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PubMed1985

Antithrombin Milano: a new variant with monomeric and dimeric inactive antithrombin III.

A qualitative defect of antithrombin III (AT III) has been demonstrated over three generations in eight members of an Italian family by the discrepancy between a normal amount of antigen and decreased antithrombin and anti-Xa activity in the presence or in the absence of heparin. By two-dimensional immunoelectrophoresis in the absence of heparin, two peaks of AT III were present in all patients' plasma. AT III was purified from normal and propositus plasma by sulfate dextran precipitation followed by heparin affinity chromatography. The elution profile of the patient's AT III was abnormal and allowed the separation of two populations of AT III, normal and abnormal. The first fraction (normal AT III) contained AT III activity, migrated as a single peak by two-dimensional immunoelectrophoresis and by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE), demonstrated a single band with a molecular weight (mol wt) identical to that of normal AT III (60,000). Conversely, the last fraction, devoid of AT III activity, migrated as a single abnormal peak by two-dimensional immunoelectrophoresis in the absence of heparin. By SDS-PAGE, two bands were observed: one with a mol wt of 60,000 and a second one with a mol wt of 120,000. Western blots clearly demonstrated cross-reactivity of the 120,000 and 60,000 mol wt bands with monospecific antisera to human AT III. Reduction of the 120,000 mol wt band converted it to a single 60,000 mol wt band, suggesting the presence of an abnormal dimeric form of AT III. The name AT III Milano is proposed for this new variant.

Adult↗
PubMed1997

Acquired antithrombin deficiency following severe traumatic injury: rationale for study of antithrombin supplementation.

Hemorrhage, head injury, and multiple organ dysfunction are the most frequent causes of mortality in patients who experience severe injury. Acceleration of the coagulation cascade is known to result in hemorrhage secondary to disseminated intravascular coagulation (DIC) and end-organ dysfunction, as manifest by pulmonary and renal failure. Few studies have been conducted to evaluate the effects of injury on the endogenous anticoagulants that inhibit excessive coagulation activation. We evaluated a group of patients following severe injury and found that procoagulant markers (prothrombin fragment 1.2, thrombin antithrombin complexes, and D dimers) were significantly elevated for the population as a whole. Levels of circulating endogenous anticoagulants [antithrombin (AT) and protein C] were relatively unchanged for the total population. However, patients with adverse outcomes [DIC and adult respiratory distress syndrome (ARDS)] had significant reductions in AT and protein C activities. Decreased levels of AT and protein C 8 hours after admission served as independent predictors of both DIC and ARDS. Prospective, randomized studies should be conducted to evaluate the effect of supplementation of these factors after severe injury has occurred.

Adolescent↗
PubMed1994

Genetic linkage studies in antithrombin-deficient kindreds using a highly polymorphic trinucleotide short tandem repeat (STR) within the human antithrombin gene.

PCR amplification and analysis of short tandem repeats (STR) have provided a useful tool for genetic linkage studies and for the diagnosis of genetic disorders. We have recently identified a novel trinucleotide STR, (ATT).(TAA), in the fifth intron of the human antithrombin gene (AT3) located on chromosome 1q23. PCR amplification, cloning, and sequence analysis revealed this AT3-STR to be highly polymorphic with repeat units ranging in size from (ATT)5 to (ATT)18. Ten distinct alleles were found in 81 unrelated Caucasian individuals (162 alleles) with an observed heterozygosity of 81%. Genetic linkage studies using the AT3-STR in two previously described antithrombin (AT)-deficient kindreds, AT-Hamilton (Ala 382 Thr) and AT-Amiens (Arg 47 Cys), demonstrate, in a given kindred, that a specific AT3-STR polymorphism is strongly associated with a particular AT mutation. Thus, this highly polymorphic AT3-STR should be very useful in performing linkage studies in AT-deficient kindreds as well as in investigating other chromosome 1-related genetic disorders.

Antithrombins↗
PubMed1991

Release of a small two-chain form of antithrombin III from a conformationally changed antithrombin III-thrombin complex.

Reaction of antithrombin III (AT) with thrombin results in the formation of stable antithrombin III-thrombin (AT-T) complex with a Mr of 92.5-kDa, accompanied by the appearance of a proteolytically modified form of the inhibitor (ATM). Under these conditions AT-T is also transformed to a smaller complex (AT-TS). This smaller complex (81-kDa), a product of a conformational change at the AT moiety of the AT-T complex, is further transformed to a very small complex (AT-TVS) with a Mr of 71-kDa. Along with this process, AT-TS slowly dissociates to a free enzyme and a small, presumably two-chain product of AT (ATMS) with a Mr of 49-kDa. The newly described component, ATMS, naturally occurs in plasma and serum and accumulates significantly in plasma of patients suffering from cardiovascular disease.

Amino Acid Sequence↗
PubMed1988

Heparin-like tubings. III. Kinetics and mechanism of thrombin, antithrombin III and thrombin-antithrombin complex adsorption under controlled-flow conditions.

In previous papers, we described treated tubular materials which exhibit an heparin-like antithrombic activity under dynamic conditions. In order to ascertain the heparin-like mechanism of this activity, we have studied the interactions of thrombin, antithrombin III and thrombin-antithrombin III complex with the inner face of these treated tubings under controlled-flow conditions. Moreover, the kinetics of the adsorption of thrombin were studied at different flow rates to establish the rate-determining step.

Adsorption↗
PubMed1995

Kinetic characterization of the proteinase binding defect in a reactive site variant of the serpin, antithrombin. Role of the P1' residue in transition-state stabilization of antithrombin-proteinase complex formation.

To elucidate the role of the P1' residue of the serpin, antithrombin (AT), in proteinase inhibition, the source of the functional defect in a natural Ser-394-->Leu variant, AT-Denver, was investigated. AT-Denver inhibited thrombin, Factor IXa, plasmin, and Factor Xa with second order rate constants that were 430-, 120-, 40-, and 7-fold slower, respectively, than those of native AT, consistent with an altered specificity of the variant inhibitor for its target proteinases. AT-Denver inhibited thrombin and Factor Xa with nearly equimolar stoichiometries and formed SDS-stable complexes with these proteinases, indicating that the diminished inhibitor activity was not due to an enhanced turnover of the inhibitor as a substrate. Binding and kinetic studies showed that heparin binding to AT-Denver as well as heparin accelerations of AT-Denver-proteinase reactions were normal, consistent with the P1' mutation not affecting the heparin activation mechanism. Resolution of the two-step reaction of AT-Denver with thrombin revealed that the majority of the defective function was localized in the second reaction step and resulted from a 190-fold decreased rate constant for conversion of a noncovalent proteinase-inhibitor encounter complex to a stable, covalent complex. Little or no effects of the mutation on the binding constant for encounter complex formation or on the rate constant for stable complex dissociation were evident. These results support a role for the P1' residue of antithrombin in transition-state stabilization of a substrate-like attack of the proteinase on the inhibitor-reactive bond following the formation of a proteinase-inhibitor encounter complex but prior to the conformational change leading to the trapping of proteinase in a stable, covalent complex. Such a role indicates that the P1' residue does not contribute to thermodynamic stabilization of AT-proteinase complexes and instead favors a kinetic stabilization of these complexes by a suicide substrate reaction mechanism.

Antithrombins↗
PubMed2003

Mechanisms responsible for catalysis of the inhibition of factor Xa or thrombin by antithrombin using a covalent antithrombin-heparin complex.

Covalent antithrombin-heparin (ATH) complexes, formed spontaneously between antithrombin (AT) and unfractionated standard heparin (H), have a potent ability to catalyze the inhibition of factor Xa (or thrombin) by added AT. Although approximately 30% of ATH molecules contain two AT-binding sites on their heparin chains, the secondary site does not solely account for the increased activity of ATH. We studied the possibility that all pentasaccharide AT-binding sequences in ATH may catalyze factor Xa inhibition. Chromatography of ATH on Sepharose-AT resulted in >80% binding of the load. Similar chromatographies of non-covalent AT + H mixtures lead to a lack of binding for AT and fractionation of H into unbound (separate from AT) or bound material. Gradient elution of ATH from Sepharose-AT gave 2 peaks, a peak containing higher affinity material that had greater anti-factor Xa catalytic activity (708 units/mg heparin) compared with the peak containing lower affinity material (112 units/mg). Sepharose-AT chromatography of the ATH component with short heparin chains (<or=12 monosaccharides) resulted in active unbound (40%) and bound fractions (190 and 560 units/mg, respectively). Factor Xa-ATH or thrombin-ATH inhibitor complexes gave chromatograms on Sepharose-AT with more unbound material compared with that of free ATH. Also, ATH did not bind to Sepharose-heparin, and the intrinsic fluorescence due to activation of AT in ATH by its heparin chain was reversed at higher [NaCl] than that required to dissociate non-covalent AT.H complexes. Thus, exogenous AT can compete with the AT moiety of ATH for binding to the covalently linked heparin chain, leading to catalytic inhibition of factor Xa or thrombin. These data may suggest that access to pentasaccharide units in non-covalent AT.H complexes by free AT may be facile.

Antithrombin III↗
PubMed1976

Antithrombin and heparin antithrombin patterns in pre-thrombosis and thrombosis.

An antithrombin assay (AA) and an antithrombin assay modified by the addition of heparin (H-AA) were performed using sera from healthy subjects, patients predisposed to thrombosis, and patients with thromboembolic disease. Characteristic AA, and H-AA patterns were found in each group. Normal controls and four of 39 "pill" patients (10%) had normal AA and H-AA findings (Pattern A). Normal AA, with "decreasing" H-AA (Pattern B) was found in sera of 31 of 39 "pill" patients (80%) and three patients who had non-embolic arterial occlusive disease. Low AA and "decreasing" H-AA (Pattern C) occurred in sera of four "pill"-takers (10%) and one patient who had an arterial embolus. Low AA and low H-AA (Pattern D) developed in sera of eight patients with thrombophlebitis and seven patients with pulmonary embolus. It is concluded that the AA and H-AA assays help to identify thrombosis-prone (Pattern C) and thrombotic (Pattern D) individuals for whom antiplatelet (aspirin; dipyridamole) or anticoagulant therapy might be beneficial.

Antithrombins↗
PubMed1996

Effect of critical injury on plasma antithrombin activity: low antithrombin levels are associated with thromboembolic complications.

OBJECTIVE: Determine whether severe injury results in decreased plasma antithrombin (AT) activity and whether this decreased AT activity is associated with thromboembolic complications. DESIGN: Prospective observational. SUBJECTS: A total of 157 critically injured trauma patients. METHODS: Each patient underwent laboratory analysis on arrival to the emergency room at hours 8, 16, 24, and 48, and days 3, 4, 5, and 6. Laboratory analyses included AT, tissue factor pathway inhibitor, protein C, prothrombin fragment 1.2, thrombin-antithrombin complex, and D-dimer. Patients were followed for thromboembolic complications including: deep venous thrombosis (DVT), pulmonary embolus, disseminated intravascular coagulation (DIC) and adult respiratory distress syndrome (ARDS). RESULTS: Mean Injury Severity Score was 23 (+/-11). AT activity fell below normal in 95 (61%) patients; AT activity rose to greater than normal in 51 (32%) patients. Nine (6%) patients developed DVT, two (1%) pulmonary embolus, 13 (8%) DIC and 26 (17%) ARDS. Using logistic regression analysis, low AT levels were a significant predictor of DVT, DIC, and ARDS (p < 0.05). Supranormal At levels were associated with closed head injury (p < 0.05). D-dimer levels were inversely correlated with AT (p < 0.05). CONCLUSIONS: AT activity was depressed in critically injured patients. Patients with head injury developed supranormal AT activity. The risk factors for AT deficiency mimicked those for thromboembolism. Patients with decreased AT activity were at increased risk for thromboembolic complications. Given heparin's dependence on AT, these data call into question the use of unmonitored heparin thromboembolism prophylaxis.

Adult↗
PubMed2007

Serum albumin levels anticipate antithrombin III activities before and after antithrombin III agent in critical patients with disseminated intravascular coagulation.

Elevated thrombin-antithrombin complex (TAT) or decreased serum albumin levels suggest heightened vascular permeability in disseminated intravascular coagulation (DIC). In such a situation, plasma antithrombin III (AT-III) may decrease because of the leakage. We thus examined whether AT-III activity before and after administration of an AT-III agent changed depending on plasma TAT and/or serum albumin levels in 20 consecutive patients with DIC. We also analyzed the pharmacokinetics for AT-III using a two-compartment model. Serum albumin levels before AT-III administration correlated with preadministered and postadministered AT-III activity, but TAT levels did not. Regardless of TAT levels, AT-III trough activity on the third day increased significantly. In patients with albumin levels of 2.5 g/dL or less, AT-III trough levels on the third day were significantly lower than those with higher levels of albumin. The half-life of the distribution phase for AT-III agent in the patients was shortened to less than one third the value reported in congenital AT-III deficiency, suggesting increased vascular permeability in the acute state patients here. The distribution volume of the agent increased remarkably compared with the previous control. We report here for the first time that in critical patients with DIC, plasma AT-III levels before and after AT-III administration could be predicted by preadministered serum albumin levels, but not by TAT. These findings could be explained by the pharmacokinetic profile, increased vascular permeability and distribution volume, observed in critical patients.

Adult↗
PubMed1994

Antithrombin and thrombolytic effects of a new antithrombin agent: angioscopic and angiographic comparison with heparin or batroxobin.

The antithrombotic effect of three different types of antithrombotic agents (antithrombin:argatroban, heparin, defibrinogenating agent:batroxobin) were evaluated in canine coronary and iliac arteries. An occlusive thrombus was produced by balloon injury. One of the three agents was infused intravenously at 1 hour after thrombus formation (heparin 250 U/kg, argatroban 0.5 mg/kg, batroxobin 0.5 U/kg) and the effect of thrombus size reduction was evaluated. On the contralateral side of the iliac artery, the preventive effect of these agents on thrombus formation was evaluated after balloon injury. In the iliac artery, angioscopic percent area obstruction by the thrombus before and 60 minutes after treatment reduced from 69% to 32% in the argatroban group, and from 64% to 51% in the batroxobin group (P < 0.0001 and P < 0.05, respectively). No significant change was observed in the heparin group. Angiography demonstrated the same trend. The percent area stenosis with thrombus at 60 minutes following balloon injury was 0.75% in the argatroban group, 18.9% in the heparin group (P < 0.05 vs argatroban), and 12.9% in the batroxobin group. Thrombus size at the treated site was smaller than that at the control site in all three groups (P < 0.05 vs control). In the coronary artery, angioscopic percent area obstruction by the thrombus before and 60 minutes after treatment reduced from 84% to 53% in the argatroban group, and from 86% to 68% in the batroxobin group (P < 0.0001 and P < 0.05, respectively). No significant change was observed in the heparin group. Angiography also demonstrated the same trend. The activated partial thromboplastin time (APTT) was prolonged to 189% of the control value with argatroban and to 1253% of the value with heparin (P < 0.0001). Fibrinogen was markedly reduced with batroxobin. These results showed that both the antithrombin agent and the defibrinogenating agent have a preventive effect on thrombus formation and the effect on thrombus size reduction, without marked prolongation of the APTT.

Angiography↗
PubMed1997

Thrombin-antithrombin III complexes and antithrombin III in amniotic fluid.

We measured thrombin-antithrombin III (TAT) complexes and antithrombin III (AT III) in amniotic fluid and blood plasma of 39 parturient women. TAT was measured by ELISA. Partigen plates were used for measuring the antigen of AT III, and activity was determined using chromogenic substrate. While AT III activity and AT III antigen were below 20% of plasma values, TAT concentration was 2-4 times higher in amniotic fluid than in blood plasma (over twice at the onset of labour, i.e. 54.2 +/- 26.4 and 20.7 +/- 10.7 ng/ml, and approximately 4 times after childbirth, i.e. 108.9 +/- 49.2 ng/ml in amniotic fluid and 27.8 +/- 13.2 ng/ml in blood plasma, respectively). We have concluded that thrombin generation and TAT formation in amniotic fluid are are of significantly higher intensity than in plasma, and they increase during labour.

Adult↗
PubMed1983

Structure-activity relationships of heparin. Independence of heparin charge density and antithrombin-binding domains in thrombin inhibition by antithrombin and heparin cofactor II.

To better understand how heparin structure affects its activity the relationships between the functional domains for inhibitor binding and charge density were investigated to determine how these domains affect heparin-mediated thrombin inhibition by two different heparin-dependent protease inhibitors, antithrombin (AT) and heparin cofactor II (HC II). A series of heparins, fractionated systematically by charge density, was further fractionated on antithrombin agarose to isolate more homogeneous subfractions that were either inactive or highly active with respect to thrombin inhibition by AT. With AT, the activities of the AT-active subfractions increased sharply with heparin charge density, while those with little or no affinity for AT were virtually inactive. In contrast, with HC II inhibitor, the activities of the heparins depended only upon their charge densities and were independent of AT affinity. At any given charge density, the heparin before fractionation by AT affinity and the fractions that were highly active and inactive with AT were all equally active with HC II. The two inhibitors also differed in their reactivity with heparan sulfate and dermatan sulfate. A charge-density effect with the subfractions having similar high affinity for AT demonstrates that charge density represents a heparin functional domain that is independent of the AT-binding domain. The behavior of the AT-inactive heparins, being fully active with HC II, demonstrates the functional domain necessary for AT binding is not needed to produce HC II activity.

Animals↗
PubMed1991

Importance of measuring plasma thrombin-antithrombin III complex levels when using antithrombin III concentrate therapy in fulminant hepatic failure.

We investigated changes in the concentrations of thrombin-antithrombin III complex (TAT) and plasmin-alpha 2 plasmin inhibitor complex (PIC) after the intravenous administration of 4000 units of antithrombin III (AT III) concentrate to patients with fulminant hepatic failure (FHF), subacute hepatitis (SH), or liver cirrhosis (LC). FHF patients showed shortening of the initial half-life of exogenous AT III. In addition, a marked rise in plasma TAT was noted 3 to 6 h after the intravenous administration of AT III, even in patients who had a normal plasma TAT level before AT III therapy. In contrast, SH and LC patients showed no marked changes of plasma TAT levels after AT III administration. No marked changes were observed in the PIC concentration in any of the patients. These findings suggest that thrombin formation is increased in FHF and that simple measurement of the plasma TAT concentration is not an adequate method for assessing thrombin formation in FHF patients who have suspected disseminated intravascular coagulation associated with an apparent decrease in AT III synthesis. Instead, it seems necessary to measure the plasma TAT concentration in FHF patients after replacement therapy with AT III concentrate has been performed, to evaluate their hypercoagulability more accurately.

Adult↗
PubMed1990

Comparative studies of heparin cofactor activity toward antithrombin III and heparin cofactor II, and antithrombin III affinity between low molecular weight heparin and unfractionated heparin.

The accelerating effects of an UF heparin (Novo) and two LMW heparins (Fragmin and PK 10169) on AT III and HC II were investigated in a purified system. The effects of these heparins on APTTs were examined using human plasma. Fractionation of these heparins by affinity column chromatography yielded the following results: UF heparin was separated into two distinct fractions, LA and HA for AT III. Both LMW heparins were separated into three fractions: NA, LA, and HA for AT III. The accelerating effects of these fractions on both antithrombin and anti-Factor Xa activity of AT III were dependent on the strength of their affinity to AT III. The accelerating effects of these fractions on the antithrombin activity of HC II was independent of the strength of their affinity for AT III. LA had a much stronger anticoagulant activity of HC II toward thrombin than did HA. It is concluded that LA for AT III is necessary to show HC II activity.

Antithrombin III↗
PubMed1991

Antithrombin-III-Hamilton, Ala 382 to Thr: an antithrombin-III variant that acts as a substrate but not an inhibitor of alpha-thrombin and factor Xa.

Antithrombin-III-Hamilton has been shown to be a structural variant of antithrombin-III (AT-III) with normal heparin affinity but impaired protease inhibitory activity. The molecular defect of AT-III-Hamilton is the substitution of Thr for Ala at amino acid residue 382. The plasma of affected individuals contains approximately equal quantities of normal AT-III and AT-III-Hamilton. When AT-III was isolated from the plasma of the propositus by heparin-Sepharose chromatography, it had identical mobility on sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) to normal plasma-derived AT-III, under both reducing and nonreducing conditions. However, the AT-III-Hamilton species, separated from the propositus' normal AT-III by a combination of heparin-Sepharose and thrombin-Sepharose chromatography, had increased mobility on reductive SDS-PAGE compared with AT-III from the propositus isolated by heparin-Sepharose chromatography alone. Under nonreducing conditions this AT-III-Hamilton species had decreased mobility compared with AT-III from the propositus (or normal AT-III) isolated only by heparin-Sepharose chromatography. When incubated with either human alpha-thrombin or human factor Xa, this AT-III-Hamilton species was unreactive. Approximately 50% of the AT-III from the propositus isolated by heparin-Sepharose chromatography, when incubated with either human alpha-thrombin or factor Xa, did not form complex but was cleaved, presumably at the reactive center Arg393-Ser394. To further substantiate the biological behavior of this variant, AT-III-Hamilton polypeptides were synthesized in a cell-free system. This recombinantly produced AT-III-Hamilton, when incubated with either human alpha-thrombin or factor Xa, was cleaved by both these proteases, but did not show any complex formation. The results indicate that AT-III-Hamilton does not form a stable covalent inhibitory complex with these serine proteases but can be cleaved at the reactive center. Thus, the inhibition of serine proteases by their natural inhibitors (the serpins) involves at least two separate, but interrelated events; hydrolysis at the reactive center followed by complex formation. AT-III-Hamilton is capable of only the first of these events.

Alleles↗
PubMed1988

Antithrombin III Avranches, a new variant with defective serine-protease inhibition--comparison with antithrombin III Charleville.

A decreased plasma antithrombin activity in presence or in absence of heparin was discovered in a 47-year-old patient presenting with recurrent venous thromboembolism. The immunoreactive material (AT III-IR) was normal. The same biological abnormalities were found in two relatives of the patient, leading to the diagnosis of hereditary qualitative AT III deficiency. The propositus' AT III was coeluted with normal AT III from an heparin-sepharose column. An additional step of ion-exchange chromatography on a Mono Q column using a FPLC system (Pharmacia, St-Quentin en Yvelines, France) allowed the purification of a protein which was homogenous in SDS-10% polyacrylamide electrophoresis gel (PAGE). AT III purified from propositus' plasma, normal plasma and the plasma of the patient known to have an AT III variant with defective protease binding (AT III Charleville) were compared. The specific activities measured as heparin cofactor antithrombin or factor Xa inhibition in absence of heparin were decreased to half the normal value. Kinetic studies confirmed a decreased rate of thrombin inhibition for both abnormal AT III preparations. SDS-PAGE experiments performed in purified system and immunoblots obtained from plasma showed that the two variants have different behaviour: in the case of AT III Charleville thrombin induced an apparent 5 k delta increase in molecular mass, probably due to a conformational change. AT III Avranches did not form stoechiometric complexes with thrombin, but was unmodified by the protease.

Antithrombin III↗