by Robert F. Kelley, Canio J. Refino, Mark P

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A Soluble Tissue Factor Mutant Is a Selective Anticoagulant and Antithrombotic Agent by Robert F. Kelley, Canio J. Refino, Mark P. O'Connell, Nishit Modi, Pat Sehl, David Lowe, Cheryl Pater, and Stuart Bunting Blood Volume 89(9):3219-3227 May 1, 1997 ©1997 by American Society of Hematology

Cofactor function of hTFAA. Cofactor function of hTFAA. (A) Stimulation of amidolytic activity of 100 nmol/L human factor VIIa on the chromogenic substrate Spectrozyme FXa by wild-type sTF (▴) or hTFAA (▪). (B) Activation of FX by FVIIa in complex with mTF (⋅), sTF (▴, ▵) or hTFAA (▪, □). For measurements with mTF, the mTF concentration was 25 nmol/L and the FVIIa concentration was 5 nmol/L. Experiments with sTF and hTFAA used 250 nmol/L sTF or hTFAA and 50 nmol/L FVIIa (▵, □) or 500 nmol/L FVIIa and 2.5 μmol/L sTF or hTFAA (▴, ▪). The substrate (FX) concentration in these experiments was 1 μmol/L. Robert F. Kelley et al. Blood 1997;89:3219-3227 ©1997 by American Society of Hematology

Activation of human factor X by the complex formed between 10 nmol/L FVIIa and 1 nmol/L wild-type sTF (▴) or hTFAA (▪) in the presence of phospholipid vesicles (0.5 mmol/L phospholipid) prepared from a 70/30 mixture of PC/PS. Activation of human factor X by the complex formed between 10 nmol/L FVIIa and 1 nmol/L wild-type sTF (▴) or hTFAA (▪) in the presence of phospholipid vesicles (0.5 mmol/L phospholipid) prepared from a 70/30 mixture of PC/PS. Initial rates of FXa formation were determined and are plotted versus substrate (FX) concentration. The solid lines are the result of nonlinear regression analysis by using the Michaelis-Menten equation. Robert F. Kelley et al. Blood 1997;89:3219-3227 ©1997 by American Society of Hematology

hTFAA functions in vitro as an antagonist of membrane bound TF hTFAA functions in vitro as an antagonist of membrane bound TF. (A) hTFAA inhibition of FX activation catalyzed by mTF⋅FVIIa. hTFAA functions in vitro as an antagonist of membrane bound TF. (A) hTFAA inhibition of FX activation catalyzed by mTF⋅FVIIa. The concentrations of FVIIa, mTF, and FX were 1 nmol/L, 10 nmol/L, and 1 μmol/L, respectively. Rate of FXa generation is shown for 0 (○), 100 nmol/L (▴), 1 μmol/L (▪), and 10 μmol/L (⋅) hTFAA. (B) hTFAA inhibition of relipidated TF(1-243)⋅FVIIa catalyzed activation of FX. For these experiments, the FVIIa concentration was 0.05 nmol/L, the substrate (FX) concentration was 200 nmol/L, and the TF(1-243) concentration was 0.05 nmol/L (⋅), 0.2 nmol/L (▪), 1 nmol/L (▴), or 5 nmol/L (▾). The rate of FXa production in the presence of the indicated hTFAA concentration was measured and is reported as the fraction of the rate observed in the absence of hTFAA. Solid lines are the result of nonlinear regression analysis by using equation 2 yielding the binding constants shown in Table 3. Robert F. Kelley et al. Blood 1997;89:3219-3227 ©1997 by American Society of Hematology

hTFAA inhibition of coagulation initiated by mTF. hTFAA inhibition of coagulation initiated by mTF. (A) Fold prolongation of clotting by hTFAA relative to no added antagonist is shown for human plasma (▴), rhesus plasma (♦) and rabbit plasma (▪). For comparison, effects of WT sTF on clotting with human plasma are also shown (⋅). Open symbols show the effect of rTFAA on clotting time with human (▵) and rabbit (□) plasma. Coagulation experiments with human plasma used human mTF to initiate clotting whereas measurements with rhesus and rabbit plasma used rabbit brain thromboplastin to initiate coagulation. In the absence of inhibitor the clotting times were 26.9 ± 1.7 seconds (human plasma), 14.2 ± 0.3 seconds (rhesus plasma), and 7.3 ± 0.5 seconds (rabbit plasma). (B) Comparison of hTFAA effects in human (⋅) and rabbit (▪) plasma. For these experiments, a standard curve relating clotting time to the concentration of relipidated human TF(1-243) (human plasma) or dilution of rabbit brain thromboplastin (rabbit plasma) was used to evaluate the apparent TF activity as a function of inhibitor concentration. The amount of initiator added was adjusted to give a clot time of 21 seconds in the absence of hTFAA. For human plasma, this clotting time was obtained with 1 nmol/L relipidated human TF(1-243). The solid lines are the result of nonlinear regression analysis using equation 1. Robert F. Kelley et al. Blood 1997;89:3219-3227 ©1997 by American Society of Hematology

Pharmacokinetics of hTFAA in the rabbit Pharmacokinetics of hTFAA in the rabbit. hTFAA concentration in plasma (⋅) was analyzed by nonlinear regression analysis using a two exponential decay (solid line). Pharmacokinetics of hTFAA in the rabbit. hTFAA concentration in plasma (⋅) was analyzed by nonlinear regression analysis using a two exponential decay (solid line). Samples were also measured for clotting time in PT (▴) and APTT (▾) assays. Robert F. Kelley et al. Blood 1997;89:3219-3227 ©1997 by American Society of Hematology

Superimposed recordings of carotid artery blood flow in representative rabbits treated with saline or rTFAA. Superimposed recordings of carotid artery blood flow in representative rabbits treated with saline or rTFAA. Blood flow through the carotid artery of anesthetized rabbits was monitored with an ultrasonic flow probe (Transonics). The following procedures were performed at the times designated by the symbols in the figure: () IV bolus administration of test compounds, (▾) embolectomy catheter inserted, (▴) embolectomy catheter removed, (✖) cuticle bleeding time determined, (+) blood sample collected for APTT and PT determination. The rapid changes in blood flow that occur between catheter insertion and catheter removal are the result of inflating and deflating the balloon between six repeated passes through a 2-cm segment of artery. Robert F. Kelley et al. Blood 1997;89:3219-3227 ©1997 by American Society of Hematology