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PubMed2004

Recombinant human antithrombin III: rhATIII.

GTC Biotherapeutics (formerly Genzyme Transgenics Corporation) is developing a transgenic form of antithrombin III known as recombinant human antithrombin III [rhATIII]. It is produced by inserting human DNA into the cells of goats so that the targeted protein is excreted in the milk of the female offspring. The transgenic goats have been cloned in collaboration with the Louisiana State University Agriculture Center. GTC Biotherapeutics is conducting clinical trials of rhATIII in coagulation disorders. rhATIII is believed to be both safer and more cost-effective than the currently available plasma-derived product. rhATIII is also being investigated in cancer and acute lung injury. Genzyme Transgenics Corporation, originally a subsidiary of Genzyme Corporation, changed its name to GTC Biotherapeutics in June 2002; it is no longer a subsidiary of Genzyme Corporation. GTC Biotherapeutics is seeking partners for the commercialisation of rhATIII. Restructuring of GTC Biotherapeutics to support its commercialisation programmes was announced in February 2004. Genzyme Transgenics Corporation was developing rhATIII in association with Genzyme General (Genzyme Corporation) in the ATIII LLC joint venture, but in November 2000 a letter of intent was signed for the reacquisition of the rights by Genzyme Transgenics Corporation. It was announced in February 2001 that this reacquisition was not going to be completed and that the development of rhATIII was to continue with ATIII LLC. However, in July 2001, Genzyme Transgenics Corporation reacquired all the rights in the transgenic antithrombin III programme. SMI Genzyme Ltd, a joint venture between Sumitomo Metal Industries, Japan, and Genzyme Transgenics Corporation, USA, was set up to fund development of transgenic antithrombin III in Asia. However, in October 2000, Genzyme Transgenics Corporation reacquired, from Sumitomo Metal Industries, the rights to its technology for production of medicines from milk in 18 Asian countries, including Japan. The 10-year-old joint venture, SMI Genzyme Ltd, was dissolved. In June 2002, GTC Biotherapeutics estimated the current market size for plasma ATIII products to be approximately $US250 million - of which sales in Europe amounted to $US110 million, Japan $US130 million and the US $US10 million.

Animals↗

PubMed1984

Inhibition of heparin-catalyzed human antithrombin III activity by nonenzymatic glycosylation. Possible role in fibrin deposition in diabetes.

The effect of nonenzymatic glycosylation on the biologic function of human antithrombin III was evaluated using a chromogenic thrombin substrate assay in the presence of catalytic amounts of heparin. Experimental conditions that increased the rate of nonenzymatic protein glycosylation were associated with decreases in the thrombin-inhibiting activity of antithrombin III. This glycosylation-induced inhibition of heparin-catalyzed antithrombin III activity was completely reversible by preassay incubation with excess sodium heparin. These observations provide a biochemical explanation for the heparin-reversible, accelerated fibrinogen disappearance rate induced by hyperglycemia in diabetic patients. Defective inhibition of the coagulation cascade induced by excessive nonenzymatic glycosylation of antithrombin III in vivo could contribute to accumulation of fibrin in various diabetic tissues.

Antithrombin III↗

PubMed1991

Functional antithrombin-III variant (41 Pro----Leu) identified by liquid secondary ion mass spectrometry.

A genetic variant of antithrombin with impaired heparin cofactor activity was identified in 4 members of a French family. Both the variant and normal antithrombin component were purified by affinity chromatography on heparin Sepharose. Reverse phase peptide mapping revealed a single altered peak when tryptic digests of both antithrombins were compared. After further purification of the aberrant peptide, amino acid analysis indicated a substitution of 41 Leu----Pro (antithrombin Basel). This result was confirmed by liquid secondary ion mass spectrometry which gave a measured mass of 816.4655 Da for the new peptide compared to a calculated mass of 800.3579 Da for the normal peptide and 816.4579 for the Leu----Pro substitution.

Adult↗

PubMedDate not supplied

The effects of hormone replacement therapy on antithrombin III and protein C levels in menopausal women.

OBJECTIVE: To determine if menopausal women taking estrogen with and without progestin are at increased risk for thrombotic disease as evidenced by decreased levels of antithrombin III and protein C. DESIGN: A case controlled study. SETTING: General community in southeastern New Hampshire. PARTICIPANTS: One hundred seventy-one healthy women aged 38 to 65 years. Women were defined as premenopausal if follicle stimulating hormone levels were < 40 mIU/ml and menopausal if follicle stimulating hormone levels were > 40 mIU/ml. Menopausal women were subdivided according to hormone replacement therapy status; women not taking estrogen or progestin, and women taking estrogen with and without progestin for at least 1 year. MAIN OUTCOME MEASURES: Significant differences in antithrombin III and protein C levels. RESULTS: Premenopausal women had significantly less antithrombin III than menopausal women not taking hormone replacement therapy. Premenopausal women had significantly less protein C than menopausal women taking estrogen for at least 1 year with and without progestin. CONCLUSION: Estrogen taken for at least 1 year with and without progestin by menopausal women will not increase the risk of thrombotic disease by lowering the levels of antithrombin III or protein C. On the contrary, estrogen is associated with an increase in circulating levels of protein C in menopausal women, and could create a protective effect not seen in premenopausal women or menopausal women not taking estrogen therapy.

Adult↗

PubMed1999

Antithrombin replacement in patients with sepsis and septic shock.

Sepsis is a frequent complication of critically ill patients and its incidence is increasing. Currently, septic shock is the most common cause of death in non-coronary intensive care units. Over the last 10 to 15 years, new antibiotics and increasingly sophisticated critical care have had little impact on the mortality rate of septic shock. The Italian SEPSIS Study, carried out in 99 intensive care units in 1994, reported mortality rates of 52% and 82% for severe sepsis and septic shock respectively. New therapeutic approaches aimed at neutralizing microbial toxins and modulating host mediators have shown some efficacy in large clinical trials and/or in animal models, but to date, no therapy of sepsis aimed at reversing the effects of bacterial toxins or of harmful endogenous mediators of inflammation has gained widespread clinical acceptance. Because of the strong association of severe sepsis with a state of activation of blood coagulation and of the potential role of capillary thrombosis in the development of the multiple organ dysfunction syndrome, anticoagulant agents have been tested in the setting of septic shock. However, neither administration of heparin nor of active site-blocked factor Xa or of anti-tissue factor antibodies have proven effective in preventing deaths due to septic shock in animal models. In contrast, infusion of antithrombin, protein C, or tissue factor pathway inhibitor all resulted in a significant survival advantage in animals receiving lethal doses of E. Coli. Antithrombin concentrates have been used in a significant number of critically ill patients. A double-blind, placebo controlled study carried out in 3 italian intensive care units has recently shown that the administration of antithrombin aimed to normalize plasma antithrombin activity had a net beneficial effect on 30-day survival of patients requiring respiratory and/or hemodynamic support because of severe sepsis and/or post-surgery complications.

Antithrombins↗

PubMed1999

Plasma antithrombin III deficiency in ischaemic stroke in the young.

A deficiency of plasma antithrombin III has been identified as a potential risk factor for thrombosis. In a pilot study of 56 patients aged less than 40 years who presented with ischaemic stroke of unknown etiology, we detected only one case of plasma antithrombin III deficiency. Antithrombin III activity was estimated by a chromogenic assay. Hence, antithrombin III deficiency, though rare, should be considered while evaluating young patients with stroke of unknown etiology.

Adult↗

PubMed1999

A collaborative study to establish the 2nd International Standard for Antithrombin Concentrate.

Eighteen laboratories participated in a collaborative study to calibrate a replacement for the 1st International Standard for Antithrombin. Concentrate (88/548). Excellent agreement between laboratories, as indicated by mean % gcv of 3.3 and 5.9 for functional and antigenic assays, was observed when the candidate concentrate (96/520) was assayed against the 1st International Standard for Antithrombin, Concentrate (88/548). The functional potency was found to be 7.9% (p<0.05) lower than the antigenic potency. Based on the results and with the agreement of the participants of this study and the authorisation of the Expert Committee on Biological Standardisation of the World Health Organisation, the antithrombin concentrate, coded 96/520, has been established as the 2nd International Standard for Antithrombin, Concentrate, with labelled potencies for both functional (4.7 IU/ampoule) and antigenic (5.1 IU/ampoule) activities.

Antithrombins↗

PubMed1999

The incidence of venous thromboembolism in asymptomatic carriers of a deficiency of antithrombin, protein C, or protein S: a prospective cohort study.

Deficiencies of antithrombin, protein C, and protein S are associated with an increased risk of venous thromboembolism. The objective of this study was to prospectively assess the incidence of venous thromboembolism in nontreated asymptomatic subjects with such a deficiency. We conducted a prospective cohort study in asymptomatic family members of unselected patients who presented with a venous thromboembolic event and who were found to have a deficiency of antithrombin, protein C, or protein S. No anticoagulant prophylaxis was given to the study participants, except during risk periods for venous thromboembolism. All venous thromboembolic events were diagnosed by objective diagnostic tests. A total of 208 individuals with a mean age of 37 years (range, 15 to 79) were included in the study. A total of 611 patient observation years was obtained. Nine venous thromboembolic events occurred, resulting in an annual incidence of 1.5% (95% confidence interval [CI], 0.7 to 2.8) for the 3 deficiencies combined. Five of these events occurred spontaneously, resulting in an annual incidence of spontaneous venous thromboembolism of 0.8% (95% CI, 0.3 to 1.9). For antithrombin, protein C, and protein S deficiencies separately, this figure was 1.6%, 1.0%, and 0.4%, respectively. Thirty-four subjects experienced a total of 40 risk periods during which 4 venous thromboembolic events occurred (10% per risk period). We conclude that the use of continuous anticoagulant prophylaxis seems not warranted in asymptomatic individuals with a deficiency of antithrombin, protein C, or protein S. During risk periods for venous thromboembolism, adequate anticoagulant prophylaxis is necessary.

Adult↗

PubMed1975

Activation of human prothrombin by highly purified human factors V and X-a in presence of human antithrombin.

In this communication we describe the first method for isolating human Factor V. The final product contains no other coagulation components as judged by functional assays and is physically homogeneous as shown by isofocusing gel electrophoresis. In addition, we present a means for obtaining intrinsically activated human Factor X-a. This preparation is usually homogeneous as judged by isofocusing gel electrophoresis. However, on occasion, an additional minor electrophoretic species with Factor X-a activity is observed. Furthermore, we describe the use of isoelectric focusing in sucrose density gradients to free human prothrombin from contamination by coagulation factors and other components. These homogeneous human proteins are employed to examine the conversion of prothrombin to thrombin in the presence and absence of human antithrombin. The latter component is responsible for virtually all of the plasm's capacity to neutralize Factor X-a and thrombin. In the absence of antithrombin, prothrombin (67,800) is converted to the precursor P-2 (51,600) and the fragment F-a (19,500). Subsquently, P-2 is cleaved to form the precursor P-3 (37,000), and the fragment F-b (11,500). Finally, P3 IS proteolyzed to form the heavy chain T-h (29,500) and the light chain T-L (6,500) of active thrombin. In the presence of antithrombin, an additional prothrombin conversion pathway is observed in which the zymogen is directly cleaved to form P-3 and F-A + B (30,000) prior to thrombin generation. Trace amounts of free thrombin remain uninhibited by antithrombin and could bias the zymogen activation pathway. Hirudin is known to neutralized thrombin instantaneoulsly. We demonstrate that the purified leech protein also binds to P-3 and prevents thrombin formation. When hirudin is added to activation mixtures at concentrations sufficient to virtually suppress P-3 conversion to thrombin, molecular species from both activation pathways are observed. Thus two human prothrombin conversion sequences appear to be initiated by Factor X-3 and may be of physiological significance.

Antithrombins↗

PubMed2002

[Standardization of the laboratory method for antithrombin activity measurement].

Measurement of antithrombin (AT) activity in plasma provides important information for the diagnosis of congential antithrombin deficiency and disseminated intravascular coagulation. When measured in the presence of heparin, plasma antithrombin activity includes heparin cofactor II activity as about 20-30% of the total activity. Antithrombin assay methods measuring plasma anti-F.Xa activity or those measured in the presence of 0.22 M NaCl exclude the influence of HC II activity. Dilution of the plasma sample is necessary to measure the heparin cofactor anti-thrombin activity of AT correctly. A laboratory method that precisely reflects plasma heparin cofactor anti-thrombin activity of AT should be established as the standard laboratory method.

Antithrombins↗

PubMed1992

Insertions/deletions in the antithrombin gene: 3 mutations associated with non-expression.

We have investigated the molecular basis of antithrombin deficiency in 3 individuals, 2 of whom had a proven family history of thromboembolic disease. An approximate 50% reduction in functional and immunologic levels of antithrombin was detected in plasma from the propositi indicating an allelic deficiency of antithrombin. In each case direct sequencing of amplified DNA revealed a novel mutation involving single bases: two being insertions, of a T in codon 48 and an A in codon 208, and the third being the deletion of an A in codon 370. The three mutations, which were confirmed by cloning and sequencing the normal and variant alleles, all caused frameshifts leading to premature termination of protein translation. In no case could a truncated antithrombin be detected in plasma from the propositus suggesting either that it fails to be secreted, or is rapidly degraded.

Adult↗

PubMed1997

[The antithrombin action of stichopus japonicus acid mucopolysaccharide (Sjamp) is mediated by heparin cofactor II].

OBJECTIVE: To further evaluate the antithrombin mechanism of stichopus japonicus acid mucopolysaccharide (Sjamp). METHODS: The antithrombin mechanism of Sjamp was checked by assaying its effects on the thrombin activity in normal human pooled plasma,purified human heparin cofactor II (HC II) system and antithrombin III (AT III) system. RESULTS: Sjamp inhibited thrombin activity in the presence of HC II with a second order rate constant of 1.56 x 10(7) m(-1) x min(-1), which was 4.6 times as much as that of AT III. CONCLUSION: Sjamp was similar to dermatan sulfate both in the efficiency and in the mechanism of antithrombin.

Animals↗

PubMed2006

[Antithrombotics (Antithrombin therapy)].

Thrombus on the atherosclerotic plaque is mainly responsible for acute coronary syndromes. Antithrombin therapy continues to be the mainstay of the therapy defeating thrombus. Up-to-date antithrombin therapy consists of vitamin K antagonists, unfractionated and low molecular heparins, direct thrombin inhibitors and selective inhibitors of factor Xa. Today, none of these drugs is effective enough in every aspect. The need for new antithrombin drugs, as well as the need for new antiplatelet drugs which can be safely and effectively used together with other antithrombin drugs, persists.

Antithrombins↗

PubMed1990

Hydrophobic residues 382-386 of antithrombin III, Ala-Ala-Ala-Ser-Thr, serve as the epitope for an antibody which facilitates hydrolysis of the inhibitor by thrombin.

In the presence of a monoclonal antibody raised against the human thrombin-antithrombin III complex, the reaction between thrombin and antithrombin III proceeded to form preferentially a two-chain form of the inhibitor rather than to follow the major pathway of stable acyl complex formation. We thus propose the term "switching antibody" for an antibody that switches the enzyme-inhibitor reaction (Asakura, S., Matsuda, M., Yoshida, N., Terukina, S., and Kihara, H. (1989) J. Biol. Chem. 264, 13736-13739). By analyzing a CNBr fragment of the thrombin-antithrombin III complex that reacts with the antibody we localized the epitope for the antibody to a strongly hydrophobic residue 382-386 peptide segment, Ala-Ala-Ala-Ser-Thr, of the inhibitor, which is also contiguous with a hydrophobic amino acid Ala at its carboxyl terminus. This particular region should be cryptic in nascent antithrombin III, but could have been exposed to provide the reactive site for the antibody at an early stage of the reaction. Thereby a conformational change may have been induced at or near the reactive site of the complex, facilitating hydrolysis of the inhibitor by the enzyme. Interestingly, this hydrophobic region is highly conserved among members of the serpin family.

Amino Acid Sequence↗

PubMed1990

[Oral contraceptive agents and antithrombin III].

Antithrombin III is one of the most important inhibitors of serine proteases of coagulation and fibrinolysis. It inhibits the activity of thrombin and factor X. Its congenital or acquired reduction leads to an increased risk of thrombosis. In their study the authors aimed to investigate the influence of oral contraceptive preparations--Gravistat and Nonovolan on the activity of antithrombin III. Thirty five women, receiving these drugs for a period of one month to ten years (on the average two and a half years were examined. All women received the drugs in accordance with the physician prescription, taking into consideration the lack of history data on increased frequency of thrombosis. Part of the examined group (the first ten on the table of the results) were smokers with mean usage of 15 cigarettes per day. The study was carried out on 25 women at the three stages of the hormonal cycle, but singly on the remaining 10 women in its beginning. Blood sample for examination was taken with anticoagulant (citrate) in the morning before breakfast and the activity of the inhibitor was determined by kinetic colorimetric method and chromatogenic Chromasin TN (a modification of Kamenov). The results were presented in percentages. The mean activity of antithrombin III was: means = 107.5%, which did not differ from the reference values. The activities at the three phases of the menstrual cycle did not differ significantly (p greater than 0.05). The results, obtained from the study, proved that hormonal contraceptive drugs did not reduce the activity of antithrombin III.

Adult↗

PubMed1991

Platelet function, antithrombin-III activity, and fibrinogen concentration in heartworm-infected and heartworm-negative dogs treated with thiacetarsamide.

Platelet aggregation and release, platelet number, mean platelet volume, antithrombin-III activity, and fibrinogen concentration were evaluated in heartworm-negative and heartworm-infected dogs at baseline and on days 3, 10, and 21 after treatment with thiacetarsamide. Platelet reactivity was enhanced in a group of dogs naturally infected with Dirofilaria immitis, compared with 2 groups of heartworm-negative dogs, but platelet reactivity was not further enhanced after treatment with thiacetarsamide. A significant decrease in antithrombin-III activity was detected 21 days after treatment. The platelets from a group of laboratory Beagles implanted with 50 adult D immitis displayed enhanced reactivity 6 months after implantation, but by 18 months, platelet reactivity had returned to near, or less than, baseline. Platelet reactivity was enhanced after thiacetarsamide treatment in this group. Thiacetarsamide-associated changes were not observed in platelet number or size; antithrombin-III activity decreased, but the change was not significant. Fibrinogen concentration was increased significantly (P less than 0.05) on day 10. Enhanced adenosine diphosphate (ADP)-induced platelet aggregation was observed on days 3, 10, and 21 after treatment in heartworm-negative dogs. This change was not observed in 6 control Beagles not treated with thiacetarsamide. Although antithrombin-III activity was decreased on day 3 and fibrinogen concentration was increased on day 10, paralleling changes observed in the heartworm-infected dogs, the changes were not statistically significant. In this study, thiacetarsamide was procagulatory in heartworm-negative dogs and may be an important contributing factor to the thromboembolism observed with adulticidal therapy.

Animals↗

PubMed1991

Influence of tryptophan modification upon digestion of antithrombin III by elastase.

Chemical modification of tryptophan residues in antithrombin III by dimethyl (2-hydroxy-5-nitrobenzyl) sulfonium bromide (HNBSB) generates products with similar levels of modification (equivalent to 0.9 mole 2-hydroxy-5-nitrobenzyl [HNB] incorporated/mole of antithrombin III) but with high or low affinity for heparin-Sepharose. Upon digestion with pancreatic or neutrophil elastase the low affinity forms generate a product of molecular weight form (55 kDa) not seen in digests of native antithrombin III or modified forms with high affinity for heparin. When measured as loss of activity the observed rate of digestion of the latter in the absence of heparin was more rapid than that of native antithrombin III. The differences in digestion are considered to be related to conformation at differences between the various forms.

Antithrombin III↗

PubMed1990

[Danazol and antithrombin III deficiency].

The study concerned 7 subjects (3 men, 4 women) with nonfamilial antithrombin III deficit which, in the absence of known causes of acquired deficiency, was defined as "sporadic". Danazol (an attenuated synthetic androgen) already shown to be capable of compensating for a lack of certain antiproteases, was given in doses of 200 mg 3 times per day for 10 days, resulting in a rapid rise (mean 21.2%) in antithrombin III values. Unlike results reported in the literature in cases of familial antithrombin III deficit, the levels did not drop below their initial values despite discontinuance of the drug but unexpectedly remained high and even shows a slight subsequent rise. Although our study was limited to 11 cases, these data seem worthy of being reported, with the prospect of other confirmations concerning either this sort of "sporadic" antithrombin III deficit or the favorable effect of Danazol, even at long term.

Antithrombin III Deficiency↗