Dahlbäck B, Carlsson M, Svensson P J
Department of Clinical Chemistry, University of Lund, Malmö General Hospital, Sweden.
Proc Natl Acad Sci U S A. 1993 Feb 1;90(3):1004-8. doi: 10.1073/pnas.90.3.1004.
Although patients with thromboembolic disease frequently have family histories of thrombosis, well-defined defects such as inherited deficiencies of anticoagulant proteins are found only in a minority of cases. Based on the hypothesis that a poor anticoagulant response to activated protein C (APC) would predispose to thrombosis, a set of new coagulation assays was developed that measure the anticoagulant response in plasma to APC. A middle-aged man with a history of multiple thrombotic events was identified. The addition of APC to his plasma did not result in a normal anticoagulant response as measured by prolongation of clotting time in an activated partial thromboplastin time (APTT) assay. Four of the proband's relatives had medical histories of multiple thrombotic events, and they and several other family members responded poorly to APC in the APTT-based assay. Subnormal anticoagulant responses to APC were also found in factor IXa- and Xa-based assays. Several possible mechanisms for the observed phenomenon were ruled out, such as functional protein S deficiency, a protein C-inhibitory antibody, or a fast-acting protease inhibitor against APC. Moreover, restriction fragment-length polymorphism analysis excluded possible linkage of the underlying molecular defect to factor VIII and von Willebrand factor genes. We now describe a previously unrecognized mechanism for familial thromboembolic disease that is characterized by poor anticoagulant response to APC. This would appear to be explained best by a hypothesized inherited deficiency of a previously unrecognized cofactor to APC. As we have identified two additional, unrelated cases with thrombosis and inherited poor anticoagulant response to APC, this may constitute an important cause for familial thrombophilia.
尽管血栓栓塞性疾病患者常有血栓形成的家族史，但仅在少数病例中发现明确的缺陷，如抗凝蛋白的遗传性缺乏。基于对活化蛋白C（APC）抗凝反应不佳会易患血栓形成的假设，开发了一组新的凝血试验，用于测量血浆对APC的抗凝反应。识别出一名有多次血栓形成事件病史的中年男子。在活化部分凝血活酶时间（APTT）试验中，向其血浆中添加APC后，凝血时间延长所测得的抗凝反应未恢复正常。先证者的四名亲属有多次血栓形成事件的病史，他们以及其他几名家庭成员在基于APTT的试验中对APC反应不佳。在基于因子IXa和Xa的试验中也发现对APC的抗凝反应低于正常水平。排除了几种观察到的现象的可能机制，如功能性蛋白S缺乏、蛋白C抑制性抗体或针对APC的快速作用蛋白酶抑制剂。此外，限制性片段长度多态性分析排除了潜在分子缺陷与因子VIII和血管性血友病因子基因的可能连锁。我们现在描述一种以前未被认识的家族性血栓栓塞性疾病机制，其特征是对APC的抗凝反应不佳。这似乎最好由假设的APC以前未被认识的辅助因子的遗传性缺乏来解释。由于我们又发现了另外两例不相关的血栓形成病例，且对APC的抗凝反应呈遗传性不佳，这可能是家族性血栓形成倾向的一个重要原因。
