Journal
BLOOD
Volume 113, Issue 21, Pages 5323-5329Publisher
AMER SOC HEMATOLOGY
DOI: 10.1182/blood-2008-07-169359
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Funding
- Ministry of Health, Labor, and Welfare of Japan, Tokyo, Japan
- Ministry of Education, Culture, Sports, Science, and Technology of Japan, Tokyo, Japan
- Japan Society for the Promotion of Science, Tokyo, Japan
- Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biochemical Innovation of Japan, Ibaraki, Japan
- Baxter Bioscience, Vienna, Austria
- National Heart, Lung, and Blood Institute of the National Institutes of Health [P01-HL066105]
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ADAMTS13 is a multidomain protease that limits platelet thrombogenesis through the cleavage of von Willebrand factor (VWF). We previously identified 2 types of mouse Adamts13 gene: the 129/Sv-strain Adamts13 gene encodes the long-form ADAMTS13 having the same domains as human ADAMTS13, whereas the C57BL/6-strain Adamts13 gene encodes the short-form ADAMTS13 lacking the distal C-terminal domains. To assess the physiologic significance of the distal C-terminal domains of ADAMTS13, we generated and analyzed 129/Sv-genetic background congenic mice (Adamts13(S/S)) that carry the short-form ADAMTS13. Similar to wild-type 129/Sv mice (Adamts13(L/L)), Adamts13S/S did not have ultralarge VWF multimers in plasma, in contrast to 129/Sv-genetic background ADAMTS13-deficient mice (Adamts13(-/-)). However, in vitro thrombogenesis under flow at a shear rate of 5000 s(-1) was accelerated in Adamts13(S/S) compared with Adamts13(L/L). Both in vivo thrombus formation in ferric chloride-injured arterioles and thrombocytopenia induced by collagen plus epinephrine challenge were more dramatic in Adamts13(S/S) than in Adamts13(L/L) but less than in Adamts13(-/-). These results suggested that the C-terminally truncated ADAMTS13 exhibited decreased activity in the cleavage of VWF under high shear rate. Role of the C-terminal domains may become increasingly important under prothrombotic conditions. (Blood. 2009; 113: 5323-5329)
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