by Cornelis van 't Veer, Neal J. Golden, and Kenneth G. Mann Inhibition of thrombin generation by the zymogen factor VII: implications for the treatment of hemophilia A by factor VIIa by Cornelis van 't Veer, Neal J. Golden, and Kenneth G. Mann Blood Volume 95(4):1330-1335 February 15, 2000 ©2000 by American Society of Hematology

Inhibition of TF-dependent thrombin generation by factor VII Inhibition of TF-dependent thrombin generation by factor VII.Thrombin generation was initiated by mixing a solution that contained relipidated TF, factor V, and factor VIII with a solution that contained factor VIIa, factor X, factor IX, prothrombin, and va... Inhibition of TF-dependent thrombin generation by factor VII.Thrombin generation was initiated by mixing a solution that contained relipidated TF, factor V, and factor VIII with a solution that contained factor VIIa, factor X, factor IX, prothrombin, and various concentrations of zymogen factor VII. Final concentrations in the reaction were 1.25 pmol/L TF, 100 pmol/L factor VIIa, and plasma concentrations of the other coagulation factors, except for factor VII, which is at 0.5 (▪), 1 (♦), 2.5 (▴), 5 (*), or 10 nmol/L (▾) and absent in the control reaction (○). Factor VII inhibits only the initial phase of thrombin generation in the absence of other coagulation inhibitors. Cornelis van 't Veer et al. Blood 2000;95:1330-1335 ©2000 by American Society of Hematology

Inhibition of TF-dependent factor Xa generation by factor VII Inhibition of TF-dependent factor Xa generation by factor VII.The effect of zymogen factor VII on factor Xa generation by TF and the physiologic trace of factor VIIa was investigated by mixing a solution containing a limited amount of relipidated TF with a ... Inhibition of TF-dependent factor Xa generation by factor VII.The effect of zymogen factor VII on factor Xa generation by TF and the physiologic trace of factor VIIa was investigated by mixing a solution containing a limited amount of relipidated TF with a solution containing factor X and factor VIIa without (□) or with (▪) 10 nmol/L factor VII. Final concentrations in the reaction were as follows: 1.25 pmol/L TF, 100 pmol/L factor VIIa, and 500 nmol/L factor X. The initial inhibition and final identical rate of factor X activation in the reaction with factor VII is consistent with competitive binding to TF and feedback activation of the zymogen by factor Xa formed in the reaction. Cornelis van 't Veer et al. Blood 2000;95:1330-1335 ©2000 by American Society of Hematology

Effect of factor VII on thrombin generation in the presence of TFPI and AT-III.The effect of zymogen factor VII on TF-dependent thrombin generation was investigated as described in Figure 1, except that the natural coagulation inhibitors TFPI and AT-III wer... Effect of factor VII on thrombin generation in the presence of TFPI and AT-III.The effect of zymogen factor VII on TF-dependent thrombin generation was investigated as described in Figure 1, except that the natural coagulation inhibitors TFPI and AT-III were present at their respective plasma concentrations in the final reaction mixture. Reactions were initiated by 10 (panel A), 20 (panel B), or 100 (panel C) pmol/L TF in the presence of 100 pmol/L factor VIIa in the absence (□) or presence (▪) of 10 nmol/L factor VII. In the presence of TFPI and AT-III the inhibitory effect of factor VII on TF-dependent thrombin generation is not only restricted to the initial part of the reaction, but also decreases the maximal observed thrombin generation in reactions initiated by TF concentrations of ≤ 20 pmol/L. At TF concentrations of 100 pmol/L and higher thrombin generation occurs explosively, regardless of the presence of inhibitors or zymogen factor VII. Cornelis van 't Veer et al. Blood 2000;95:1330-1335 ©2000 by American Society of Hematology

Effects of factor VII and factor VIIa in the absence of factor VIII Effects of factor VII and factor VIIa in the absence of factor VIII.The effects of factor VII and factor VIIa under hemophilia A conditions (without factor VIII) were studied on TF-dependent (5 small pMTF) thrombin generation in the presence of TFPI and AT-... Effects of factor VII and factor VIIa in the absence of factor VIII.The effects of factor VII and factor VIIa under hemophilia A conditions (without factor VIII) were studied on TF-dependent (5 small pMTF) thrombin generation in the presence of TFPI and AT-III as described in Figure 3. Panel A shows thrombin generation curves in the presence of the physiologic ratio of factor VIIa:factor VII (100 pmol/L:10 nmol/L) in the absence (○) or presence (•) of factor VIII. Omission of factor VII from the reaction in the absence of factor VIII (panel A, □) results in a considerable increase in the rate of thrombin generation. Addition of 10 nmol/L factor VIIa to the reaction with factor VII and absence of factor VIII (panel A, ⋄) results in a normalization of the thrombin generation profile. Panel B displays thrombin generation curves, from the contemporaneous experiment shown in panel A, which were performed in the absence of factor VIII and presence of 10 nmol/L factor VII with a range of factor VIIa concentrations, namely, 0.1 (▿), 0.5 (*), 1 (♦), 2 (▴), 0.5 (▪), and 10 nmol/L (•). Panel C shows the maximal observed rates thrombin generation in curves shown in panel A as a function of the factor VIIa concentration; absence and presence of factor VIII and factor VII are indicated in the figure in panel C. Cornelis van 't Veer et al. Blood 2000;95:1330-1335 ©2000 by American Society of Hematology