Laboratório de Tecido Conjuntivo, Hospital Universitário Clementino Fraga Filho and Programa de Glicobiologia, Instituto de Bioquímica Médica, Centro de Ciências da Saúde,Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil.
Thromb Haemost. 2010 May;103(5):994-1004. doi: 10.1160/TH09-10-0734. Epub 2010 Mar 29.
We report the effects of a chemically oversulfated chondroitin sulfate and a naturally fucosylated chondroitin sulfate on the coagulation system. The former has been recently identified as a contaminant of heparin preparations and the latter has been proposed as an alternative anticoagulant. The mechanism of action of these polymers on coagulation is complex and target different components of the coagulation system. They have serpin-independent anticoagulant activity, which preponderates in plasma. They also have serpin-dependent anticoagulant activity but differ significantly in the target coagulation protease and preferential serpin. Their anticoagulant effects differ even more markedly when tested as inhibitors of coagulation proteases using plasma as a source of serpins. It is possible that the difference is due to the high availability of fucosylated chondroitin sulfate whereas oversulfated chondroitin sulfate has strong unspecific binding to plasma protein and low availability for the binding to serpins. When tested using a venous thrombosis experimental model, oversulfated chondroitin sulfate is less potent as an antithrombotic agent than fucosylated chondroitin sulfate. These highly sulfated chondroitin sulfates activate factor XII in in vitro assays, based on kallikrein release. However, only fucosylated chondroitin sulfate induces hypotension when intravenously injected into rats. In conclusion, the complexity of the regulatory mechanisms involved in the action of highly sulfated polysaccharides in coagulation requires their analysis by a combination of in vitro and in vivo assays. Our results are relevant due to the urgent need for new anticoagulant drugs or alternative sources of heparin.
我们报告了一种化学过度硫酸化的软骨素硫酸盐和一种天然岩藻糖基化的软骨素硫酸盐对凝血系统的影响。前者最近被鉴定为肝素制剂的污染物，后者被提议作为替代抗凝剂。这些聚合物对凝血的作用机制很复杂，针对凝血系统的不同成分。它们具有丝氨酸蛋白酶抑制剂非依赖性的抗凝活性，在血浆中占优势。它们也具有丝氨酸蛋白酶抑制剂依赖性的抗凝活性，但在靶向凝血蛋白酶和优先丝氨酸蛋白酶抑制剂方面有很大的不同。当使用血浆作为丝氨酸蛋白酶抑制剂来源，以测试它们作为凝血蛋白酶抑制剂的抗凝效果时，它们的抗凝效果差异更加明显。这可能是由于岩藻糖基化软骨素硫酸盐的高可用性，而过度硫酸化软骨素硫酸盐对血浆蛋白具有强烈的非特异性结合，并且与丝氨酸蛋白酶抑制剂的结合可用性较低。在使用静脉血栓形成实验模型进行测试时，过度硫酸化软骨素硫酸盐作为抗血栓形成剂的效力不如岩藻糖基化软骨素硫酸盐。这些高度硫酸化的软骨素硫酸盐在体外测定中基于激肽释放激活因子 XII。然而，只有岩藻糖基化软骨素硫酸盐在静脉注射到大鼠时会引起低血压。总之，高度硫酸化多糖在凝血中作用的调节机制的复杂性需要通过体外和体内测定的组合来分析。我们的结果是相关的，因为迫切需要新的抗凝药物或肝素的替代来源。
