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PubMed1997

Genetic analysis in Japanese kindreds of congenital type I antithrombin deficiency causing thrombosis.

We have identified two novel minor deletions (case 1; -TA or -AT at nucleotide 9831-3 in exon 5 and case 2; -A at nucleotide 7640-1 in exon 4), one novel nonsense mutation (case 3; TAT to TAA at nucleotide 7491 in exon 4), and one recurrent nonsense mutation (case 4; CGA to TGA at nucleotide 5381 in exon 3A) in Japanese kindreds with congenital type I antithrombin deficiency. The deletion detected in case 1 represented a symmetric element (CTCTGTCTC) and possessed a direct repeat (CTCTATGTCTC). The deletion in case 2 was recognized in a consensus sequence (TGAAT) and possessed a direct repeat (GATGAA). The nonsense mutation in case 3 formed a palindrome (CCGTTAACGG) and that in case 4 was caused by a CpG dinucleotide mutation. These results confirm that the mutations of congenital type I antithrombin deficiency are not random events but are influenced strongly by DNA sequences.

Adult↗
PubMed1996

[Genetic polymorphism of antithrombin III in five Chinese populations].

The genetic polymorphisms of antithrombin III (AT III) in 5 Chinese populations were studied by isoelectric focusing on polyacrylamide gels followed by immunoblotting. The products of two alleles at the antithrombin III locus together with 1 AT III anodic variant and 3 cathode variants were observed. The results revealed that the predominant allele of AT III blood group system in Chinese populations was AT III *1, with frequencies between 0.9773-0.9850. Frequencies of AT III *2 ranged from 0.0091 to 0.0169. These results indicate that the polymorphic information content of AT III blood group system in Chinese populations is limited.

Alleles↗
PubMed1997

[Mesenteric venous thrombosis and antithrombin III deficiency: diagnosis before an acute digestive hemorrhage].

Mesenteric venous thromboses are often associated with antithrombin III deficiency. We can suspect this clinical diagnosis in patients with nonspecific abdominal pain syndrome and personal or familial history of mesenteric venous thrombosis. We report the case of a 63-old-male caucasian with antithrombin III deficiency and rectal bleeding who was diagnosed with mesenteric venous thrombosis at exploratory laparotomy. This case emphasizes the necessity of a careful history in all patients without an obvious diagnosis. In this way, we can invoke the diagnosis of mesenteric venous thrombosis quickly and begin the heparin therapy while waiting for the results of further confirmatory tests.

Antithrombin III Deficiency↗
PubMed1999

Antithrombin agents as anticoagulants and antithrombotics: implications in drug development.

The development of direct thrombin inhibitors goes back nearly four decades. Organic synthetic benzamidine derivatives were initially developed as direct antithrombin agents. Later, the structural analysis of fibrinogen, leading to the identification of thrombin cleavage sites, resulted in the recognition of specific peptide sequences where thrombin cleaved fibrinogen. These observations led to the development of synthetic peptide derivatives as inhibitors of thrombin. The leech salivary extract contained natural hirudin, the structural elucidation of which led to the development of a recombinant equivalent protein (r-hirudin). Understanding the biochemical actions of thrombin and the structure of various inhibitors prompted the development of hirulogs, a class of hybrid molecules with two sites of action. Currently, several of these thrombin inhibitors are being developed for various indications in both intravenous and subcutaneous protocols. The increased interest in thrombin inhibitors is also prompted by reports of heparin-induced thrombocytopenia (HIT) with heparin and the need to anticoagulate patients with alternate drugs. These agents produce a direct anticoagulant response by targeting thrombin. In addition, the amplification of the coagulation cascade by thrombin activation of factors V and VIII, stabilization of fibrin by activated factor XHI, and platelet activation is also inhibited by these thrombin inhibitors. Some of the synthetic thrombin inhibitors are also capable of inhibiting other enzymes in the coagulation cascade. Thrombin inhibitors therefore exert a complex effect on the coagulation network and should be carefully evaluated in clinical trials. These drugs can be used for prophylactic and therapeutic and surgical indications. However, the different thrombin inhibitors have shown distinct pharmacologic differences. There is now an interest in developing oral antithrombin inhibitors. Such issues as antagonism, laboratory monitoring, drug interactions, and long-term safety remain unresolved. Current research is focused on addressing these issues.

Amino Acid Sequence↗
PubMed1987

An autoantibody with potent antithrombin activity whose action could be inhibited by toluidine blue or methylene blue.

A 41-year-old man with posthepatic liver cirrhosis and bleeding tendency was found to have a circulating anticoagulant with potent antithrombin activity. The thrombin time of the patient's purified fibrinogen was normal. This anticoagulant was residing in the patient's IgG fraction, and his IgG fraction could prolong the thrombin time of purified fibrinogen, suggesting that this circulating anticoagulant was an antibody. No heparin was detected in the patient's plasma. However, the antithrombin activity of this anticoagulant could be neutralized by toluidine blue or methylene blue ex vivo.

Adult↗
PubMed1988

Heparan sulphate with no affinity for antithrombin III and the control of haemostasis.

Heparan sulphate with no affinity for antithrombin III (ATIII) was observed to cause acceleration of the factor Xa:ATIII interaction by 1100-fold (k2, 7 X 10(7) M-1.min-1) and the prothrombinase:ATIII interaction by 2900-fold (k2, 2.5 X 10(7) M-1.min-1). Although high-affinity heparan sulphate catalyzed higher acceleration and at lower concentration, in natural mixtures of the two forms the activity of the no affinity form predominated. Heparan sulphate had no significant effect on the thrombin:ATIII interaction but inhibited its potentiation by heparin (Kd 0.3 microM). From the estimated concentration of heparan sulphate on the endothelial cell surface it is proposed that the non-thrombogenic property of blood vessels is due to the acceleration of the factor Xa or prothrombinase:ATIII interaction by the greater mass of surface-bound heparan sulphate rather than by the much smaller proportion of heparin-like molecules (with high affinity for antithrombin III) which may be present.

Angiotensin II↗
PubMed1992

Anticoagulant and antithrombin activities of oversulfated fucans.

Three species of oversulfated fucans having different sulfate contents (the ratio of sulfate/total sugar residues, 1.38-1.98) were prepared by chemical sulfation of a fucan sulfate (sulfate/sugar ratio, 1.28) isolated from the brown seaweed Ecklonia kurome. The anticoagulant activities of the oversulfated fucans were compared with that of a parent fucan with respect to activated partial thromboplastin time (APTT) and thrombin time (TT) in plasma. The respective activities (for APTT and TT) of the oversulfated fucans increased to 110-119% and 108-140% of the original values with increase in their sulfate content. The anticoagulant activity with respect to APTT (173 units/mg) of an oversulfated fucan (sulfate/sugar ratio, 1.98) was higher than that (167 units/mg) of heparin used as a standard. The heparin cofactor II-mediated antithrombin activity of the oversulfated fucans also increased significantly with increase in sulfate content. The maximum activity was higher than those of the parent fucan and heparin. However, the increment of the anticoagulant and the antithrombin effects gradually decreased with increase in the sulfate content of the fucans. These results indicate that the effects of the fucan sulfate are dependent on its sulfate content until a plateau is reached.

Anticoagulants↗
PubMed2000

Anticoagulant and antithrombin effects of intimatan, a heparin cofactor II agonist.

Surface-bound thrombin, which is resistant to inhibition by heparin/antithrombin III (/AT), plays a key role in vessel wall disease. In contrast, surface-bound thrombin is not resistant to inhibition by heparin cofactor II (HCII) and its acceleration of its inhibitory effect by dermatan sulfate. However, the potential use of dermatan sulfate to prevent thrombus formation in vivo is limited by its low specific activity, which in turn, necessitates excessively high doses when given on a gravimetric basis. Recently, a novel HCII agonist, Intimatan, has been synthesized by site-specific sulphation of highly purified dermatan sulfate comprising primarily of L-iduronic acid-4-O-sulphated N-acetyl-D-galactosamine, yielding a 4, 6-O-disulphate compound on the galactopyranose ring with a lower molecular weight, higher solubility, and specific activity than its parent, dermatan sulfate. In this study, we compared the abilities of Intimatan with its parent compound, dermatan sulfate, and with heparin to affect coagulation and to inhibit surface-bound thrombin both in vitro and in vivo, to determine if Intimatan demonstrates a better potential than either other compound in preventing thrombus formation in vivo. Intimatan prolonged the activated partial thromboplastin time (APTT) more effectively than either dermatan sulfate or heparin at comparable antithrombin concentrations. This activity was attributed to the more selective action of Intimatan against surface-bound thrombin in vitro. Intimatan also inhibited thrombin bound to an injured vessel wall surface in vivo more effectively than heparin, i.e., when measured in injured carotid arteries of rabbits injected with Intimatan or with heparin at the time of injury. We conclude that Intimatan effectively inhibits surface-bound thrombin, thereby exhibiting better anticoagulant and antithrombin properties than heparin and dermatan sulfate.

Animals↗
PubMed1999

Heparin induced thrombocytopenia: diagnosis and contemporary antithrombin management.

Heparin-induced thrombocytopenia (HIT) may be complicated by severe thrombotic complications and death. Currently no specific laboratory test is available to make the diagnosis. When HIT is clinically suspected, heparin should be discontinued immediately. While no specific therapy for HIT exists, there is increasing evidence that acute antithrombin therapy may significantly reduce morbidity and mortality. Among several agents, the direct antithrombins, such as r-hirudin and argatroban, look the most promising for acute treatment.

Ancrod↗
PubMed1990

Novel sulfated polysaccharides: dissociation of anti-human immunodeficiency virus activity from antithrombin activity.

Novel sulfated polysaccharides, sulfated bacterial glycosaminoglycan (Org 31581) and chemically degraded heparin (Org 31733), have proved to be potent and selective inhibitors of human immunodeficiency virus (HIV) in vitro. Their 50% inhibitory concentrations for HIV type 1 (HIV-1) in MT-4 cells were 0.67 and 0.52 micrograms/ml, respectively. These values are comparable to those obtained for dextran sulfate and standard heparin (0.39 and 0.89 micrograms/ml, respectively). Org 31581 and Org 31733 showed much less antithrombin activity than did dextran sulfate and standard heparin. These results indicate that the anti-HIV activity of sulfated polysaccharides can be dissociated from their antithrombin activity. Org 31581 and Org 31733 were equally inhibitory to HIV-2 and HIV-1 and were also inhibitory to the replication of human cytomegalovirus. Syncytium formation, induced by cocultivation of MOLT-4 (clone 8) cells with chronically HIV-1-infected HuT 78 cells, was also inhibited by Org 31581. As previously demonstrated with dextran sulfate and heparin, both Org 31581 and Org 31733 blocked virus adsorption to the host cells. These compounds offer great promise as candidate drugs for the chemotherapy of HIV infections.

Blood Coagulation↗
PubMed1999

Detection of two novel mutations (nt2762, exon 2, CAG to TAG, and nt2483 or 2484, exon 2, +A) in individuals with congenital type I antithrombin deficiencies.

Genetic analyses were performed on two Japanese kindreds with congenital type I antithrombin deficiency causing recurrent thrombosis. The seven exons and flanking intron regions of the antithrombin gene were amplified by polymerase chain reaction followed by direct nucleotide sequencing. In case 1, one novel nonsense mutation, CAG to TAG at codon 100, nucleotide 2762, in exon 2, was detected. In case 2, one novel minor insertion, AT to AAT at codon 7, nucleotide 2483 or 2484, in exon 2, was detected, leading to a frameshift which resulted in a stop codon TGA at codon 32.

Adolescent↗
PubMed1997

Effect of nonspecific binding to plasma proteins on the antithrombin activities of unfractionated heparin, low-molecular-weight heparin, and dermatan sulfate.

BACKGROUND: Nonspecific binding to plasma proteins decreases the anti-factor Xa (anti-Xa) activity of unfractionated heparin (UFH) but not that of low-molecular-weight heparin (LMWH). However, plasma proteins could influence the anti-thrombin (anti-IIa) activity of LMWH. To explore this possibility, we compared the effects of plasma proteins on the anti-IIa activities of UFH and LMWH. We also examined their effects on the anti-IIa activity of dermatan sulfate (DS) because, like UFH, DS binds to plasma proteins. METHODS AND RESULTS: There was almost complete recovery of anti-IIa activity when UFH, LMWH, or DS was added to plasma from each of 20 healthy volunteers. The addition of a chemically modified heparin with low affinity for antithrombin III to plasma containing UFH increased the anti-IIa activity in a concentration-dependent fashion by displacing UFH from plasma proteins. In contrast, addition of low-affinity heparin had no effect on the anti-IIa activity of LMWH. LMWH does not bind to plasma proteins because the bulk of the LMWH chains are < 6000 D, and only heparin fractions > 6000 D bind nonspecifically to plasma proteins. As further evidence that plasma proteins do not influence the anti-IIa activity of LMWH, the rate of thrombin inhibition in plasma in the presence of LMWH is virtually identical to that in buffer containing physiological amounts of the major antithrombins. In contrast, with UFH or DS, the rate of thrombin inhibition is twofold slower in plasma than in buffer. CONCLUSIONS: Nonspecific binding of UFH to plasma proteins most likely contributes to the variable anti-IIa response to UFH in patients with thromboembolic disease. Although DS also binds to plasma proteins, the clinical significance of this finding is unclear. In contrast, because LMWH does not bind to plasma proteins, the anti-IIa activity of LMWH should be just as predictable as its anti-Xa activity.

Anticoagulants↗
PubMed2002

Direct antithrombin agents ameliorate disseminated intravascular coagulation in suspected heparin-induced thrombocytopenia thrombosis syndrome.

This is a case series of 5 patients who were treated with the direct antithrombin agents (lepirudin or argatroban) for known or suspected heparin-induced thrombocytopenia thrombosis syndrome (HITTs). Coincidentally all had evidence of disseminated intravascular coagulation (DIC). The DIC parameters improved with treatment and each patient was successfully discharged from the hospital. These observations provide evidence that the direct antithrombin inhibitors, lepirudin and argatroban, can improve DIC. Moreover the presence of DIC in a patient with suspected HlTTs should not mitigate against the use of these agents.

Adult↗
PubMed2006

Antithrombin III (AT) and recombinant tissue plasminogen activator (R-TPA) used singly and in combination versus supportive care for treatment of endotoxin-induced disseminated intravascular coagulation (DIC) in the neonatal pig.

BACKGROUND: Disseminated intravascular coagulation (DIC) is a pathological disturbance of the complex balance between coagulation and anticoagulation that is precipitated by vascular injury, acidosis, endotoxin release and/or sepsis and characterized by severe bleeding and excessive clotting. The innately low levels of coagulation factors found in newborn infants place them at extremely high risk for DIC. Anecdotal reports suggest that either anticoagulant or fibrinolytic therapy may alleviate some of the manifestations of DIC. To test the hypothesis that replacement of both anticoagulants and fibrinolytics may improve survival and outcome better than either single agent or supportive care alone, we utilized a neonatal piglet model of endotoxin-induced DIC. METHODS: DIC was induced in twenty-seven neonatal pigs (7 to 14 days of age) by intravenous administration of E. coli endotoxin (800 microg/kg over 30 min). The piglets were divided into 4 groups on the basis of treatment protocol [A: supportive care alone; B: Antithrombin III (AT, 50 microg/kg bolus, 25 microg/kg per hr continuous infusion) and supportive care; C: Recombinant Tissue Plasminogen Activator (R-TPA, 25 microg/kg per hr continuous infusion) and supportive care; D: AT, R-TPA and supportive care] and monitored for 3 primary outcome parameters (survival time, macroscopic and microscopic organ involvement) and 4 secondary outcome parameters (hematocrit; platelet count; fibrinogen level; and antithrombin III level). RESULTS: Compared with supportive care alone, combination therapy with AT and R-TPA resulted in a significant improvement of survival time, hematocrit, AT level, macroscopic and microscopic organ involvement, p < 0.05. Compared with supportive care alone, R-TPA alone significantly reduced macroscopic organ involvement and AT alone increased AT levels. CONCLUSION: The findings suggest that combining AT, R-TPA and supportive care may prove more advantageous in treating the clinical manifestations of DIC in this neonatal pig model than either single modality or supportive care alone.

Journal Article↗
PubMed1998

Chemical structure of antithrombin-active Rhamnan sulfate from Monostrom nitidum.

Rhamnan sulfate was extracted with boiling water from the cell wall of Monostroma nitridum, and the resulting extract was purified by ion-exchange and size-exclusion chromatography. The polysaccharide, which is regarded as a homopolysaccharide, was 6-fold more antithrombin-active than the heparin standard. The antithrombin activity was decreased, by desulfation, although the non-active product still retained 8% of the sulfate ester. A comparative structural study of the intact rhamnan sulfate and rhamnan, its desulfated product, by periodate oxidation, Smith degradation and methylation analysis revealed the rhamnan sulfate to consist of alpha-1,3-linked L-rhamnose residues, some of which were substituted with sulfate groups mainly at position O-2. Minor amounts of internal 1,2-linked rhamnose and branched rhamnose linkages were also detected.

Carbohydrate Sequence↗
PubMed2003

Advances in antithrombin therapy for ST-elevation myocardial infarction.

Thrombin is a pivotal molecule in acute myocardial infarction (MI) because of its extensive procoagulant and prothrombotic actions. Antithrombin therapy is an important component of the pharmacotherapy for acute MI. The standard agent used in clinical practice, unfractionated heparin (UFH), is associated with the disadvantages of variable anticoagulant effect, inability to inhibit clot-bound thrombin, neutralization by platelet factor 4, and the propensity to cause thrombocytopenic complications. Novel thrombin inhibitors have been developed to overcome these disadvantages. Although possessing the property of inhibiting both fluid-phase and clot-bound thrombin, the direct thrombin inhibitor hirudin has been shown to give marginal benefits over UFH as adjunct to fibrinolysis in ST-elevation MI. Bivalirudin, another direct thrombin inhibitor, is able to reduce reinfarction in patients treated with streptokinase and is a new anticoagulant treatment option in this setting. The pharmacokinetic characteristics of better availability, longer half-life, and dose-independent clearance together with the ability of inhibiting both thrombin generation and activity make the low-molecular-weight heparins (LMWHs) an attractive alternative to UFH. The favorable benefit/risk profile of the LMWHs as adjunct to different generations of fibrinolytic agents is setting the stage for larger clinical trials to confirm their role as the antithrombin agent of choice for STEMI.

Anticoagulants↗
PubMed1979

[Heparin inhibition of the antithrombin activity of alpha-2-macroglobulin].

The interaction between thrombin and alpha-2-macroglobulin was studied on human purified materials, either in the presence or in the absence of heparin, by kinetic analysis of thrombin inhibition and polyacrylamide gel electrophoresis. In the absence of heparin, binding of thrombin to alpha-2-macroglobulin, shown by electrophoresis, leads to the loss of the coagulant property of the enzyme. In the presence of heparin the rate of inhibition of thrombin clotting activity by alpha-2-macroglobulin is strongly decreased. Heparin binds to thrombin, impairing the formation of thrombin-alpha-2-macroglobulin complex. These data show that heparin paradoxically protects thrombin from inhibition by alpha-2-macroglobulin whereas it increases the enzyme inhibition by antithrombin III. Such a phenomenon could be of practical interest for treatment of thrombosis in patients with high plasma level of alpha-2-macroglobulin and low level of antithrombin III, such as occurs in the nephrotic syndrome.

Heparin↗
PubMed1991

P1 variant antithrombins Glasgow (393 Arg to His) and Pescara (393 Arg to Pro) have increased heparin affinity and are resistant to catalytic cleavage by elastase. Implications for the heparin activation mechanism.

The heparin affinity of normal and two P1 variants of antithrombin-III (AT) was studied by gradient elution with NaCl in Tris buffer on heparin-Sepharose. At pH 7.4 normal AT eluted at [Na+] 0.78 mol/l and the variants both showed increased affinity with AT Pescara eluting at [Na+] 0.86 mol/l and AT Glasgow at [Na+] 0.92 mol/l. We have earlier proposed a model for heparin activation in which the native state of AT maintains a salt bridge involving the P1 Arg-393 residue. Binding of heparin induces a higher heparin affinity conformation in which the salt bridge is disrupted to reveal the reactive centre for inhibition of thrombin. The Glasgow and Pescara variants, lacking a reactive centre P1 basic residue, would be unable to form this salt bridge, and we suggested that the high affinity conformation which they adopt as their native state would resemble the heparin induced conformation. To examine this model, we measured the heparin induced fluorescence of two P1 variants and tested the susceptibility of their reactive loops to catalytic cleavage. Both variants had fluorescence spectra indistinguishable from normal AT. In the absence of heparin, neither variant was more susceptible than normal to catalytic cleavage by human neutrophil elastase. These findings suggest that the conformation of these P1 variants is different to that of fully heparinized normal AT.

Antithrombin III↗