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PubMed2001

Regulation of glycosaminoglycan function by osmotic potentials. Measurement of water transfer during antithrombin activation by heparin.

The sulfated glycosaminoglycan heparin is an important anticoagulant, widely used to treat and to prevent arterial thrombosis. Heparin triggers conformational changes in, and the functional activation of, the serine proteinase inhibitor antithrombin. We investigated water-transfer reactions during the activation process to explore the possibility that functional interaction between antithrombin and sulfated glycosaminoglycans can be regulated by osmotic potentials. Volume of water transferred upon heparin binding was measured from differences in free energy change, Delta(Delta G), with osmotic stress, pi. Osmotic stress was induced with chemically inert probes that are geometrically excluded from the water-permeable spaces of antithrombin and from intermolecular spaces formed during the association reaction. The free energy change, Delta G, for the antithrombin/heparin interaction was calculated from the dissociation constant, determined by functional titrations of heparin with antithrombin at fixed concentrations of the coagulation protease factor Xa. The effect of osmotic stress was independent of the chemical nature of osmotic probes but correlated with their radius up to radius >17 A. In mixtures including a large and a small probe, the effect of the large probe was not modified by the small probe added at a large molar excess. With an osmotic probe of 4-A radius, the Delta(Delta G)/pi slope corresponds to a transfer of 119 +/- 25 water molecules to bulk solution on formation of the complex. Analytical characterization of water-permeable volumes in x-ray-derived bound and free antithrombin structures revealed complex surfaces with smaller hydration volumes in the bound relative to the free conformation. The residue distribution in, and atomic composition of, the pockets containing atoms from residues implicated in heparin binding were distinct in the bound versus free conformer. The results demonstrate that the heparin/antithrombin interaction is linked to net water transfer and, therefore, can be regulated in biological gels by osmotic potentials.

Antithrombins↗

PubMed2003

Localization of an antithrombin exosite that promotes rapid inhibition of factors Xa and IXa dependent on heparin activation of the serpin.

We have previously shown that exosites in antithrombin outside the P6-P3' reactive loop region become available upon heparin activation to promote rapid inhibition of the target proteases, factor Xa and factor IXa. To identify these exosites, we prepared six antithrombin-alpha 1-proteinase inhibitor chimeras in which antithrombin residues 224-286 and 310-322 that circumscribe a region surrounding the reactive loop on the inhibitor surface were replaced in 10-16-residue segments with the homologous segments of alpha1-proteinase inhibitor. All chimeras bound heparin with a high affinity similar to wild-type, underwent heparin-induced fluorescence changes indicative of normal conformational activation, and were able to form SDS-stable complexes with thrombin, factor Xa, and factor IXa and inhibit these proteases with stoichiometries minimally altered from those of wild-type antithrombin. With only one exception, conformational activation of the chimeras with a heparin pentasaccharide resulted in normal approximately 100-300-fold enhancements in reactivity with factor Xa and factor IXa. The exception was the chimera in which residues 246-258 were replaced, corresponding to strand 3 of beta-sheet C, which showed little or no enhancement of its reactivity with these proteases following pentasaccharide activation. By contrast, all chimeras including the strand 3C chimera showed essentially wild-type reactivities with thrombin after pentasaccharide activation as well as normal full-length heparin enhancements in reactivity with all proteases due to heparin bridging. These findings suggest that antithrombin exosites responsible for enhancing the rates of factor Xa and factor IXa inhibition in the conformationally activated inhibitor lie in strand 3 of beta-sheet C of the serpin.

Amino Acid Sequence↗

PubMed1996

Homozygous variant of antithrombin with lack of affinity for heparin: management of severe thrombotic complications associated with intrauterine fetal demise.

Patients with homozygous heparin-binding-site (HBS) qualitative antithrombin deficiencies are at significant risk of venous and arterial thrombosis. We report on the eighth case of homozygous HBS deficiency, and the fourth case concerning the Arg 47-Cys mutation. The proposita is a 25 year old, without known thrombotic antecedent, despite an oral contraceptive therapy for 7 years. After 25 weeks of a first pregnancy, she presented an intrauterine fetal demise complicated with deep vein thrombosis and pulmonary embolism. Heparin therapy was inefficient (no clinical nor angiographic improvement, no biological hypocoagulability). Heparin cofactor activity was < 10%, antigen concentration was normal. The crossed immunoelectrophoresis of patient's plasma, with and without heparin, showed a typical profile of qualitative HBS antithrombin deficiency. The molecular analysis revealed an homozygous Arg 4-Cys mutation. Antithrombotic therapy was achieved with continuous infusion of antithrombin concentrates (80 IU/kg/day) and unfractionated heparin (500 IU/kg/day) during 12 days, leading to clinical improvement, and followed by treatment with vitamin K antagonists. This observation emphasizes the risk of intrauterine fetal demise and the inefficiency of heparin therapy without antithrombin infusion in type II HBS homozygous deficiency. The management of a future pregnancy will probably require repeated infusions of antithrombin.

Adult↗

PubMed2001

A new global test for the evaluation of the activated factor II-antithrombin system.

We developed a new simple test to evaluate the global function of the activated factor II-antithrombin system. The new test measures the clotting time of plasma samples after the addition of a reagent containing a snake venom (Echis carinatus) that can activate prothrombin, with (Ta) and without (To) heparin. The prolongation of clotting times (Ta - To) is directly related to the function of the activated factor II-antithrombin system. The presence of quantitative or functional defects of the natural inhibitors (antithrombin and heparin co-factor II), or high levels of factor II and/or fibrinogen, can trigger a resistance to the inhibition of activated factor II. This new test was used to examine 134 thrombophilic patients as well as 157 normal subjects as controls. The results obtained confirm that the presence of abnormalities relating to the activated factor II-antithrombin system causes a resistance to activated factor II inhibition even if a significant number of patients was found to have a resistance that could not be accounted for. Since the new test can be easily performed automatically and has a good inter- and intra-assay variation coefficient (CV < 4%) it is useful for evaluating the global function of the activated factor II-antithrombin system in screening thrombophilic patients, alongside the tests already known and used to diagnose these patients.

Antithrombins↗

PubMed2002

Predictive value of antithrombin III and serum C-reactive protein concentration in critically ill patients with suspected sepsis.

OBJECTIVE: To evaluate at admission the performance of serum antithrombin III, serum C-reactive protein, white blood cell and platelet counts, and thromboplastin time values in prediction of hospital mortality rates in critically ill patients with suspected sepsis. DESIGN: Prospective, cohort study. SETTING: University hospital medical-surgical intensive care unit. PATIENTS: One hundred eight consecutive critically ill patients with suspected sepsis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The outcome measure was hospital mortality rate. Hospital survivors (n = 66) and nonsurvivors (n = 42) differed statistically significantly in admission antithrombin III activity (percentage of normal): survivors' median 66% (interquartile range, 48% to 82%) vs. nonsurvivors' median 46% (37% to 65%, p =.0002 by Mann-Whitney test). Analysis revealed similarly statistically significant differences between survivors and nonsurvivors in admission platelet count, admission thromboplastin time, day 1 Logistic Organ Dysfunction score, and Acute Physiology and Chronic Health Evaluation III score, but not in serum C-reactive protein concentrations or in white blood cells. However, the areas under the receiver operating curves (AUC) showed significantly worse discriminative power for admission antithrombin III concentration (AUC, 0.71; SE, 0.05), platelet count (AUC, 0.67; SE, 0.05), thromboplastin time (AUC, 0.65; SE, 0.05), C-reactive protein concentration (AUC, 0.60; SE, 0.05), and white blood cell count (AUC, 0.53; SE, 0.06) than did the day 1 Logistic Organ Dysfunction score (AUC, 0.82; SE, 0.04) and the Acute Physiology and Chronic Health Evaluation III score (AUC, 0.84; SE, 0.04). Multivariate logistic regression analysis revealed that only the Acute Physiology and Chronic Health Evaluation III score was independently associated with hospital mortality rate. CONCLUSIONS: Admission antithrombin III concentrations, but not C-reactive protein concentrations, differ significantly between hospital survivors and nonsurvivors among critically ill patients with septic infection. However, in prediction of hospital mortality rate, the discriminative power of admission antithrombin III concentration is poor, as judged by analysis of areas under the receiver operating curves, and is not independently associated with hospital mortality rate.

Adult↗

PubMed1988

The mechanism of reduced antithrombin III activity in women with preeclampsia.

The cause(s) of the low plasma antithrombin III activity in women with preeclampsia is unknown. The purpose of this study was to evaluate the relationship between plasma antithrombin III activity and both clotting parameters (platelet count and fibrinopeptide A) and renal parameters (serum creatinine and uric acid concentration). Forty-seven preeclamptic women were studied within the 2-day interval before delivery. Creatinine did not correlate significantly with any of the other study parameters. However, there were significant correlations between antithrombin III activity and platelet count (r = 0.53, P less than .005) and between antithrombin III and fibrinopeptide A (r = -0.29, P less than .05). The correlation between platelet count and fibrinopeptide A was not significant. These findings support the hypothesis that antithrombin III consumption by fibrin generation is initiated by platelet activation, and is at least one cause of the low activity level known to occur in women with preeclampsia.

Antithrombin III↗

PubMed2006

Microcirculatory disorders in sepsis and transplantation: therapy with natural coagulatory inhibitors antithrombin and activated protein C.

PURPOSE OF REVIEW: Modern technologies allow visualization of microcirculatory disorders. This review describes how the coagulatory inhibitors antithrombin and activated protein C (APC) can improve microcirculation in sepsis and transplantation. RECENT FINDINGS: The effects of antithrombin and APC on microcirculatory disorders in ischemia reperfusion and experimental sepsis have been reported recently. In addition, antithrombin has recently been clinically used to reduce graft pancreatitis after pancreas-kidney transplantation, and to improve kidney perfusion. It was demonstrated that septic capillary perfusion failure as well as leukocyte-endothelial cell interactions can be reversed by high-dose prophylactic antithrombin application. APC was also highly effective in this context. Thus, APC could improve microcirculatory blood flow in septic patients as recently measured by in-vivo orthogonal polarization spectral imaging techniques. For antithrombin, comparable measurements in humans are currently not available. SUMMARY: Microcirculatory dysfunction plays a key role in the development of organ dysfunction in septic patients and after solid organ transplantation. The exogenous application of coagulatory inhibitors may provide a new important strategy for prevention and treatment of microcirculatory disorders. This mode of action may be the reason why coagulatory inhibitors could improve mortality in septic patients without directly influencing inflammatory mediator concentrations.

Animals↗

PubMed1978

The binding of low-affinity and high-affinity heparin to antithrombin. Fluorescence studies.

The interaction between antithrombin and two forms of heparin, differing in their affinity for the matrix-linked protein, has been studied by fluorescence. The binding of the high-affinity heparin fraction to antithrombin leads to activation of the inhibitor, allowing it to react more rapidly with a number of serine proteases of the coagulation cascade. The interaction with the low-affinity heparin fraction, however, has considerably less influence on this inhibition rate. The binding of either fraction to antithrombin was found to result in an increase of the tryptophan fluorescence of the protein. This increase was much larger for high-affinity heparin than for low-affinity heparin, suggesting a different mode of binding of the two fractions to the protein. The fluorescence enhancement caused by high-affinity heparin is consistent with a conformational change of antithrombin related to its activation. Only the fluorescence enhancement observed on the binding of high-affinity heparin was of a sufficient magnitude to allow quantitative studies. These showed high-affinity heparin to bind to antithrombin with a stoichiometry of about one and with a binding constant at physiological ionic strength of about 8 X 10(7) M-1. At higher ionic strengths, however, the affinity decreased markedly.

Animals↗

PubMed1979

Evidence by chemical modification for the involvement of one or more tryptophanyl residues of bovine antithrombin in the binding of high-affinity heparin.

Tryptophanyl residues of bovine antithrombin were modified with N-bromosuccinimide at near-neutral pH. The reaction was found to be specific for tryptophan at low levels of modification, i.e. when only up to 1--1.3 mol tryptophan/mol protein were oxidized. Further modification led to extensive side reactions. Modification of an average of about one tryptophanyl residue per protein molecule did not affect antithrombin activity measured in the absence of heparin, but decreased the activity assayed in the presence of heparin to about half the value given by unmodified antithrombin. Addition of an excess of high-affinity heparin to a similarly modified antithrombin sample resulted in much smaller circular dichroism, ultraviolet absorption and fluorescence changes than those observed with the intact protein. Modification experiments in the presence of excess high-affinity heparin gave a definitely lower extent of modification than when heparin was excluded. These studies thus reinforce the conclusion from previous spectroscopic analyses that one or more tryptophanyl residues of antithrombin are involved in the binding of high-affinity heparin, presumably by being located at or close to the heparin binding site.

Animals↗

PubMed1990

The role of hyperglycaemia-induced alterations of antithrombin III and factor X activation in the thrombin hyperactivity of diabetes mellitus.

Factor X concentration and factor X activation, antithrombin III anti-Xa activity and plasma concentration, and fibrinopeptide A were measured in 20 diabetic patients and 20 normal subjects. Although factor X activation (81.3 +/- 2.2 vs 97.3 +/- 2.1%, p less than 0.01; mean +/- SE) and antithrombin III activity (76.5 +/- 2.2 vs 96.3 +/- 1.8%, p less than 0.01) were reduced in the diabetic patients, fibrinopeptide A concentration was increased (3.7 +/- 0.4 vs 1.7 +/- 0.2 ng ml-1, p less than 0.01). The ratio of factor X activation to antithrombin III anti-factor Xa activity was increased in the diabetic patients (1.10 +/- 0.01 vs 1.01 +/- 0.02, p less than 0.01). Induced hyperglycaemia was able to mimic all these abnormalities, without changing factor X or antithrombin III concentration. The results suggest that in vivo hyperglycaemia produces a decrease of factor X activation, but at the same time increases fibrinopeptide A formation due to a greater decrease of antithrombin III anti-Xa activity.

Adult↗

PubMed1982

Circulating antithrombins in pregnancy.

In a cross-sectional study circulating levels of antithrombins, antithrombin III, alpha 1-antitrypsin and alpha 2-macroglobulin were measured in groups of 20 women before pregnancy, during each trimester and post partum. Blood levels of antithrombin III were significantly lower, alpha 1-antitrypsin higher and alpha 2-macroglobulin no different when compared with those of the non-pregnant and puerperal states. These findings suggest that there may be not only an increase in total antithrombin production, but also a qualitative change in antithrombin 'activity', the principal protein during pregnancy being alpha 1-antitrypsin.

Alpha-Globulins↗

PubMed1979

Determination of antithrombin activity by an amidolytic and a clotting procedure.

Plasma antithrombin activity was measured using an amidolytic method (substrate Chromozym TH) and a clotting method. The mean antithrombin values found in 76 hospital outpatients were 9.4 micronmol/min/ml with the amidolytic procedure and 100.1% of antithrombin activity with the clotting procedure. The two methods correlate fairly well (r = 0.85, P less than 0.01) and show satisfactory reproducibility. Coefficients of variation of 5.9% and 8.8% were obtained respectively with the amidolytic and the clotting procedures. In the presence of very high levels of fibrinogen degradation products, falsely elevated antithrombin activity levels were observed with the clotting procedure but the amidolytic method is essentially unaffected. It is concluded that both methods are suitable for determining antithrombin activity but a well-standardised amidolytic procedure has advantages.

Aniline Compounds↗

PubMed1984

Depressed antithrombin III biological activity in opiate addicts.

Antithrombin III activity was significantly decreased in opiate addicts, but no difference was found between addict and control groups in antithrombin III plasma concentration. Moreover, glycosylated haemoglobin concentration was increased in opiate addicts, but no correlation between glycosylated haemoglobin and antithrombin III activity was found. These data show that in opiate addicts there is depressed biological activity of antithrombin III. Further characterisation of the molecular changes in antithrombin III in addicts is needed to establish whether the impaired activity is affected by altered glucose metabolism.

Adolescent↗

PubMed2004

[Oral antithrombins and the future of antithrombotic therapy].

The coagulation cascade leads, via thrombin activation, to the formation of fibrin (from its precursor fibrinogen) and platelet thrombus. Several drugs are able to interfere with some of the enzymatic factors involved in thrombin activation, but thrombin inhibitors (heparin, hirudin and hirulog [bivalirudin]) are of particular interest because they disrupt the coagulation cascade by acting upon one of its final steps. Among the thrombin inhibitors, oral antithrombins (ximelagatran) appear to hold great promise for the control of thrombogenicity in a number of clinical contexts. Oral antithrombins do not require the participation of cofactors to exert their action, and in contrast to thrombin inhibitors administered parenterally, they bind specifically to the active site of thrombin without interfering with other portions of the molecule. Their specificity makes these drugs safe and obviates the need to monitor coagulability. Moreover, they show a low rate of interaction with other drugs or with foods, and the response to fixed doses is predictable. A number of clinical studies have investigated antithrombins for prophylaxis prior to orthopedic surgery, in the prevention of cerebrovascular accidents associated with atrial fibrillation, and in the control of coronary artery disease. These studies have shown that antithrombins are superior to other habitually used treatment options. Surprisingly, their use in long-term studies has not been associated with an increased rate of bleeding events. Their interesting molecular characteristics and considerable therapeutic efficacy and safety suggest that oral antithrombins will in the near future become a valuable therapeutic option.

Administration, Oral↗

PubMed2006

Antiangiogenic antithrombin induces global changes in the gene expression profile of endothelial cells.

Antithrombin, a serpin family protease inhibitor crucial to hemostasis, acquires antiangiogenic properties on undergoing conformational alterations induced by limited proteolysis or elevated temperature. To better understand the biochemical mechanisms underlying antithrombin antiangiogenic activity, we did genome-wide expression profiling, coupled with quantitative reverse transcription-PCR, Northern blot, and Western blot analyses, to characterize the gene expression patterns that are induced by antiangiogenic antithrombin in cultured primary human umbilical vein endothelial cells. Overall, 35 genes with significantly increased expression and 93 genes with significantly reduced expression (> or =2-fold changes) due to antiangiogenic antithrombin treatment were identified. More than half of the down-regulated genes have well-established proangiogenic functions in endothelial cells, including cell-surface and matrix proteoglycans (e.g., perlecan, biglycan, and syndecans 1 and 3) and mitogenesis-related signaling proteins (e.g., mitogen-activated protein kinase 3, signal transducers and activators of transcription 2, 3, and 6, and early growth response factor 1). In contrast, most up-regulated genes (e.g., caspase-3, p21, tissue inhibitor of metalloproteinases 1, 2, and 3, and adenomatosis polyposis coli) are known for their antiangiogenic functions which include the promotion of cell apoptosis and cell cycle arrest and the inhibition of tumor growth and metastasis. These results show that the antiangiogenic activity of antithrombin is mediated at least in part by a global genetic reprogramming of endothelial cells and strongly implicate an endothelial cell ligand-receptor signaling mechanism in this reprogramming.

Angiogenesis Inhibitors↗

PubMed2003

Can the administration of antithrombin III decrease the risk of cerebral hemorrhage in premature infants?

This study was carried out to determine whether the administration of antithrombin III decreases the risk of intraventricular hemorrhage in premature infants. In a randomized study, 60 infants born before 30 weeks of gestation were assigned to receive a loading dose of antithrombin III or placebo. There was no significant difference in the incidence of intraventricular hemorrhage between the antithrombin III and the placebo group (27.5 vs. 32%). Partial thromboplastin time, Quick's prothrombin time and platelet count were also not significantly different between the 2 groups. We conclude that the administration of antithrombin III during the first 2 days of life does not decrease incidence of intraventricular hemorrhage. Antithrombin III is a very expensive therapy and its benefits should be carefully investigated before being recommended as valuable therapy.

Antithrombin III↗

PubMed1988

Evidence that rabbit 125I-antithrombin III binds to proteoheparan sulphate at the subendothelium of the rabbit aorta in vitro.

The endothelium of the rabbit thoracic aorta was removed from the vessel wall by one of two procedures, and the freshly exposed subendothelial surface was used for 125I-antithrombin III binding studies. Pretreatment of the subendothelium with either heparitinase or thrombin diminished the uptake of 125I-antithrombin III by up to 80%, whereas pretreatment with plasmin, hyaluronidase or FPR thrombin had little effect. Morphometric analysis of the subendothelium from enzyme-treated and -untreated tissues showed that, whereas plasmin, thrombin and heparitinase each caused a dramatic reduction of the large proteoglycan granules of the extracellular matrix, only exposure to heparitinase and thrombin caused a reduction in the small proteoglycans which populate the basement membrane of smooth muscle cells. Of the subendothelium-bound 125I-antithrombin III, more than 80% was efficiently removed by excess thrombin or by excess heparin. Evidence was obtained for the formation of high molecular weight thrombin-antithrombin III complexes. We conclude that antithrombin III binds largely to proteoheparan sulphate located in the basement membrane of the intimal smooth muscle cells for the purpose of inactivating certain proteases which arise during haemostatic change.

Animals↗

PubMedDate not supplied

Circadian rhythms of fibrinogen antithrombin III and plasminogen in chronic liver diseases of increasing severity.

Acquired deficiencies of fibrinogen, antithrombin III and plasminogen are reported in liver disease, and it is known that their plasma levels fluctuate during the day. The aim of this study was to investigate the circadian rhythms of these three factors in chronic liver disease. Five groups of subjects were considered: (A) 15 healthy controls: (B) 15 patients with hepatic alcoholic steatosis; (C) 15 patients with chronic active hepatitis; (D) 15 patients with compensated cirrhosis of the liver, and (E) 15 patients with decompensated cirrhosis with ascites. The levels of fibrinogen, antithrombin III and plasminogen were determined in blood samples drawn in each subject during the span of a day every 3 h starting from midnight. The time-related values were analyzed using the 'population-mean cosinor' method. Groups A and B presented a significant (p < 0.05) circadian rhythm for each variable, group C a significant (p < 0.05) circadian rhythm for fibrinogen and antithrombin III and groups D and E no significant (p > 0.05) circadian rhythms. Statistically significant differences (p < 0.05) were demonstrated among the groups in the mean daily levels of the three variables by ANOVA, the concentrations decreasing with disease severity. These data confirm the existence of a significant diurnal periodicity in the circulating levels of fibrinogen, antithrombin III and plasminogen in controls and suggest that liver disease is associated with progressive circadian modifications in the temporal structure of fibrinogen, antithrombin III and plasminogen, related to the stage of the liver disease. The rhythm derangements may be considered markers of evolution in liver disease.

Adult↗