Antithrombin III (ATILL) replacement therapy in patients with sepsis and/or postsurgical complications: a controlled double-blind, randomized, multicenter study
F. BaudoTeresa Maria CaimiFrancesco DecataldoA. RavizzaSergio ArlatiGianni CasellaDario CarugoGualtiero PalaretiCristina LegnaniLorenza RidolfiR RossiArmando D’AngeloL. CrippaD. GiudiciG GallioliAndrea WolflerGiliola Calori
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Summary Natural coagulation inhibitor factors were studied in sera, or in fractions of sera, from patients with congenital partial deficiency of antithrombin and from normal persons. In the patients’ sera the progressive antithrombin (antithrombin III) and heparin cofactor (antithrombin II) had both been measured around 50 per cent of normal level. No decreased activity could be demonstrated in the patients’ sera as to antiprothrombinase, the inhibitor against blood intrinsic prothrombinase activity. For anticonvertin, the inhibitor against the tissue convertin complex, the activity was found decreased to about the same level as that demonstrated for antithrombin III and II. The results lend strong support to the hypothesis that the activities measured as anticonvertin, antithrombin III and antithrombin II represent functions of the same blood protein, which on the other side appears to be distinct from antiprothrombinase. In accordance with this explanation, an antithrombin III concentrate had also antithrombin II and anticonvertin activity, and further, adsorption of a normal human serum with convertin appeared to specifically reduce its antithrombin III activity. The inhibitor against activated antihemophilic C factor (AHC’ = activated f. XI) was studied in sera adsorbed with BaS04 and celite. The inhibitor activity was found at normal level in the patients’ sera, consistent with the view that anti-AHC’ is distinct from antithrombin III, II and from anticonvertin. No acceleration of the anti-AHC’ activity could be demonstrated after addition to the inhibition mixture of weak solutions of heparin. The results are discussed.
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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.
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Immunoelectrophoresis
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To the Editor.—
In a letter to the editor, Roger L. Bick, MD (239:296, 1978), commented on the clinical determination of antithrombin III, pointing out the usefulness of chromogenic substrate and that an increased predisposition to thromboembolic phenomena is associated with a decreased antithrombin III level. In reply, Harry L. Messmore, MD, and Jawed Fareed, PhD (240:345, 1978), questioned the use of autolytic forms of thrombin and the chromogenic substrate in the antithrombin III assay. The methods employed for antithrombin III assay can be roughly classified into two categories: immunological and functional. There are two types of functional assays available: the rate determination procedure and the end-point analysis. The rate of the inhibition of thrombin by antithrombin III depends on (1) the amount of antithrombin III present, (2) the amount of heparin or heparin-like substance present in the sample, and (3) the quantity of thrombin employed. It was first pointedChromogenic
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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.
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Many unrelated clinical conditions that are associated with significant decreases in antithrombin III have been summarized. In addition, prospects for future therapy with antithrombin III concentrates have been discussed. The clinical indications for antithrombin III determinations, including the reasons for performing the assay and those specific patient populations subjected to antithrombin III assays in this author's clinical practice, have been outlined. It is to be anticipated that with the new general availability of simple reliable antithrombin III assay systems using synthetic substrates that more and more populations will be adequately studied and clinical indications for the use of antithrombin III determinations and concentrates may become more firm or may change.
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