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PubMed2004

Study of protein C, protein S, and antithrombin III in hypoxic newborns.

OBJECTIVE: The aim of this study was to clarify the effect of hypoxia on the physiologic inhibition system of coagulation including protein S, protein C, and antithrombin III and to study their effect on thromboembolic accidents of hypoxic newborns. DESIGN: Clinical study including ten hypoxic-ischemic neonates and ten normal neonates as a control group. DATA SOURCES: MEDLINE, pediatric textbooks, neonatal intensive care unit, Department of Paediatrics, Faculty of Medicine, Cairo University. RESULTS: The results of this study revealed a marked decrease in the level of the physiologic inhibition system of coagulation including antithrombin III, protein C, and protein S in 100% of the hypoxic-ischemic neonates compared with the control group (p <.001) before the occurrence of thromboembolic complications. Fifty percent of the hypoxic-ischemic neonates developed disseminated intravascular coagulation and died, 40% developed necrotizing enterocolitis and rectal bleeding, 20% developed hematuria, 30% developed hematemesis, 20% developed intracranial hemorrhage, and 100% had convulsions. CONCLUSIONS: In this study, we evaluated the effect of asphyxia on the physiologic inhibition system of coagulation in neonates. Care providers should suspect hypoxia resulting from any obstructed labor and perform the necessary laboratory investigations for coagulation, including antithrombin III, protein C, and protein S levels, to help prevent thromboembolic accidents in asphyxiated neonates, including disseminated intravascular coagulation, necrotizing enterocolitis, and intracranial hemorrhage. Based on the development of antithrombin III and protein C concentrates, which are commercially available, require minimal monitoring, and have very few side effects, the time is ripe for evaluation of optimal treatment for thromboembolic accidents after neonatal asphyxia. This could be even more important if successful neuroprotectant strategies are also developed.

Antithrombin III↗

PubMed2003

Antithrombin modulates the leukocyte-endothelial cell interaction in the staphylococcal enterotoxin B-challenged mouse.

BACKGROUND: The beneficial effects of antithrombin on endotoxemia are well known. The purpose of this study was to examine the effects of antithrombin in a supertoxin-induced sepsis. METHODS: Mice were injected with staphylococcal enterotoxin B simultaneously with antithrombin. At 1 hour after injection, the mesenteric microcirculation was observed under intravital microscopy. In addition, humoral mediators were measured at the same time. RESULTS: The number of rolling leukocytes on the endothelium was significantly reduced in the treated mice (p < 0.01). The decrease of white blood cell and platelet counts was significantly inhibited in the treated animals (p < 0.01 for both). A comparison of the intercellular adhesion molecule-1 (p < 0.05), soluble tumor necrosis factor-alpha receptor (p < 0.05), and interleukin-6 (p < 0.01) levels showed less increase in the treated mice. CONCLUSION: Antithrombin showed a protective effects on the microcirculation of staphylococcal enterotoxin B-challenged mice by attenuating leukocyte-endothelial cell interaction. Suppression of adhesive molecule expression and cytokine production appears to play roles in this effect.

Animals↗

PubMed1975

A new assay for the measurement of total progressive antithrombin.

A new rapid method for assaying total antithrombin activity has been developed based on the inactivation of thrombin incorporated into an agarose gel, during the radial diffusion of plasma in the gel. The area of thrombin inactivation is subsequently observed by the coagulation of fibrinogen in a separate agarose gel layer poured over the thrombin gel. The method is described in detail and its accuracy assessed with respect to other antithrombin assays. Using specific antisera to alpha2-globulin (antithrombin III), alpha2-macroglobin and alpha1-antitrypsin, total antithrombin activity measured by this assay consisted of 47% alpha2-globulin, 29% alpha2-macroglobulin and 26% alpha1-antitrypsin.

Alpha-Globulins↗

PubMed1987

Antithrombin III Northwick Park: demonstration of an inactive high MW complex with increased affinity for heparin.

It has been shown previously that antithrombin III Northwick Park has reduced ability to inactivate thrombin and is characterized by an additional anodal component on crossed immunoelectrophoresis (Howarth et al, 1985). We have applied plasma from an affected family member to heparin-Sepharose and eluted the antithrombin III with a salt gradient. Evidence is presented that a variant component has slightly higher affinity for heparin than normal antithrombin III. Furthermore, this variant component is present in plasma as an approximately 120,000 MW inactive antithrombin III complex that can be reduced with dithiothreitol to MW approximately 60,000, indicating disulphide bridging. Using ion-exchange chromatography, the inactive complex has been isolated and shown to migrate in the same position as the anodal peak on crossed immunoelectrophoresis.

Antithrombin III↗

PubMed1977

The size and shape of human and bovine antithrombin III.

Human and bovine antithrombin, purified by affinity chromatography on heparin-agarose, have been characterized with regard to chemical composition, size, shape and conformation. Both preparations were found to contain several active components of identical or similar size but different electrical charge. Amino acids and carbohydrate analyses revealed striking similarities between human and bovine antithrombin, while immunological analyses failed to demonstrate any cross-reactivity. The molecular weights were determined by sedimentation equilibrium to be 58 000 for human and 56 000 for bovine antithrombin. The small molecular weight difference suggested by these values was verified by several empirical methods of molecular weight estimation. Hydrodynamic measurements indicated that the two proteins have similar molecular shapes, both of which are slightly more extended that that of typical globular proteins. The internal folding of the two polypeptide chains is also similar, as evidenced by the identity of the far-ultraviolet circular dichroism spectra. Specifically, these analyses suggested a low alpha-helix content of both proteins. In conclusion, the marked structural similarity of human and bovine antithrombin indicates that the two proteins may also exhibit extensive functional similarities in the binding of heparin and the inhibition of various coagulation factors.

Amino Acids↗

PubMed1981

The interaction of protein-bound heparin and antithrombin III.

When commercially prepared porcine mucosal heparin is added to human plasma, some of the heparin fractions form a complex with antithrombin III activating it to an immediate inhibitor of thrombin as well as of other serine proteases. Certain fractions of heparin may complex with other proteins such as alpha 2-macroglobulin, another progressive inhibitor of thrombin. Without complexing with antithrombin III, this protein-bound heparin fraction(s) still retains the capacity to activate it to an immediate inhibitor of thrombin. Protamine sulfate inactivates those heparin fractions that bind to antithrombin III but not those bound to alpha 2-macroglobulin. Activated antithrombin III may undergo a molecular change in the presence of protamine which not only changes it back to a progressive inhibitor but makes it resistant to activation by the protein-bound heparin fraction(s). However, it can still be reactivated by other heparin fractions in fresh whole heparin. The observations presented may help explain heparin "rebound" in patients believed adequately neutralized with protamine.

Animals↗

PubMed1999

Antiangiogenic activity of the cleaved conformation of the serpin antithrombin.

Antithrombin, a member of the serpin family, functions as an inhibitor of thrombin and other enzymes. Cleavage of the carboxyl-terminal loop of antithrombin induces a conformational change in the molecule. Here it is shown that the cleaved conformation of antithrombin has potent antiangiogenic and antitumor activity in mouse models. The latent form of intact antithrombin, which is similar in conformation to the cleaved molecule, also inhibited angiogenesis and tumor growth. These data provide further evidence that the clotting and fibrinolytic pathways are directly involved in the regulation of angiogenesis.

Animals↗

PubMed1984

Antithrombin III, plasminogen and alpha 2 antiplasmin in jaundice. Clinical usefulness and prognostic significance.

In this prospective study, antithrombin III, plasminogen and alpha 2 antiplasmin which are synthetised by the liver were measured and compared with the Normotest, Thrombotest and fibrinogen concentrations in 92 consecutive jaundiced patients. Antithrombin III appeared to be the most discriminant coagulation test in differentiating hepatocellular from cholestatic jaundice. A high correlation was observed between antithrombin III, plasminogen and alpha 2 antiplasmin values suggesting that the liver synthesis of these parameters was closely linked. The prognostic significance of the blood coagulation tests in patients with jaundice has been studied. In parenchymatous liver disease, antithrombin III, plasminogen and alpha 2 antiplasmin were superior to the Normotest, Thrombotest and fibrinogen concentrations in predicting the prognosis of the patients at the time of admission. In cholestatic jaundice, however, none of the blood coagulation tests studied had a prognostic significance.

Adult↗

PubMed1979

Antithrombin activities in childhood malnutrition.

Antithrombin activities in 30 severely malnourished children and 40 normal children were estimated in clotting tests by thrombin neutralisation as anti-Xa and by a heparin antithrombin assay; and by immunodiffusion as alpha 2-globulin and alpha 1-antitrypsin. The patients' mean alpha 2-globulin was severely depressed, and there were less marked depletions in mean values for thrombin neutralisation, anti-Xa, and in the heparin antithrombin assay (which showed the flat curve thought to reflect a thrombotic tendency). The alpha 1-antitrypsin values were normal. The findings support the concept of antithrombin as the summation of alpha 2-globulin and alpha 1-antitrypsin (with alpha 2-macroglobulin); and the low values may be related to the high incidence of thrombosis reported in childhood malnutrition, although it was not seen in these patients.

Antithrombins↗

PubMed1981

Relation between postoperative antithrombin III concentrations and site of operation.

Antithrombin III concentrations were measured in 305 patients before and at intervals after operation for up to 12 days. The blood concentrations fell significantly after both major and minor surgery, but there was no relation between the expected degree of surgical trauma or the amount of blood transfused and the fall in concentration of antithrombin III. Some surgical procedures such as cholecystectomy, laparotomy, hernia repair, highly selective vagotomy, and transurethral resection of the prostate were associated with a greater depletion of antithrombin III than were other common operations and it is suggested that there are factors related to the actual site of the operation which affect the concentration of circulating antithrombin III in the postsurgical period.

Antithrombin III↗

PubMed2002

Protein C, antithrombin, and venous thromboembolism incidence: a prospective population-based study.

Although deficiencies of protein C and antithrombin, 2 natural plasma anticoagulants, are known risk factors for venous thrombosis, population-based prospective incidence data on these associations are lacking. Venous thromboembolic events have been identified in adults in 2 longitudinal cohort studies, the Atherosclerosis Risk in Communities (ARIC) Study and the Cardiovascular Health Study (CHS). Incidence was examined in relation to prediagnostic plasma levels of protein C (ARIC Study only) and antithrombin. Over a mean of 8.1 years of follow-up, there were 130 incident venous thromboembolic events that were not due to cancer in the ARIC Study. The age-adjusted incidence was elevated 3.36-fold (95% CI 1.24 to 9.11) in the 1.1% of subjects with protein C values <2.0 mg/L compared with subjects with higher values. In contrast, in the ARIC Study and the CHS, there was no association between low plasma antithrombin and venous thromboembolism. In conclusion, in this population-based study, a low protein C, but not antithrombin, level has been determined to be associated with an increased incidence of venous thromboembolism. Attributable risk estimates suggest that low protein C levels account for approximately 2.5% of venous thromboembolic events in the ARIC population.

Adult↗

PubMed1977

The rabbit as an animal model for the activated factor X-antithrombin III-heparin reaction.

When activated factor X (Xa) inhibitory activity of serially diluted human and rabbit plasma is determined in a low salt assay, a lineare plot is obtained for human, but not for rabbit plasma. When a high salt assay is used, the dilution curves for both human and rabbit plasma are linear, and qualititive as well as quantitative differences are essentially eliminated. On Sephadex G-200 chromatography Xa inhibitory activity of human and rabbit plasma appears in two peaks. With the low salt assay the first and second peaks for human plasma contain respectively 30%, and 70% of the activity; whereas with rabbit plasma these values are greater than 95% and less than 5% of the activity. With the high salt assay the figures for human plasma are less than 5% and greater than 95%, and with rabbit plasma 65 +/- 3% and 35 +/- 3%, respectively. With the high salt system, rabbit plasma shows a continuous increase in Xa inhibitory activity with increasing heparin concentrations, similar to that obtained with human plasma. In the high salt system the relative contributions of antithrombin III to Xa neutralization in human and rabbit plasma are different. However, in experiments in which Xa inhibitory activity of antithrombin III is altered by heparin, a simple formula, Total activity (%) = 65% + 0.35 x human plasma (%), permits translation of rabbit data on the Xa-antithrombin III-heparin reaction to man. On the basis of these findings, the rabbit model can effectively be used to study the Xa-antithrombin III reaction.

Animals↗

PubMed1999

Antithrombin agents: the new class of anticoagulant and antithrombotic drugs.

Antithrombin drugs represent a wide group of natural agents, recombinant agents equivalent to some of the naturally occurring proteins, and synthetic agents. This group of drugs is characterized by marked structural and functional heterogeneity. Several of these drugs are currently in various phases of development. Argatroban represents the first clinically approved antithrombin agent, which was made available in Japan several years ago. Two recombinant hirudin preparations, Revasc (Novartis) and Refludan (Aventis), are available for postsurgical DVT prophylaxis and alternate anticoagulant use in patients with heparin-induced thrombocytopenia. A synthetic antithrombin agent based on the combined structures of hirudin and antithrombin peptides, hirulog (Bivalirudin), is undergoing clinical trials in cardiovascular indications. Additional studies on the hirudins are being carried out to test their efficacy as surgical and interventional anticoagulants as replacements for heparin. However, the need for a proper antagonist is one of the limiting factors for the optimal development of hirudin in this indication. Several of the synthetic thrombin inhibitors are also being developed for oral use for the prophylaxis of DVT in surgical patients. Since the therapeutic index of thrombin inhibitors is narrower than that of heparin, this route may not be an optimal approach for the development of these agents. Despite several unresolved developmental issues, the thrombin inhibitors provide a useful alternative to heparin anticoagulation and may prove to be useful in validated clinical use.

Anticoagulants↗

PubMed2005

Antithrombin in sepsis revisited.

As the pivotal phase III randomized controlled clinical trial on antithrombin concentrate in patients with severe sepsis did not show a beneficial effect of antithrombin treatment on 28-day mortality, the interest in the potential use of this treatment modality in sepsis has diminished. However, recent data on the effect of antithrombin administration on coagulation in combination with recent analyses from the clinical trials that were aimed to restore physiological anticoagulant pathways in patients with sepsis may revitalize the interest in antithrombin concentrate for the treatment of severe sepsis.

Anticoagulants↗

PubMed2000

Most clot-bound thrombin activity is inhibited by plasma antithrombin during clot aging, but a very small fraction survives.

Inhibitory effects of thrombin inhibitors against clot-bound thrombin have been evaluated using clots prepared from human plasma as the source of clot-immobilized active enzyme, and the clot-bound thrombin has been reported to be protected from its inhibition by antithrombin. However, we found that the clot-bound thrombin was not intrinsically protected from inhibition by antithrombin, i.e., a large fraction of initially active clot-bound thrombin was inhibited by antithrombin present in human plasma time dependently, and only very small fractions (0.04--0.08%) of the thrombin retained their enzymatic activity after clot-aging. These results suggest that the extent of clot-aging determines the sensitivity of clot-bound thrombin to antithrombin, and that inhibitory effects of drugs against clot-bound thrombin in vitro must be interpreted with caution to estimate their effects in vivo.

Antithrombins↗

PubMed2004

Inhibition of human pancreatic proteinases by human plasma alpha2-antiplasmin and antithrombin.

Human plasma alpha1-antitrypsin inhibits human pancreatic trypsin, chymotrypsin and elastase, which are massively released into the blood stream during acute pancreatitis. To examine whether the plasma proteins of individuals with genetic deficiency of alpha1-antitrypsin are protected against the deleterious action of these enzymes by other inhibitors, we have tested their inhibition by alpha2-antiplasmin and antithrombin. We have determined the inhibition rate constants kass and calculated d(t), the in vivo inhibition time. Surprisingly, trypsin is inhibited faster by alpha2-antiplasmin [kass=2.5 x 10(6) M(-1)S(-1), d(t)=2.3 s] and antithrombin [kass=1.7 x 10(5) M(-1)s(-1), d(t)=5.8 s] than by alpha1-antitrypsin [d(t)=17 s or 116 s in alpha1-antitrypsin-sufficient or alpha1-antitrypsin-deficient individuals, respectively]. Low molecular weight heparin accelerates the inhibition of trypsin by antithrombin by a factor of 16 [d(t)=0.36 s]. Antithrombin and alpha2-antiplasmin are not physiological inhibitors of chymotrypsin and elastase. These enzymes are, however, physiologically inhibited by alpha1-antitrypsin and alpha1-antichymotrypsin even in alpha1-antitrypsin-deficient individuals. We conclude that (i) low molecular weight heparin may be helpful in the management of acute pancreatitis, and (ii) genetically determined alpha1-antitrypsin deficiency probably does not lead to a significantly increased risk of plasma protein degradation during this disease.

Antithrombins↗

PubMed1994

The value of antithrombin-III and fibronectin in hypertensive disorders of pregnancy.

In this study we evaluated fibronectin as a marker of endothelial cell injury and antithrombin III as a marker of chronic activation of intravascular coagulation. The aim of the study was to establish to normal trends of plasma antithrombin III and fibronectin in general obstetric population and to determine the value of both in predicting, distinguishing and understanding the pathophysiology of pregnancy induced hypertension. The all cases consisted of 173 pregnant, 19 of them were chronic hypertensive, 45 were pregnancy induced hypertensive and 119 were normotensive at blood sampling. Out of 119 normotensive cases, 109 cases had no adverse outcome during their pregnancy. These cases were used as a control group and for the normal trends of antithrombin III and fibronectin in general obstetric population. Ten out of 119 cases who developed preeclampsia during follow up, 19 cases with chronic hypertension and 45 cases with pregnancy induced hypertension consisted of the study group. In the cases who developed preeclampsia during follow up, the value of plasma fibronectin level (above 95% confidence limit for that gestational week) to predict preeclampsia had 90% sensitivity and 94.4% specificity. In distinguishing hypertensive disorders of pregnancy (chronic hypertension or pregnancy induced hypertension) fibronectin had 71.1% sensitivity and 100% specificity. Plasma antithrombin III level (of antigenicity) measured by immunodiffusion method had no value in predicting and distinguishing pregnancy induced hypertension.

Antithrombin III↗

PubMed2004

Argatroban therapy for antithrombin deficiency and mesenteric thrombosis: case report and review of the literature.

Antithrombin deficiency is a hypercoagulable state that can increase the risk for thrombosis, especially in the presence of other procoagulant triggers. Unfractionated heparin and low-molecular-weight heparins may not provide effective anticoagulation since they require antithrombin for activity. Direct thrombin inhibitors, however, work independently of antithrombin. A 21-year-old man with a history of heavy alcohol consumption had thrombosis of the superior mesenteric vein. Infusion with unfractionated heparin was started, and despite repeated boluses and increases to 21 U/kg/hour, the maximum activated partial thromboplastin time reached was 39 seconds. The unfractionated heparin was discontinued, and the direct thrombin inhibitor argatroban was infused at rates of 0.4-0.5 microg/kg/minute. Over the course of several weeks, the patient had numerous operations to remove and repair necrotic bowel. When no further surgery was anticipated, warfarin therapy was started; the argatroban infusion was discontinued when the patient reached the therapeutic target international normalized ratio with warfarin. No recurrent thrombosis or major bleeding occurred. Direct thrombin inhibitors, such as argatroban, seem to be suitable alternatives for acute anticoagulation in patients with antithrombin deficiency.

Adult↗