Prevention of arterial thrombosis using a novel heparin with enhanced antiplatelet activity and reduced anticoagulant activity.
Prevention of arterial thrombosis using a novel heparin with enhanced antiplatelet activity and reduced anticoagulant activity.
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使用具有增强抗血小板活性和降低抗凝活性的新型肝素预防动脉血栓形成。
DOI：
10.1016/s0741-5214(97)70029-6
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发表时间：
1997
影响因子：
4.3
通讯作者：
Sobel,M
中科院分区：
文献类型：
--
作者：
Poletti,LF;Bird,K;Harris,RB;Marques,D;Sobel,M
目的动脉损伤后血栓形成常由血管性血友病因子（vWF）依赖性血小板聚集引起。一种有前途的抗血栓形成策略是中断血小板/vWF相互作用。以前，我们证明了化学和亲和修饰如何增强肝素的抗vWF活性，同时减少常规抗凝。在这里，我们研究了是否可以阻止血小板为主的动脉thrombosis.MethodsStandard肝素氧化与高碘酸盐，精制具有高vWF亲和力和抑制效力，并在豚鼠模型血小板依赖性动脉血栓形成测试。在这个模型中，一个受控的机械性动脉损伤产生周期性流量变化（CFVs）所造成的血小板thrombi.ResultsAll六个对照动物开发CFVs（平均值，10.4 ± 2.6 CFVs），和6的7只动物用标准肝素治疗也开发CFVs（平均值，7.6 ± 4.6）。用抗vWF肝素处理的6只动物中仅1只和用AJvW-2（抗vWF抗体）处理的6只动物中仅1只产生CFV（平均值分别为2.0 ± 4.9和0.5 ± 1.2）。因此，改良肝素和AJvW-2均比标准肝素更有效（p < 0.03）。出血时间和血小板计数不受影响。改良高亲和力肝素（91 ± 17秒）比标准肝素（144 ± 30秒; p < 0.01）延长的活化部分凝血活酶时间少。结论高vWF亲和力的改良肝素是一种更有效的动脉抗血栓药物，其常规抗凝作用比标准肝素少。阻断vWF/血小板相互作用是一种很有前途的抗血栓策略，可通过新型肝素类抗血栓药物实现。
PurposeThrombosis after arterial injury is often initiated by von Willebrand factor (vWF)–dependent platelet accumulation. A promising antithrombotic strategy is the interruption of platelet/vWF interactions. Previously, we demonstrated how chemical and affinity modification can enhance heparin's anti-vWF activity while reducing conventional anticoagulation. Here, we investigated whether a modified heparin can block platelet-dominated arterial thrombosis.MethodsStandard heparin was oxidized with periodate, refined to have high vWF affinity and inhibitory potency, and tested in a guinea pig model of platelet-dependent arterial thrombosis. In this model, a controlled mechanical arterial injury yields cyclic flow variations (CFVs) caused by recurrent accumulation of platelet thrombi.ResultsAll six control animals developed CFVs (mean, 10.4 ± 2.6 CFVs), and six of seven animals treated with standard heparin also developed CFVs (mean, 7.6 ± 4.6). Only one of six animals treated with the anti-vWF heparin and one of six treated with AJvW-2 (an anti-vWF antibody) developed CFVs (mean, 2.0 ± 4.9 and 0.5 ± 1.2, respectively). Thus both the modified heparin and AJvW-2 were more effective than standard heparin (p < 0.03). Bleeding times and platelet counts were unaffected. A modified activated partial thromboplastin time was less prolonged by the modified high-affinity heparin (91 ± 17 seconds) than by standard heparin (144 ± 30 seconds; p < 0.01).ConclusionsThe modified heparin with high vWF affinity was a more effective arterial antithrombotic agent, with fewer conventional anticoagulant effects than standard heparin. Interruption of the vWF/platelet interaction is a promising antithrombotic strategy that may be met by novel heparin-based antithrombotic drugs.
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剪切诱导的血小板聚集可由血小板释放的 vWF 以及外源性大或异常大的 vWF 多聚体介导，需要二磷酸腺苷，并且对阿司匹林具有耐药性
影响因子：
20.3
作者：
J. Moake;N. Turner;N. Stathopoulos;L. Nolasco;J. Hellums
通讯作者：
J. Hellums
介导豚鼠血小板聚集的纤维蛋白原和冯维勒布兰德因子受体的鉴定。
影响因子：
7.5
作者：
Kupinski,JM;Miller,JL
通讯作者：
Miller,JL
冯维勒布兰德因子作为抗血栓干预的目标。
影响因子：
37.8
作者：
Z. M. Ruggeri
通讯作者：
Z. M. Ruggeri
肝素在体外和体内抑制血管性血友病因子依赖性血小板功能。
DOI：
10.1172/jci115198
发表时间：
1991
期刊：
The Journal of clinical investigation
影响因子：
--
作者：
Sobel,M;McNeill,PM;Carlson,PL;Kermode,JC;Adelman,B;Conroy,R;Marques,D
通讯作者：
Marques,D
DOI：
10.1016/s0021-9258(19)50359-3
发表时间：
1992-05
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
M. Sobel;D. Soler;J. Kermode;R. Harris
通讯作者：
M. Sobel;D. Soler;J. Kermode;R. Harris