Effect of Endotoxin on Kinetics of Antithrombin III

1979 ◽  
Author(s):  
H. Tanaka ◽  
N. Kobayashi ◽  
T. Takeuchi ◽  
M. Takada ◽  
T. Haekawa
Keyword(s):  
Half Life ◽  
Antithrombin Iii ◽  
Coagulation Factors ◽  
Synthesis Rate ◽  
Blood Samples ◽  
At Iii ◽  
Kinetics Of ◽  
Plasma Half Life

The kinetics of antithrombin III(AT III) in dogs were studied using I-125-labelled AT III and Se-75-methionine. As reported at the last meeting of ISH, the plasma half-life of AT III was 1.7±0.2 days in normal 5 control dogs. The double i.v. administration of 200 ug/ltg of endotoxin and the single i.v. administration of 1 mg/kg of endotoxin resulted in 30% decrease of plasma AT III, 60% decrease of coagulation Factors (I, II, V, VII, VIII, IX), the shortening of plasma half-life of AT III to 1.4 days and the increase of J3u values, suggesting increase of the synthesis rate of AT III. Then, the synthesis of AT III was studied directly using Se-75-methionine. After i.v. injection of Se-75-methionine, blood samples were obtained. One ml of sample plasma was incubated for 24 hrs with 1 ml of anti-AT III antiserum, which was produied in rabbits and the radioactivity of the precipitates were determined. About 80% of AT III was recovered in the precipitates by this method. The maximum radioactivity was obtained 18 hrs after injection of Se-75-methionine, and 0.27 % of total injected Se-75-methionine were utilized to the production of AT III.These results indicates that; 1. Endotoxin accelerates the metabolism of AT III. 2. The analysis of AT III production is possible using Se-75-methionine as a tracer.

Factor II Related Antigen and Antithrombin III Levels as Indicators of Liver Failure in Consumption Coagulopathy

1982 ◽  
Vol 47 (03) ◽  
pp. 218-220 ◽  
Author(s):  
P Sié ◽  
E Letrenne ◽  
C Caranobe ◽  
M Genestal ◽  
B Cathala ◽  
...  
Keyword(s):  
Liver Failure ◽  
Antithrombin Iii ◽  
Coagulation Factors ◽  
Consumption Coagulopathy ◽  
Blood Coagulation Factors ◽  
Factor Ii ◽  
At Iii ◽  
Group A ◽  
Group B

SummaryIn order to detect impaired synthesis of blood coagulation factors associated to consumption coagulopathy, a simultaneous evaluation of factor II-related antigen (II rAg) and of antithrombin III (AT III) was carried out in 16 patients affected with severe defibrination. An in vitro preliminary study on plasma and serum demonstrated that the levels of II rAg and of AT III, assessed by the Laurell technique with Behring antisera, were not reduced by the coagulation process. The patients were, a posteriori, classified into two groups according to the absence (group A) or the presence (group B) of factors predisposing to liver failure such as metastasis, cirrhosis, and prolonged shock. II rAg and AT III levels are significantly correlated; they are in the normal range in group A but reduced in group B. Thus II rAg or AT III level determinations are useful markers in the detection of liver failure associated to the consumption phenomenon. These results also suggest that part of the decreased AT III levels reported in severe cases of disseminated intravascular coagulation may be the consequence of an associated liver failure.

Covalent Complexes Between Low Molecular Weight Heparin Fragments and Antithrombin III – Inhibition Kinetics and Turnover Parameters

1983 ◽  
Vol 49 (02) ◽  
pp. 109-115 ◽  
Author(s):  
M Hoylaerts ◽  
E Holmer ◽  
M de Mol ◽  
D Collen
Keyword(s):  
Molecular Weight ◽  
Half Life ◽  
Low Molecular Weight Heparin ◽  
Antithrombin Iii ◽  
Factor Xa ◽  
Life Time ◽  
Low Molecular Weight ◽  
High Affinity ◽  
Plasma Half Life ◽  
Covalent Complex

SummaryTwo high affinity heparin fragments (A/r 4,300 and M, 3,200) were covalently coupled to antithrombin III (J. Biol. Chem. 1982; 257: 3401-3408) with an apparent 1:1 stoichiometry and a 30-35% yield.The purified covalent complexes inhibited factor Xa with second order rate constants very similar to those obtained for antithrombin III saturated with these heparin fragments and to that obtained for the covalent complex between antithrombin III and native high affinity heparin.The disappearance rates from plasma in rabbits of both low molecular weight heparin fragments and their complexes could adequately be represented by two-compartment mammillary models. The plasma half-life (t'/j) of both low Afr-heparin fragments was approximately 2.4 hr. Covalent coupling of the fragments to antithrombin III increased this half-life about 3.5 fold (t1/2 ≃ 7.7 hr), approaching that of free antithrombin III (t1/2 ≃ 11 ± 0.4 hr) and resulting in a 30fold longer life time of factor Xa inhibitory activity in plasma as compared to that of free intact heparin (t1/2 ≃ 0.25 ± 0.04 hr).

scholarly journals In Vitro Characterization of Rabbit Thrombin, Antithrombin III, and Thrombin-Antithrombin III Complex, and Determination of Their Survival Times in Vivo

1977 ◽  
Author(s):  
Christine N. Vogel ◽  
Kingdon S. Henry ◽  
Roger L. Lundblad
Keyword(s):  
Gel Electrophoresis ◽  
Half Life ◽  
Antithrombin Iii ◽  
Specific Activity ◽  
Sodium Dodecyl ◽  
In Vivo Studies ◽  
Survival Times ◽  
At Iii

Our intention is to study the interaction of rabbit thrombin with antithrombin III (AT-III) in vitro and in vivo. After activation of crude prothrombin with tissue thromboplastin and CaCl2, thrombin was purified and showed two species of thrombin with molecular weights of 36,000 and 39,000 daltons as determined by sodium dodecyl sulfate discontinuous gel electrophoresis. Rabbit AT-III was purified using a heparin agarose column and had a molecular weight of 55,000 daltons. The inhibition of thrombin by AT-III was followed by fibrinogen clotting assays and an AT-III-thrombin complex was observed on gel electrophoresis. For the in vivo studies both thrombin and AT-III were radiolabelled with Na125i using the solid state lactoperoxidase method and retained 99% of the pre-iodinated specific activity. Radiolabelled thrombin and a radiolabelled AT-III-thrombin complex were injected into different rabbits. The rate of removal of both was very similar with a half-life of approximately 9 hours. When radiolabelled AT-III was injected, the half-life was approximately 60 hours. Since the disappearance rate of thrombin more closely approximates that of the preformed AT-III-thrombin complex and is clearly shorter than the turnover rate of AT-III, the possibility is raised that thrombin combines in vivo with a native inhibitor such as AT-III and may in fact be removed from the circulation as a complex rather than as a native molecule.

PROTEINASE-INHIBITOR COMPLEXES (PIC) IN SEPTIC AND NON-SEPTIC SHOCK. COAGULATION; LEUKOCYTE AND BACTERIAL PROTEASE INHIBITION BY MEANS OF PLASMA-INHIBITOR REPLACEMENT

1987 ◽  
Author(s):  
R Egbring ◽  
R Seitz ◽  
M Wolf ◽  
L Lerch ◽  
T Menges
Keyword(s):  
Antithrombin Iii ◽  
Coagulation Factors ◽  
In Vitro Models ◽  
Protease Inhibition ◽  
E Coli ◽  
Bacterial Protease ◽  
Bacterial Endotoxins ◽  
At Iii ◽  
Cardiac Shock

In septic or cardiac shock antithrombin III-thrombin (AT III-Thr) and a1antitrypsin-elastase(a1AT-ELP) as well as a2antiplas-min-plasmin (a2AP-Pl) are found to be elevated to different extents. In cardiac shock AT III-Thr is predominantly increased, while in septic disorders a2AT-ELP as indicator of leukocyte stimulation is additionally found to be elevated. Stimuli for leukocyte activation are bacterial endotoxins, immune complexes, factor Xlla and others. The possible action of bacterial proteases during septic infections is only known in animal models. To stop hemorrhagic complications in disseminated intravascular coagulation (DIC) following septic (n=24) or non-septic (n=15) shock, we treated the patients with AT III concentrate and FFP in relatively high amounts containing a2macroglobulin (a2M), a1antitrypsin (a1AT) and others which are not available as concentrates. Subsequent to the procedure PIC's decreased, coagulation factors and inhibitors as well as thrombocyte counts increased. In in vitro models bacterial proteases have been shown to destroy a1AT, activate prothrombin and others. Only a2M may inhibit proteolytic activity of Staph aureus, N. meningitidis, P. aeroginosa and K1. pneumoniae and E. coli as our in vitro studies, using fibrin plates containing a2M, demonstrated. Not only bleeding or microthrombotic complications might be influenced by plasma derivative substitution, but also proteases released from bacteria

ALTERED INTERACTION OF THROMBIN AND ANTITHROMBIN III WITH THE VASCULAR WALL

1987 ◽  
Author(s):  
G Bashkov ◽  
T Kalishevekaya ◽  
S Strukova
Keyword(s):  
Nephrotic Syndrome ◽  
Half Life ◽  
Antithrombin Iii ◽  
Fold Increase ◽  
Vascular Wall ◽  
Blood Stream ◽  
Soluble Fibrin ◽  
Heymann Nephritis ◽  
Plasma Half Life

The role of the endothelial injury in the development of the thrombophylic state was studied in rats with nephrotic syndrome (NS,Heymann nephritis).There were a 6-fold increase of the soluble fibrin concentration and a 30% decrease of plasma antithrombin III (AT) activity in the NSIt was found that the plasma half-life of 125 J-labelled α-thrombin (10-7 M) is 3,0 ± 0,6 min in control animals and 4,0 ± 0,1 min in NS rats. At 20 min following the administration of bovine 125J-thrombin it was observed that in normal animals 84% of the radiolabelled enzyme was bound with vessel wall.while in NS rats the figure was only 63% (p< 0,05). The alteration of thrombin binding to the vascular wall lead to an increase in the amount of soluble fibrin-monomer and AT-proteinase complexes.AT-thrombin complexes and a proteolytically modified form of AT (Mr<68 kDa) were isolated from NS rats plasma by affinity chromatography on heparin-sepharose and chromatofocusing.At 3 min following injection of a 100-fold molar excess of bovine AT (1,7 .10-5 M) it was observed that 35% of thrombin reversibly bound to the endothelium could be detected in the circulation of normal rats. The same excess of AT induced only a 10% (p<0,001) release of 125J-thrombin to the blood stream in the NS rats through the formation of 125 J-thrombin complexes with Mr≥100 kDa.It is being proposed that injury of the vascular wall in the NS animals facilitated the interaction of the enzyme with the substrate (fibrinogen) and inhibitor (AT), and leads to ineffective inactivation of thrombin bound to the endothelium by AT.

Kinetics Of Thrombin, Antithrombin III And Heparin Interactions

1981 ◽  
Author(s):  
S T Olson ◽  
S A Evans ◽  
J D Shore
Keyword(s):  
Rate Constant ◽  
Antithrombin Iii ◽  
Heart Association ◽  
Slow Phase ◽  
Rapid Phase ◽  
Bimolecular Rate Constant ◽  
At Iii ◽  
Active Site Probe ◽  
Initial Binding ◽  
Kinetics Of

The rates of thrombin inactivation by AT III were studied by stopped-flow fluorimetry using p-aminobenzami- dine as an active site probe. p-Aminobenzamidine binds to thrombin with a of KD of 35 μM and a 50-fold fluorescence enhancement. The bimolecular rate constant for the thrombin-AT III reaction was 8.7 × 103 M-1 s-1 at 25° C and pH 7.4, with no diminished amplitude or evidence for a limiting rate at AT III concentrations as high as 10-4 M. Using lower AT III concentrations, an identical bimolecular rate constant was obtained by discontinuous assay of residual thrombin activity. Inactivation of thrombin by antithrombin III complexed with stoichiometric high affinity heparin at concentrations between 2.5 to 20 μM resulted in biphasic reactions: a rapid phase complete in less than 10 milliseconds and a slow phase with a rate constant of 4-6 s-1 . Relative amplitudes and slow phase rate constants showed slight changes over this AT III-heparin concentration range. These results are consistent with weak initial binding of AT III to thrombin in the absence of heparin (KD> 10-4 M), with a major part of the heparin rate enhancement due to a substantial decrease in the KD for the initial binding step. Supported by Michigan Heart Association and USPHS grant F32 HL06171-01.

Evaluation of the safety, recovery, half-life, and clinical efficacy of antithrombin III (human) in patients with hereditary antithrombin III deficiency. Cooperative Study Group [see comments]

Blood ◽  
1990 ◽  
Vol 75 (1) ◽  
pp. 33-39 ◽  
Author(s):  
D Menache ◽  
JP O'Malley ◽  
JB Schorr ◽  
B Wagner ◽  
C Williams ◽  
...  
Keyword(s):  
Half Life ◽  
Antithrombin Iii ◽  
Clinical Symptoms ◽  
Cooperative Study Group ◽  
Significant Difference ◽  
At Iii ◽  
Thrombotic Complications ◽  
Antithrombin Iii Deficiency

Antithrombin III (Human) (AT III) was administered to 18 patients with documented hereditary AT III deficiency. In eight patients with no ongoing clinical symptoms of thrombosis, the percent increase per unit AT III infused per kilogram of body weight ranged from 1.56% to 2.74%, and the half-life from 43.3 to 77.0 hours. No significant difference was noted between patients receiving and those not receiving coumarin therapy. In clinically ill patients, the in vivo recovery was significantly lower and ranged from 0.64% to 1.90% increase per unit AT III infused/kg. Efficacy of AT III was evaluated in 13 patients for the prevention or treatment of thrombosis. AT III was efficacious as assessed by the absence of thrombotic complications after surgery and/or parturition, and the nonextension and nonrecurrence of thrombosis in patients exhibiting an acute thrombotic episode. No side effects were noted. Follow-up studies indicated no hepatitis B seroconversion and no alanine aminotransferase elevations in patients who were not transfused with other blood products.

Antithrombin III Treatment In Acute Liver Failure

1981 ◽  
Author(s):  
G E Vogel ◽  
P Bottennann ◽  
M v Clarmann ◽  
Ch Komm ◽  
A Oberdorfer
Keyword(s):  
Liver Failure ◽  
Acute Liver Failure ◽  
Time Course ◽  
Antithrombin Iii ◽  
Liver Perfusion ◽  
Coagulation Factors ◽  
Average Dose ◽  
Intravascular Coagulation ◽  
At Iii ◽  
Coma Grade

In acute liver failure (alf) there is a defect in synthesis of coagulation factors in addition there is a disseminated intravascular coagulation which is followed by an impairment of the microcirculation. With an early substitution of Antithrombin III (AT III) we tried to stop this situation. In 22 patients (10 female, 12 male, age 10-68) with alf presenting with hepatic coma (grade I-IV) we studied the time course of AT III plasma activity (the study started in December 1978 and is continued until now). AT III was measured with the chromogenic substrate method. When AT III activity fell below the level of 80% of normal, we started to substitute AT III and to give low dose heparin (125-500 U/hrs). In addition in case of bleeding or a decrease of coagulation factors or fibrinogen under the hemostatic active concentration, complexes of prothrombin and fibrinogen were administered. Besides the usual conservative treatment for alf, patients in coma (grade IV) were undergoing baboon liver perfusion. The rapid fall of the hepatic coagulation factors stopped. In patients, who still were able to synthesize coagulation factors a reincrease of these factors after administration of AT III was seen and there was a further fall in fibrinogen. The dosage of AT III in alf required to bring AT III to normal values depended on the degree of intravascular coagulation. The average dose in our study was 250 U/3 hrs. The clinical course of alf was prolonged in all patients and 7 patients with the prognostic deleterious colombindex (sum of factors II + V + VIII) < 75% eventually survived the alf. The coagulation disorders in alf can be treated with an early substitution of AT III; thus, there is more time for liver regeneration. Our results suggest an improved prognosis of the acute liver failure.

scholarly journals Evaluation of the safety, recovery, half-life, and clinical efficacy of antithrombin III (human) in patients with hereditary antithrombin III deficiency. Cooperative Study Group [see comments]

Blood ◽  
1990 ◽  
Vol 75 (1) ◽  
pp. 33-39 ◽  
Author(s):  
D Menache ◽  
JP O'Malley ◽  
JB Schorr ◽  
B Wagner ◽  
C Williams ◽  
...  
Keyword(s):  
Half Life ◽  
Antithrombin Iii ◽  
Clinical Symptoms ◽  
Cooperative Study Group ◽  
Significant Difference ◽  
At Iii ◽  
Thrombotic Complications ◽  
Antithrombin Iii Deficiency

Abstract Antithrombin III (Human) (AT III) was administered to 18 patients with documented hereditary AT III deficiency. In eight patients with no ongoing clinical symptoms of thrombosis, the percent increase per unit AT III infused per kilogram of body weight ranged from 1.56% to 2.74%, and the half-life from 43.3 to 77.0 hours. No significant difference was noted between patients receiving and those not receiving coumarin therapy. In clinically ill patients, the in vivo recovery was significantly lower and ranged from 0.64% to 1.90% increase per unit AT III infused/kg. Efficacy of AT III was evaluated in 13 patients for the prevention or treatment of thrombosis. AT III was efficacious as assessed by the absence of thrombotic complications after surgery and/or parturition, and the nonextension and nonrecurrence of thrombosis in patients exhibiting an acute thrombotic episode. No side effects were noted. Follow-up studies indicated no hepatitis B seroconversion and no alanine aminotransferase elevations in patients who were not transfused with other blood products.

Disposition Kinetics of lincomycin following intravenous administration in hypothyroid goats

2019 ◽  
Author(s):  
Meemansha Sharma ◽  
Vinod Kumar Dumka ◽  
Saloni Singla ◽  
Rajdeep Kaur ◽  
Raushan Kumar Singh
Keyword(s):  
Dose Rate ◽  
Intravenous Administration ◽  
Half Life ◽  
Total Body Clearance ◽  
Small Ruminants ◽  
Blood Samples ◽  
Elimination Half ◽  
Total Body ◽  
Kinetics Of ◽  
Body Clearance

Hypothyroidism is a common disorder of small ruminants and is expected to alter the pharmacokinetics of drugs. Hypothyroidism was induced by feeding thiourea at the dose rate 50 mg.kg-1 daily for 28 days to goats. Disposition of lincomycin, after intravenous administration at dose rate 10 mg/kg, was investigated in hypothyroid goats to determine the potential dosage regimen against susceptible microorganisms. Blood samples were collected from 1 min to 24 h of drug administration. The drug was detected in plasma up to 8 h and lincomycin was rapidly distributed from blood to the tissue, as evidenced by the high value of the distribution coefficient (mean ± SEM) 12.3±1.09 h-1. The large Vd (1.78±0.18 L/kg) indicated vast tissue distribution of lincomycin in goats. The elimination half life, AUC and total body clearance were 3.99± 0.25 h, 33.2±1.71 ìg.h/mL and 0.31±0.02 L/h/kg, respectively. Based on results, lincomycin in hypothyroid goats is suggested to be repeated at 12 h interval for organisms sensitive to lincomycin having MIC up to 0.1 µg.ml-1.

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