Further studies of the turnover of dog antithrombin III. Study of 131I-labelled antithrombin protease complexes

Leonard, B. D.; Bies, R. D.; Carlson, Timothy H.; Reeve, E. B.

doi:10.1016/0049-3848(83)90239-6

Cited by 14 publications

(5 citation statements)

References 18 publications

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“…With 88 ± 24 min the calculated half-life of F1+2 was nearly comparable with our results, but the estimated half-life time of TAT of 9 ± 6 min was substantially shorter than the 44 min (0.7 h) observed in our study [ 43 ]. However, the results obtained with radiolabeled TAT in animal studies (10–55 min) were in line with our findings [ 25 – 27 ]. One might speculate that the presence of high doses of unfractionated heparin in the cardiopulmonary bypass setting may have enhanced the elimination of TAT [ 44 ].…”

Section: Discussionsupporting

confidence: 92%

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Label-Free Kinetic Studies of Hemostasis-Related Biomarkers Including D-Dimer Using Autologous Serum Transfusion

et al. 2015

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The objective of this study was to evaluate the elimination kinetics of hemostasis-related biomarkers including the prothrombin activation fragment F1+2, thrombin-antithrombin complex (TAT), plasmin-α2-antiplasmin complex (PAP), and D-dimer in humans. Autologous serum was used as a biomarker source and infused into 15 healthy volunteers. Serum was prepared from whole blood in the presence of recombinant tissue-type plasminogen activator (final concentration 20 μg/mL) to induce plasmin generation required for PAP and D-dimer formation. Serum transfusions (50 mL/30 min) were well tolerated by all subjects. Endogenous thrombin formation was not induced by serum infusions as measured using a highly sensitive oligonucleotide-based enzyme capture assay. Median peak levels (x-fold increase over baseline) of F1+2, TAT, PAP, and D-dimer of 3.7 nmol/L (28.9), 393 ng/mL (189.6), 3,829 ng/mL (7.0), and 13.4 mg/L (34.2) were achieved at the end of serum infusions. During a 48 h lasting follow-up period all biomarkers showed elimination kinetics of a two-compartment model. Median (interquartile range) terminal half-lives were 1.9 (1.3–3.6) h for F1+2, 0.7 (0.7–2.6) h for TAT, and 10.8 (8.8–11.4) h for PAP. With 15.8 (13.1–23.1) h the D-dimer half-life was about twice as long as previously estimated from radiolabeling studies in animals and small numbers of human subjects. The serum approach presented here allows label-free and simultaneous analysis of the elimination kinetics of various hemostasis-related biomarkers. Based on these data changes in biomarker levels could more precisely used to estimate the activity level of the hemostatic system.

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Section: Discussionsupporting

confidence: 92%

“…However, studies in humans are sparse, and they have been conducted with small numbers of subjects only [ 21 , 23 ]. This also applies to studies on the elimination kinetics of F1+2 [ 24 ], TAT [ 25 – 27 ], and PAP [ 28 ], in which similar radiolabeling techniques were used.…”

Section: Introductionmentioning

confidence: 99%

Label-Free Kinetic Studies of Hemostasis-Related Biomarkers Including D-Dimer Using Autologous Serum Transfusion

et al. 2015

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“…reduced affinity for heparin of populations of I-AT with more than one atom of iodine per AT molecule (Leonard et al, 1983), or could occur because of a slightly reduced affinity of singly labelled I-AT for heparin. If the first of these possibilities were the case, the distribution of iodinated AT within the total AT population would be expected to change in vivo over time, because it has been shown previously that plasma proteins labelled with several iodine atoms per protein molecule are more rapidly catabolized than those containing a single atom per molecule (Atencio et al, 1965).…”

Section: Resultsmentioning

confidence: 99%

Comparison of the behaviour in vivo of two molecular forms of antithrombin III

Carlson¹,

Atencio²,

Simon³

1985

Biochemical Journal

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The distribution and rates of catabolism were determined for rabbit antithrombin III (AT) isoforms differing in affinity for heparin-agarose. After isolation from rabbit plasma by heparin-affinity chromatography, the very-high-affinity form, ATvh, was labelled with 131I, and its high-affinity congener, ATh, with 125I. The two forms were separated from free iodine by heparin-affinity chromatography, and then injected simultaneously into young recipient rabbits. The disappearance-of-plasma-AT-radioactivity data were fitted to three exponential equations, and the resulting constants were used to calculate fractional catabolic rates and the various pool sizes for ATh and ATvh. The fractions of plasma ATh and ATvh catabolized daily (j3) were 0.763 +/- 0.023 and 1.88 +/- 0.057 day-1 respectively. Average values of jT, the daily fractional catabolic rates for the total-body ATh and ATvh, were 0.2633 +/- 0.0113 and 0.3832 +/- 0.0211 day-1. The ratios, ATh/ATvh, of the sizes of the plasma, non-circulating vascular-associated and extra-vascular compartments were 0.593, 0.990 and 1.30. By using a previous estimate of a 9:1 ATh/ATvh ratio in rabbit plasma and the calculated compartment sizes, the calculated relative ratio of ATh to ATvh was 5.4:1 in the non-circulating vascular-associated compartment. The data fit a model of antithrombin III distribution and catabolism in which a pool of endothelial-cell heparin-like receptors is seen to mediate the transfer of the inhibitor from plasma to interstitium with catabolism serving as an alternative to this transport.

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“…The best fit half-lives from the model were similar to the measured half-lives from previous studies. 1,21,22 We also evaluated the potential effect of other thrombin inhibitors, such as heparin cofactor II, concluding that a model assuming 100% of thrombin was inhibited by antithrombin was simpler without significant change to the results. Finally we compared the thrombin generation rates estimated by the model based on 2 different markers of thrombin generation, F1.2 and TAT.…”

Section: Discussionmentioning

confidence: 99%

“…Overall the average best fit half-lives for F1.2 and TAT were 88 Ϯ 24 minutes and 9 Ϯ 6 minutes, respectively, similar to values previously reported. 1,21,22 Effect of hemodilution, blood loss, and transfusion Figure 5 shows the effect of CPB on the levels of fibrinogen, F1.2, and TAT in subject 2 and the corresponding predicted levels and thrombin generation rates using 3 different models. In model E ( Figure 5), it is assumed there is no CPB circuit, no hemodilution, and no blood loss or transfusion.…”

Section: Effect Of Tat Half-life On Predicted Thrombin Generationmentioning

confidence: 99%

Estimating the rate of thrombin and fibrin generation in vivo during cardiopulmonary bypass

Chandler

Velan

2003

Blood

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Our objective was to estimate the in vivo rates of thrombin and fibrin generation to better understand how coagulation is regulated. Studied were 9 males undergoing cardiopulmonary bypass (CPB). The rates of thrombin, total fibrin, and soluble fibrin generation in vivo were based on measured levels of prothrombin activation peptide F1.2, thrombin-antithrombin complex, fibrinopeptide A, and soluble fibrin, combined with a computer model of the patient's vascular system that accounted for marker clearance, hemodilution, blood loss, and transfusion. Prior to surgery, the average thrombin generation rate was 0.24 ؎ 0.11 pmol/s. Each thrombin molecule in turn generated about 100 fibrin molecules, of which 1% was soluble fibrin. The thrombin generation rate did not change after sternotomy or administration of heparin, then rapidly increased 20-fold to 5.60 ؎ 6.65 pmol/s after 5 minutes of CPB (P ‫؍‬ .000 05). Early in CPB each new thrombin generated only 4 fibrin molecules, of which 35% was soluble fibrin. The thrombin generation rate was 2.14 ؎ 1.88 pmol/s during the remainder of CPB, increasing again to 5.47 ؎ 4.08 pmol/s after reperfusion of the ischemic heart (P ‫؍‬ .000 08). After heparin neutralization with protamine, thrombin generation remained high (5.34 ؎ 4.01 pmol/s, P ‫؍‬ .0002) and total fibrin generation increased, while soluble fibrin generation decreased. By 2 hours after surgery, thrombin and fibrin generation rates were returning to baseline levels. We conclude that cardiopulmonary bypass and reperfusion of the ischemic heart results in bursts of nonhemostatic thrombin generation and dysregulated fibrin formation, not just a steady increase in thrombin generation as suggested by previous studies.

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Further studies of the turnover of dog antithrombin III. Study of 131I-labelled antithrombin protease complexes

Cited by 14 publications

References 18 publications

Label-Free Kinetic Studies of Hemostasis-Related Biomarkers Including D-Dimer Using Autologous Serum Transfusion

Label-Free Kinetic Studies of Hemostasis-Related Biomarkers Including D-Dimer Using Autologous Serum Transfusion

Comparison of the behaviour in vivo of two molecular forms of antithrombin III

Estimating the rate of thrombin and fibrin generation in vivo during cardiopulmonary bypass

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