Regulation of extrinsic pathway factor Xa formation by tissue factor pathway inhibitor
Regulation of extrinsic pathway factor Xa formation by tissue factor pathway inhibitor
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DOI：
10.1074/jbc.273.8.4378
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发表时间：
1998-02-20
影响因子：
4.8
通讯作者：
Krishnaswamy, S
中科院分区：
文献类型：
--
作者：
Baugh, RJ;Broze, GJ;Krishnaswamy, S
组织因子（TF）途径抑制剂（TFPI）通过依次抑制因子Xa和因子VIIa来调节因子X的活化。在纯化的重构系统中，在因子X和TFPI的血浆浓度、因子VIIa的饱和浓度以及重构为磷脂酰胆碱：磷脂酰丝氨酸膜（TF/PCPS）或PC膜（TF/PC）的TF的增加浓度下，研究了TF复合物，因子Xa的形成。在存在或不存在2.4 nM TFPI的情况下，因子Xa形成的初始速率相当，然而，反应程度很小（10（8）M-1.s（-1）），远大于直接测量的值（7.34 +/- 0.8 x 10（6）M-1.s（-1））。因此，VIIa.TF在接近扩散限制的速率下被催化过程中形成的Xa.TFPI抑制，这不能通过对分离反应的研究来解释。我们提出，在因子X活化过程中的主要抑制途径可能涉及因子Xa的初始抑制，该抑制要么与膜表面上的VIIa.TF结合，要么在其附近。结果，VIIa.TF抑制出乎意料地迅速，并且逃避调节的活性因子Xa的浓度线性依赖于TF的可用性。
Tissue factor (TF) pathway inhibitor (TFPI) regulates factor X activation through the sequential inhibition of factor Xa and the VIIa.TF complex, Factor Xa formation was studied in a purified, reconstituted system, at plasma concentrations of factor X and TFPI, saturating concentrations of factor VIIa, and increasing concentrations of TF reconstituted into phosphatidylcholine: phosphatidylserine membranes (TF/PCPS) or PC membranes (TF/PC). The initial rate of factor Xa formation was equivalent in the presence or absence of 2.4 nM TFPI, However, reaction extent was small (10(8) M-1.s(-1)) that was substantially greater than the value (7.34 +/- 0.8 x 10(6) M-1.s(-1)) directly measured. Thus, VIIa.TF is inhibited at near diffusion-limited rates by Xa.TFPI formed during catalysis which cannot be explained by studies of the isolated reaction, We propose that the predominant inhibitory pathway during factor X activation may involve the initial inhibition of factor Xa either bound to or in the near vicinity of VIIa.TF on the membrane surface. As a result, VIIa.TF inhibition is unexpectedly rapid, and the concentration of active factor Xa that escapes regulation is linearly dependent on the availability of TF.