A novel mutation p.Met1Val in SERPINC1 gene causes hereditary antithrombin deficiency in a Chinese family with thrombotic disease
0
Citation
10
Reference
10
Related Paper
Introduction: Heparin-based anticoagulation in children is challenging as they have a high prevalence of heparin resistance. Antithrombin, one of the main natural anticoagulant inhibitors that potentiate heparin anticoagulation activity, might be a critical component of heparin response and anticoagulation effectiveness. Objectives: Determine the impact of antithrombin levels on anticoagulation (heparin sensitivity and effectiveness) during cardiopulmonary bypass (CPB) in children <1 year old. Methods: Secondary analysis of a randomized controlled trial of individualized vs weight based heparin management in 90 infants <1-year-old undergoing cardiac surgery. All analyses combined both patient groups and were used linear regression models. Results: As expected, older patients had higher blood antithrombin levels (relative increase of 16±6% for patients >6 months old vs. those <6 month old, p=0.009). Response to heparin, reflected by change in anti-Xa levels from baseline after the initial heparin bolus (a laboratory measure of heparin sensitivity), was highest in patients with higher baseline antithrombin circulating levels (top tier: +0.94(0.16) U/ml per 100U/kg heparin vs. middle tier: +0.89(0.19) U/ml vs. lowest tier: +0.77(0.20) U/ml, p<0.001). Those patients with very low antithrombin levels during CPB (<0.35U/ml) had much greater heparin requirements (+165(30) U/kg/hr representing an increase of 243%, p<0.001) indicating greater heparin resistance. Insufficient anticoagulation on bypass (as measured by end of bypass anti-Xa level) was associated with higher clotting potential, reflected by higher plasma levels of thrombin-antithrombin complexes (+4.8(2.4) ng/ml per anti-Xa U/ml, p=0.05), and prothrombin activation fragment 1.2 (+85(32) pg/ml per anti-Xa U/ml, p=0.008). Moreover, lower circulating antithrombin level was associated with increased D-dimer levels after CPB (+53(25) ng/ml per 0.1 U/ml antithrombin, p=0.03). Conclusions: Low antithrombin level is associated with resistance to heparin and decreased anticoagulation activity, ultimately leading to lower ability to suppress thrombin generation during CPB. Antithrombin supplementation may potentially individualize and improve anticoagulation.
Bolus (digestion)
Activated clotting time
Cite
Citations (0)
Protamine sulfate
Cite
Citations (28)
Cite
Citations (2)
Antithrombin III was purified from normal plasma by DEAE-Sephadex chromatography and heparin affinity chromatography; the protein was subsequently radiolabelled with 125I. 125I-antithrombin III alone and 125I-antithrombin III in the presence of high affinity 35S-heparin fractions were injected into normal humans. 125I-radiolabel and protein bound 35S-radioactivity were followed separately. In semilogarithmic plots 125I-antithrombin III disappeared according to a double exponential curve with a half-life in the second phase of 56.8 hr in the absence of heparin and of 33.7 hr in the presence of heparin. Protein bound 35S-radioactivity disappeared much faster than the 125I-radiolabel. These data support the concept that heparin disappears as free heparin from the equilibrium heparin - antithrombin III in equilibrium heparin + antithrombin III. Immuno-reactive antithrombin III decreased from 100% to 85-90% immediately after injection of 125I-antithrombin III in the presence of heparin and returned to normal values within 30 min. This suggests that antithrombin III is transiently sequestered, possibly in trimolecular complexes consisting of antithrombin III, heparin and either lipases or other vascular bound proteins.
Sephadex
Cite
Citations (28)
The availability of automated anti-Xa heparin assays provides the opportunity to manage patient unfractionated heparin levels directly, rather than by the activated partial thromboplastin time. Because critically ill patients can acquire an antithrombin deficiency, we compared the performance of 3 anti-Xa heparin assays, 1 with and 2 without antithrombin supplementation, by analyzing in vitro aliquots of plasma with defined antithrombin levels and specimens from intensive care patients receiving intravenous heparin therapy. Heparin concentration recovery, in vitro, was dependent on the plasma antithrombin concentration for all 3 assays. The antithrombin-supplemented assay demonstrated improved heparin recovery in direct correlation to the heparin concentration in the plasma. The greatest effect of antithrombin supplementation occurred when the antithrombin level dropped below 40%, a level present in only 5% of the patient specimens. Analysis of patient specimens demonstrated significant correlation among the 3 assays. Classification of the clinical adequacy of patient heparin levels showed agreement of 80% or more between the antithrombin-supplemented and nonsupplemented assays. The antithrombin-supplemented assay did not significantly improve clinical usefulness.
Cite
Citations (32)
Summary Antithrombin III was purified from normal plasma by DEAE- Sephadex chromatography and heparin affinity chromatography; the protein was subsequently radiolabelled with 125I. 125I-anti- thrombin III alone and 125I-antithrombin III in the presence of high affinity 35S-heparin fractions were injected into normal humans. 125I-radiolabel and protein bound 35S-radioactivity were followed separately. In semilogarithmic plots 125I-antithrombin III disappeared according to a double exponential curve with a half-life in the second phase of 56.8 hr in the absence of heparin and of 33.7 hr in the presence of heparin. Protein bound 35S- radioactivity disappeared much faster than the 125I-radiolabel. These data support the concept that heparin disappears as free heparin from the equilibrium heparin – antithrombin III ⇄ heparin + antithrombin III. Immuno-reactive antithrombin III decreased from 100% to 85-90% immediately after injection of 125I-antithrombin III in the presence of heparin and returned to normal values within 30 min. This suggests that antithrombin III is transiently sequestered, possibly in trimolecular complexes consisting of antithrombin III, heparin and either lipases or other vascular bound proteins.
Sephadex
Cite
Citations (20)
The effect of various well-characterized heparin preparations on the inactivation of human Factor XIa by human antithrombin III was studied. The heparin preparations used were unfractionated heparin and four heparin fractions obtained after anion-exchange chromatography. Inactivation of Factor XIa was monitored with S2366 as chromogenic substrate and followed pseudo-first-order reaction kinetics under all reaction conditions tested. Enhancement of the rate of inhibition of Factor XIa in the presence of unfractionated heparin correlated to the binding of antithrombin III to heparin. From the kinetic data a binding constant of 0.1 microM was inferred. The maximum rate enhancement, achieved at saturating heparin concentrations, was 30-fold. The rate enhancement achieved in the presence of each of the heparin fractions could also be correlated to the binding of antithrombin III to the heparin. The binding constant inferred from the kinetic data varied from 0.10 to 0.28 microM and the number of binding sites for antithrombin III varied from 0.06 to 0.74 site per heparin molecule. The maximum rate enhancements, achieved at saturating heparin concentrations, were strongly dependent on the type of heparin used and varied from 7-fold for fraction A to 41-fold for fraction D. Therefore, although the stimulation of Factor XIa inactivation by antithrombin III could be quantitatively correlated to the binding of antithrombin III to heparin, the heparin-catalysed inhibition of Factor XIa is dependent not only upon the degree of binding of antithrombin III to heparin but also upon the type of heparin to which antithrombin III is bound.
Cite
Citations (5)
Cite
Citations (25)
Cite
Citations (42)
The availability of automated anti-Xa heparin assays provides the opportunity to manage patient unfractionated heparin levels directly, rather than by the activated partial thromboplastin time. Because critically ill patients can acquire an antithrombin deficiency, we compared the performance of 3 anti-Xa heparin assays, 1 with and 2 without antithrombin supplementation, by analyzing in vitro aliquots of plasma with defined antithrombin levels and specimens from intensive care patients receiving intravenous heparin therapy. Heparin concentration recovery, in vitro, was dependent on the plasma antithrombin concentration for all 3 assays. The antithrombin-supplemented assay demonstrated improved heparin recovery in direct correlation to the heparin concentration in the plasma. The greatest effect of antithrombin supplementation occurred when the antithrombin level dropped below 40%, a level present in only 5% of the patient specimens. Analysis of patient specimens demonstrated significant correlation among the 3 assays. Classification of the clinical adequacy of patient heparin levels showed agreement of 80% or more between the antithrombin-supplemented and nonsupplemented assays. The antithrombin-supplemented assay did not significantly improve clinical usefulness.
Cite
Citations (1)