Adequate Antithrombin III Level Predicts Survival in Severe COVID-19 Pneumonia

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.

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Diphasic Increase in Thrombin-Antithrombin III Complex in Blood from the Internal Jugular Vein Following Severe Head Injury

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642402 ◽

1994 ◽

Vol 71 (01) ◽

pp. 155-157 ◽

Cited By ~ 13

Author(s):

M Suzuki ◽

O Motohashi ◽

A Nishino ◽

V Shiina ◽

K Mizoi ◽

...

Keyword(s):

Head Injury ◽

Internal Jugular Vein ◽

Severe Head Injury ◽

Antithrombin Iii ◽

Jugular Vein ◽

Thrombin Antithrombin Iii Complex

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The Frequency of Type I Heterozygous Protein S and Protein C Deficiency in 141 Unrelated Young Patients with Venous Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1642558 ◽

1988 ◽

Vol 59 (01) ◽

pp. 018-022 ◽

Cited By ~ 139

Author(s):

C L Gladson ◽

I Scharrer ◽

V Hach ◽

K H Beck ◽

J H Griffin

Keyword(s):

Venous Thrombosis ◽

Protein C ◽

Antithrombin Iii ◽

Young Patients ◽

Protein S ◽

Type I ◽

Protein S Deficiency ◽

Protein C Deficiency ◽

Low Protein ◽

S Deficiency

SummaryThe frequency of heterozygous protein C and protein S deficiency, detected by measuring total plasma antigen, in a group (n = 141) of young unrelated patients (<45 years old) with venous thrombotic disease was studied and compared to that of antithrombin III, fibrinogen, and plasminogen deficiencies. Among 91 patients not receiving oral anticoagulants, six had low protein S antigen levels and one had a low protein C antigen level. Among 50 patients receiving oral anticoagulant therapy, abnormally low ratios of protein S or C to other vitamin K-dependent factors were presented by one patient for protein S and five for protein C. Thus, heterozygous Type I protein S deficiency appeared in seven of 141 patients (5%) and heterozygous Type I protein C deficiency in six of 141 patients (4%). Eleven of thirteen deficient patients had recurrent venous thrombosis. In this group of 141 patients, 1% had an identifiable fibrinogen abnormality, 2% a plasminogen abnormality, and 3% an antithrombin III deficiency. Thus, among the known plasma protein deficiencies associated with venous thrombosis, protein S and protein C. deficiencies (9%) emerge as the leading identifiable associated abnormalities.

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Further Studies on the Mechanisms for the Antithrombotic Effects of Sulfated Polysaccharides in Rabbits

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647027 ◽

1988 ◽

Vol 60 (02) ◽

pp. 188-192 ◽

Cited By ~ 15

Author(s):

F A Ofosu ◽

F Fernandez ◽

N Anvari ◽

C Caranobe ◽

F Dol ◽

...

Keyword(s):

Antithrombin Iii ◽

Ex Vivo ◽

Thrombus Formation ◽

Minimum Weight ◽

Sulfated Polysaccharides ◽

Pentosan Polysulfate ◽

Heparin Cofactor Ii ◽

Thrombin Inhibition ◽

The Relationship ◽

Prothrombin Activation

SummaryA recent study (Fernandez et al., Thromb. Haemostas. 1987; 57: 286-93) demonstrated that when rabbits were injected with the minimum weight of a variety of glycosaminoglycans required to inhibit tissue factor-induced thrombus formation by —80%, exogenous thrombin was inactivated —twice as fast in the post-treatment plasmas as the pre-treatment plasmas. In this study, we investigated the relationship between inhibition of thrombus formation and the extent of thrombin inhibition ex vivo. We also investigated the relationship between inhibition of thrombus formation and inhibition of prothrombin activation ex vivo. Four sulfated polysaccharides (SPS) which influence coagulation in a variety of ways were used in this study. Unfractionated heparin and the fraction of heparin with high affinity to antithrombin III potentiate the antiproteinase activity of antithrombin III. Pentosan polysulfate potentiates the activity of heparin cofactor II. At less than 10 pg/ml of plasma, all three SPS also inhibit intrinsic prothrombin activation. The fourth agent, dermatan sulfate, potentiates the activity of heparin cofactor II but fails to inhibit intrinsic prothrombin activation even at concentrations which exceed 60 pg/ml of plasma. Inhibition of thrombus formation by each sulfated polysaccharides was linearly related to the extent of thrombin inhibition achieved ex vivo. These observations confirm the utility of catalysis of thrombin inhibition as an index for assessing antithrombotic potential of glycosaminoglycans and other sulfated polysaccharides in rabbits. With the exception of pentosan polysulfate, there was no clear relationship between inhibition of thrombus formation and inhibition of prothrombin activation ex vivo.

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The Effect of Antithrombin III on the Activity of the Coagulation Factors VII, IX and X

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647922 ◽

1976 ◽

Vol 35 (02) ◽

pp. 295-304 ◽

Cited By ~ 49

Author(s):

B Østerud ◽

M Miller-Andersson ◽

U Abildgaard ◽

H Prydz

Keyword(s):

Antithrombin Iii ◽

Factor Xa ◽

Coagulation Factors ◽

Disc Electrophoresis ◽

Polyacrylamide Gel ◽

Factor Vii ◽

Native Form ◽

Factor Ixa ◽

Plasma Factor

SummaryAntithrombin III, purified to homogeneity according to Polyacrylamide gel disc electrophoresis and immunoelectrophoresis, inhibited the activity of purified factor IXa and Xa, whereas factor VII was not inhibited either in the active or in the native form.Antithrombin III is the single most important inhibitor of factor Xa in plasma. Factor Xa does not, however, reduce the activity of antithrombin III against thrombin.

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Increased Heparin Cofactor II Levels in Women Taking Oral Contraceptives

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647320 ◽

1990 ◽

Vol 64 (03) ◽

pp. 365-368 ◽

Cited By ~ 6

Author(s):

P Toulon ◽

J M Bardin ◽

N M Blumenfeld

Keyword(s):

Oral Contraceptives ◽

Antithrombin Iii ◽

Thrombin Inhibitor ◽

Control Groups ◽

Normal Range ◽

Heparin Cofactor Ii ◽

Men And Women ◽

Pooled Data ◽

Contraceptive Pills ◽

Increased Risk

SummaryHeparin cofactor II (HCII) is a thrombin inhibitor present in human plasma whose activity is enhanced by heparin. HCII exhibits important homologies with antithrombin III, the main heparin-enhanced thrombin inhibitor. Cases of recurrent thromboembolism have been recently reported in patients with HCII deficiency. Since the use of oral contraceptives (OC) is associated with an increased risk of thrombosis, the study of the plasma levels of HCII was undertaken in women taking contraceptive pills. Plasma HCII levels were found significantly higher in 62 women taking low-estrogen content OC (1.20 ± 0.28 U/ml) than in 62 age matched women not taking OC (0.94 ± 0.16 U/ml) or in 62 men (0.96 ± 0.19 U/ml). Significant correlations between HCII and fibrinogen levels were reported in the three groups. From the pooled data of the two control groups (men and women not taking OC), the normal range for plasma HCII levels was defined to be between 0.60 and 1.30 U/ml (mean ± 2 SD). Two cases of low HCII levels (<0.60 U/ml) were found in the control groups, but none in the group of women taking OC. It is concluded that the use of oral contraceptives is associated with a rise in HCII levels and that the screening for HCII deficiency has to be performed at distance of any OC therapy.

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D-Dimers, Thrombin Antithrombin III Complexes and Prothrombin Fragments 1 + 2: Diagnostic value in Clinically Suspected Deep Vein Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647449 ◽

1991 ◽

Vol 65 (01) ◽

pp. 028-032 ◽

Cited By ~ 105

Author(s):

B Boneu ◽

G Bes ◽

H Pelzer ◽

P Sié ◽

H Boccalon

Keyword(s):

Deep Vein Thrombosis ◽

Antithrombin Iii ◽

High Sensitivity ◽

Diagnostic Value ◽

Predictive Values ◽

Vein Thrombosis ◽

High Negative Predictive Value ◽

Deep Vein ◽

D Dimer ◽

Mercury Strain Gauge

SummaryThis study was performed to determine the accuracy of D-Dimer fibrin derivatives, thrombin-antithrombin III (TAT) complexes and prothrombin fragments 1 + 2 (F 1 + 2) determinations for the diagnosis of deep vein thrombosis (DVT). One hundred and sixteen consecutive patients referred to the angiology unit of our hospital for a clinically suspected DVT were investigated. They were submitted to mercury strain gauge plethysmography and to ultrasonic duplex scanning examination; in cases of inconclusive results or of proximal DVT (n = 35), an ascending phlebography was performed. After these investigations were completed, the diagnosis of DVT was confirmed in 34 and excluded in 82. One half of the patients were already under anticoagulant therapy at the time of investigation. The 3 biological markers were assayed using commercially available ELISA techniques and the D-Dimer was also assayed with a fast latex method. The normal distribution of these markers was established in 40 healthy blood donors. The most accurate assay for the diagnosis of DVT was the D-Dimer ELISA which had both a high sensitivity (94%) and a high negative predictive value (95%). The D-Dirner latex, TAT complexes and F 1 + 2 were far less sensitive and provided negative predictive values which ranged between 78 and 85%. In spite of positive and significant correlations between the levels of ihe 3 markers, their association did not improve their overall accuracy for detecting D\/L Therefore, with the exception of the D-Dimer ELISA, these markers were of little value for the diagnosis of DVT in this specific population.

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Antithrombin III Binding to Surface Immobilized Heparin and Its Relation to F Xa Inhibition

Thrombosis and Haemostasis ◽

10.1055/s-0038-1646057 ◽

1987 ◽

Vol 58 (04) ◽

pp. 1064-1067 ◽

Cited By ~ 41

Author(s):

K Kodama ◽

B Pasche ◽

P Olsson ◽

J Swedenborg ◽

L Adolfsson ◽

...

Keyword(s):

Molecular Weight ◽

Ionic Strength ◽

Surface Coating ◽

Antithrombin Iii ◽

Lower Class ◽

Biologically Active ◽

High Affinity ◽

Heparin Coating ◽

Continuous Surface ◽

Approximate Molecular Weight

SummaryThe mode of F Xa inhibition was investigated on a thromboresistant surface with end-point attached partially depoly-merized heparin of an approximate molecular weight of 8000. Affinity chromatography revealed that one fourth of the heparin used in surface coating had high affinity for antithrombin III (AT). The heparin surface adsorbed AT from both human plasma and solutions of purified AT. By increasing the ionic strength in the AT solution the existence of high and low affinity sites could be shown. The uptake of AT was measured and the density of available high and low affinity sites was found to be in the range of 5 HTid 11 pic.omoles/cmf, respectively Thus the estimated density of biologically active high and low ailmity heparm respectively would be 40 and 90 ng/cm2 The heparin coating did not take up or exert F Xa inhibition by itself. With AT adsorbed on both high and low affinity heparin the surface had the capacity to inhibit several consecutive aliquots of F Xa exposed to the surface. When mainly high affinity sites were saturated with AT the inhibition capacity was considerably lower. Tt was demonstrated that the density of AT on both high and low affinity heparin determines the F Xa inhibition capacity whereas the amount of AT on high affinity sites limits the rate of the reaction. This implies that during the inhibition of F Xa there is a continuous surface-diffusion of AT from sites of a lower class to the high affinity sites where the F Xa/AT complex is formed and leaves the surface. The ability of the immobilized heparin to catalyze inhibition of F Xa is likely to be an important component for the thromboresistant properties of a heparin coating with non-compromized AT binding sequences.

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