Antithrombin III: Biodistribution in Healthy Volunteers

1987 ◽  
Vol 58 (04) ◽  
pp. 1008-1011 ◽  
Author(s):  
E A R Knot ◽  
E de Jong ◽  
J W ten Cate ◽  
Liem Kian Gie ◽  
E A van Royen
Keyword(s):  
Healthy Volunteers ◽  
Antithrombin Iii ◽  
Compartment Model ◽  
Fixed Time ◽  
Whole Body ◽  
Catabolic Rate ◽  
At Iii ◽  
Great Vessels ◽  
Static Images ◽  
Liver Region

SummaryFive healthy volunteers were injected intravenously with 73-90 uCi purified human 131I-Antithrombin III (AT III), specific biological activity 5.6 U/mg. The tracer data were analysed using a three compartment model. The plasma radioactivity half life was 66.2 ± 1.2 (sem) h, the fractional catabolic rate constant of the plasma pool was 0.025 ± 0.002 (sem) h-1. These data were comparable with those described in the literature. Because of the difficulty in translating the mathematical analysis of various compartments into the biological model, biodistribiition was monitored by a gamma camera linked to a DEC PDF 11/34 computer system. Dynamic and static images were obtained at fixed time intervals following the injection of 131I-AT III.Whole body scanning at intervals between the time of injection (t=0)and t=24.5 h showed 131I-AT III distribution over the heart, lungs, liver, spleen and great vessels. Dynamic scanning was performed over the heart, spleen and liver. Overlayed frames in the first ten minutes after the 131I-AT III injection showed the following radioactivity expressed as percentage of the injected dose; 5.9% ± 0.3(sem) over the heart, 10.6% ± 0.9 (sem) over the liver and 1.1% ⊥ 0.1(sem) over the spleen.A slower decline of the radioactivity between t = 0 and t = 24 h; (19%) was measured over the liver compared with the radioactivity disappearance over the heart region. This shows, in combination with the fact that the radioactivity disappearance over the heart was identical with the radioactivity decline measured in the plasma samples that retention of 131I-AT III occurred in the liver. Heparin iv injected 6 h after the 131I-AT III injection in two volunteers induced a sharp increase of radioactivity over the liver region during the scanning demonstrating that heparin enhances the 131I-AT III uptake in the liver.

scholarly journals Purified radiolabeled antithrombin III metabolism in three families with hereditary AT III deficiency: application of a three-compartment model

Blood ◽  
1986 ◽  
Vol 67 (1) ◽  
pp. 93-98
Author(s):  
EA Knot ◽  
E de Jong ◽  
JW ten Cate ◽  
AH Iburg ◽  
CP Henny ◽  
...  
Keyword(s):  
Antithrombin Iii ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Compartment Model ◽  
Control Group ◽  
Surface Binding ◽  
Catabolic Rate ◽  
At Iii ◽  
Three Compartment Model ◽  
The Mean

Purified human radioiodinated antithrombin III (125I-AT III) was used to study its metabolism in six members from three different families with a known hereditary AT III deficiency. Six healthy volunteers served as a control group. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and crossed immunoelectrophoresis (CIE) showed the purified AT III to be homogeneous. Amino acid analysis of the protein revealed a composition identical to a highly purified internal standard. The specific activity was 5.6 U/mg. Analysis of plasma radioactivity data was performed, using a three-compartment model. Neither plasma disappearance half-times nor fractional catabolic rate constants differed significantly between patients and control subjects. The mean absolute catabolic rate in the patient group was significantly lower than that of the control group at 2.57 +/- 0.44 and 4.46 +/- 0.80 mg/kg/day, respectively. In addition, the mean patient alpha 1-phase, flux ratio (k1,2 and k2,1) of the second compartment alpha 2-phase and influx (k3,1) of the third compartment were significantly reduced as compared with control values. It has been tentatively concluded that the observed reduction in the second compartment may be caused by a decrease in endothelial cell surface binding.

scholarly journals Purified radiolabeled antithrombin III metabolism in three families with hereditary AT III deficiency: application of a three-compartment model

Blood ◽  
1986 ◽  
Vol 67 (1) ◽  
pp. 93-98 ◽  
Author(s):  
EA Knot ◽  
E de Jong ◽  
JW ten Cate ◽  
AH Iburg ◽  
CP Henny ◽  
...  
Keyword(s):  
Antithrombin Iii ◽  
Polyacrylamide Gel Electrophoresis ◽  
Sodium Dodecyl ◽  
Compartment Model ◽  
Control Group ◽  
Surface Binding ◽  
Catabolic Rate ◽  
At Iii ◽  
Three Compartment Model ◽  
The Mean

Abstract Purified human radioiodinated antithrombin III (125I-AT III) was used to study its metabolism in six members from three different families with a known hereditary AT III deficiency. Six healthy volunteers served as a control group. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and crossed immunoelectrophoresis (CIE) showed the purified AT III to be homogeneous. Amino acid analysis of the protein revealed a composition identical to a highly purified internal standard. The specific activity was 5.6 U/mg. Analysis of plasma radioactivity data was performed, using a three-compartment model. Neither plasma disappearance half-times nor fractional catabolic rate constants differed significantly between patients and control subjects. The mean absolute catabolic rate in the patient group was significantly lower than that of the control group at 2.57 +/- 0.44 and 4.46 +/- 0.80 mg/kg/day, respectively. In addition, the mean patient alpha 1-phase, flux ratio (k1,2 and k2,1) of the second compartment alpha 2-phase and influx (k3,1) of the third compartment were significantly reduced as compared with control values. It has been tentatively concluded that the observed reduction in the second compartment may be caused by a decrease in endothelial cell surface binding.

Autologous 131I-Antithrombin III Turnover Studies in Man

1979 ◽  
Author(s):  
E. B. Reeve ◽  
B. Leonard ◽  
G. Zimet ◽  
T. H. Carlson
Keyword(s):  
Antithrombin Iii ◽  
Protective Role ◽  
Anomalous Behavior ◽  
Whole Body ◽  
Catabolic Rate ◽  
Whole Body Counter ◽  
Rate Of Reaction ◽  
One Step ◽  
Serial Measurements ◽  
Better Than

A simple one-step heparin sepharose preparation of better than 95% pure human antithrombin III (AT3) has been developed along with a modification of the iodine monochloride method that allows consistent iodination of it. Iodination at a ratio of ~0.7 I atom/1.0 AT3 molecule results in loss of ca. 5% total thrombin neutralizing activity but negligible reduction in rate of reaction with thrombin. After iodination with 131I unreached 131I-products are removed by washing the 131I-AT3 on a second heparin sepharose column. Before injection the *I-AT3 is sterilized by millipore filtration. By this method autologous *I-AT3 can be prepared and reinjected into the patient in 36-48 titor less if desired. Serial measurements are made of plasma 131I-AT3, plasma TCA-soluble 131I, and whole body 131I, (using a whole body counter). Since human AT3 is ~ the same molecular weight as albumin if allowance is made for its increased catabolic rate its kinetic behavior should be predictable from results of our earlier studies with human autologous albumin. This is not found to be so and human *I-AT3 shows the same delay in catabolismos dog *I-AT3. Current studies indicate that this anomalous behavior is unlikely to invalidate estimates of AT3 catabolism but may result in considerable errors in estimates of total Interstitial AT3. As with our dog studies these suggest a protective role for AT3 in the interstitial fluids

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.

Studies on Production of Antithrombin III with Special Reference to Endotoxin-Induced DIC in Dogs

1986 ◽  
Vol 56 (02) ◽  
pp. 137-143 ◽  
Author(s):  
H Tanaka ◽  
N Kobayashi ◽  
T Maekawa
Keyword(s):  
Body Weight ◽  
Plasma Level ◽  
Normal Control ◽  
Antithrombin Iii ◽  
Rabbit Serum ◽  
Single Infusion ◽  
Rapid Decay ◽  
Endotoxin Infusion ◽  
Catabolic Rate ◽  
At Iii

SummaryThe production of antithrombin III (AT III) was studied using Se-75-selenomethionine as a tracer in dogs with disseminated intravascular coagulation (DIC) experimentally induced by endotoxin infusion. Using canine AT III purified by heparin-Sepharose affinity chromatography, antiserum against canine AT III was raised in rabbit. To study the production of plasma AT III, Se-75-selenomethionine was injected into the dog and thereafter the radioactivity incorporated into plasma AT III immunoprecipitated by anti-AT III rabbit serum was serially measured. In normal control dogs, peak radioactivity incorporated into AT III fraction was 970 ± 55 (mean ± SE) cpm/mg of AT III. It was 1196 ± 51.5 cpm/mg, 2748 ± 826 cpm/mg and 1057 ± 74 cpm/mg when Se-75-selenomethionine was injected 6 h, 24 h and 48 h after a single infusion with one mg of endotoxin/kg body weight of dogs, and was 1.2 times, 2.8 times and 1.1 times more than normal control dogs, respectively. Plasma AT III levels decreased to a minimum of 26.7 ± 4.9 mg/dl within 6 h after endotoxin infusion and returned to normal levels by 2 to 3 days after the infusion. Since the catabolic rate of AT III was evidently accelerated, judging from the more rapid decay of the AT III radioactivity, it is suggested that the production of AT III is markedly increased in dogs with DIC induced by endotoxin infusion even during a period of low plasma level.

Comparative metabolism and distribution of rabbit heparin cofactor II and rabbit antithrombin in rabbits

1997 ◽  
Vol 272 (5) ◽  
pp. E824-E831 ◽  
Author(s):  
M. W. Hatton ◽  
H. Hoogendoorn ◽  
S. M. Southward ◽  
B. Ross ◽  
M. A. Blajchman
Keyword(s):  
Compartment Model ◽  
Thrombin Inhibitors ◽  
Whole Body ◽  
Molar Ratio ◽  
Heparin Cofactor Ii ◽  
Blood Concentrations ◽  
Metabolic Characteristics ◽  
Comparative Metabolism ◽  
Catabolic Rate

The metabolic characteristics of two rabbit plasma thrombin inhibitors, heparin cofactor II (HCII) and antithrombin (AT), have been compared in healthy young rabbits. Purified HCII and AT-alpha were differentially radiolabeled (125I, 131I) and injected intravenously; blood samples were taken at prescribed intervals over 7 days. From the plasma clearance curves of protein-bound radioactivities, fractional catabolic rates and compartmental distributions were calculated using a three-compartment model. The whole body fractional catabolic rate for HCII (jt, 0.43/day, equivalent to t1/2 = 1.61 days) was significantly faster than for AT (jt, 0.37/day; t1/2 = 1.89 days; P < 0.005). The fractional distribution of HCII in the intravascular compartment (Ap, 0.20) and in the extravascular compartment (Ac, 0.63) differed significantly from AT (Ap, 0.30; Ac, 0.56). From the catabolic data and blood concentrations, absolute quantities of HCII and AT catabolized by a 3-kg rabbit amounted to 12.8 and 19.9 mg/day, respectively, equivalent to a molar ratio, AT/HCII, of 1.7. The catabolic molar ratio was compared with the relative release rates of HCII and AT from perfused rabbit livers. Both proteins were released from the liver, the molar ratio in the perfusate rising to approximately 1.4 at 2.5 h. This report increases our understanding of the in vivo dynamics of these two proteins.

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.

Immunologic Studies of Antithrombin III Heparin Cofactor in the Newborn

1978 ◽  
Vol 39 (03) ◽  
pp. 624-630 ◽  
Author(s):  
W E Hathaway ◽  
L L Neumann ◽  
C A Borden ◽  
L J Jacobson
Keyword(s):  
Gestational Age ◽  
Antithrombin Iii ◽  
Newborn Infants ◽  
Term Infant ◽  
Sick Newborn ◽  
At Iii ◽  
Thrombotic Complications ◽  
Low Levels ◽  
Collection Methods ◽  
Made In

SummarySerial quantitative immunoelectrophoretic (IE) measurements of antithrombin III heparin cofactor (AT III) were made in groups of well and sick newborn infants classified by gestational age. Collection methods (venous vs. capillary) did not influence the results; serum IE measurements were comparable to AT III activity by a clotting method. AT III is gestational age-dependent, increasing from 28.7% of normal adult values at 28-32 weeks to 50.9% at 37-40 weeks, and shows a gradual increase to term infant levels (57.4%) by 3-4 weeks of age. Infants with the respiratory distress syndrome (RDS) show lower levels of AT III in the 33-36 week group, 22% vs. 44% and in the 37-40 week group, 33.6% vs. 50.9%, than prematures without RDS. Infants of 28-32 week gestational age had only slight differences, RDS = 24%, non-RDS = 28.7%. The lowest levels of AT III were seen in patients with RDS complicated by disseminated intravascular coagulation and those with necrotizing enterocolitis. Crossed IE on representative infants displayed a consistent pattern which was identical to adult controls except for appropriate decreases in the amplitude of the peaks. The thrombotic complications seen in the sick preterm infant may be related to the low levels of AT III.

Antithrombin III and Heparin Cofactor II in Patients with Chronic Renal Failure Undergoing Regular Hemodialysis

1987 ◽  
Vol 57 (03) ◽  
pp. 263-268 ◽  
Author(s):  
P Toulon ◽  
C Jacquot ◽  
L Capron ◽  
M -O Frydman ◽  
D Vignon ◽  
...  
Keyword(s):  
Renal Failure ◽  
Chronic Renal Failure ◽  
Plasma Proteins ◽  
Antithrombin Iii ◽  
Vascular Wall ◽  
Relative Increase ◽  
Heparin Cofactor Ii ◽  
Normal Ranges ◽  
At Iii ◽  
Regular Hemodialysis

SummaryHeparin enhances the inhibition rate of thrombin by both antithrombin III (AT III) and heparin cofactor II (HC II). We studied the activity of these two plasma proteins in patients with chronic renal failure (CRF) undergoing regular hemodialysis as their heparin requirements varied widely. In 77 normal blood donors, normal ranges (mean ± 2 SD) were 82-122% for AT III and 65-145% for HC II. When compared with these controls 82 dialyzed CRF patients had a subnormal AT III activity and a significantly (p <0.001) lower HC II activity. To evaluate the effect of hemodialysis we compared AT III, HC II and total proteins in plasma before and after dialysis in. 24 patients (12 with normal and 12 with low basal HC II activity). AT III and HC II activities significantly (p <0.001) increased in absolute value. When related to total plasma proteins, in order to suppress the influence of hemoconcentration induced by dialysis, AT III decreased significantly (p <0.01) whereas HC II increased slightly but significantly (p <0.01) in the 12 patients with low initial HC II activity. The decrease of AT III induced by heparin administrated during dialysis is likely to account for this relative decrease of AT III activity. A modification of the distribution of both HC II and heparin between the vascular wall and the circulating blood is evoked to explain the relative increase in HC II activity and the need for higher heparin dosage in patients with low HC II levels.

Severe Antithrombin III Deficiency in an Infant Associated with Multiple Arterial and Venous Thromboses

1976 ◽  
Vol 36 (03) ◽  
pp. 495-502 ◽  
Author(s):  
Geoffrey Mendelsohn ◽  
Edward D. Gomperts ◽  
Dennis Gurwitz
Keyword(s):  
Antithrombin Iii ◽  
Adult Life ◽  
Rare Condition ◽  
Male Infant ◽  
Liver Cells ◽  
Liver Pathology ◽  
Fixed Tissue ◽  
Formalin Fixed Tissue ◽  
First Case ◽  
At Iii

SummaryInherited antithrombin III (AT-II, heparin cofactor) deficiency is a rare condition, presenting with thrombotic disease in adult life. This paper reports an 8 months old South African Black male infant with multiple large vessel venous and arterial thromboses, and E. coli septicaemia. This was associated with an extremely low plasma AT-II level. Micronodular cirrhosis and intracytoplasmic hyaline globules in the liver cells were present. These globules were eosinophilic, and PAS-positive after diastase. They measured approximately 5 μ to 30 μ in diameter, occurred singly in the liver cells and were located mainly in the periportal areas. The histological findings in the liver are similar to those observed in α1-antitrypsin (AAT) deficiency in which the intracytoplasmic globules represent accumulation of altered AAT. Immunochemical studies carried out on formalin fixed tissue failed to detect cross reaction material with anti-α1 antitrypsin or anti-AT III antiserum. This is the first case report of AT-III deficiency presenting in infancy. It is also the first case associated with distinctive liver pathology.The available data presented are insufficient to distinguish between an inborn defect and acquired causes of the severely depressed AT-III plasma level and the distinctive liver pathology.

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