最多， 血栓栓塞并发症

Protein S is a cofactor for the anticoagulant effects of activated protein C. We have discovered that individuals who lack functional protein S activity are prone to thromboembolic disease, presumably due to an inability to regulate blood clotting. However, while these individuals lack functional protein S activity, protein S antigenic levels are normal or mildly reduced. All or most of their protein S is complexed with C4-binding protein, an inhibitor of the complement system, and is not functionally active. In normals only 60% of the total protein S is complexed to C4-binding protein. We wish to determine why this shift in protein S distribution occurs in the familial functional protein S deficiency. To accomplish this goal, we will investigate the possible causes for the shift in the following order: First, initial determinations indicate that C4-binding protein is elevated in the functionally deficient individuals and we will determine if the levels of C4-binding protein in the patients' plasma are sufficient to explain the shift by mass action. This will require well-validated assays for C4-binding protein levels in plasma. Secondly, we find that activation of complement in vitro results in a shift from free protein S to bound. We will determine if complement activation is also involved in the in vivo changes observed in the patients and if the observed shift is mediated through binding of C4b to C4-binding protein. If complement activation does not prove responsible for the changes in protein S states observed in patients, we will isolate patient protein S and C4-binding and characterize these proteins both kinetically and structurally to determine if an abnormality in one of these proteins is responsible for the altered protein S distribution. We find that an acquired functional deficiency occurs in two major medical conditions which have thromboembolic complications - systemic lupus erythematosis and the nephrotic syndrome. Again, the protein S is shifted to the bound and inactive form. We will determine the mechanism(s) by which this shift occurs. We will investigate other medical conditions known to have thromboembolic complications to determine if acquired protein S deficiency occurs. These patient studies are the first step in the pursuit of our long-term goal which is the determination of whether or not monitoring protein S status may serve as a rational way of deciding which patients will benefit most from phrophylactic measures to prevent thromboembolic complications.