Yamashita A, Nishihira K, Kitazawa T, Yoshihashi K, Soeda T, Esaki K, Imamura T, Hattori K, Asada Y
Department of Pathology, Faculty of Medicine, University of Miyazaki, 5200 Kihara, Kiyotake, Miyazaki 889-1692, Japan.
J Thromb Haemost. 2006 Jul;4(7):1496-501. doi: 10.1111/j.1538-7836.2006.01973.x.
Thrombus formation through the activation of tissue factor (TF) and factor (F) XI is a critical event in the onset of cardiovascular disease. TF expressed in atherosclerotic plaques and circulating blood is an important determinant of thrombogenicity that contributes to fibrin-rich thrombus formation after plaque disruption. However, the contribution of FXI to thrombus formation on disrupted plaques remains unclear.
A mouse monoclonal antibody against FXI and activated FXI (FXIa) (XI-5108) was generated by immunization with activated human FXI. Prothrombin time (PT), activated partial thromboplastin time (APTT), bleeding time, and ex vivo platelet aggregation in rabbits were measured before and after an intravenous bolus injection of XI-5108. We investigated the role of FXI upon arterial thrombus growth in the rabbit iliac artery in the presence of repeated balloon injury.
The XI-5108 antibody reacted to the light chain of human and rabbit FXI/FXIa, and inhibited FXIa-initiated FXa and FXIa generation. Fibrin-rich thrombi developed on the injured neointima that was obviously immunopositive for glycoprotein IIb-IIIa, fibrin, TF, and FXI. Intravenous administration of XI-5108 (3.0 mg kg(-1)) remarkably reduced thrombus growth, and the APTT was significantly prolonged. However, PT, bleeding time and platelet aggregation were not affected.
These results indicate that plasma FXI plays a potent role in thrombus growth on the injured neointima. Inhibition of plasma FXI activity might help to reduce thrombus growth on ruptured plaques without prolonging bleeding time.
通过组织因子（TF）和因子（F）XI的激活形成血栓是心血管疾病发病过程中的关键事件。在动脉粥样硬化斑块和循环血液中表达的TF是血栓形成的一个重要决定因素，在斑块破裂后有助于富含纤维蛋白的血栓形成。然而，FXI对破裂斑块上血栓形成的作用仍不清楚。
用活化的人FXI免疫制备了一种抗FXI和活化FXI（FXIa）的小鼠单克隆抗体（XI-5108）。在静脉推注XI-5108前后，测量兔的凝血酶原时间（PT）、活化部分凝血活酶时间（APTT）、出血时间和体外血小板聚集。我们研究了在反复球囊损伤的情况下，FXI对兔髂动脉中动脉血栓生长的作用。
XI-5108抗体与人及兔FXI/FXIa的轻链反应，并抑制FXIa启动的FXa和FXIa生成。在损伤的新生内膜上形成了富含纤维蛋白的血栓，该血栓对糖蛋白IIb-IIIa、纤维蛋白、TF和FXI明显呈免疫阳性。静脉注射XI-5108（3.0 mg kg(-1)）显著减少了血栓生长，APTT显著延长。然而，PT、出血时间和血小板聚集未受影响。
这些结果表明，血浆FXI在损伤的新生内膜上的血栓生长中起重要作用。抑制血浆FXI活性可能有助于减少破裂斑块上的血栓生长，而不延长出血时间。
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