HEREDITARY AND ACQUIRED PROTEIN S DEFICIENCY

S蛋白是活化蛋白抗凝作用的辅因子 C.我们发现，缺乏功能蛋白的个体S 活动容易患血栓栓塞症，推测是由于 不能调节血液凝结。然而，虽然这些人 缺乏功能蛋白S活性，蛋白S抗原水平正常 或者略微降低。它们的全部或大部分蛋白质S与之形成络合 C4结合蛋白，补体系统的抑制因子，而不是 在功能上是活跃的。在正常人中，S只有60%的总蛋白质是 与C4结合蛋白络合。我们希望确定为什么这一转变 S蛋白分布在家族功能蛋白S中 缺乏症。 为了实现这一目标，我们将调查导致 按以下顺序变化：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 等离子体足以解释这种由质量作用引起的变化。这将是 需要对血浆中C4结合蛋白水平进行充分验证的分析。 其次，我们发现补体在体外的激活导致了一种转变 从游离蛋白质S到束缚。我们将确定补体激活是否 也参与了在患者体内观察到的变化，如果 观察到的变化是通过C4b与C4结合蛋白的结合来调节的。 如果补体激活被证明不是导致这些变化的原因 在观察到患者S状态的蛋白后，我们将分离出患者蛋白S 和C4结合，并从动力学和动力学两个方面表征这些蛋白质 从结构上确定这些蛋白质中的一种异常是否 S负责改变蛋白质的分布。 我们发现获得性功能缺陷发生在两个主要的医学领域 出现血栓栓塞症并发症的情况--系统性狼疮 红斑病和肾病综合征。再一次，S的蛋白质发生了移位 到绑定和非活动的形式。我们将通过以下方式确定机制(S) 这一转变就发生在这里。我们将调查其他医疗状况 已知有血栓栓塞症并发症以确定是否获得蛋白质 S缺乏症时有发生。这些患者研究是 我们追求的是长远的目标，这是决定是否 监测S蛋白的状态可能是决定 患者将从预防肺炎的措施中受益最大 血栓栓塞症并发症。

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.