蜱源抗凝血因子研究进展

Research advances in anticoagulant factors from ticks

蜱是一种人畜共患体表寄生虫,通过叮咬宿主和吸血,将病原体传播给宿主,引发多种疾病。凝血反应是人和动物的重要生理过程,是生理性止血的重要环节。蜱叮咬和吸食宿主血液周期长,在吸血过程中分泌多种抗凝物质,抑制凝血反应,可帮助蜱长时间保持吸血状态。目前,已知的蜱源抗凝物质依据其功能主要包括蛋白酶抑制剂、纤维蛋白(原)溶解剂、血小板聚集抑制剂和血管活性蛋白4大类。这些抗凝血物质可分别作用于凝血级联反应中内源性通路、外源性通路、共同通路中的关键步骤,以及促进纤蛋白溶解和抑制血小板激活,从而抑制宿主血管中的凝血反应。蛋白酶抑制剂主要通过抑制凝血级联反应共同通路中凝血酶和Xa因子活性;纤维蛋白(原)溶解剂引起纤维蛋白原的水解并延迟纤维蛋白凝块的形成;血小板聚集抑制剂通过降解血小板聚集激动剂,并结合血栓素A2(thromboxane A2,TXA2)和血小板上的αIIbβ3整合素抑制血小板聚集;血管活性蛋白抑制宿主血管收缩以及伤口愈合和血管生成。此外,还有一些蜱分泌的其他蛋白分子可通过不同的通路来实现抗凝血作用。本文对迄今为止各类蜱中发现的具有抗凝血活性的蛋白和小分子及其抗凝血作用机制进行总结阐述,将促进对蜱抗宿主凝血的作用机制和生理意义的理解,也为研制蜱源新型抗凝血药物、开发新的抗血栓疗法提供重要参考。

Ticks are zoonotic ectoparasites transmitting pathogens to hosts via biting and feeding on hosts,which are associated with various diseases.Coagulation reaction is an important physiological process and plays critical roles in physiological hemostasis in humans and animals.During the long time of biting and feeding processes on hosts,ticks can secrete a variety of anticoagulants to inhibit coagulation reactions,which would guarantee the ticks to have blood meals for a long time.To date,the major tick-derived anticoagulants which have been identified and recognized according to their functions include protease inhibitors,fibrin(ogen)olytic agents,platelet aggregation inhibitors,and vasoactive proteins.These anticoagulants can act on the intrinsic pathway,extrinsic pathway,and key steps in the common pathway of the coagulation cascade,promote fibrinolysis,and inhibit platelet activation,thereby inhibiting the coagulation response in the host blood vessels.Protease inhibitors mainly inhibit the activities of thrombin and factor Xa in the common pathway of coagulation cascade.Fibrin(ogen)olytic agents cause the hydrolysis of fibrinogen and delay the formation of fibrin clots.Platelet aggregation inhibitors can suppress platelet aggregation by degrading platelet aggregation agonists and binding thromboxane A2(TXA2)andαIIBβ3 integrin on platelet surface.Vasoactive proteins inhibit host vasoconstriction,and wound healing and angiogenesis.In addition,there are some other protein molecules secreted by ticks that pose anticoagulation effects through different pathways.In this article,we summarized the anticoagulant proteins and small molecules found in ticks so far and their anticoagulant mechanisms,which will promote understanding of the mechanism and physiological significance of anticoagulation process in hosts triggered by ticks,and will provide important reference for developing new tick-derived anticoagulant drugs and new antithrombotic therapies.