Complete deficiency in ADAMTS13 is prothrombotic, but it alone is not sufficient to cause thrombotic thrombocytopenic purpura
Complete deficiency in ADAMTS13 is prothrombotic, but it alone is not sufficient to cause thrombotic thrombocytopenic purpura
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DOI：
10.1182/blood-2005-07-2765
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发表时间：
2006-04-15
期刊：
影响因子：
20.3
通讯作者：
Miyata, T
中科院分区：
文献类型：
--
作者：
Banno, F;Kokame, K;Miyata, T
ADAMTS13是一种血浆金属蛋白酶，通过裂解von Willebrand因子(VWF)多聚体来调节血小板的黏附和聚集。在人类中，ADAMTS13的遗传或获得性缺陷会导致血栓性血小板减少性紫癜(TTP)，这种疾病的特征是血小板减少和溶血性贫血伴微血管血小板血栓。在这项研究中，我们报告了携带ADAMTS13基因靶向中断的小鼠的特征。ADAMTS13缺陷小鼠出生时符合预期的孟德尔分布；纯合子小鼠存活并具有生育能力。血液学和组织学分析没有发现任何血小板减少、溶血性贫血或微血管血栓形成的证据。然而，在纯合子的血浆中观察到异常大的VWF多聚体。与野生型小鼠相比，纯合子小鼠在流动状态下固定的胶原上的血栓形成显著增加。在静脉注射胶原蛋白和肾上腺素混合物后，纯合子小鼠的血小板减少症比野生型小鼠更严重。因此，小鼠完全缺乏ADAMTS13是一种血栓前状态，但仅有它还不足以引起TTP样症状。人类和小鼠之间ADAMTS13缺陷的表型差异可能反映了这些物种在止血系统功能上的差异。另外，除了ADAMTS13缺乏外，其他因素也可能是TTP发生所必需的。
ADAMTS13 is a plasma metalloproteinase that regulates platelet adhesion and aggregation through cleavage of von Willebrand factor (VWF) multimers. In humans, genetic or acquired deficiency in ADAMTS13 causes thrombotic thrombocytopenic purpura (TTP), a condition characterized by thrombocytopenia and hemolytic anemia with microvascular platelet thrombi. In this study, we report characterization of mice bearing a targeted disruption of the Adamts13-gene. ADAMTS13-deficient mice were born in the expected mendelian distribution; homozygous mice were viable and fertile. Hematologic and histologic analyses failed to detect any evidence of thrombocytopenia, hemolytic anemia, or microvascular thrombosis. However, unusually large VWF multimers were observed in plasma of homozygotes. Thrombus formation on immobilized collagen under flow was significantly elevated in homozygotes in comparison with wild-type mice. Thrombocytopenia was more severely induced in homozygotes than in wild-type mice after intravenous injection of a mixture of collagen and epinephrine. Thus, a complete lack of ADAMTS13 in mice was a prothrombotic state, but it alone was not sufficient to cause TTP-like symptoms. The phenotypic differences of ADAMTS13 deficiencies between humans and mice may reflect differences in hemostatic system functioning in these species. Alternatively, factors in addition to ADAMTS13 deficiency may be necessary for development of TTP.