Heparins designed to specifically inhibit platelet interactions with von Willebrand factor.
Heparins designed to specifically inhibit platelet interactions with von Willebrand factor.
复制标题
肝素旨在特异性抑制血小板与血管性血友病因子的相互作用。
DOI：
10.1161/01.cir.93.5.992
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发表时间：
1996
期刊：
影响因子：
37.8
通讯作者：
Harris,RB
中科院分区：
文献类型：
--
作者：
Sobel,M;Bird,KE;Tyler-Cross,R;Marques,D;Toma,N;Conrad,HE;Harris,RB
血小板与受损血管壁的相互作用可能是许多心血管介入治疗早期和晚期失败的重要原因，粘附蛋白血管性血友病因子（vWF）被认为在其中起重要作用。以前，我们证明肝素通过与负责结合血小板vWF受体（糖蛋白Ib）的蛋白质结构域内的vWF结合来干扰血小板/vWF止血机制。本研究的目的是开发和精制具有更强抑制血小板/vWF相互作用效力的肝素。方法和结果基于vWF已知的肝素结合结构域的固定化合成肽用于产生标准肝素的新型组分，这些组分显示其抑制vWF依赖性血小板凝集和vWF/血小板结合的能力增加了七倍。高vWF亲和力肝素显示增强的抗Xa因子活性，但相当的活化部分凝血活酶时间活性。通过高碘酸盐氧化和硼氢化物还原对标准肝素进行化学修饰，使其抑制血小板/vWF相互作用的能力提高了三倍，同时消除了90%以上的活化部分凝血活酶时间和抗Xa因子活性。亲和层析的化学修饰的肝素产生了一个肝素具有8倍以上的抑制效力比原来的heparin.ConclusionsSubspecies的肝素可以开发具有显着增强的效力，抑制vWF/血小板相互作用。肝素的vWF抑制特性可与其抗凝血酶结合活性分离。基于对肝素/vWF相互作用的日益了解，可以设计亲和分离和化学修饰的组合以产生独特适合于预防动脉血栓形成的肝素。
BackgroundPlatelet interactions with the injured vessel wall may contribute significantly to the early and late failures of many cardiovascular interventions; the adhesive protein von Willebrand factor (vWF) is thought to play an important role. Previously, we demonstrated that heparin interfered with platelet/vWF hemostatic mechanisms by binding to vWF within the protein’s domain responsible for binding the platelet vWF receptor, glycoprotein Ib. The purpose of the present study was to develop and refine heparins with greater potency to inhibit platelet/vWF interactions.Methods and ResultsImmobilized synthetic peptides based on a known heparin-binding domain of vWF were used to yield novel fractions of standard heparin that demonstrated a sevenfold increase in their ability to inhibit vWF-dependent platelet agglutination and vWF/platelet binding. The high vWF affinity heparin showed enhanced anti–factor Xa activity but comparable activated partial thromboplastin time activity. Chemical modification of a standard heparin by periodate oxidation and borohydride reduction enhanced its ability to inhibit platelet/vWF interactions by threefold, while eliminating more than 90% of its activated partial thromboplastin time and anti–factor Xa activity. Affinity chromatography of the chemically modified heparin yielded a heparin with an eightfold higher inhibitory potency than the original heparin.ConclusionsSubspecies of heparin can be developed with significantly enhanced potency to inhibit vWF/platelet interactions. The vWF-inhibiting property of heparin can be dissociated from its antithrombin-binding activity. Based on a growing understanding of heparin/vWF interactions, combinations of affinity separations and chemical modifications could be designed to yield heparins uniquely suitable for prevention of arterial thrombosis.