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PubMedDate not supplied

Antithrombin III-beta associates more readily than antithrombin III-alpha with uninjured and de-endothelialized aortic wall in vitro and in vivo.

The properties of two isoforms, alpha and beta, of rabbit antithrombin III (ATIII) were compared in the presence of undamaged or de-endothelialized rabbit aortic wall. Similar quantities of ATIII-alpha and ATIII-beta bound to and rapidly saturated the endothelium in vitro, but the rate of transendothelial passage of ATIII-beta exceeded that of ATIII-alpha by 22%. Furthermore, ATIII-beta was adsorbed approximately twice as rapidly as ATIII-alpha by the subendothelium of the de-endothelialized aorta. Binding of both isoforms was decreased (ATIII-beta more than ATIII-alpha) by pretreating the subendothelial surface with heparitinase. Also, subendothelium-bound ATIII-beta was desorbed more readily than bound ATIII-alpha by thrombin. In vivo, the rate of uptake of iodine-131-labeled ATIII-beta from the circulation by the aortic wall and the major organs was 30-50% faster than that of iodine-125-labeled ATIII-alpha. In contrast, the uptake of 131I-ATIII-beta by the de-endothelialized aorta in vivo was three times faster than that of 125I-ATIII-alpha. By these criteria, ATIII-beta is the more active of the two isoforms. We surmise that plasma and, consequently, vessel wall levels of ATIII-beta may be vital for controlling thrombogenic events caused by injury to the vascular wall.

Adsorption↗

PubMed2002

Impact of antithrombin deficiency in thrombogenesis: lipopolysaccharide and stress-induced thrombus formation in heterozygous antithrombin-deficient mice.

Antithrombin (AT) deficiency is an autosomal disorder associated with venous thromboembolism. However, a diagnosis of homozygous AT deficiency is seldom made. Most patients are heterozygous and have approximately 50% AT activities, and they are at higher risk for the development of thromboembolism. Through gene targeting we generated AT-deficient mice and previously reported that completely AT-deficient mice could not survive the prenatal period because of extensive thrombosis in the myocardium and liver sinusoids. In contrast, heterozygous AT-deficient mice with 50% AT activities have not shown spontaneous thromboembolic episodes. To demonstrate a thrombotic tendency in heterozygous AT deficiency, we challenged heterozygous AT-deficient mice (AT+/- mice) with the administration of lipopolysaccharide (LPS) or with restraint stress by immobilization. LPS injection markedly induced fibrin deposition in the kidney glomeruli, myocardium, and liver sinusoids in AT+/- mice compared with wild-type mice (AT+/+ mice). Restraint stress tests were performed by placing mice in 50-mL conical centrifuge tubes for 20 hours. Fibrin deposition was observed in the kidney of AT+/+ and AT+/- mice, but AT+/- mice exhibited more extensive fibrin deposition than AT+/+ mice. After prophylactic administration of human AT concentrates to increase plasma AT activities of AT+/- mice, LPS-induced fibrin deposition was effectively prevented. These results suggest that heterozygous AT deficiency is significantly associated with a tendency toward thrombosis formation in the kidney. The AT+/- mouse thus is a useful model for studying the effect of environmental or genetic risk factors on thrombogenesis.

Animals↗

PubMed2005

Reduction of D-dimer levels after therapeutic administration of antithrombin in acquired antithrombin deficiency of severe sepsis.

INTRODUCTION: In acute disseminated intravascular coagulation, the effect of antithrombin (AT) administration on elevated levels of D-dimer is not well established. In the present study, we report on changes in circulating levels of D-dimer in response to administration of AT in a series of patients with acquired AT deficiency due to severe sepsis. METHODS: Eight consecutive critically ill medical patients presenting with acute disseminated intravascular coagulation associated with severe sepsis/septic shock received a single bolus infusion of AT over 30 minutes, aiming to achieve physiological AT levels. Haemostatic parameters including D-dimer were assessed prior to, 6 and 24 h after AT administration. An average of 42 +/- 9 U/kg body weight was infused. RESULTS: Following AT substitution, elevated levels of D-dimer fell whereas AT levels rose. CONCLUSION: These observations support the notion that AT can favourably affect fibrin degradation accompanying disseminated intravascular coagulation of severe sepsis.

Adult↗

PubMed2006

Hepatic veno-occlusive disease in pediatric stem cell transplantation: impact of pre-emptive antithrombin III replacement and combined antithrombin III/defibrotide therapy.

BACKGROUND AND OBJECTIVES: Hepatic veno-occlusive disease (VOD) remains a serious complication after hematopoietic stem cell transplantation (HSCT). Based on a protective effect of antithrombin III (ATIII) on endothelial cells, we assessed the incidence of VOD after pre-emptive ATIII replacement and the outcome of VOD after combined high dose defibrotide (DF) and ATIII therapy. DESIGN AND METHODS: This prospective case series comprised two phases. In the first phase 71 children did not receive any specific VOD prophylaxis or therapy (controls). In the second phase 91 children were given pre-emptive ATIII replacement in case of decreased ATIII activity (< or =70%). If VOD was diagnosed clinically (according to modified Seattle criteria), high dose defibrotide (60 mg/day) and ATIII replacement therapy were combined. The severity of VOD was determined according to the degree of multiple organ dysfunction. RESULTS: The incidence of VOD was similar in both groups (13/71, 18% vs. 14/91, 15%). All 14 patients in the second group who developed VOD showed decreased ATIII activity not more than 1 day prior to the clinical diagnosis of VOD. The resulting short duration of pre-emptive ATIII therapy failed to prevent VOD (OR 0.96). None of the patients (n=72) maintaining normal ATIII levels developed VOD. All 14 patients with VOD who received combined therapy achieved complete remission and 93 % (13/14) survived until day +100, compared to six survivors (46%) in the first group. INTERPRETATION AND CONCLUSIONS: Pre-emptive ATIII administration did not alter the incidence of VOD. Combination treatment with ATIII and defibrotide was safe and yielded excellent remission and survival rates.

Adolescent↗

PubMed2006

Future perspectives on antithrombin and antiplatelet therapies: novel antiplatelet and antithrombin therapies.

The recognition that thrombosis is fundamental to acute coronary syndromes (ACS) has inspired the development of novel therapies to inhibit platelet aggregation and thrombus formation. Several recent advances have been made in the management of patients undergoing percutaneous coronary revascularization and those with acute coronary syndromes to improve early and late clinical outcomes. The research efforts leading to these improvements in care have focused on antiplatelet and anticoagulant therapies coupled with early invasive treatment options. In particular, ongoing clinical trials seek to refine treatment strategies for patients relative to individual risk presentation and to determine the appropriate timing of the administration of antithrombotic therapies and revascularization. Simultaneous with attention toward improving efficacy with novel antithrombotic therapies, however, is an ongoing need to minimize bleeding risk. The purpose of this review is to provide a pathophysiologic rationale for the development of novel antiplatelet and antithrombin therapies in ACS and percutaneous coronary intervention, to examine the results of recent trials, and to present future directions for clinical investigation.

Antithrombins↗

PubMed1991

[Plasma levels of antithrombin III, thrombin-antithrombin III complex, alpha 2 plasmin inhibitor and plasmin alpha 2 plasmin inhibitor complex in normal and sick newborn infants].

Both bleeding and thrombosis are commonly seen in newborn infants because of their imbalance of coagulation and fibrinolysis system. In order to clarify some aspects of the hemostatic characteristics during neonatal period, we measured the levels of antithrombin-III (AT-III), thrombin AT-III complex (TAT), alpha 2-plasmin inhibitor (alpha 2PI) and plasmin alpha 2PI complex (PIC) in 137 normal and sick newborn infants. The results were as follows 1) AT-III levels in normal neonates were significantly low as compared with them in normal adults, and further lower levels were found in sick neonates. 2) TAT levels in sick neonates were significantly higher than those in either normal neonates and adults. In sick neonates, the incidence of abnormally high TAT values increased with DIC score points. 3) No significant difference of alpha 2PI level was seen between normal term neonates and adults. However, alpha 2PI levels in sick neonates were significantly low as compared with them in normal term neonates and adults. 4) PIC levels in either normal and sick infants were significantly higher than those in adults, but there was no significant difference in PIC levels between normal and sick newborn infants.

Antifibrinolytic Agents↗

PubMed1987

Antithrombin III loss in patients with nephrotic syndrome or receiving continuous ambulatory peritoneal dialysis. Evidence of inactive antithrombin III in urine of patients with nephrotic syndrome.

Antithrombin III (AT III) was measured as antigen (Ag) and as heparin cofactor (HC) in plasma and urine or dialysate from nine patients with nephrotic syndrome and nine patients receiving continuous ambulatory peritoneal dialysis (CAPD), respectively. Crossed immunoelectrophoresis on heparin-agarose (H-CIE) and crossed immunoelectrofocusing (CIEF) runs were carried out on plasma and urine or dialysate samples. AT III plasma levels of the patients receiving CAPD were in the normal range, whereas levels in the patients with nephrotic syndrome showed a significant reduction. Nevertheless the AT III Ag daily loss was the same in both patient groups, so that an additional AT III loss caused by renal metabolism was suggested in patients with nephrotic syndrome. No alteration in the isoantithrombin plasma distribution was found in any patient. The AT III recovered in urine was almost all inactive, as demonstrated by the quantitative assays and by the H-CIE runs; on the contrary, the findings obtained by functional assays, H-CIE, and CIEF runs on dialysate samples failed to demonstrate any major alteration in the AT III molecule. In urine the AT III CIEF pattern displayed a more acid distribution (pH 4.9 to 4.5) in respect to the plasma AT III (pH 5.2 to 4.6); this pattern was suggested to be related to the renal AT III functional inactivation, whose exact mechanism remains to be clarified.

Adult↗

PubMed1986

Interaction of S-protein of complement with thrombin and antithrombin III during coagulation. Protection of thrombin by S-protein from antithrombin III inactivation.

S-protein, the inhibitor in plasma of the membrane attack complex of complement, appears to have a second function in coagulation. S-protein during clotting enters into a trimolecular complex with thrombin and antithrombin III (ATIII). Functionally, S-protein in the presence of low concentrations of heparin, protects thrombin from inactivation by ATIII. Complex formation between S-protein and thrombin, and between S-protein, thrombin, and ATIII, was demonstrated by agarose gel electrophoresis and by two-dimensional immunoelectrophoresis of purified proteins and in recalcified, clotted plasma. Formation of the trimolecular S-thrombin-ATIII complex was strictly dependent on the presence of thrombin. No association was detectable between S-protein and ATIII or between S-protein and prothrombin. Heparin was not required for the formation of the bimolecular S-protein-thrombin complex or the trimolecular S-protein-ATIII complex. The protective effect of S-protein on inactivation of thrombin by ATIII was demonstrated in functional assays with purified proteins and in plasma only in the presence of low concentrations of heparin. Thus, S-protein may mediate its effect by scavenging heparin required for ATIII activation. It is suggested that the protection of thrombin by S-protein from inactivation by ATIII may be of physiological importance.

Antithrombin III↗

PubMed1983

Functional and antigenic antithrombin III values in plasma and serum from 115 regular blood donors and antithrombin III in prediction of postoperative thrombosis.

Antithrombin III (AT-III) was determined functionally using chromogenic substrate (S-2238) and immunologically using radial immunodiffusion (RID) in plasma and serum from 115 blood donors. There was a decrease in functional activity by 43.5% and in antigen concentration by 18.4% during in vitro coagulation when corresponding serum and plasma samples were compared. A positive correlation was found between the two methods in plasma (r = 0.784) as well as in serum ( r = 0.658). RID in serum correlated well with RID in plasma (r = 0.811), but the correlation for S-2238 in plasma and serum was poor (r = 0.411). Functional AT-III decrease during coagulation was uncorrelated with age and fibrinogen, and was not statistically affected by sex, smoking or blood groups. Preoperative functional AT-III activity was measured in 25 patients undergoing elective hip replacement, 60% of whom developed postoperative thrombosis. The functional activity in serum discriminated well between the thrombotic and nonthrombotic group of patients (p less than 0.025), whereas the activity in plasma showed only a minor difference.

Adolescent↗

PubMedDate not supplied

Comparative behaviour of antithrombin III antigen and antithrombin III activity in cardiovascular patients.

Antithrombin III-functional (AT III F) and immunoprotein (AT III I) assessed by two comparative methods in various cardiovascular conditions, showed significant differences between the two parameters, namely: a simultaneous decrease of both AT III F and AT III I during acute embolic episodes of only AT III F in transient ischemic attacks (with normal level of AT III I) and increase of AT III I (with apparently normal AT III F) in patient with mitral valve prosthesis. It is considered that in condition of "hypercoagulability" various patterns of AT III F/AT III I ratio can be obtained: decompensated, compensated and hypercompensated consumption.

Adult↗

PubMed1993

Self-association of antithrombin III relates to multimer formation of thrombin-antithrombin III complexes.

During the reaction of antithrombin III (AT III) with target proteases the inhibitor serves as pseudo-substrate and undergoes profound conformational changes, becomes incorporated into a covalent stoichiometric enzyme-inhibitor complex which is, in contrast to native AT III, recognized by monoclonal antibody 4C9. In the absence of the target enzyme thrombin, incubation of AT III with 1-2 M guanidine, 0.6% deoxycholate, heating to 56 degrees C, or buffer at pH 4 resulted in inactivation of the inhibitor with concomitant exposure of the epitope for 4C9 and formation of AT III multimers (from 3.9 S to 7.1-7.4 S). Loss of activity, formation of multimers and exposure of neoepitope(s) of AT III occurred in a concerted fashion and followed second order kinetics with an activation energy of Ea = 31 kcal/mol. AT III-multimerization induced by treatment with 1 M guanidine (mainly AT III-tetramers with M(r) of 250,000) and formation of the binary AT III-thrombin complex revealed similar self-association patterns as judged by gel electrophoresis under non-denaturing conditions. In the presence of heparin, even higher multimers of AT III-thrombin complexes were noted. Moreover, self-association products of the ternary vitronectin-thrombin-AT III complex, which is the ultimate reaction product following thrombin inhibition in the circulation, could be recognized and quantitated due to exposure of the 4C9 epitope on AT III, indicating that AT III exists in multimeric forms within binary and ternary complexes.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibodies, Monoclonal↗

PubMed1998

Transgenically produced human antithrombin: structural and functional comparison to human plasma-derived antithrombin.

Recombinant human antithrombin (rhAT) produced in transgenic goat milk was purified to greater than 99%. The specific activity of the rhAT was identical to human plasma-derived AT (phAT) in an in vitro thrombin inhibition assay. However, rhAT had a fourfold higher affinity for heparin than phAT. The rhAT was analyzed and compared with phAT by reverse phase high-performance liquid chromatography, circular dichroism, fluorophore-assisted carbohydrate electrophoresis (FACE), amino acid sequence, and liquid chromatography/mass spectrography peptide mapping. Based on these analyses, rhAT was determined to be structurally identical to phAT except for differences in glycosylation. Oligomannose structures were found on the Asn 155 site of the transgenic protein, whereas only complex structures were observed on the plasma protein. RhAT contained a GalNAc for galactose substitution on some N-linked oligosaccharides, as well as a high degree of fucosylation. RhAT was less sialylated than phAT and contained both N-acetylneuraminic and N-glycolylneuraminic acid. We postulate that the increase in affinity for heparin found with rhAT resulted from the presence of oligomannose-type structures on the Asn 155 glycosylation site and differences in sialylation.

Animals↗

PubMed1998

[Hereditary antithrombin deficiency and pregnancy. Pregnancy course in six women with known hereditary antithrombin deficiency].

Inherited antithrombin (AT) deficiency is a major cause of venous thromboembolism, especially in relation to surgery and pregnancy. We present six AT deficient pregnant women, who successfully delivered seven babies at the Department of Gynaecology/Obstetrics, Aalborg Hospital. From conception, or if possible prior to conception, the women were treated with unfractionated (UFH) or low molecular weight heparin (LMWH) throughout the pregnancy. If the pregnancy was without complication, AT substitution was only used at delivery and for approximately a week post-partum, when warfarin treatment was re-instituted.

Antithrombin III Deficiency↗

PubMed1997

Thyroid antibodies and their relation to antithrombin antibodies, anticardiolipin antibodies and lupus anticoagulant in women with recurrent spontaneous abortions (antithyroid, anticardiolipin and antithrombin autoantibodies and lupus anticoagulant in habitual aborters).

OBJECTIVE: This study was undertaken to evaluate the incidence of thyroid autoantibodies in women with a history of recurrent spontaneous abortions (RSA) and to investigate their relationship to non-organ specific autoantibodies. STUDY DESIGN: 28 euthyroid non-pregnant habitual aborters were analysed for thyreoglobulin (TG), thyroid peroxidase antibodies (TPO), and autoantibodies to thromboplastin, cardiolipin and lupus anticoagulant. 28 multigravidae without previous abortions or endocrine dysfunctions served as controls. RESULTS: 11 of 28 women with recurrent spontaneous miscarriage (39%), but only 2 of 28 controls (7%) (Chi square test: p < 0.01) demonstrated positive titres of TG, TPO, or both antibodies, 12 patients were positive for antithrombin antibodies and 3 for anticardiolipin. Only one women was lupus anticoagulant positive. No significant correlation between thyroid antibody positivity and positivity for antiphospholipids (Fisher's exact test: p = 0.441), anticardiolipin (p = 0.664) or lupus coagulant (p = 0.607) was found. CONCLUSIONS: The incidence of thyroid antibodies in euthyroid women with recurrent pregnancy loss appears to be significantly increased compared with controls of reproductive age without previous abortions. No correlation between the presence of thyroid autoantibodies and non-organ specific autoantibodies could be established.

Abortion, Habitual↗

PubMed2004