The Formation of the Extrinsic Prothrombin Activator

1961 ◽  
Vol 05 (03) ◽  
pp. 402-425 ◽  
Author(s):  
W Straub ◽  
F Duckert
Keyword(s):  
Tissue Factor ◽  
Factor Vii ◽  
Factor V ◽  
Factor X ◽  
Clotting Factors ◽  
Second Stage ◽  
Ca Ions ◽  
Tissue Thromboplastin ◽  
Congenital Factor

SummaryThe formation of the extrinsic activator of prothrombin conversion is investigated. We use the term “extrinsic activator” to avoid ambiguity which could arise when employing the name tissue thromboplastin.The experiments are carried out with purified clotting factors and congenital factor VII and X-deficient sera. Two steps can be distinguished. First, tissue factor and factor X react together as substrates in presence of Ca ions to form the extrinsic reaction product. The reaction is catalyzed enzymatically by factor VII. In the second stage, the reaction product and factor V (substrate) form the extrinsic activator which in turn can convert the prothrombin to thrombin.

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.

scholarly journals Reduction of salivary tissue factor (thromboplastin) activity by warfarin therapy

Blood ◽  
1979 ◽  
Vol 53 (3) ◽  
pp. 366-374 ◽  
Author(s):  
LR Zacharski ◽  
R Rosenstein
Keyword(s):  
Tissue Factor ◽  
Vitamin K ◽  
Coagulation Factors ◽  
Human Saliva ◽  
Factor Vii ◽  
Clotting Factor ◽  
Activate Factor ◽  
Total Protein Content ◽  
Factor X ◽  
Clotting Factors

Abstract The coagulant of normal human saliva has been identified as tissue factor (thromboplastin, TF) by virtue of its ability to cause rapid coagulation in plasmas deficient in first-stage coagulation factors and to activate factor x in the presence of factor VII and by virtue of the fact that its activity is expressed only in the presence of factor VII and is inhibited by an antibody to TF. The TF is related to cells and cell fragments in saliva. Salivary TF activity has been found to be significantly reduced in patients taking warfarin. The decline in TF activity during induction of warfarin anticoagulation occurs during the warfarin-induced decline in vitamin-K-dependent clotting factor activity, as judged by the prothrombin time. The decrease in TF activity is not related to a reduction in salivary cell count or total protein content or to a direct effect of warfarin on the assay. It is hypothesized that the mechanism by which warfarin inhibits TF activity may be related to the mechanism by which it inhibits expression of the activity of the vitamin-K-dependent clotting factors. Inhibition of the TF activity may be involved in the antithrombotic effect of warfarin.

scholarly journals Airway tissue factor-dependent coagulation activity in response to sulfur mustard analog 2-chloroethyl ethyl sulfide

2012 ◽  
Vol 302 (1) ◽  
pp. L82-L92 ◽  
Author(s):  
Raymond C. Rancourt ◽  
Livia A. Veress ◽  
XiaoLing Guo ◽  
Tara N. Jones ◽  
Tara B. Hendry-Hofer ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Tissue Factor ◽  
Sulfur Mustard ◽  
Culture Media ◽  
Active Form ◽  
Coagulation Cascade ◽  
Factor Vii ◽  
Factor X ◽  
Clotting Factors ◽  
Airway Injury

Acute lung injury is a principal cause of morbidity and mortality in response to mustard gas (SM) inhalation. Obstructive, fibrin-containing airway casts have recently been reported in a rat inhalation model employing the SM analog 2-chloroethyl ethyl sulfide (CEES). The present study was designed to identify the mechanism(s) causing activation of the coagulation cascade after CEES-induced airway injury. Here we report that CEES inhalation elevates tissue factor (TF) activity and numbers of detached epithelial cells present in lavage fluid (BALF) from rats after exposure (18 h). In vitro studies using 16HBE cells, or with rat BALF, indicated that detached epithelial cells could convert factor X (FX) to the active form FXa when incubated with factor VII and could elicit rapid clotting of plasma. In addition, immunocytochemical analysis demonstrated elevated cell surface (TF) expression on CEES-exposed 16HBE cells as a function of time. However, total cell TF expression did not increase. Since membrane surfaces bearing TF are important determinants of clot initiation, anticoagulants directed against these entities were tested for ability to limit plasma clotting or FX activation capacity of BALF or culture media. Addition of tifacogin, a TF pathway inhibitor, effectively blocked either activity, demonstrating that the procoagulant actions of CEES were TF pathway dependent. Lactadherin, a protein capable of competing with clotting factors for phospholipid-binding sites, was partially effective in limiting these procoagulant actions. These findings indicate that TF pathway inhibition could be an effective strategy to prevent airway obstruction after SM or CEES inhalation.

scholarly journals Reduction of salivary tissue factor (thromboplastin) activity by warfarin therapy

Blood ◽  
1979 ◽  
Vol 53 (3) ◽  
pp. 366-374 ◽  
Author(s):  
LR Zacharski ◽  
R Rosenstein
Keyword(s):  
Tissue Factor ◽  
Vitamin K ◽  
Coagulation Factors ◽  
Human Saliva ◽  
Factor Vii ◽  
Clotting Factor ◽  
Activate Factor ◽  
Total Protein Content ◽  
Factor X ◽  
Clotting Factors

The coagulant of normal human saliva has been identified as tissue factor (thromboplastin, TF) by virtue of its ability to cause rapid coagulation in plasmas deficient in first-stage coagulation factors and to activate factor x in the presence of factor VII and by virtue of the fact that its activity is expressed only in the presence of factor VII and is inhibited by an antibody to TF. The TF is related to cells and cell fragments in saliva. Salivary TF activity has been found to be significantly reduced in patients taking warfarin. The decline in TF activity during induction of warfarin anticoagulation occurs during the warfarin-induced decline in vitamin-K-dependent clotting factor activity, as judged by the prothrombin time. The decrease in TF activity is not related to a reduction in salivary cell count or total protein content or to a direct effect of warfarin on the assay. It is hypothesized that the mechanism by which warfarin inhibits TF activity may be related to the mechanism by which it inhibits expression of the activity of the vitamin-K-dependent clotting factors. Inhibition of the TF activity may be involved in the antithrombotic effect of warfarin.

scholarly journals A new regulatory function of activated factor V: inhibition of the activation by tissue factor/factor VII(a) of factor X

2013 ◽  
Vol 11 (3) ◽  
pp. 503-511 ◽  
Author(s):  
R. Al Dieri ◽  
S. Bloemen ◽  
H. Kelchtermans ◽  
R. Wagenvoord ◽  
H. C. Hemker
Keyword(s):  
Tissue Factor ◽  
Factor Vii ◽  
Regulatory Function ◽  
Factor V ◽  
Factor X

Severe Congenital Factor X Deficiency in 5-Month-Old Child

1970 ◽  
Vol 24 (01/02) ◽  
pp. 175-184 ◽  
Author(s):  
A Girolami ◽  
G Molaro ◽  
A Calligaris ◽  
G De Luca
Keyword(s):  
Normal Serum ◽  
Factor Vii ◽  
Brain Hemorrhage ◽  
Factor X ◽  
Clotting Factors ◽  
Normal Limits ◽  
Factor X Deficiency ◽  
Normal Plasma ◽  
Generation Test ◽  
Congenital Factor

SummaryA case of severe congenital factor X deficiency is presented. The patient was a 5 month old child who had several episodes of melena since the first weeks of life. Other bleeding manifestations were subcutaneous hematomas and a massive brain hemorrhage. The prothrombin time was severely prolonged and was corrected by normal serum, aged normal plasma and by the plasma of patients with parahemophilia, congenital hypoprothrombinemia and factor VII deficiency. On the contrary adsorbed normal plasma and Mr. Stuart’s plasma failed to correct the abnormality.The partial thromboplastin time, prothrombin consumption and the thromboplastin generation test were abnormal too. The T.G.T. was corrected by the substitution of the patient’s serum with normal serum. The factor X level was less then 0.1% of normal. All other clotting factors were within normal limits.Both parents of the “propositus” showed slightly decreased levels of factor X in their plasmas and were considered to be heterozygotes for the defect.

Some Effects of Factor VII on Rates of Thrombin Production and one Stage Pi’s

1979 ◽  
Author(s):  
D. J. Baughman ◽  
A. Lytwyn
Keyword(s):  
Plasma Concentrations ◽  
Factor Vii ◽  
Thrombin Inhibitor ◽  
Factor V ◽  
Factor X ◽  
One Stage ◽  
Feedback Scheme ◽  
Plasma Factor ◽  
Initial Generation ◽  
Tissue Thromboplastin

Attempts to automate a chromogenic one stage PT assay required hastening the onset of thrombin production without altering the rate of production. Assays were performed by combining 0.25ml chromogenic substrate S-2238 (2mM), 0.40ml tissue thromboplastin,0.050ml plasma, and 0.050ml diluted serum (40%v/v) in 1.35ml TRIS buffer (pH=8-5,I=0.15). Sera were prepared by using the supernatant of a) whole blood, b) recalcified plasma, c) recalc fied plasma and tissue thromboplastin, d)recalcified plasma and partial thromboplastin (cephalin and ellagic acid) and e) thrombin clotted plasma. The results indicated that S-2238, a potent thrombin inhibitor, delayed the onset and altered the rate of thrombin; production. Small amounts of thrombin shortened the initial generation of thrombin without altering its rate. Sera from a), c) and d) but not b) and e) resulted in immediate thrombin production at most plasma concentrations without affecting the rate, had no residual prothrombin, and had similar residual S-2238 activity not reduced by hirudin or At III-heparin. In particular, scrum b) had ~80% plasma Factor X which could be adsorbed without affecting thrombin production, had ~40% Factor V and ~300% Factor VII. These results suggest that when Factor VII activity is greater than ~7% there is an effect on the time but not on the rate of thrombin production via positive thrombin feedback scheme. Thus, the standard PT can measure the time of thrombin appearance, and/or the rate of thrombin production, and/or fibrin polymerization.

scholarly journals RASopathies and hemostatic abnormalities: key role of platelet dysfunction

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Francesca Di Candia ◽  
Valeria Marchetti ◽  
Ferdinando Cirillo ◽  
Alessandro Di Minno ◽  
Carmen Rosano ◽  
...  
Keyword(s):  
Coagulation Factor ◽  
Screening Tests ◽  
Factor Vii ◽  
Bleeding Complications ◽  
Factor V ◽  
Bleeding Tendency ◽  
Factor X ◽  
Platelet Response ◽  
Platelet Dysfunction ◽  
Clotting Factors

Abstract Background Bleeding anomalies have been reported in patients affected by Noonan syndrome. No study has been performed in patients with molecularly confirmed RASopathy. We aimed to characterize the frequency and types of bleeding disorders in patients with RASopathies and evaluate any significant association with laboratory findings. Patients and methods Forty-nine individuals (PTPN11, n = 27; SOS1, n = 7; RIT1, n = 3; SPRED1, n = 1; LZTR1, N = 3; RAF1, n = 2; BRAF, n = 4; MEK1, n = 1; MEK2, n = 1), and 49 age- and sex-matched controls were enrolled. The “Paediatric Bleeding Questionnaire Scoring Key” was administered to patients and families. Laboratory screening tests including clotting factors dosing, platelet count, Prothrombin Time and Partial Thromboplastin Time, were employed both in patients and controls to characterize the bleeding diathesis. A subgroup of 29/49 patients and 29/49 controls was also tested for platelet function. Results Regardless of the gene involved, pathological paediatric bleeding scores were recorded in 14/49 (28.5%) patients. Indeed, 7 were mutated in PTPN11, 3 in SOS1, 2 in RIT1, 1 in BRAF, and 1 in MEK1. Compared to patients with normal bleeding scores, those with pathologic bleeding score showed higher prevalence of splenomegaly (p = 0.006), prolonged aPTT (p = 0.04), lower levels of coagulation factor V (FV, p = 0.001), FVII (p = 0.003), FX (p = 0.0008) and FXIII (p = 0.002), higher vWAg (p = 0.04), and lower platelet sensitivity to Ristocetin (p = 0.001), arachidonic acid (AA) (p = 0.009) and collagen (p = 0.01). The presence of hematomas inversely correlated with factor V (p = 0.002), factor VII (p = 0.003), factor X (p = 0.002) and factor XIII (p = 0.004) levels, and directly correlated with platelet response to collagen (p = 0.02) and AA (p = 0.01). The presence of splenomegaly directly correlated with the presence of hematoma (p = 0.006), platelet response to Ristocetin (p = 0.04) and AA (p = 0.04), and inversely correlated with factor V levels (p = 0.03). Conclusions Patients with RASopathies and a bleeding tendency exhibit multiple laboratory abnormalities, including platelet-related disorders. Splenomegaly is frequently detected and might be a suggestive sign for qualitative platelet dysfunction. A comprehensive clinical assessment should be carried out at diagnosis, during the follow-up and before any surgical procedures. Since there is currently no consensus on management of bleeding complications, it is important that physicians closely monitor these patients.

Factors Affecting the lnteraction of Tissue Factor/Factor Vll with Factor X in a Heterogeneous Tubular Reactor

1991 ◽  
Vol 65 (02) ◽  
pp. 139-143 ◽  
Author(s):  
Cynthia H Gemmell ◽  
Vincet T Turitto ◽  
Yale Nemerson
Keyword(s):  
Steady State ◽  
Tissue Factor ◽  
Factor Viia ◽  
Transmembrane Protein ◽  
Strong Association ◽  
Tubular Reactor ◽  
Factor Xa ◽  
Phospholipid Bilayer ◽  
Factor Vii ◽  
Factor X

SummaryA novel reactor recently described for studying phospholipiddependent blood coagulation reactions under flow conditions similar to those occurring in the vasculature has been further charactenzed. The reactor is a capitlary whose inner wall is coated with a stable phospholipid bilayer (or two bilayers) containing tissue factor, a transmembrane protein that is required for the enzymatic activation of factor X by factor VIIa. Perfusion of the capillary at wall shear rates ranging from 25 s−1 to 1,200 s−1 with purified bovine factors X and VIIa led to steady state factor Xa levels at the outlet. Assay were performed using a chromogenic substrate, SpectrozymeTMFXa, or by using a radiometric technique. In the absence of Ca2+ or factor VIIa there was no product formation. No difference was noted in the levels of factor Xa achieved when non-activated factor VII was perfused. Once steady state was achieved further factor Xa production continued in the absence of factor VIIa implying a very strong association of factor VIIa with the tissue factor in the phospholipid membrane. In agreement with static vesicle-type studies the reactor was sensitive to wall tissue factor concentration, temperature and the presence of phosphatidylserine in the bilayer.

scholarly journals Inhibition of tissue factor/factor VIIa activity in plasma requires factor X and an additional plasma component

Blood ◽  
1985 ◽  
Vol 66 (1) ◽  
pp. 204-212
Author(s):  
NL Sanders ◽  
SP Bajaj ◽  
A Zivelin ◽  
SI Rapaport
Keyword(s):  
Tissue Factor ◽  
Factor Viia ◽  
Factor Ix ◽  
Factor Vii ◽  
Factor X ◽  
Additional Material ◽  
Plasma Reaction ◽  
Progress Curve ◽  
Peptide Release ◽  
Release Data

A study was carried out to explore requirements for the inhibition of tissue factor-factor VIIa enzymatic activity in plasma. Reaction mixtures contained plasma, 3H-factor IX or 3H-factor X, tissue factor (vol/vol 2.4% to 24%), and calcium. Tissue factor-factor VIIa activity was evaluated from progress curves of activation of factor IX or factor X, plotted from tritiated activation peptide release data. With normal plasma, progress curves exhibited initial limited activation followed by a plateau indicative of loss of tissue factor-factor VIIa activity. With hereditary factor X-deficient plasma treated with factor X antibodies, progress curves revealed full factor IX activation. Adding only 0.4 micrograms/mL factor X (final concentration) could restore inhibition. Inhibition was not observed in purified systems containing 6% to 24% tissue factor, factor VII, 0.5 micrograms/mL, factor IX, 13 micrograms/mL, and factor X up to 0.8 micrograms/mL, but could be induced by adding barium-absorbed plasma to the reaction mixture. Thus, both factor X and an additional material in plasma were required for inhibition. The amount of factor X needed appeared related to the concentration of tissue factor; adding more tissue factor at the plateau of a progress curve induced further activation. These results also indicate that inhibited reaction mixtures contained active free factor VII(a). Preliminary data suggest that inhibition may stem from loss of activity of the tissue factor component of the tissue factor- factor VII(a) complex.

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