ten Cate H, Bauer K A, Levi M, Edgington T S, Sublett R D, Barzegar S, Kass B L, Rosenberg R D
Department of Internal Medicine, Slotervaart Hospital, Amsterdam, The Netherlands.
J Clin Invest. 1993 Sep;92(3):1207-12. doi: 10.1172/JCI116691.
The human coagulation system continuously generates very small quantities of Factor Xa and thrombin. Current evidence suggests that basal level activation of the hemostatic mechanism occurs via Factor VIIa-dependent activation of Factor X, but direct proof has not been available for the participation of tissue factor in this pathway. To examine this issue, we infused relatively high concentrations of recombinant Factor VIIa (approximately 50 micrograms/kg body wt) into normal chimpanzees and observed significant increases in the plasma levels of Factor IX activation peptide, Factor X activation peptide, and prothrombin activation fragment F1+2. Metabolic turnover studies with radiolabeled Factor IX activation peptide, Factor X activation peptide, and F1+2 indicate that elevated levels of the activation peptides are due to accelerated conversion of the three coagulation system zymogens into serine proteases. The administration of a potent monoclonal antibody to tissue factor, which immediately neutralizes function of the Factor VIIa-tissue factor complex in vitro, abolishes the activation of Factor X and prothrombin mediated by the infused recombinant protein, and also suppresses basal level activation of Factor IX and Factor X. The above results suggest that recombinant Factor VIIa functions as a prohemostatic agent by interacting with endogenous tissue factor sites, but definitive proof will require studies in hemophilic animals using relevant hemostatic endpoints.
人体凝血系统持续产生极少量的Xa因子和凝血酶。目前的证据表明，止血机制的基础水平激活是通过VIIa因子依赖的X因子激活实现的，但组织因子参与该途径的直接证据尚未获得。为了研究这个问题，我们向正常黑猩猩输注了相对高浓度的重组VIIa因子（约50微克/千克体重），并观察到IX因子激活肽、X因子激活肽和凝血酶原激活片段F1+2的血浆水平显著升高。对放射性标记的IX因子激活肽、X因子激活肽和F1+2进行的代谢周转率研究表明，激活肽水平升高是由于三种凝血系统酶原加速转化为丝氨酸蛋白酶所致。给予一种强效的组织因子单克隆抗体，该抗体能在体外立即中和VIIa因子-组织因子复合物的功能，消除输注的重组蛋白介导的X因子和凝血酶原的激活，同时也抑制IX因子和X因子的基础水平激活。上述结果表明，重组VIIa因子通过与内源性组织因子位点相互作用发挥促止血剂的作用，但确凿的证据需要在血友病动物中使用相关的止血终点进行研究。
