EXTRINSIC PATHWAY INHIBITOR (EPI) DURING ELECTUVE SUGERY : A COMPARISON WITH OTHER COAGULATION INHIBITORS

1987 ◽  
Author(s):  
P M Sandset ◽  
T R Anderson ◽  
O R Ødegaard ◽  
M L Larsen
Keyword(s):  
Potent Inhibitor ◽  
Hip Prosthesis ◽  
The Other ◽  
Factor Vii ◽  
Surgical Trauma ◽  
Factor X ◽  
Extrinsic Pathway ◽  
Heparin Cofactor Ii ◽  
Coagulation Inhibitors ◽  
Tissue Thromboplastin

Hypercoagulation after surgical trauma is probably induced by tissue thromboplastin (TP) released into the circulation. EPI, in conjuction with activated factor x (FXa), is a potent inhibitor of the IP-factor VII complex. EPI levels (chromogenic substance assay) were compared to other inhibitors; antithrombin (AT), heparin cofactor II (HCII), andprotein C (PC) in patients undergoing cholecystectomy(n=4), hip prosthesis operation (n=5),and aortic grafts operationa(n=5) Mean AT and PC levels parallelled the decrease in albumin. HCII decreased more suggesting a real consumption ofsurgery. The changes in EPI levels depended on the type ofsurgery. In hip surgery, the decline in EI levels was marked and parallelled HCII. In constrast to the other inhibitors, EPI levels stayed low over the first week after surgery:In cholecystectomy, changes were less marked and all inhibitors behaved similar. During aortic operations, EPI increased from mean 110% preoperatively to 252% peroperatively. It decreased to 86% the first day after operation. It then increased similar to the other inhibitors, but the level stayed higher than expected from the preoperative value. The patients received 3000 IU heparin peroperatively.In conclusion, hip operations produce a sustained drop in EPI activity.In aortic operations injection of heparin induced a dramatic, shortlived increase peroperatively followed by a restoration to high normal levels.

Self-Damping Mechanism in Blood Coagulation

1974 ◽  
Vol 32 (01) ◽  
pp. 057-064 ◽  
Author(s):  
Y Nemerson ◽  
S.A Silverberg ◽  
J Jesty
Keyword(s):  
Tissue Factor ◽  
Blood Coagulation ◽  
Calcium Ions ◽  
Control Mechanism ◽  
Factor Vii ◽  
Damping Factor ◽  
Factor V ◽  
Factor X ◽  
Extrinsic Pathway ◽  
Two Systems

SummaryTwo reactions of the extrinsic pathway of coagulation, the activations of Factor X and prothrombin, have been studied in purified systems and shown to be self-damping. Factor X was activated by the tissue factor - Factor VII complex, and prothrombin by two systems: the coagulant protein of Taipan venom, and the physiological complex of activated Factor X, Factor V, lipid, and calcium ions. In each case the yield of enzyme, activated Factor X or thrombin, is a function of the concentration of activator. These and other observations are considered as a basis for a control mechanism in coagulation.

Extrinsic Pathway Inhibitor in Elective Surgery: A Comparison with other Coagulation Inhibitors

1989 ◽  
Vol 62 (03) ◽  
pp. 856-860 ◽  
Author(s):  
P M Sandset ◽  
H E Høgevold ◽  
T Lyberg ◽  
T R Andersson ◽  
U Abildgaard
Keyword(s):  
Vascular Surgery ◽  
Protein C ◽  
Elective Surgery ◽  
Perioperative Period ◽  
Acute Phase Reactant ◽  
Hip Surgery ◽  
Albumin Concentration ◽  
Extrinsic Pathway ◽  
Heparin Cofactor Ii ◽  
Coagulation Inhibitors

SummaryExtrinsic coagulation pathway inhibitor may be an important regulator of haemostasis to prevent thrombosis after tissue damage. The functional activity of this inhibitor was determined using a chromogenic substrate assay, and compared to the activities of anti thrombin, heparin cofactor II and protein C during the perioperative period of elective hip replacement (n = 28), cholecystectomy (n = 11), and vascular surgery (n = 5). Peroperatively, all the inhibitors decreased rather similarly and to the same degree as the decrease in albumin concentration. The decreases during hip surgery were about 2-fold the decreases observed during cholecystectomy. A significant peroperative increase in extrinsic pathway inhibitor activity was observed in vascular surgery, probably due to a bolus injection of heparin. Antithrombin, heparin cofactor II and protein C levels normalized on days 3-5 postoperatively in all three patient groups. Sustained low levels of extrinsic pathway inhibitor were observed on postoperative days 1 to 7 in hip surgery patients. Apparently, extrinsic pathway inhibitor is not an acute phase reactant. In uncomplicated surgery, the decreases of the coagulation inhibitor levels are mainly due to hemodilution.

scholarly journals Studies of a mechanism inhibiting the initiation of the extrinsic pathway of coagulation

Blood ◽  
1987 ◽  
Vol 69 (2) ◽  
pp. 645-651 ◽  
Author(s):  
LV Rao ◽  
SI Rapaport
Keyword(s):  
Tissue Factor ◽  
Factor Viia ◽  
Factor Xa ◽  
Factor Ix ◽  
Factor Vii ◽  
Factor X ◽  
Extrinsic Pathway ◽  
Mechanism Of Inhibition ◽  
Peptide Release ◽  
Release Assay

Abstract We have extended earlier studies (Blood 66:204, 1985) of a mechanism of inhibition of factor VIIa/tissue factor activity that requires a plasma component (called herein extrinsic pathway inhibitor or EPI) and factor Xa. An activated peptide release assay using 3H-factor IX as a substrate was used to evaluate inhibition. Increasing the tissue factor concentration from 20% to 40% (vol/vol) overcame the inhibitory mechanism in normal plasma but not in factor VII-deficient plasma supplemented with a low concentration of factor VII. A second wave of factor IX activation obtained by a second addition of tissue factor to plasma with a normal factor VII concentration was almost abolished by supplementing the reaction mixture with additional EPI and factor X. Factor Xa's active site was necessary for factor Xa's contribution to inhibition, but preliminary incubation of factor Xa with EPI in the absence of factor VIIa/tissue factor complex or of factor VIIa/tissue factor complex in the absence of EPI did not replace the need for the simultaneous presence of factor Xa, factor VIIa/tissue factor, calcium, and EPI in an inhibitory reaction mixture. Inhibition of factor VIIa/tissue factor was reversible; both tissue factor and factor VIIa activity could be recovered from a dissociated, inhibited factor VIIa/tissue factor complex. EPI appeared to bind to a factor VIIa/tissue factor complex formed in the presence of factor Xa but not to a factor VIIa/tissue factor complex formed in the absence of factor Xa.

scholarly journals The contributions of Ca2+, phospholipids and tissue-factor apoprotein to the activation of human blood-coagulation factor X by activated factor VII

1990 ◽  
Vol 265 (2) ◽  
pp. 327-336 ◽  
Author(s):  
V J J Bom ◽  
R M Bertina
Keyword(s):  
Tissue Factor ◽  
Blood Coagulation ◽  
Reaction Rate ◽  
Factor Viia ◽  
Coagulation Factor ◽  
Fluid Phase ◽  
Fold Increase ◽  
Factor Vii ◽  
Factor X ◽  
Extrinsic Pathway

In the extrinsic pathway of blood coagulation, Factor X is activated by a complex of tissue factor, factor VII(a) and Ca2+ ions. Using purified human coagulation factors and a sensitive spectrophotometric assay for Factor Xa, we could demonstrate activation of Factor X by Factor VIIa in the absence of tissue-factor apoprotein, phospholipids and Ca2+. This finding allowed a kinetic analysis of the contribution of each of the cofactors. Ca2+ stimulated the reaction rate 10-fold at an optimum of 6 mM (Vmax. of 1.1 x 10(-3) min-1) mainly by decreasing the Km of Factor X (to 11.4 microM). In the presence of Ca2+, 25 microM-phospholipid caused a 150-fold decrease of the apparent Km and a 2-fold increase of the apparent Vmax. of the reaction; however, both kinetic parameters increased with increasing phospholipid concentration. Tissue-factor apoprotein contributed to the reaction rate mainly by an increase of the Vmax., in both the presence (40,500-fold) and absence (4900-fold) of phospholipid. The formation of a ternary complex of Factor VIIa with tissue-factor apoprotein and phospholipid was responsible for a 15 million-fold increase in the catalytic efficiency of Factor X activation. The presence of Ca2+ was absolutely required for the stimulatory effects of phospholipid and apoprotein. The data fit a general model in which the Ca2(+)-dependent conformation allows Factor VIIa to bind tissue-factor apoprotein and/or a negatively charged phospholipid surface resulting into a decreased intrinsic Km and an increased Vmax. for the activation of fluid-phase Factor X.

FACTOR II ACTIVATING ACTIVITY IN EXTRACTS OF TUMORAL NECROSIS FROM TWO MURINE BREAST ADENOCARCINOMAS

1987 ◽  
Author(s):  
A Blanco ◽  
R Bonfil ◽  
O Bustoabad ◽  
M Lazzari
Keyword(s):  
Coagulation Factors ◽  
Factor Vii ◽  
Factor V ◽  
Factor X ◽  
Extrinsic Pathway ◽  
Factor Ii ◽  
Metastatic Capacity ◽  
Plasma Recalcification Time ◽  
Recalcification Time ◽  
Breast Adenocarcinomas

Increased deposition and lysis of fibrin, associated with malignant tissue, has led to look for activators of both the coagulation and fibrinolytic systems produced by tumor cells. We report the evidences of a procoagblant activity (PA) in the extracts of intratumoral necrosis from two experimental breast adenocarcinomas in murine model (BALB/c). The tumors have different metastatic capacity (MC). M3 without MC and MM3 with high MC.The addition of the extracts to: 1- Normal Plasma, 2- Deficient substrates in coagulation factors, 3- Purified, fibrinogen (I), showed: 1- Shortening of the plasma recalcification time (PRT) and APTT, without ;modification on prothrombin time (PT), 2- Reduction of the PRT on deficient substrates in factors: VIII; VII; VII and X; V; V, VII and X; without modification on II deficient substrate, 3- No PA on I. Table:C: Control, s: seconds, m: minutes. The PA was not affected by heparin. The results suggest that the PA is independent of the presence of either factor VIII or factor VII (intrinsic or extrinsic pathway respectively), as well as presence of either factor V or factor X. Any effect was observed either on factor II deficient substrate or on I, so, there was no evidence of thrombin activity The PA could be act directly on factor II, suggesting that fibrin formation could be induced by a “non-classical” activation pathway. No significant differences (p>0.5) in PA were observed between both tumoral necrosis extracts. The necrotic area in M3 (37%) is bigger than in MM3 (18%). So, much more PA could be present in MM3 and this could play a role in the MC of this tumor.

scholarly journals Initiation of the extrinsic pathway of coagulation by human and rabbit alveolar macrophages: a kinetic study

Blood ◽  
1989 ◽  
Vol 74 (5) ◽  
pp. 1583-1590 ◽  
Author(s):  
MP McGee ◽  
R Wallin ◽  
FB Wheeler ◽  
H Rothberger
Keyword(s):  
Alveolar Macrophage ◽  
Alveolar Macrophages ◽  
Plasma Concentrations ◽  
Factor Xa ◽  
Factor Vii ◽  
Factor X ◽  
Extrinsic Pathway ◽  
Activation Rate ◽  
Factor X Activation

We examined assembly and expression of the factor X activating complex on human and rabbit alveolar macrophages. Kinetic parameters of the factor X activating reaction were determined by functional titrations of factors VII and X with macrophage tissue factor (TF) added. We found rapid activation of factor X to Xa on alveolar macrophage surfaces. Detection of rapid factor Xa formation on macrophages required addition of exogenous factors VII and X. At plasma concentrations of the purified factors, factor Xa was formed on freshly isolated macrophages at approximately 5.4 pmol/min/10(6) cells. After macrophage maturation in culture for 20 hours with LPS (endotoxin) added, the factor X activation rate was increased two- to sixfold. The km' (apparent km) of TF-factor VII enzymatic complexes assembled on alveolar macrophages for factor X were (258 +/- 55 and 475 +/- 264 nmol/L for human and rabbit cells, respectively). The km' did not change during macrophage maturation in culture, but V'max (apparent Vmax) was consistently increased. The K1/2 of human factor VII (concentrations giving half maximal rates of factor X activation) for the interaction with human and rabbit alveolar macrophage TF were 0.191 +/- 0.096 and 1.7 +/- 0.7 etamol/L, respectively. The K1/2 were not significantly changed after maturation, whereas rates of Xa formation at saturation with factor VII were increased. The fast rates of factor X activation observed at physiologic concentrations of plasma-derived factors VII and X indicate that TF on alveolar macrophages is likely to provide sites for binding of factor VII and activation of factor X in vivo during clotting reactions associated with alveolar edema and inflammation.

A Comparison of Plasma and Serum Factor VII Activity and the Formation of Tissue Thromboplastin

1962 ◽  
Vol 08 (02) ◽  
pp. 286-296
Author(s):  
P Fantl ◽  
E. C Osborn
Keyword(s):  
Human Brain ◽  
Human Plasma ◽  
Factor Vii ◽  
Brain Extract ◽  
Factor X ◽  
Similar Activity ◽  
Bovine Plasma ◽  
Tissue Thromboplastin ◽  
Species Specific ◽  
Glass Surfaces

Summary1. A mixture of human serum or plasma and bovine plasma free of factors VII and X gave, with human brain extract, identical clotting times.2. An assay of factor VII in materials low in prothrombin using human plasma euglobulin was devised.3. Factor VII isolated from human plasma or serum gave similar activity with human brain extract.4. From a preparation containing factors VII and X which was added to human brain extract in the average 31% factor VII and 25% factor X was recovered. This was not dependent on the activity of factors VII and X in the original preparation. This indicates that factors VII and X are in equilibrium with tissue thromboplastin.5. Factors VII and X are not species specific but a higher concentration of these factors is required for prothrombin conversion in a heterologous reaction mixture.6. Factor VII activity is identical in silicone-coated or uncoated glass surfaces.

MECHANISMS OF PROCOAGULANT GENERATION BY ALVEOLAR MACROPHAGES DURING MATURATION

1987 ◽  
Author(s):  
Maria McGee ◽  
Henry Rothberger
Keyword(s):  
Alveolar Macrophages ◽  
Cultured Cells ◽  
Factor Xa ◽  
Procoagulant Activity ◽  
Factor Vii ◽  
Factor X ◽  
Extrinsic Pathway ◽  
Complex Assembly

During maturation in vivo and in vitro alveolar macrophages generate procoagulant(s) capable of activating the extrinsic pathway. It is generally agreed that at least part of the activity is due to TF (tissue factor). However, whether or not macrophages also generate functional factor VII or X is controversial. To characterize procoagulant activity increases, we measured kinetic parameters defining interactions between components of the TF-VII complex on membranes of alveolar macrophages either freshly isolated or cultured in serum free medium. In incubation mixtures with fixed concentrations of macrophages and added factor VII, the rate of factor Xa formation (measured by S-2222 hydrolysis) approached a maximum as factor X concentration was increased. Estimated concentrations of factor X yielding 1/2 maximal activation rates, (apparent Km) were 127.1±26 nM and 99.7±34 nM for fresh and cultured cells, respectively. Vmax (maximal velocities) were 1.21±0.24 and 8.9±5 nM Xa/min/106 cells. When concentrations of added factor X were kept constant, the rate of factor X activation increased as the added factor VII concentration was increased. For fresh and cultured cells, the respective apparent Kd were 1.810.7 and 1.410.25 nM. Maximal rates observed with X concentration fixed at 108 nM were 0.46±10.06 and 5.7±1.6 nM Xa/min/106 cells. In the absence of either added factor X or added factor VII, no factor Xa generation was detected in fresh or cultured cells, during 10-20 min incubation periods used for kinetic studies. The observed increase in Vmax without changes in apparent Km and Kd indicate that gains in procoagulant activity during macrophage maturation are due to increases in the number of functional binding sites for factor VII, without significant generation of functional vitamin K dependent factors (VII and X) by the cells. The data also indicate that maturation does not alter the rate behaviour of the TF-VII enzymatic complex on macrophage membranes. Mechanisms of complex assembly that we observed on macrophage membranes are similar to those described for the TF-VII complex assembly on purified systems.

scholarly journals Studies of a mechanism inhibiting the initiation of the extrinsic pathway of coagulation

Blood ◽  
1987 ◽  
Vol 69 (2) ◽  
pp. 645-651 ◽  
Author(s):  
LV Rao ◽  
SI Rapaport
Keyword(s):  
Tissue Factor ◽  
Factor Viia ◽  
Factor Xa ◽  
Factor Ix ◽  
Factor Vii ◽  
Factor X ◽  
Extrinsic Pathway ◽  
Mechanism Of Inhibition ◽  
Peptide Release ◽  
Release Assay

We have extended earlier studies (Blood 66:204, 1985) of a mechanism of inhibition of factor VIIa/tissue factor activity that requires a plasma component (called herein extrinsic pathway inhibitor or EPI) and factor Xa. An activated peptide release assay using 3H-factor IX as a substrate was used to evaluate inhibition. Increasing the tissue factor concentration from 20% to 40% (vol/vol) overcame the inhibitory mechanism in normal plasma but not in factor VII-deficient plasma supplemented with a low concentration of factor VII. A second wave of factor IX activation obtained by a second addition of tissue factor to plasma with a normal factor VII concentration was almost abolished by supplementing the reaction mixture with additional EPI and factor X. Factor Xa's active site was necessary for factor Xa's contribution to inhibition, but preliminary incubation of factor Xa with EPI in the absence of factor VIIa/tissue factor complex or of factor VIIa/tissue factor complex in the absence of EPI did not replace the need for the simultaneous presence of factor Xa, factor VIIa/tissue factor, calcium, and EPI in an inhibitory reaction mixture. Inhibition of factor VIIa/tissue factor was reversible; both tissue factor and factor VIIa activity could be recovered from a dissociated, inhibited factor VIIa/tissue factor complex. EPI appeared to bind to a factor VIIa/tissue factor complex formed in the presence of factor Xa but not to a factor VIIa/tissue factor complex formed in the absence of factor Xa.

scholarly journals Monocytes can be induced by lipopolysaccharide-triggered T lymphocytes to express functional factor VII/VIIa protease activity.

1984 ◽  
Vol 159 (4) ◽  
pp. 1042-1057 ◽  
Author(s):  
B P Tsao ◽  
D S Fair ◽  
L K Curtiss ◽  
T S Edgington
Keyword(s):  
Protease Activity ◽  
Factor Xa ◽  
Molecular Assembly ◽  
Factor Vii ◽  
Factor X ◽  
Extrinsic Pathway ◽  
Exogenous Factor ◽  
Factor Va ◽  
Initiation And Propagation ◽  
Functional Factor

In the present study we demonstrate that human monocytes can be induced by the model stimulus, lipopolysaccharide (LPS), to produce and assemble on their surface functional Factor VII/VIIa. This protease was not induced in relatively purified monocytes alone following exposure to LPS; but was induced in the presence of Leu-3a positive helper/inducer T cells. The Factor VII/VIIa protease activity represented 35-40% of the potential initiating activity for the extrinsic coagulation pathway and was demonstrated using functional coagulation assays, as well as in amidolytic assays for the activation of Factor X. This activity of cell-bound Factor VII/VIIa appeared to involve a tight adduct of calcium. The identity of the Factor X-activating protease as Factor VII/VIIa was confirmed by the capacity of antibody specific for Factor VII/VIIa to neutralize the cell-bound protease. Further propagation of the extrinsic pathway following generation of Factor Xa required addition of exogenous Factor Va. These results expand the repertoire of proteases that have been identified with appropriately triggered cells of the monocyte/macrophage series, and suggest that initiation and propagation of the extrinsic coagulation protease network on induced monocytes involves not only expression of the initiating cofactor molecule, tissue factor, but also production of Factor VII and its organization into the molecular assembly. Thus, in the absence of exogenous Factor VII/VIIa a directly proteolytic effector cell can be generated. Further molecular assembly of the extrinsic pathway on the monocyte surface sequentially expands the proteolytic capacity of this response. The synthesis and assembly of the extrinsic activation complex by the monocyte and its derived progeny, the macrophage, provides a mechanism by which coagulation is initiated under T cell instruction at sites of immunologic responses.

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