ANTITHROMBIN III GENEVA : AN HEREDITARY ABNORMAL ANTITHROMBIN III (AT III) WITH DEFECTIVE HEPARIN COFACTOR ACTIVITY

1987 ◽  
Author(s):  
Ph de Moerloose ◽  
G Reber ◽  
Ph Minazio ◽  
C A Bouvier
Keyword(s):  
Antithrombin Iii ◽  
Protein S ◽  
The Family ◽  
Coagulation Tests ◽  
At Iii ◽  
Cofactor Activity ◽  
Low Incidence ◽  
Immunological Assays ◽  
Normal Inhibition ◽  
Two Populations

A 43-year old man presented a pulmonary embolism. Despite a negative family history for thromboembolic disorders, the unusual circumstances of apparition and the relatively young age of the patient prompted us to study carefully the coagulation parameters. Routine coagulation tests, as well as plasminogen, alpha-2-anti-plasmin, protein C and protein S were all within normal range. Biological and immunological assays of AT III were performed on 12 members of the family and showed a low AT III activity in the propositus and other members of this family (mean 50%), but normal immunologic levels. Crossed immunoelectrophoresis in absence of heparin showed a normal pattern, but in presence of heparin showed an abnormal peak as compared with controls. Kinetics experiments showed a normal inhibition of Xa and 11a in absence of heparin, but abnormal in presence of heparin. An affinity chromatography on heparin Sepharose revealed two populations of AT III, one of which was devoid of heparin cofactor activity.The toponym AT III Geneva is proposed for this new familial abnormal AT III with defective heparin cofactor activity. This family confirms the low incidence of thromboembolic events reported in this type of AT III variant.

Antithrombin III Geneva: A Hereditary Abnormal AT III with Defective Heparin Cofactor Activity

1987 ◽  
Vol 57 (02) ◽  
pp. 154-157 ◽  
Author(s):  
P A de Moerloose ◽  
G Reber ◽  
Ph Vernet ◽  
Ph Minazio ◽  
C A Bouvier
Keyword(s):  
Antithrombin Iii ◽  
Normal Pattern ◽  
Crossed Immunoelectrophoresis ◽  
At Iii ◽  
Normal Mean ◽  
Cofactor Activity ◽  
Normal Inhibition ◽  
Heparin Affinity ◽  
Two Populations ◽  
Inhibition Of Thrombin

SummaryA 43-year-old man presented a pulmonary embolism. The unusual circumstances of apparition, the age and the increased heparin requirements suggested an antithrombin III (AT III) deficiency. AT III activity was low in the propositus and seven other members of his family (mean 55%), but immunologic levels were normal (mean 110%). Crossed immunoelectrophoresis in absence of heparin showed a normal pattern, but in presence of heparin showed an abnormal peak as compared with controls. Kinetics experiments showed a normal inhibition of thrombin and Xa in absence of heparin, but abnormal in presence of heparin. Affinity chromatography on heparin-Sepharose revealed two populations of AT III, one of which was devoid of heparin cofactor activity. The toponym AT III Geneva is proposed for this new familial abnormal AT III with defective heparin cofactor activity.

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 “Northwick Park”: A Variant Antithrombin with Normal Affinity for Heparin but Reduced Heparin Cofactor Activity

1985 ◽  
Vol 53 (03) ◽  
pp. 314-319 ◽  
Author(s):  
D J Howarth ◽  
Diana Samson ◽  
Yvonne Stirling ◽  
M J Seghatchian
Keyword(s):  
Venous Thrombosis ◽  
Fast Moving ◽  
Autosomal Dominant ◽  
Antithrombin Iii ◽  
Two Dimensional ◽  
Antithrombin Activity ◽  
The Family ◽  
At Iii ◽  
History Of ◽  
Cofactor Activity

SummaryFurther studies have been carried out in a previously reported family with congenital antithrombin III (AT III) deficiency due to an abnormal variant of AT III (AT III Northwick Park). The variant has been identified in five members of the family, three of whom had a history of venous thrombosis. Inheritance followed an autosomal dominant pattern. The affected family members have reduced levels of antithrombin heparin cofactor (41–67%) and progressive antithrombin activity (44–62%) but normal levels of immunoreactive AT III (91–162%). Two dimensional immunoelectrophoresis (2 DIE) of AT III in the absence of heparin revealed an abnormal fast-moving peak in addition to the normal peak but 2 DIE in the presence of heparin appeared normal. Further studies confirmed that the abnormal AT III binds completely to heparin but has no heparin cofactor or progressive antithrombin activity. These results would be consistent with a mutation affecting the binding site for thrombin.

Molekularbiologische Grundlagen und Diagnostik der hereditären Defekte von Antithrombin III, Protein C und Protein S

2002 ◽  
Vol 22 (02) ◽  
pp. 57-66
Author(s):  
I. Witt
Keyword(s):  
Protein C ◽  
Antithrombin Iii ◽  
Protein S ◽  
Klinische Relevanz ◽  
At Iii

ZusammenfassungDie enormen Fortschritte in der Molekularbiologie in den letzten Jahren ermöglichten sowohl die Aufklärung der Nukleotidsequenzen der Gene für Antithrombin III (AT III), Protein C (PROC) und Protein S (PROS) als auch die Identifizierung zahlreicher Mutationen bei hereditären Defekten dieser wichtigen Inhibitoren des plasmatischen Gerinnungssystems. Da die Gene für AT III (13,8 kb) und PROC (11,2 kb) nicht groß und relativ leicht zu analysieren sind, gibt es bereits umfangreiche »databases« der Mutationen (50, 73). Für AT III sind 79 und für PROC 160 unterschiedliche Mutationen beschrieben.Sowohl beim AT-III-Mangel als auch beim Protein-C-Mangel hat die Mutationsaufklärung neue Erkenntnisse über die Struktur-Funktions-Beziehung der Proteine gebracht. Beim Protein-C-Mangel steht die klinische Relevanz der DNA-Analyse im Vordergrund, da die Diagnostik des Protein-C-Mangels auf der Proteinebene nicht immer zuverlässig möglich ist.Das Protein-S-Gen ist für die Analytik schwer zugänglich, da es groß ist (80 kb) und außerdem ein Pseudogen existiert. Es sind schon zahlreiche Mutationen bei Patienten mit Protein-S-Mangel identifiziert worden. Eine Database ist bisher nicht publiziert. Die klinische Notwendigkeit zur Mutationsaufklärung besteht ebenso wie beim Protein-C-Mangel. Es ist zu erwarten, dass zukünftig die Identifizierung von Mutationen auch beim Protein-S-Mangel beschleunigt vorangeht.

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, 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.

The Thrombin Protecting Function of a Complement Inhibitor in Human Plasma

1979 ◽  
Author(s):  
E.R. Podack ◽  
J.G. Curd ◽  
J.H. Griffin ◽  
H.J. Müller-Eberherd
Keyword(s):  
Complex Formation ◽  
Antithrombin Iii ◽  
Membrane Attack Complex ◽  
Protein S ◽  
Thrombin Time ◽  
Two Dimensional ◽  
Complement Inhibitor ◽  
Functional Studies ◽  
Sds Page ◽  
At Iii

S-protein (S) is a newly discovered 80,000 MW plosma glycoprotein. It functions as an inhibitor of the membrane attack complex of complement. We now wish to report that S also functions as thrombin protecting factor in coagulation; S forms a reversible complex with thrombin which is more resistant to inactivation by antithrombin III (AT III) than thrombin alone. An S-thrombin complex and on S-throm-bin-AT III complex were formed in clotted plasma and with isolated proteins as demonstrated by two dimensional Immunoelectrophoresis. Functional studies measuring the esterolytic or clotting activity of thrombin showed that S in the presence and absence of heparin decreased the rate of inactivation of thrombin by AT III. Similar results were observed using plasma. For example, in the presence of 0.04 u/ml heparin and 1.6 u/ml thrombin, the thrombin time of plasma depleted in S was 150 sec. as opposed to 15 sec. when the plasma was reconstituted with purified S. That this effect of S was due to a decreased inactivation of thrombin by AT III was demonstrated directly by SDS-PAGE analysis of plasma containing 125l-thrombin. In the presence of S the rate of formation of the 95,000 dalton 125I-thrombin-AT III complex was markedly decreased compared to the rate of complex formation in the S-depleted plasma. These data suggest that S may modulate the interactions of thrombin and AT III.

Edoxaban: Impact on routine and specific coagulation assays

2016 ◽  
Vol 115 (02) ◽  
pp. 368-381 ◽  
Author(s):  
Bernard Chatelain ◽  
Christian Chatelain ◽  
Jonathan Douxfils ◽  
Jean-Michel Dogné ◽  
François Mullier
Keyword(s):  
Plasma Concentration ◽  
Diagnostic Tests ◽  
High Sensitivity ◽  
Protein S ◽  
Turnaround Time ◽  
Clotting Factor ◽  
Coagulation Assays ◽  
Coagulation Tests ◽  
Supplementary Material ◽  
Immunological Assays

SummaryAssessment of plasma concentration/effect of edoxaban may be useful in some situations. Also, clinicians need to know how routine coagulation assays are influenced. It was our aim to determine coagulation tests useful for the assessment of edoxaban’s pharmacodynamics and provide recommendations for the interpretation of haemostasis diagnostic tests. Edoxaban was spiked at concentrations ranging from 0 to 1,000 ng/ml in platelet-poor plasma which covers the on-therapy range (from ± 25 ng/ml at Ctrough to ± 170 ng/ml at Cmax). aPTT, PT, dRVVT, chromogenic anti-Xa assays, TGA and a large panel of haemostasis diagnostic tests were performed using several reagents. A concentration-dependent prolongation of aPTT, PT and dRVVT was observed. The effect was dependent on the reagents. FXa chromogenic assays showed high sensitivity and a linear correlation depending on the methodology. TGA may be useful to assess the pharmacodynamics of edoxaban but its turnaround time and the lack of standardisation are limitations. Edoxaban impairs the assessment of lupus anticoagulant, protein S (clotting method), APC-R, antithrombin (FXa-based assay) and measurement of clotting factor activity. Immunological assays and assays acting below the FXa are not influenced by edoxaban. In conclusion, some PT reagents could be used to estimate edoxaban activity. Chromogenic anti-Xa assays are required to assess the plasma concentration. TGA may be useful but requires standardisation. In case of thrombophilia or in the exploration of a haemorrhagic event, immunological assays should be recommended, when applicable. Standardisation of the time between the last intake and the sampling is mandatory to provide a proper assessment of the result.Supplementary Material to this article is available online at www.thrombosis-online.com.

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.

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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