Nucleic acid scavengers inhibit thrombosis without increasing bleeding

被引:90
作者
Jain, Shashank [1 ]
Pitoc, George A. [1 ]
Holl, Eda K. [1 ]
Zhang, Ying [2 ]
Borst, Luke [3 ]
Leong, Kam W. [2 ]
Lee, Jaewoo [1 ]
Sullenger, Bruce A. [1 ]
机构
[1] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA
[2] Duke Univ, Dept Biomed Engn, Durham, NC 27708 USA
[3] N Carolina State Univ, Coll Vet Med, Dept Pathol, Raleigh, NC 27607 USA
基金
美国国家科学基金会;
关键词
polyphosphates/DNA/RNA; platelet; hemorrhage; ACUTE CORONARY SYNDROMES; ADVERSE DRUG EVENTS; IN-VIVO; BIOMEDICAL APPLICATIONS; EXTRACELLULAR RNA; MURINE MODEL; FACTOR-XI; ANTICOAGULANTS; POLYPHOSPHATE; DENDRIMERS;
D O I
10.1073/pnas.1204928109
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Development of effective, yet safe, antithrombotic agents has been challenging because such agents increase the propensity of patients to bleed. Recently, naturally occurring polyphosphates such as extracellular DNA, RNA, and inorganic polyphosphates have been shown to activate blood coagulation. In this report, we evaluate the anticoagulant and antithrombotic activity of nucleic acid-binding polymers in vitro and in vivo. Such polymers bind to DNA, RNA, and inorganic polyphosphate molecules with high affinity and inhibit RNA- and polyphosphate-induced clotting and the activation of the intrinsic pathway of coagulation in vitro. Moreover, [NH2(CH2)(2)NH2]: (G = 3); dendri PAMAM(NH2)(32) (PA-MAM G-3) prevents thrombosis following carotid artery injury and pulmonary thromboembolism in mice without significantly increasing blood loss from surgically challenged animals. These studies indicate that nucleic acid-binding polymers are able to scavenge effectively prothrombotic nucleic acids and other polyphosphates in vivo and represent a new and potentially safer class of antithrombotic agents.
引用
收藏
页码:12938 / 12943
页数:6
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