Aptamer-based factor IXa inhibition preserves hemostasis and prevents thrombosis in a piglet model of ECMO.
Aptamer-based factor IXa inhibition preserves hemostasis and prevents thrombosis in a piglet model of ECMO.
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DOI：
10.1016/j.omtn.2021.12.011
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发表时间：
2022-03-08
期刊：
影响因子：
--
通讯作者：
Tracy ET
中科院分区：
文献类型：
--
作者：
Reed CR;Bonadonna D;Otto JC;McDaniel CG;Chabata CV;Kuchibhatla M;Frederiksen J;Layzer JM;Arepally GM;Sullenger BA;Tracy ET
体外膜氧合(ECMO)需要抗凝，以防止患者的血液接触电路时发生凝血。普通肝素(UFH)通常可以防止凝血，但可能会导致危及生命的出血。一种选择性地抑制接触激活(内在)途径，同时保留组织因子(外在)凝血途径的抗凝血剂，可能防止由电路触发的凝血，同时允许手术部位的生理性凝血。DTRI-178是一种与聚乙二醇结合的RNA抗凝血剂适配子，可延长其在循环中的半衰期。该适配子基于先前描述的一个分子(9.3T)，该分子通过与外向体上的因子IXa结合来抑制固有的张力酶活性。使用儿童静脉动脉(VA)ECMO的仔猪模型，我们比较了单剂DTRI-178和UFH预防血栓和失血的情况。在五个实验中的每一个实验中，我们让两窝配对的小猪，一只用DTRI-178抗凝，另一只用UFH抗凝，同时进行12小时的VA ECMO。两种抗凝剂都达到了令人满意的和可比的血栓保护作用。然而，与使用DTRI-178抗凝的仔猪相比，UFH仔猪的手术部位出血增加，需要的输血量显著增加。我们的结果表明，DTRI-178，一个因子IXa的适配子，可能是可行的，更安全的，并导致ECMO中较少的输血和临床出血事件。DTRI-178是一种基于RNA的适体，可以抑制凝血因子IXa，凝血因子IXa是血液接触激活系统的一部分。与标准治疗(肝素)相比，DTRI-178使仔猪在体外膜氧合12小时内没有凝血，并减少了出血。新的分子策略可以利用接触激活来预防血栓形成但防止出血。
Extracorporeal membrane oxygenation (ECMO) requires anticoagulation to prevent clotting when the patient’s blood contacts the circuit. Unfractionated heparin (UFH) usually prevents clotting but can cause life-threatening bleeding. An anticoagulant that selectively inhibits the contact activation (intrinsic) pathway while sparing the tissue factor (extrinsic) pathway of coagulation might prevent clotting triggered by the circuit while permitting physiologic coagulation at surgical sites. DTRI-178 is an RNA anticoagulant aptamer conjugated to polyethylene glycol that increases its half-life in circulation. This aptamer is based on a previously described molecule (9.3t) that inhibits intrinsic tenase activity by binding to factor IXa on an exosite. Using a piglet model of pediatric venoarterial (VA) ECMO, we compared thromboprevention and blood loss using a single dose of DTRI-178 versus UFH. In each of five experiments, we subjected two litter-matched piglets, one anticoagulated with DTRI-178 and the other with UFH, to simultaneous 12-h periods of VA ECMO. Both anticoagulants achieved satisfactory and comparable thromboprotection. However, UFH piglets had increased surgical site bleeding and required significantly greater blood transfusion volumes than piglets anticoagulated with DTRI-178. Our results indicate that DTRI-178, an aptamer against factor IXa, may be feasible, safer, and result in fewer transfusions and clinical bleeding events in ECMO. DTRI-178 is an RNA-based aptamer that inhibits coagulation factor IXa, part of blood’s contact activation system. DTRI-178 maintained piglets on extracorporeal membrane oxygenation for 12 h without clotting and reduced bleeding compared with standard treatment (heparin). Novel molecular strategies may exploit contact activation to prevent thrombosis but prevent bleeding.
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DOI：
10.1164/rccm.200711-1637oc
发表时间：
2008-07-01
影响因子：
24.7
作者：
Bateman, Scot T.;Lacroix, Jacques;Randolph, Adrienne G.
通讯作者：
Randolph, Adrienne G.
影响因子：
46.9
作者：
Gunaratne R;Kumar S;Frederiksen JW;Stayrook S;Lohrmann JL;Perry K;Bompiani KM;Chabata CV;Thalji NK;Ho MD;Arepally G;Camire RM;Krishnaswamy S;Sullenger BA
通讯作者：
Sullenger BA
影响因子：
64.8
作者：
通讯作者：
--
影响因子：
6.7
作者：
Gopinath, Subash C. B.;Shikamoto, Yasuo;Kumar, Penmetcha K. R.
通讯作者：
Kumar, Penmetcha K. R.
影响因子：
2.4
作者：
KOSTERING, H;MAST, WP;HOLTZ, WH
通讯作者：
HOLTZ, WH