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PubMedDate not supplied

Antithrombin III deficiency.

Data on clinical features and laboratory diagnosis of familial antithrombin deficiency, a rather heterogeneous group of disorders, are illustrated by observations on two Romanian kindreds afflicted by recurrent thrombotic episodes. In a first family, both plasma antithrombin III antigen and activity were reduced to 50% of normal, a condition characteristic for a heterozygous type I (quantitative) familial antithrombin III deficiency. In a second kindred, the two brothers who had experienced thrombotic events since they were teenagers, displayed exceedingly low AT III heparin cofactor activity (13% and 16% of the normal, respectively) while values around 50% of the normal were recorded in their parents who had not experienced thrombotic episodes. Since plasma antithrombin III antigen and total progressive antithrombin III activity were within normal limits in all the investigated members of this family it was considered that the two brothers were homozygotes or compound heterozygotes and the parents were heterozygotes for a qualitative-antithrombin III deficiency caused by an abnormality of the heparin binding site.

Adolescent↗

PubMed1994

Hereditary antithrombin deficiency: heterogeneity of the molecular basis and mortality in Dutch families.

We studied the molecular basis and genetic heterogeneity of hereditary antithrombin (III) deficiency in nine Dutch families. Polymerase chain reaction (PCR) amplification and direct sequencing of all antithrombin gene exons and flanking intronic regions identified mutations in eight families. Given the opportunity to correlate the molecular basis with survival, we addressed the relevance of molecular defects to mortality in inherited antithrombin deficiency. The defects included single nucleotide deletions (7671 del G, 7768-69 del G) and insertions (5501 ins A, 2463 G-->TC) that lead to frameshifts, a single base substitution [5381 C-->T (129Arg-->stop)] leading to a premature termination codon, and single base substitutions resulting in amino acid substitutions [2652 A-->C (63Tyr-->Ser), 13380 T-->C (421Ile-->Thr), and 13407 G-->T (430Cys-->Phe)]. All affected individuals were heterozygous for the defects. Previously we found in Dutch families that antithrombin deficiency did not lead to higher mortality compared with the general population. In accordance with these findings, we observed no excess mortality in the nine families [Observed:Expected, 52:52.6; standardised mortality ratio (SMR) 1.0, 95% confidence interval (CI), 0.7-1.3]. Our findings confirmed a considerable genetic heterogeneity underlying antithrombin deficiency. We therefore concluded that the lack of excess mortality in these families is not caused by a Dutch mild defect. We suggest that the longevity is not affected by molecular defects in the antithrombin gene and hypothesize that differences in mortality or natural history between families most likely result from other (genetic) risk factors.

Antithrombin III↗

PubMed1997

Antithrombin and its inherited deficiency states.

Antithrombin is the primary inhibitor of thrombin that also inhibits many of the other activated serine proteinases involved in blood coagulation. A hypercoagulable state occurs when a deficiency of antithrombin exists in plasma; the deficiency may be either inherited or acquired. This failure to regulate adequately the activity of coagulation proteinases can, with additional provocation, result in clot formation and in the clinical presentation of thromboembolic disease. The structure and function of antithrombin, nature and heterogeneity of the molecular defects in the antithrombin gene associated with inherited antithrombin deficiency, prevalence and the natural history of inherited antithrombin deficiency are all reviewed here.

Antithrombin III↗

PubMed1996

High dose of intravenous antithrombin III without heparin in the treatment of disseminated intravascular coagulation and organ failure in four children.

In several animal experiments, high doses of antithrombin III concentrates have shown beneficial effects on mortality and reversal of coagulation abnormalities which had resulted from disseminated intravascular coagulation. Other experiments have suggested that antithrombin III infusion without heparin is effective in the treatment of organ failure. We clinically treated children suffering disseminated intravascular coagulation only with antithrombin concentrate. Four patients suffering disseminated intravascular coagulation with organ failure were selected. We started antithrombin III concentrate infusion as soon as the diagnosis was established. The dosage of antithrombin III was 120-250 units/kg/day for 2 or 3 days. Heparin was not used. All 4 patients recovered completely and quickly without any complications within 14 days. We suggest that the high-dose antithrombin III infusion without heparin is an effective and safe therapy for disseminated intravascular coagulation with organ failure.

Antithrombin III↗

PubMed1976

Hereditary antithrombin III deficiency and thromboembolic disease.

Two teenage brothers with recurrent thromboembolic disease were found to have antithrombin III deficiency. A family study spanning four generations revealed a total of 10 members with antithrombin III deficiency. Five of the 10 affected family members have had thrombotic problems. Antithrombin III deficiency was documented by coagulation assays measuring heparin cofactor, anti-Factor Xa, and progressive antithrombin activity; the level of antithrombin III antigenic material measured by immunoelectrophoresis was low in subjects with abnormal coagulation assays. The clinical features which may lead one to suspect the hereditary hypercoagulable condition of antithrombin III deficiency are reviewed.

Antithrombins↗

PubMed1991

Interaction of poly(sodium vinyl sulfonate) and its surface graft with antithrombin III.

Poly(sodium vinyl sulfonate) (PVS) was found to be 1/14 times as active as heparin in inducing the conformational change and activation of antithrombin III. The conformational change of antithrombin III was investigated in terms of the intrinsic fluorescence of tryptophan residue, the extrinsic fluorescence using 1,6-diphenyl-1,3,5-hexatriene as fluorescent probe, and Fourier-transform infrared spectroscopy. It was evident in the experiment using 2,4,6-trinitrobenzene sulfonate that PVS elicited the activity of antithrombin III by interacting with amino groups of the protein as does heparin. Sodium vinyl sulfonate was graft-polymerized onto polyetherurethane (PEU) film that was treated with glow discharge in advance. PVS-grafted PEU film adsorbed antithrombin III easily and, like ungrafted PVS, induced conformational change and activation of antithrombin III. However, the mechanism of interaction of the PVS graft with antithrombin III did not seem to be completely the same as that of ungrafted PVS in solution.

Antithrombin III↗

PubMed1998

The N-terminal segment of antithrombin acts as a steric gate for the binding of heparin.

The binding of heparin causes a conformational change in antithrombin to give an increased heparin binding affinity and activate the inhibition of thrombin and factor Xa. The areas of antithrombin involved in binding heparin and stabilizing the interaction in the high-affinity form have been partially resolved through the study of both recombinant and natural variants. The role of a section of the N-terminal segment of antithrombin, residues 22-46 (segment 22-46), in heparin binding was investigated using rapid kinetic analysis of the protein cleaved at residues 29-30 by limited proteolysis with thermolysin. The cleaved antithrombin had 5.5-fold lowered affinity for heparin pentasaccharide and 1.8-fold for full-length, high-affinity heparin. It was shown that, although the initial binding of heparin is slightly enhanced by the cleavage, it dissociates much faster from the cleaved form, giving rise to the overall decrease in heparin affinity. This implies that the segment constituting residues 22-46 in the N terminus of antithrombin hinders access to the binding site for heparin, hence the increased initial binding for the cleaved form, whereas, when heparin is bound, segment 22-46 is involved in the stabilization of the binding interaction, as indicated by the increased dissociation constant. When the heparin pentasaccharide is bound to antithrombin prior to incubation with thermolysin, it protects the N-terminal cleavage site, implying that segment 22-46 moves to interact with heparin in the conformational change and thus stabilizes the complex.

Antithrombin III↗

PubMed1993

Mechanisms for the anticoagulant effects of synthetic antithrombins.

The important roles of thrombin in the development and propagation of thrombosis are well recognized. In addition to being the enzyme for clotting fibrinogen (the major protein component of blood clots), thrombin accelerates its own generation by activating factor V, factor VIII, factor XI and platelets. It accelerates the stabilization of clots by activating factor XIII to factor XIIIa, the enzyme which crosslinks fibrin. There are probably two major pathways for regulating the availability of thrombin in vivo: inactivation of thrombin (by antithrombin III/vessel wall heparan sulfate and perhaps by other endogenous antithrombins) and the inactivation of factor Va and factor VIIIa by activated protein C. Factor Va and factor VIIIa accelerate the production of thrombin. However, when thrombin becomes bound to fibrin (in clots or possibly on cell surfaces), the ability of antithrombin III/heparin to inactivate thrombin is then reduced significantly. Impairment by fibrin of thrombin inhibition by antithrombin III may account in part for the inability of unfractionated heparin to prevent post-operative deep vein thrombosis in up to 20% of patients who undergo major elective orthopaedic surgery, and may also explain the need for oral anticoagulants after unfractionated and low molecular weight heparins are used to initiate the treatment of established deep vein thrombi. The ineffectiveness of the antithrombin III/heparin pathway for inhibiting thrombin under some circumstances has been a contributory factor for the development, evaluation and identification of other inhibitors of thrombin which are more able than antithrombin III/heparin to inactivate thrombin when the enzyme is bound to fibrin. The focus of this review is to detail how these synthetic agents, by directly or indirectly inactivating thrombin, can also effectively inhibit prothrombin activation in vitro.

Amino Acid Sequence↗

PubMed2000

Evolution of serpin specificity: cooperative interactions in the reactive-site loop sequence of antithrombin specifically restrict the inhibition of activated protein C.

Protease cascades and their inhibitors are a common feature of many biological regulatory systems, and the various components of such cascades have been subjected to a long and concerted evolution. We present here evidence that in the coagulation cascade, the sequence of the protease-binding reactive-site loop of antithrombin has evolved such that the majority of its residues has been acquired not for the efficient inhibition of its target proteases, thrombin and factor Xa, but to avoid the inhibition of activated protein C (APC). We substituted residues of the reactive-site loop of antithrombin into alpha(1)-antitrypsin and tested the chimeras against thrombin, factor Xa, and APC. With respect to factor Xa and thrombin, the difference in association rate between the fastest and the slowest inhibitors was 5.5- and 88-fold, respectively. However, with respect to APC the difference was 12,500-fold. While most of the variation in the inhibition rates of thrombin could be accounted for by P2 Gly-to-Pro substitutions, for APC almost every residue had an effect on inhibition. In 22 of 25 direct comparisons of antitrypsin residues with antithrombin residues, either singly or in blocs, the antithrombin residues caused a decrease in the rate of inhibition of APC. The antithrombin residue Asn393, at position P'3, emerged as particularly important for avoiding the inhibition of APC, however, its 190-fold effect was seen only when in conjunction with antithrombin P7 to P'2 residues. Cooperative effects among residues of the reactive-site loop thus emerged as critical for restricting the activity of this sequence against APC.

Amino Acid Substitution↗

PubMed1978

Acquired antithrombin III deficiency and thrombosis in the nephrotic syndrome.

Antithrombin III levels were studied in relation to the occurrence of thromboembolism in 48 patients with various degrees of proteinuria. Nine of these patients had clinical signs of thrombosis, including four with renal vein thrombosis. In eight of these nine patients, antithrombin III concentrations were below 70 per cent. There was a significant negative correlation between the antithrombin III concentration and the urinary protein excreation (P less than 0.001). Antithrombin III was found in the urine of 32 of 42 patients. There was a significant correlation between the renal clearance and the degree of antithrombin III serum deficiency (P less that 0.001). The clearance and serum level of albumin closely paralleled these changes. We conclude that thrombosis in patients with severe proteinuria is associated with a deficiency of antithrombin III due to urinary excretion of this protein.

Adolescent↗

PubMed1983

Calcium inhibits the heparin-catalyzed antithrombin III/thrombin reaction by decreasing the apparent binding affinity of heparin for thrombin.

The present study has shown that calcium inhibits the heparin-catalyzed antithrombin III/thrombin reaction. The initial rate of thrombin (4.0 nM) inhibition by antithrombin III (200 nM) in the presence of heparin (2.5 ng/ml) decreased from 3.6 nM/min (in the absence of calcium) to 0.12 nM/min in the presence of 10 mM calcium. In the absence of heparin, the initial rate of thrombin inhibition by antithrombin III was not affected by calcium. The heparin-catalyzed antithrombin III/thrombin reaction is described by the general rate equation for a random-order, bireactant, enzyme-catalyzed reaction (M. J. Griffith (1982) J. Biol. Chem. 257, 13899-13902). As such, the reaction is saturable with respect to both thrombin and antithrombin III. The apparent kinetic parameters for the heparin-catalyzed antithrombin III/thrombin reaction were determined in the presence and absence of calcium. The apparent heparin/antithrombin III dissociation constant values were not measurably different in the presence of 0, 1.0, and 3.0 mM calcium. The apparent heparin/thrombin dissociation constant value increased from 7.0 nM, in the absence of calcium, to 10 and 30 nM in the presence of 1.0 and 3.0 mM calcium, respectively. The maximum reaction velocity, at saturation with respect to both proteins, was not affected by calcium. It is concluded that calcium binds to functional groups within the heparin molecule which are required for thrombin binding.

Animals↗

PubMed1988

Plasma antithrombin III levels in pre-eclampsia and chronic hypertension.

Plasma levels of antithrombin III were tested during pregnancy in a control group of normal patients and in a study group that included patients with moderate and severe pre-eclampsia and chronic hypertension. The control group showed mean antithrombin III activity of 97.9 +/- 20.9%, the severe pre-eclamptic patients 22.33 +/- 18.22%, the moderate pre-eclamptic patients 56.0 +/- 7.56%, and the chronic hypertensive patients 77.5 +/- 6.69%. The difference between normal pregnancy and moderate pre-eclampsia was significant at P less than 0.002, normal pregnancy and severe pre-eclampsia P less than 0.002, moderate and severe pre-eclampsia P less than 0.002, chronic hypertension and normal pregnancy P less than 0.1, and chronic hypertension and severe pre-eclampsia P less than 0.002. All the severe pre-eclamptic patients and 2 out of 6 of the moderate pre-eclamptic women were below 55.7% (mean - 2S.D.) of normal antithrombin III activity. Patients with heavy proteinuria had depressed antithrombin III activity. However, chronic hypertensive pregnancies, although rather a small group, had almost normal values of plasma antithrombin III activity. The plasma antithrombin III value may thus help to distinguish between chronic hypertension and severe pre-eclamptic disease.

Adult↗

PubMed1994

Modulation of coagulation and fibrinolysis in hepatic resection: a randomized prospective control study using antithrombin III concentrates.

A randomized prospective control trial for determining the efficacy of antithrombin III concentrates in hepatic resection was performed using 24 patients with hepatocellular carcinoma. Thirteen patients were given antithrombin III concentrates (1,500 IU) immediately before operation, during hepatectomy and immediately after operation. Coagulant and fibrinolytic profiles were determined by molecular markers such as thrombin-antithrombin III complex and plasmin-alpha 2plasmin inhibitor complex. During hepatic resection, both hypercoagulability and mainly primary hyperfibrinolysis occurred. Regarding the effectiveness of antithrombin III concentrates, in the antithrombin III treatment group, only a significant lower incidence of positive soluble fibrin monomer complex at postoperative days 1 and 5 was found among all the parameters studied. Therefore, no definite evidence of clinical usefulness of the perioperative administration of antithrombin III concentrates in hepatic resection was proved.

Aged↗

PubMed1995

Some functional properties of teleost antithrombin.

Antithrombin from bony fish (Teleostei), represented by an ancient salmonid, Atlantic salmon (Salmo salar L.), and a more evolved species from the same family, rainbow trout (Oncorhynchus mykiss Walbaum), functions in vitro as does its human counterpart: it inactivates thrombin almost instantaneously in the presence of heparin and only slowly when heparin is absent. The inhibitory activity of salmonid antithrombin towards the homologous thrombin did not differ noticeably from its inactivating capacity in heterologous (teleost) systems, and enzyme-inhibitor reactions between reagents from fish and man proceeded just as efficiently. In all enzyme-inhibitor reactions with salmonid thrombin the inactivation by salmonid antithrombin or diluted fish plasma was maximal at pH 7.8-8.4. The inactivation was clearly dependent on heparin in all systems and maximal at concentrations between 1.5 and 6 U/ml. What particularly distinguishes the salmonid thrombin-antithrombin interaction from the human one is that the former has to function over a wide range of temperatures. And the thrombin inactivating capacity of purified antithrombin and diluted plasma in the presence of heparin was indeed present at temperatures down to 3 degrees C, a capacity that human antithrombin also has retained. Even more interesting was that the teleost enzyme-inhibitor reaction was nearly independent of temperature under the conditions studied.

Animals↗

PubMed1987

Expression of human antithrombin III in Saccharomyces cerevisiae and Schizosaccharomyces pombe.

Recombinant plasmids were constructed that direct the synthesis of human antithrombin III in baker's yeast, Saccharomyces cerevisiae, and the fission yeast, Schizosaccharomyces pombe. The signal sequence of antithrombin III was recognized by both yeast species, and antithrombin III was secreted into the medium. When the signal sequence was replaced by a sequence of ten arbitrary amino acids, the product expressed from such a construct stayed inside the cell. Antithrombin III was glycosylated by the baker's and fission yeast and was immunologically identical to antithrombin III isolated from human plasma. Antithrombin III isolated from the culture media of recombinant yeasts was biologically active, as could be shown by progressive inhibitor activity and heparin cofactor activity.

Antithrombin III↗

PubMed1977

Effect of heparin modification on its activity in enhancing the inhibition of thrombin by antithrombin III.

Studies were conducted to determine the effect of modifying specific functional groups of heparin on its antithrombin III-enhancing activity. The derivatives employed were heparin methyl ester, heparinylglycine and N-desulfated heparin. The carboxyl-modified derivatives increase the rate of inhibition of thrombin by antithrombin III, although not to the same extent as heparin. N-Desulfated heparin is devoid of any activity. Heparin methyl ester is more potent than heparinylglycine in activating antithrombin III, as exhibited by its immediate effect on the thrombin-fibrinogen reaction. However, heparinylglycine is the more effective of the two, in increasing the rate of thrombin deactivation by antithrombin III. The results indicate that although free carboxyl groups of heparin are not crucial for its binding to antithrombin III, they are important for the combination of the latter with thromobin. In contrast, N-sulfates are critical for the interaction of heparin with antithrombin III.

Animals↗

PubMed1986

A comparison of the strength of binding of antithrombin III, protamine and poly(L-lysine) to heparin samples of different anticoagulant activities.

The limiting concentrations, i.e., those concentrations of sodium chloride required to completely disrupt the complexes of heparin with antithrombin III, protamine and poly(L-lysine), were determined using fluorescence techniques, in order to compare the binding strengths of these complexes. From the limiting salt concentration values, poly(L-lysine) always exhibited stronger binding to heparin of a particular anticoagulant potency (degree of sulphation) than did protamine. The binding strengths of both complexes decreased as the degree of sulphation of the heparin participating in the complex was reduced. In contrast, the limiting salt concentration values for complexes formed between antithrombin III and heparin did not change with either the degree of sulphation or the biological potency of the heparin samples. A low-potency heparin simply contained a smaller number of molecules which possessed the intact antithrombin III binding site (thus being fully 'anticoagulant active') than a high-potency sample. Low-affinity heparin did not contain these binding sites and thus showed a low affinity for antithrombin III. High-potency heparin, being highly sulphated, possessed a higher affinity for protamine and poly(L-lysine) than for antithrombin III. However, after partial N-desulphation of heparin, the subsequent heparin-protamine complex was more weakly bound than a significant proportion of the corresponding heparin-antithrombin III complexes. These in vitro findings may have particular relevance in relation to the clinical condition termed 'heparin rebound'.

Anticoagulants↗

PubMed1989

Phosphate promotes glycation of antithrombin III which interferes with heparin binding.

Nonenzymatic glycation of antithrombin III has been reported to cause the reduction of heparin-catalyzed thrombin-inhibiting activity in diabetes. The effect of in vitro nonenzymatic glycation of pure antithrombin III on heparin binding and heparin-potentiated activity under a variety of buffers and pH values was studied to further clarify the physiological significance of this reaction. The extent of glycation, measured by the fructosamine assay and [14C]glucose binding, was enhanced by the presence of phosphate ion (pH 7.45, 8.5 and 9.5) and increased linearly with increasing phosphate ion concentration from 0.01 to 0.2 M phosphate. Conversely, the heparin-catalyzed antithrombin activity decreased from 93.1% of controls for 0.01 M phosphate to 73.5% for 0.2 M phosphate as the extent of glycation increased. The increase in intrinsic fluorescence induced by binding of heparin to antithrombin III was also moderated by glycation of antithrombin III in a dose-dependent manner with a negative correlation coefficient of -0.94. Direct measurement of the heparin binding by affinity chromatography showed a decrease in the heparin-binding fraction which correlated with the degree of glycation and the decrease in heparin-catalyzed activity. These studies suggest that nonenzymatic glycation may be responsible for the reduction in antithrombin III activity observed in some diabetics.

Antithrombin III↗