The combined roles of ADAMTS13 and VWF in murine models of TTP, endotoxemia, and thrombosis

被引:58
作者
Chauhan, Anil K. [1 ,2 ]
Walsh, Meghan T. [1 ]
Zhu, Guojing [3 ]
Ginsburg, David [3 ,4 ]
Wagner, Denisa D. [1 ,2 ]
Motto, David G. [5 ,6 ]
机构
[1] Harvard Med Sch, CBR Inst Biomed Res, Boston, MA USA
[2] Harvard Med Sch, Dept Pathol, Boston, MA USA
[3] Univ Michigan, Dept Internal Med, Ann Arbor, MI 48109 USA
[4] Univ Michigan, Howard Hughes Med Inst, Ann Arbor, MI 48109 USA
[5] Univ Iowa, Coll Med, Dept Internal Med, Iowa City, IA 52242 USA
[6] Univ Iowa, Coll Med, Dept Pediat, Iowa City, IA 52242 USA
关键词
D O I
10.1182/blood-2007-08-108571
中图分类号
R5 [内科学];
学科分类号
1002 ; 100201 ;
摘要
Ultralarge von Willebrand factor (UL-VWF) multimers are thought to play a central role in pathogenesis of the disease thrombotic thrombocytopenic purpura (TTP); however, experimental evidence in support of this hypothesis has been difficult to establish. Therefore, to examine directly the requirement for VWF in TTP pathogenesis, we generated ADAMTS13-deficient mice on a TTP-susceptible genetic background that were also either haploinsufficient (Vwf(+/-)) or completely deficient (Vwf(-/-)) in VWF. Absence of VWF resulted in complete protection from shigatoxin (Stx)-induced thrombocytopenia, demonstrating an absolute requirement for VWF in this model (Stx has been shown previously to trigger TTP in ADAMTS13-deficient mice). We next investigated the requirements for ADAMTS13 and VWF in a murine model of endotoxemia. Unlike Stx-induced TTP findings, LPS-Induced thrombocytopenia and mortality were not affected by either VWF or ADAMTS13 deficiency, suggesting divergent mechanisms of thrombocy-topenia between these 2 disorders. Finally, we show that VWF deficiency abrogates the ADAMTS13-deficient prothrombotic state, suggesting VWF as the only relevant ADAMTS13 substrate under these conditions. Together, these findings shed new light on the potential roles played by ADAMTS13 and VWF in TTP, endotoxemia, and normal hemostasis.
引用
收藏
页码:3452 / 3457
页数:6
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