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].

Respective Roles of Antithrombin III and Alpha 2 Macroglobulin in Thrombin Inactivation

1981 ◽  
Vol 45 (01) ◽  
pp. 051-054 ◽  
Author(s):  
A M Fischer ◽  
J Tapon-Bretaudiere ◽  
A Bros ◽  
F Josso
Keyword(s):  
Antithrombin Iii ◽  
Practical Interest ◽  
High Plasma ◽  
At Iii ◽  
Human Material ◽  
Cofactor Activity

SummaryIn order to investigate the mechanism of thrombin inactivation in the presence of both antithrombin III (AT III) and α 2-macroglobulin (α 2 M), thrombin and the inhibitors have been purified from human material and thrombin inactivation studied using purified reagents either alone or added to defibrinated plasma. Comparison of clotting and amidolytic activities of residual thrombin allowed to measure the amount of thrombin bound to α 2 M. In a purified reagent system as well as in plasma, part of exogenous thrombin is bound to α 2 M. The amount of bound thrombin is related to α 2 M concentration. Conversely, previous plasma α 2 M depletion by immunoabsorption increases the consumption of heparin-cofactor activity by exogenous thrombin. Thus AT III and α 2 M compete for thrombin inactivation. This finding could be of practical interest in clinical situations associating high plasma α 2 M levels and a decrease of AT III concentration.

Antithrombin III Alger: A New Homozygous AT III Variant

1986 ◽  
Vol 55 (02) ◽  
pp. 218-221 ◽  
Author(s):  
A M Fischer ◽  
P Cornu ◽  
C Sternberg ◽  
F Mériane ◽  
M D Dautzenberg ◽  
...  
Keyword(s):  
Family History ◽  
Antithrombin Iii ◽  
Antigen Concentration ◽  
Crossed Immunoelectrophoresis ◽  
The Family ◽  
At Iii ◽  
Molecular Abnormality ◽  
Slow Moving ◽  
Cofactor Activity ◽  
Plasma Heparin

SummaryA qualitative abnormality of antithrombin III (AT III) was found in the plasma of a 41-year old patient. The plasmatic AT III antigen concentration was 130% and the progressive anti-F IIa and anti-F Xa activities were normal (105% and 137%). The plasma heparin cofactor activity was less than 10%, when measured by F Ila or F Xa inhibition. Crossed immunoelectrophoresis of AT III in the presence of heparin revealed in the plasma an abnormal slow-moving peak. When tested by affinity chromatography on heparin Sepharose, this abnormal AT III did not bind to heparin. Among the investigated relatives, 5 subjects had normal AT III levels, whatever the test used, the nine others having reduced levels of antithrombin heparin cofactor activity (45-61%) but normal levels of immunoreactive AT III (97-122%). Consanguinity was found in the family history. We therefore considered our patient as homozygous for an AT III molecular abnormality affecting the binding site for heparin.

Antithrombin III, Heparin Cofactor and Antifactor Xa in Relation to Age, sex And Pathological Conditions

1979 ◽  
Author(s):  
F. Panicucci ◽  
A. Sacripanti ◽  
E. Pinori ◽  
M. Vispi ◽  
B. Conte ◽  
...  
Keyword(s):  
Oral Contraceptive ◽  
Antithrombin Iii ◽  
Normal Subjects ◽  
Cerebral Thrombosis ◽  
Positive Correlation ◽  
Pathological Conditions ◽  
At Iii ◽  
The Mean ◽  
Antifactor Xa ◽  
Cofactor Activity

Determinations of AT-III activity, heparin cofactor activity, antifactor Xa activity and AT-III protein were carried out in 200 healthy adults, evenly distributed within age and sex groups, in 60 patients with cerebral thrombosis and in 20 oral contraceptive users. There was a positive correlation between AT-III protein and its activitiesin normal subjects and in patients with cerebral thrombosis. In oral contraceptive users the positive correlation was between AT-III protein and its activities, antifactor Xa activity excepted. The mean AT-III protein and heparin cofactor activity values decreased in males with age and were significantly lower in the groups between 50 and 70 years. The mean AT-III protein and heparin cofactor activity values decreased slightly in women in fertile age and were lower in the 40 to 50 age-group. The mean AT-III protein and its activities values did not show any variation in the patients with cerebral thrombosis. The mean antifactor Xa activity value in the women, taking the pill for 3 months, decreased, whereas the other AT-III activities and AT-III protein were unchanged.

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.

Coagulation Inhibitors in Plasma and Serum

1975 ◽  
Author(s):  
O. R. Ødegård ◽  
U. Abildgaard
Keyword(s):  
Antithrombin Iii ◽  
Close Correlation ◽  
The Other ◽  
At Iii ◽  
Coagulation Inhibitors ◽  
Patient Groups ◽  
Cofactor Activity ◽  
The Difference ◽  
Immuno Assay ◽  
Activity Method

Heparin cofactor activity and antithrombin III (At-III) activity measured with amidolytic methods; antifactor Xa by a clotting method (Biggs et al., Brit. J. Haemat. 19, 287, 1970) and immunoassay of At-III (Fagerhol & Abildgaard, Scand. J. Haemat. 7, 10, 1970) in plasma and serum showed:1) There was a close correlation between the plasma values as measured by all these methods (r = 0.84–0.93).2) The difference between plasma and serum values (“consumption”) was lower in warfarin treated and in haemophiliacs than in the other groups.3) The difference between plasma and serum was greater when measured by the heparin cofactor activity method than by the other methods. The reason for this discrepancy will be discussed. The results in different patient groups will be reported.4) As the heparin cofactor activity assay can be completed within 10 minutes after blood sampling, and has a higher precision than clotting assay and immuno assay, it is preferable for clinical use.

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.

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.

AT III Barcelona: A Familial Quantitative-Qualitative AT III Deficiency

1988 ◽  
Vol 59 (01) ◽  
pp. 013-017 ◽  
Author(s):  
E Grau ◽  
J Fontcuberta ◽  
J Félez ◽  
I de Diego ◽  
R Soto ◽  
...  
Keyword(s):  
Antithrombin Iii ◽  
Normal Range ◽  
Affinity Adsorption ◽  
Crossed Immunoelectrophoresis ◽  
At Iii ◽  
Spanish Family ◽  
Slow Moving ◽  
Cofactor Activity ◽  
Ph Range ◽  
Thrombotic Tendency

SummaryA quantitative and qualitative deficiency of antithrombin III (AT III) was found in four members of a Spanish family with thrombotic tendency. In all affected members, levels of AT III antigen and activity (heparin cofactor activity) were reduced to 50% of the normal range. When crossed immunoelectrophoresis (CIE) was performed in the presence of heparin, an abnormal slow-moving peak was found. Crossed immunoelectrofocusing (CIEF) from normal and affected individuals showed that normal AT III migrated between pH 4.9–5.3 while the AT III under study was asymetrically distributed between two pH ranges: 4.9–5.3 and 4.6–4.8. Affinity adsorption of affected members’ plasma to heparin-sepharose beads revealed one population of AT III in the supernatant corresponding to the abnormal AT III, devoid of heparin cofactor activity and showing a peak between pH range: 4.6–4.8 in CIEF.Our data supports the view that a quantitative-qualitative deficiency was present in the heterozygous state in all the affected family members. Both normal and abnormal ATIII were present in plasma of the affected individuals. This abnormal ATIII was characterized by a lack of affinity for heparin. This familial ATIII deficiency was named ATIII Barcelona.

Antithrombin III, Heparin Cofactor and Antifactor Xa in Relation to Age, Sex and Pathological Conditions

1979 ◽  
Author(s):  
F. Panicucci ◽  
A. Sacrioanti ◽  
E. Pinori ◽  
M. Vispi ◽  
B. Conte ◽  
...  
Keyword(s):  
Oral Contraceptive ◽  
Antithrombin Iii ◽  
Normal Subjects ◽  
Cerebral Thrombosis ◽  
Positive Correlation ◽  
Pathological Conditions ◽  
At Iii ◽  
The Mean ◽  
Antifactor Xa ◽  
Cofactor Activity

Determinations of AT-III activity, heparin cofactor activity, antifactor Xa activity and AT-III protein were carried out in 200 healthy adults, evenly distributed within age and sex groups, in 60 patients with cerebral thrombosis and in 20 oral contraceptive users. There was a positive correlation between AT-III protein and its activities in normal subjects and in patients with cerebral thrombosis. in oral contraceptive users the positive correlation was between AT-III protein and its activities, antifactor Xa activity excepted. The mean AT-III protein and heparin cofactor activity values decreased in males with age and were significantly lower in the groups between 50 and 70 years. The mean AT-III protein and heparin cofactor activity values decreased slightly in women in fertile age and were lower in the 40 to 50 age-group. The mean AT-III protein and its activities values did not show any variation in the patients with cerebral thrombosis. The mean antifactor Xa activity value in the women, taking the pill for 3 months, decreased, whereas the other AT-III activities and AT-III protein were unchanged.

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