Antithrombin III and Venous Thrombosis

1979 ◽  
Author(s):  
Duncan P. Thomas
Keyword(s):  
Venous Thrombosis ◽  
Antithrombin Iii ◽  
Physiological Role ◽  
Factor Xa ◽  
Original Description ◽  
Clear Cut ◽  
Naturally Occurring ◽  
At Iii ◽  
General Studies

Increasing interest in the physiological role of inhibitors of coagulation has highlighting the role of antithrombin III (AT III) as the most important naturally occurring inhibitor of venous thrombosis. Since Egeberg’s original description in 1965, it has been recognized that inherited deficiency of AT III is associated with an increased incidence of venous thromboembolism. The role of acquired deficiency of AT III in the pathogenesis of thromboembolism remainsless clear-cut, partly due to methodological differences. While low values have been reported in groups of patients with thromboembolism, estimations of AT III in individual patients are not allways abnormal. In general, studies which have measured protein concentration rather than functional activity, or cl otting assays which measure total antithrombin activity and not specific anti-Factor Xa activity have failed to demonstrate a clear relationship between AT III and thromboembolism. However, in two groups of patients, namely women on oral contraceptives and patients undergoing total hipreplacement, an acquired deficiency of AT III, particularly when measured by anti-Xa clotting assays, correlates highly with postoperative venous thrombosis. Although venous thrombosis may develop in patients despite normal AT III values, an activity below approximately 80% in an anti-Xa clotting assay has been found to be of predictive value in patients subjected to the stress of trauma or surgery.

AT III BINDING SITE OF HEPARIN. DETERMINATION OF THE ROLE OF SULFATE GROUPS AT THE REDUCING-END DISACCHARIDE THROUGH NEW SYNTHETIC PENTASACCHARIDES

1987 ◽  
Author(s):  
M Petitou ◽  
J C Lormeau ◽  
J Choay
Keyword(s):  
Antithrombin Iii ◽  
Factor Xa ◽  
Structural Features ◽  
Sulfate Group ◽  
Naturally Occurring ◽  
At Iii ◽  
Antifactor Xa ◽  
Similar Decrease

A unique sequence is required in heparin for binding to antithrombin III (AT III) and eliciting anti-factor Xa activity. We have previously synthesized a pentasaccharide containing all the structural features of this sequence. It binds to AT III with the same affinity as high affinity heparin. The complex thus formed has a high anti-factor Xa activity. We have now synthesized a new series of α-methylated pentasaccharides which better mimic the naturally occurring configuration at C1 of the reducing-end glucosamine unit. The synthesis of the inactive pentasaccharide II allowed us to confirm in this series the essential role of the 3-sulfate group borne by glucosamine unit F. Wehave also particularly addressed the still unanswered question regarding the role of the 2-sulfate group borne by iduronic acid G and of the 6-sulfate group borne by glucosamine unit H. Pentasaccharides III and IV elicit the same anti-factor Xa activity which is substantially decreased as compared to I. A similar decrease has been recently reported for pentasaccharide V (T. Beetz & C.A.A. van Boeckel, Tetrahedron Lett., 1986, 27, 5889). We therefore conclude that the presence of both these sin fate groups is required for full expression of the antifactor Xa activity.

Reactivity of a Hereditary Abnormal Antithrombin III Fraction in the Inhibition of Thrombin and Factor Xa

1980 ◽  
Vol 44 (02) ◽  
pp. 092-095 ◽  
Author(s):  
T H Tran ◽  
C Bondeli ◽  
G A Marbet ◽  
F Duckert
Keyword(s):  
Antithrombin Iii ◽  
Factor Xa ◽  
Heparin Binding ◽  
Thrombin Inhibition ◽  
Superficial Thrombophlebitis ◽  
Heparin Concentration ◽  
Heparin Binding Site ◽  
At Iii ◽  
The Difference ◽  
Inhibition Of Thrombin

SummaryTwo different AT-III fractions were purified from the plasma of a patient with recurrent superficial thrombophlebitis. The abnormal AT-III fraction (A-AT) was compared to the normal AT-III fraction (N-AT) in the inhibition of thrombin and factor Xa. Without heparin, both inactivate proteases in a similar manner and at the same rate. However, at low heparin concentration the thrombin inhibition proceeds more slowly with A-AT than with N-AT. At high heparin concentration the difference between A-AT and N-AT becomes very small. The inhibition of factor Xa follows a similar pattern. It is suggested that the heparin binding site of A-AT differs from that of N-AT resulting in a decreased heparin cofactor activity.

GAGs-Potentiated Inhibition of Thrombin, Factor Xa and Plasmin in Plasma and in a Purified System Containing Antithrombin III – Correlation with Total Charge Density

1981 ◽  
Vol 46 (04) ◽  
pp. 749-751 ◽  
Author(s):  
E Cofrancesco ◽  
A Vigo ◽  
E M Pogliani
Keyword(s):  
Charge Density ◽  
Chemical Structure ◽  
Antithrombin Iii ◽  
Factor Xa ◽  
Total Charge ◽  
Pure System ◽  
At Iii ◽  
Total Charge Density ◽  
The Difference ◽  
Inhibition Of Thrombin

SummaryThe ability of heparin and related glycosaminoglycans (GAGs) to accelerate the inhibition of thrombin, factor Xa and plasmin in plasma and in a purified system containing antithrombin III (At III) was studied using chromogenic peptide substrate assaysThere was a good correlation between the charge density of the mucopolysaccharides and the activities investigated. While the difference between potentiation of the antithrombin activity by GAGs in plasma and in the purified system was slight, the inhibition of factor Xa in plasma was more pronounced than in the presence of purified At III, indicating the mechanisms for GAGs-potentiated inhibition of thrombin and factor Xa are not identical.For the antiplasmin activity, there was a good correlation between the chemical structure and biological activity only in the pure system, confirming that the antithrombin-GAG complex plays a very limited role in the inactivation of plasmin in plasma.

PRODUCTION AND CHARACTERISATION OF A MONOCLONAL ANTIBODY AGAINST HUMAN ANTI-THROMBIN III

1987 ◽  
Author(s):  
Deborah A Rathjen ◽  
Carolyn L Geczy
Keyword(s):  
Cultured Cells ◽  
Factor Xa ◽  
Lymphocyte Activation ◽  
Blue Staining ◽  
Aortic Endothelial Cells ◽  
Tissue Sections ◽  
Coomassie Blue Staining ◽  
Coomassie Blue ◽  
At Iii

To study the role of anticoagulants, particularly antithrombin III (AT III) and heparin, on the activation of coagulation by monocytes/macrophages which have been stimulated with a soluble lymphocyte activation product, macrophage procoagulant inducing factor, we have prepared monoclonal antibodies (MAbs) to human AT III.In fusion experiments, in contrast to wells containing peritoneal feeder cells, positive hybrids were only found in wells containing medium conditioned by the macrophage cell line J774 (Rathjen and Geczy, 1986). Of 5 hybrids which initially produced antibody, only one hybrid, showed stable Ab production. The MAb, designated 22/23, was not cross-reactive with either 1 antitrypsin or ovalbumin and did not inhibit the biological activity of AT III in chromogenic assays which measured inhibition of thrombin and Factor Xa by AT III. An immunoadsorbent prepared using MAb 22/23 depleted AT III activity from a purified AT III preparation. Reduction and alkylat ion of the disulphide bonds of the protein portion of AT III completely abbrogated MAb binding indicating that the native configuration of AT III was important. Isoelectric focussing of AT III, followed by transfer of the focussed protein to nitrocellulose by diffusion and probing with MAb 22/23, revealed at least 8 bands in the region of pH 5.2 to 5.85. Coomassie blue staining of a gel run in parallel showed 9 bands in this region. The MAb provides a useful tool for the detection of AT III on both cultured cells (bovine aortic endothelial cells are positive by immunofluorescence) and tissue sections.Rathjen, D.A. and Geczy, C.L. Hybridomo. 5s 255-261 (1986)

Antithrombin III Infusion During Fulminant Hepatic Failure

1981 ◽  
Author(s):  
S Braude ◽  
J Arias ◽  
R D Hughes ◽  
J Canalese ◽  
A E S Gimson ◽  
...  
Keyword(s):  
Fulminant Hepatic Failure ◽  
Hepatic Failure ◽  
Hepatic Coma ◽  
Antithrombin Iii ◽  
Platelet Destruction ◽  
At Iii ◽  
Heparin Anticoagulation ◽  
Low Levels ◽  
Initial Bolus

The antithrombin III (ATIII) levels in 17 patients with fulminant hepatic failure due to viral hepatitis or paracetamol overdose were found to be 25.8%±SD 12.80 of normal on admission. The levels did not correlate with eventual survival or death and remained essentially unchanged for up to 7 days.In an attempt to assess the role of the low levels of AT III during the course of hepatic failure and in relation to treatment by charcoal haemoperfusion we have infused patients with commercially purified ATIII. Preliminary measurements of ATIII (chromogenic substrate method) were made and ATIII infused to achieve a plasma concentration of 50 to 70%. Infusion was by an initial bolus of 1500-2000 units followed by up to 500 units every 6 hours. To date 3 patients in Grade IV hepatic coma have been treated, one died 1 day after admission and the other two survived. In the latter the return of the prothrombin time to normal was similar to that in patients without the addition of ATIII. In one of the survivors the platelet count did not fall, suggesting ATIII may have had a protective effect on platelet consumption. There was also an indication, that there was a more uniform and better response to heparin anticoagulation during haemoperfusion than found previously without ATIII infusion.Further patients will be treated to evaluate whether AT III substitution can reduce the consumptive coagulopathy and platelet destruction which occurs in the course of fulminant hepatic failure.

A possible role of antithrombin III in venous thrombosis among alcoholics

1982 ◽  
Vol 9 (2) ◽  
pp. 177-179 ◽  
Author(s):  
J. Wadstein ◽  
L-H. Nilsson ◽  
L. Berglund ◽  
G. Skude
Keyword(s):  
Venous Thrombosis ◽  
Antithrombin Iii

RAT HEPAT0CYTES IN CULTURE INACTIVATE FACTOR Xa.

1987 ◽  
Author(s):  
G D Qureshi ◽  
M Sun ◽  
C Gervin ◽  
H Evans
Keyword(s):  
Serine Proteases ◽  
Antithrombin Iii ◽  
Factor Xa ◽  
Rat Hepatocytes ◽  
Factor X ◽  
Clotting Factors ◽  
Hepatocyte Cultures ◽  
The Stability ◽  
Stabilization Period

Plasma contains zymogens of clotting factors, which under various stimuli are activated to serine proteases. Whereas much knowledge has been gained about the activation of clotting factors, relatively little is known about inactivation of these proteases. Antithrombin III has been shown to inactivate some activated clotting factors in plasma. Studies in intact animals have suggested that activated clotting factors are mainly inactivated in the liver. To investigate more fully the role of liver in inactivating the activated factors, we studied the stability of activated factor X(Xa) in hepatocyte cultures. Monolayer cultures on non-proliferating rat hepatocytes were prepared according to the method of Bissell et al. The culture medium was chemically defined and was free from serum or serum products. After the 24 h stabilization period, 0.5 units/ml of 100% activated bovine factor Xa was co-cultured with hepatocytes for 8 h. Samples were collected at 0, ½, 1 2, 4 and 8 h and tested for Xa activity using chromogenic substrate S-2222. At the end of 8 h only 41.07% of the initial Xa activity remained. Xa inactivation was not affected by a commercially prepared unfractionated heparin (1 unit/ml) and estradiol at 12.5, 25, 125 nM, a potentiator and inhibitor of antithrombin III, respectively. Inactivation of Xa in hepatocyte cultures was inhibited by the addition of cycloheximide (10-4M). Our data suggests that factor Xa is inactivated in hepatocyte cultures by one or more hepatic derived factors which do not meet the functional characteristics of antithrombin III.

Distribution of antithrombin III in rabbits: role of host and protein

1987 ◽  
Vol 252 (3) ◽  
pp. R457-R461
Author(s):  
E. Regoeczi
Keyword(s):  
Plasma Proteins ◽  
Antithrombin Iii ◽  
The Body ◽  
Unknown Mechanism ◽  
A Value ◽  
Catabolic Rate ◽  
At Iii ◽  
Body Compartments ◽  
The Relationship

Unlike in the case of some other species, the plasma curve of iodine-labeled antithrombin III (I-AT-III) in rabbits requires fitting with a three-term exponential function for obtaining reliable estimates of the catabolic rate and distribution of I-AT-III among various body compartments (Carlson, Atencio, and Simon. J. Clin. Invest. 74: 191-199, 1984). To decide whether this phenomenon is referable to the host or the protein, the behavior of rabbit and human I-AT-III was comparatively analyzed in rabbits. Data obtained with rabbit I-AT-III confirmed the findings by Carlson and co-workers. Human I-AT-III assumed a distribution that closely paralleled that of homologous I-AT-III, thus suggesting that the pattern of distribution is determined by the host species rather than its AT-III. Rabbits metabolized human I-AT-III 1.61 times faster than homologous I-AT-III by an unknown mechanism not involving immune response; a facet that may prove useful for the identification of the sites of catabolism of AT-III. The exponent of the body weight was calculated for the relationship between species size and AT-III turnover. A value of 0.5 was obtained that is distinctly lower than the exponents found earlier for some other plasma proteins.

scholarly journals Arginine residues are critical for the heparin-cofactor activity of antithrombin III

1985 ◽  
Vol 231 (1) ◽  
pp. 59-63 ◽  
Author(s):  
A M Jorgensen ◽  
C L Borders ◽  
W W Fish
Keyword(s):  
Time Course ◽  
Antithrombin Iii ◽  
Rapid Rate ◽  
Rapid Loss ◽  
Inhibitor Molecule ◽  
At Iii ◽  
Lysine Residues ◽  
Arginine Residues ◽  
Cofactor Activity

A dilution/quench technique was used to monitor the time course of chemical modification on the heparin-cofactor (a) and progressive thrombin-inhibitory (b) activities of human antithrombin III. Treatment of antithrombin III (AT III) with 2,4,6-trinitrobenzenesulphonate at pH 8.3 and 25 degrees C leads to the loss of (a) at 60-fold more rapid rate than the loss of (b). This is consistent with previous reports [Rosenberg & Damus (1973) J. Biol. Chem. 248, 6490-6505; Pecon & Blackburn (1984) J. Biol. Chem. 259, 935-938] that lysine residues are involved in the binding of heparin to AT III, but not in thrombin binding. Treatment of AT III with phenylglyoxal at pH 8.3 and 25 degrees C again leads to a more rapid loss of (a) than of (b), with the loss of the former proceeding at a 4-fold faster rate. The presence of heparin during modification with phenylglyoxal significantly decreases the rate of loss of (a). Full loss of (a) correlates with the modification of seven arginine residues per inhibitor molecule, whereas loss of (b) does not commence until approximately four arginine residues are modified and is complete upon the modification of approximately eleven arginine residues per inhibitor molecule. This suggests that (the) arginine residue(s) in AT III are involved in the binding of heparin in addition to the known role of Arg-393 at the thrombin-recognition site [Rosenberg & Damus (1973) J. Biol. Chem. 248, 6490-6505; Jörnvall, Fish & Björk (1979) FEBS Lett. 106, 358-362].

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