FAMILIAL THROMBOPHILIA DUE TO A PREVIOUSLY UNRECOGNIZED MECHANISM CHARACTERIZED BY POOR ANTICOAGULANT RESPONSE TO ACTIVATED PROTEIN-C - PREDICTION OF A COFACTOR TO ACTIVATED PROTEIN-C
FAMILIAL THROMBOPHILIA DUE TO A PREVIOUSLY UNRECOGNIZED MECHANISM CHARACTERIZED BY POOR ANTICOAGULANT RESPONSE TO ACTIVATED PROTEIN-C - PREDICTION OF A COFACTOR TO ACTIVATED PROTEIN-C
复制标题
DOI：
10.1073/pnas.90.3.1004
复制
发表时间：
1993-02-01
影响因子：
11.1
通讯作者：
SVENSSON, PJ
中科院分区：
文献类型：
--
作者：
DAHLBACK, B;CARLSSON, M;SVENSSON, PJ
尽管血栓栓塞症患者经常有血栓形成的家族史，但明确的缺陷，如遗传性抗凝蛋白缺陷，只在少数病例中被发现。基于对活化蛋白C(APC)的抗凝反应不良易发生血栓的假设，建立了一套新的凝血检测方法，用于检测血浆对APC的抗凝反应。一名有多次血栓事件病史的中年男子被确认。在活化的部分凝血活酶时间(APTT)试验中，通过延长凝血时间来衡量，将APC加入到HIS血浆中并没有导致正常的抗凝反应。先证者的四名亲属有多次血栓形成事件的病史，在基于APTT的检测中，他们和其他几名家庭成员对APC的反应很差。在基于因子IXa和Xa的检测中，也发现对APC的抗凝反应低于正常。几种可能的机制被排除，如功能蛋白S缺乏，蛋白C抑制抗体，或针对蛋白原癌的快速作用的蛋白酶抑制剂。此外，限制性片段长度多态分析排除了潜在的分子缺陷与第八因子和血管性血友病因子基因的可能联系。我们现在描述一种以前未知的家族性血栓栓塞性疾病的机制，其特征是对APC的抗凝反应较差。这似乎可以用一种先前未被识别的APC辅助因子的假设遗传缺陷来最好地解释。由于我们已经发现了另外两个与血栓形成和遗传性抗凝反应差的APC无关的病例，这可能是家族性血栓形成的一个重要原因。
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 th e 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.