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PubMed1981

Antithrombin deficiency--a cause of unexplained thrombosis in vascular surgery.

Antithrombin deficiencies may be the reason for seemingly unexplained thrombosis and graft failure. We treated seven patients who developed clotting difficulties as a result of antithrombin II and/or III deficiencies. In four, arterial thrombosis occurred after arterial reconstruction--three with occluded femoral grafts and one with runoff and digital vessel thrombosis that developed during profundoplasty. Two patients has spontaneous thrombosis of the arterial system of the vessels of the lower leg, and one developed ileofemoral phlebitis. Three patients had abnormally low levels of both antithrombin II and III, whereas two had low levels of antithrombin II only and two had low levels of antithrombin III. Of the four patients in whom this disorder occurred during vascular reconstruction, three experienced graft occlusion that resulted in below-knee amputation in two. There were no common predisposing factors. Antithrombin deficiency should be suspected when there is an unusual propensity to develop thrombus, when heparin cannot prolong coagulation time, and when measurements show reduced levels of antithrombin. Fresh frozen plasma should be given initially and long-term Coumadin therapy started. Early recognition and treatment is necessary to avoid limb loss or death.

Adult↗

PubMed1995

Inhibition of thrombin by antithrombin III and heparin cofactor II in vivo.

The critical role of thrombin in the pathogenesis of venous and arterial thrombosis, and the effectiveness of glycosaminoglycans as antithrombotic drugs are well known. Antithrombin III is a major inhibitor of thrombin and augmentation of its inhibitory actions by heparin is the basis for the clinical uses of heparin. Recent clinical and experimental studies have demonstrated that another glycosaminoglycan, dermatan sulfate, is an effective antithrombotic drug. Dermatan sulfate catalyses the inhibition of thrombin by heparin cofactor II. The concentrations of heparin cofactor II are higher in the plasmas of individuals with congenital antithrombin III deficiency and pregnant women than controls. The role of heparin cofactor II as a physiologic thrombin inhibitor is unknown. Enzyme-linked immunosorbent assays were used to quantify thrombin-heparin cofactor II and thrombin-antithrombin III endogenous to the plasmas of adult antithrombin III-Hamilton deficient subjects, their siblings with normal antithrombin III levels, pregnant women at term and 3 to 5 days after delivery. Both thrombin-antithrombin III and thrombin-heparin cofactor II complexed with vitronectin were detected in all the plasmas. Significantly, the concentrations of thrombin-heparin cofactor II-vitronectin were higher in the plasmas of congenital antithrombin III deficient subjects and in pre- and post-delivery plasmas than those of normal subjects. In addition, the concentrations of thrombin-heparin cofactor II decreased 3 to 5 days after delivery, reflecting the disappearance of the catalytically active dermatan sulfate elaborated by the placenta. Thus, heparin cofactor II normally inactivates thrombin in vivo, with its role increasing in conditions associated with high levels of heparin cofactor II and/or dermatan sulfate.

Adult↗

PubMed1995

Pharmacokinetics of antithrombin concentrate during autologous hematopoietic stem cell transplantation.

Antithrombin is a naturally-occurring anticoagulant protein. Congenital deficiency of this protein predisposes to thrombotic complications. Acquired deficiency of antithrombin occurs in a variety of clinical circumstances, including hematopoietic stem cell transplantation (HSCT), and is associated with multiorgan failure and death in these situations. Normalization of antithrombin levels by infusion of concentrates of this protein has been found to be beneficial in many of these situations, but has not been routinely used in HSCT. Before antithrombin concentrates can be widely recommended in HSCT, its pharmacokinetics at various phases of the transplant process must be defined to allow estimation of the proper dose and dosing interval. To this end, the recovery and half-life of antithrombin concentrate was determined prior to and 7, 14 and 28 days after beginning the preparative regimen in nine patients with lymphoma undergoing HSCT. The recovery of the infused material was constant during the transplant hospitalization, averaging 2.0% per unit/kg. The half-life, however, dropped significantly during the latter half of the transplant procedure. The half-lives pre-chemotherapy and on day 7 were similar and averaged 20.4 h. On days 14 and 21 the the half-lives were significantly lower at 12.2 and 15.5 h, respectively. The drop in half-life during the transplant process will require antithrombin concentrate to be given more frequently during this time to maintain constant antithrombin levels.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed1987

Antithrombin antigen of high molecular weight associated with neoantigen in hemophilic plasma after factor IX concentrate therapy.

These studies were performed to investigate the cause(s) of the cathodal shift of mobility seen in crossed immunoelectrophoresis of antithrombin antigen in plasma of hemophilic patients after factor IX concentrate therapy. These plasmas were shown to contain antithrombin neoantigen with apparent identity to the neoantigen present in normal serum but not present in normal plasma. Sephacryl S-200 gel chromatography of serum demonstrated that the neoantigen eluted with the first two, early eluting protein peaks; thus the neoantigen had a higher molecular weight than native antithrombin. When the chromatographic fractions containing the neoantigen were studied by crossed immunoelectrophoresis, they were found to contain antithrombin antigen of more cathodal mobility than normal. Sephacryl S-200 chromatography of factor IX concentrate-treated hemophilic plasma also showed an early eluting peak of antithrombin antigen of more cathodal mobility than normal in crossed immunoelectrophoresis. The mobility of this peak was identical to the cathodal peak found in normal serum and in early eluting fractions from chromatography of normal serum. These results support the conclusion that factor IX concentrate-treated hemophilic plasma contained a non-functional, high molecular weight form of antithrombin, associated with the presence of neoantigen, which may represent complexed and/or modified antithrombin produced by the action of the concentrates in vivo.

Antigens↗

PubMed1995

Prolonged antithrombin activity of low-molecular-weight heparins. Clinical implications for the treatment of thromboembolic diseases.

BACKGROUND: The mechanism for the efficacy of once- or twice-daily subcutaneous injections of low-molecular-weight heparins (LMWHs) for the treatment of venous thromboembolism has been difficult to explain. The confusion exists because the observation from experimental studies that the antithrombin activity of LMWHs is necessary for their antithrombotic effect is inconsistent with the reported short half-life of the antithrombin activity of LMWHs. Previous pharmacokinetic studies were performed with lower doses of LMWHs than have been used in contemporary trials, and antithrombin activity was assessed with the barely sensitive chromogenic assay. METHODS AND RESULTS: We performed a pharmacokinetic study to compare the relative half-lives of prophylactic and therapeutic doses of LMWHs assessing antithrombin activity with both the chromogenic and a more sensitive assay (plasma thrombin neutralization assay). An eight-way cross-over randomized study in healthy volunteers was performed. Enoxaparin (20 and 40 mg and 1 and 2 mg/kg) and nadroparin (7500 and 10,000 ICU and 225 and 450 ICU/kg) were administered subcutaneously. The maximal peak activity for aPTT ratio was 1.7. A dose-dependent peak activity was found for both antifactor Xa and antithrombin activities. Disappearance time of these activities after the highest dose of both LMWHs was longer than 16 hours. Overall mean antifactor Xa activity half-life was 4.6 hours. Overall mean antithrombin activity half-life was longer than 4 hours. CONCLUSIONS: Our results provide an explanation for the effectiveness of LMWHs administered either once or twice daily. High and sustained plasma antithrombin activity is achieved when LMWHs are administered in therapeutic doses used in contemporary trials with only a moderate prolongation of the aPTT.

Adult↗

PubMed2006

L-asparaginase-induced antithrombin type I deficiency: implications for conformational diseases.

Serpinopathies, a group of diseases caused by mutations that disrupt the structurally sensitive serpins, have no known acquired cause. Interestingly, l-asparaginase treatment of acute lymphoblastic leukemia patients causes severe deficiency in the serpin antithrombin. We studied the consequences of this drug on antithrombin levels, activity, conformation, and immunohistological and ultrastructural features in plasma from acute lymphoblastic leukemia patients, HepG2 cells, and plasma and livers from mice treated with this drug. Additionally, we evaluated intracellular deposition of alpha1-antitrypsin. l-Asparaginase did not affect functional or conformational parameters of mature antithrombin; however, patients and mice displayed severe type I deficiency with no abnormal conformations of circulating antithrombin. Moreover, l-asparaginase impaired secretion of antithrombin by HepG2 cells. These effects were explained by the intracellular retention of antithrombin, forming aggregates within dilated endoplasmic reticulum cisterns. Similar effects were observed for alpha1-antitrypsin in plasma, cells, and livers, and intracellular aggregates of additional proteins were observed in frontal cortex and pancreas. This is the first report of a conformational drug-associated effect on serpins without genetic factors involved. l-Asparaginase treatment induces severe, acquired, and transient type I deficiency of antithrombin (and alpha1-antitrypsin) with intracellular accumulation of the nascent molecule, increasing the risk of thrombosis.

Animals↗

PubMed1984

An abnormal plasma antithrombin with no apparent affinity for heparin.

Congenital antithrombin abnormality was found in several members of a French family. No history of thrombotic episodes was associated with this abnormality. Plasma antithrombin concentration as well as the rate of thrombin inactivation by defibrinated plasma in the absence of heparin were normal. However, the heparin cofactor activity was decreased by about 50% in plasma of affected patients. Accordingly, about half the amount of plasma antithrombin did not bind to gel bound heparin. Moreover the crossed immunoelectrophoretic pattern in the presence of heparin demonstrated two peaks of antithrombin, the slower one migrating as normal antithrombin when heparin was omitted from the first agarose gel. It was concluded that molecular alteration of the antithrombin molecule seemed to affect only the heparin binding site thus preventing from any rate enhancement of thrombin inactivation.

Antithrombin III Deficiency↗

PubMed1989

Antithrombin Chicago, amino acid substitution of arginine 393 to histidine.

Antithrombin Chicago is a functionally inactive antithrombin variant whose inheritance is associated with thrombotic disease. The variant antithrombin was isolated from plasma of the propositus by chromatography on heparin-Sepharose, followed by passage through thrombin-Sepharose to remove the normal antithrombin component that is present. A pool of fragments ("CNBr pool 4") containing the reactive site region was prepared from the reduced and S-carboxymethylated variant by cleavage with cyanogen bromide followed by reverse-phase HPLC. Sequential treatment of CNBr pool 4 with trypsin and V8 protease produced peptides whose molecular masses were then determined by fast atom bombardment mass spectrometry. The variant protein digests were characterised by a reduction of a peptide of mass 1086, corresponding to the normal antithrombin sequence Ala382-Arg393. However, they contained a peptide of mass 1748, which arises when Arg393 is replaced by His in the sequence Ala382-Arg399. It is concluded that the functional and clinical abnormalities of antithrombin Chicago are all probably caused by a single amino acid substitution, Arg393 to His.

Amino Acid Sequence↗

PubMed1989

Antithrombin: structure, genomic organization, function and inherited deficiency.

Antithrombin is a major plasma protein inhibitor of proteinases generated during blood coagulation; it plays an important role in the regulation of thrombin in blood. The anticoagulant heparin greatly accelerates the rate of inactivation of proteinases by antithrombin, predominantly through its well defined, highly specific binding reaction with the inhibitor, but also through a less strictly defined interaction with some of the proteinases (such as thrombin). There is evidence for an analogous acceleratory mechanism in vivo, that functions by the binding of antithrombin to a subpopulation of heparan sulphate proteoglycans intercalated in the surface of endothelial cells. The location and structure of the gene for antithrombin are known. Both its overall organization and the structure of the subdomains of the expressed protein can be considered in terms of their relationships to a serine proteinase inhibitor superfamily, which is believed to have evolved from a common ancestor. The region of the antithrombin gene 5' to the coding region has been characterized. Unlike other members of the serpin family, there is no TATA-like promoter sequence. Two enhancer sequences have been identified that are homologous to enhancer regions of other genes. There are two polymorphisms: an intragenic polymorphism arising from a translationally silent A to G transition in codon 305, and a length polymorphism arising from the presence of 32 bp or 108 bp non-homologous sequences 345 bp upstream from the translation initiation codon. Inherited deficiency of antithrombin is associated with familial thromboembolism. The molecular genetic basis of some subtypes of deficiency is increasingly yielding to investigation. It is interesting to note that a number of mutations have been identified in CpG dinucleotides, supporting the suggestion that this dinucleotide sequence may represent a mutation hotspot in the human genome.

Amino Acid Sequence↗

PubMedDate not supplied

[Antithrombin III in hip surgery].

Antithrombin III is an important element of the endogenous thrombosis protection system. Congenital Anti-thrombin III deficiencies are associated with increased incidence of thrombo-embolisms. If Antithrombin III is determined at the time of operation, postoperative deficiencies resulting from an increased turnover rate can be identified. Determination of Antithrombin III is not suitable for prognosticating the occurrence of thrombo-embolic complications in isolated cases. Antithrombin III can be administered in the form of fresh frozen plasma (FFP), though it is also available as Antithrombin III concentrate. So far no investigations have been carried out to establish whether it is possible to improve thrombosis protection with or without heparin prophylaxis by concentrated Antithrombin III substitution.

Antithrombin III↗

PubMed1999

Cellular and functional characterization of three recombinant antithrombin mutants that caused pleiotropic effect-type deficiency.

Inherited antithrombin deficiency is associated with a predisposition for familial venous thromboembolic disease. Pleiotropic effect-type mutants of antithrombin that have an amino acid replacement in a distal hinge region including strands 1C, 4B, and 5B of the polypeptide chain are known to exhibit impaired interactions with both thrombin and heparin, coupled with a secretion defect. To examine the mechanism of pleiotropic effect-type antithrombin deficiency, we expressed three mutants, Oslo (Ala404-->Thr), Kyoto (Arg406-->Met), and Utah (Pro407-->Leu), in baby hamster kidney (BHK) cells, and compared their secretion rates, affinities for heparin and abilities to form thrombin-antithrombin (TAT) complexes with those of wild-type (Wt) antithrombin. Pulse-chase experiments showed that the Oslo- and Kyoto-mutants were secreted at rates similar to Wt antithrombin. In contrast, the Utah-mutant underwent partial intracellular degradation. The intracellular degradation of the Utah-mutant was not inhibited by lysosomotropic inhibitors, but by proteasome inhibitors such as carbobenzoxy-L-leucyl-L-leucyl-L-leucinal (LLL) and lactacystin, indicating that a part of the Utah-mutant was degraded by proteasome through quality control in the endoplasmic reticulum (ER). Crossed immunoelectrophoresis in the presence of heparin showed that only the Oslo-mutant lacks heparin-binding ability. Incubation with thrombin showed that the Kyoto- and Utah-mutants, but not the Oslo-mutant, formed a weak but detectable TAT complex. Furthermore, heparin enhanced the TAT complex formation by the Kyoto- and Utah-mutants, suggesting heparin cofactor activities of these mutants. These results show that each of the Oslo-, Kyoto-, and Utah-mutants exhibits different properties as to secretion, intracellular degradation and functional activity, although they are grouped as pleiotropic effect-type mutants.

Amino Acid Sequence↗

PubMed1996

Heparin cofactor II-dependent antithrombin activity of calcium spirulan.

Calcium spirulan (Ca-SP), a novel sulfated polysaccharide isolated from the blue-green alga Spirulina platensis, enhanced the antithrombin activity of heparin cofactor II (HC II) more than 10000-fold. The apparent second-order rate constant of thrombin inhibition by HC II was calculated to be 4.2 x 10(4) M-1 min-1 in the absence of Ca-SP, and it increased in the presence of 50 micrograms/ml Ca-SP to 4.5 x 10(8) M-1 min-1. Ca-SP effectively induced the formation of a thrombin-HC II complex in plasma. In the presence of Ca-SP, both the recombinant HC II variants Lys173-->Leu and Arg 189-->His, which are defective in interactions with heparin and dermatan sulfate, respectively, inhibited thrombin in a manner similar to native rHC II. This result indicates that the binding site of HC II for Ca-SP is different from the heparin- or dermatan sulfate-binding site. When we removed the calcium from the Ca-SP, the compound did not exert any antithrombin activity. Furthermore, Na-SP, which was prepared by replacement of the calcium in Ca-SP with sodium, accelerated the antithrombin activity of HC II as Ca-SP did. We therefore suggest that the molecular conformation maintained by Ca or Na is indispensable to the antithrombin activity of Ca-SP. The HC II-dependent antithrombin activity of Ca-SP was almost totally abolished by treatment with chondroitinase AC I, heparinase or heparitinase, but not by treatment with chondroitinase ABC and chondroitinase AC II, suggesting that a heparin- or dermatan sulfate-like structure is not responsible for the activation of HC II by Ca-SP. Ca-SP is therefore thought to be a unique sulfated polysaccharide which shows a strong antithrombin effect in an exclusively HC II-dependent manner.

Animals↗

PubMed2001

Prevalence of antithrombin deficiency in patients with chronic leg ulcer.

Antithrombin is one of the main endogenous anticoagulants and its deficiency is associated with deep venous thrombosis. The aim of the present study was to evaluate the prevalence of antithrombin deficiency in patients with chronic lower extremity ulcers. Forty-eight patients with chronic lower limb ulcers for longer than 10 years, evaluated during 1997, were studied: 40 were female (83.3%) and eight were male (16.6%), with ages ranging from 43 to 73 years (mean, 55.2 years). Antithrombin was dosed by the coagulometric method, with evaluation of the functional activity. Measurement was repeated in those cases where deficiency was found to be present. The highest prevalence rate for antithrombin deficiency in the general population was one in every 2000 cases. Data analysis was performed by utilizing the odds ratio with a confidence interval of 95% and P < 0.05. Deficiency in antithrombin levels was recorded in two (4.1%) of the patients with chronic ulcer. These results indicate a higher prevalence rate of antithrombin deficiency in those patients with chronic leg ulcers, suggesting that an association may be present. Further studies with a larger number of patients are required to confirm this hypothesis.

Adult↗

PubMed1989

Choice of anticoagulant in a congenital antithrombin III (AT III)-deficient patient with chronic renal failure undergoing regular haemodialysis.

We describe a 43-year-old male patient with congenital antithrombin III deficiency requiring haemodialysis due to extension of venous thrombus from recurrent deep vein thrombosis. During dialysis with adequate heparinization, the patient often revealed clot formation in the extracorporeal circuit resulting in unexpected discontinuation of dialysis. When either a combination of antithrombin III concentrate plus heparin or the newly developed synthetic antithrombin preparation, MD805, was infused during dialysis, he could be uneventfully dialysed with either of the two regimens. The functional antithrombin III activity with MD805 increased to the same level as that obtained with antithrombin III concentrate, and it was possible to achieve an antithrombotic effect, as measured from the APTT and thrombin-antithrombin III complex with MD805 during and after dialysis. We thus found that MD805 could be used as an anticoagulant drug when an AT III-deficient patient required anticoagulation in the extracorporeal circulation.

Adult↗

PubMed1988

Evidence linking familial thrombosis with a defective antithrombin III gene in two British kindreds.

Using DNA probes in a structural study of the antithrombin III gene locus we found no evidence of gene deletion in two British kindreds with inherited antithrombin III deficiency. However, linkage analysis between a common DNA polymorphism and the antithrombin III deficiency trait showed that the defect lies at or close to the antithrombin III structural gene. The lod score for linkage within the larger Scottish kindred was 3.1 (theta = 0). These results are consistent with previously published data suggesting that mutation of the antithrombin III structural gene is the cause of inherited antithrombin III deficiency in some families.

Antithrombin III↗

PubMed2006

Clinical review: molecular mechanisms underlying the role of antithrombin in sepsis.

In disseminated intravascular coagulation (DIC) there is extensive crosstalk between activation of inflammation and coagulation. Endogenous anticoagulatory pathways are downregulated by inflammation, thus decreasing the natural anti-inflammatory mechanisms that these pathways possess. Supportive strategies aimed at inhibiting activation of coagulation and inflammation may theoretically be justified and have been found to be beneficial in experimental and initial clinical studies. This review assembles the available experimental and clinical data on biological mechanisms of antithrombin in inflammatory coagulation activation. Preclinical research has demonstrated partial interference of heparin--administered even at low doses--with the therapeutic effects of antithrombin, and has confirmed--at the level of cellular mechanisms--a regulatory role for antithrombin in DIC. Against this biological background, re-analyses of data from randomized controlled trials of antithrombin in sepsis suggest that antithrombin has the potential to be developed further as a therapeutic agent in the treatment of DIC. Even though there is a lack of studies employing satisfactory methodology, the results of investigations conducted thus far into the mechanisms of action of antithrombin allow one to infer that there is biological plausibility in the value of this agent. Final assessment of the drug's effectiveness, however, must await the availability of positive, prospective, randomized and placebo-controlled studies.

Animals↗

PubMed1992

Measurement of markers of activated coagulation in antithrombin III deficient subjects.

Functional antithrombin III levels were measured by factor Xa inhibition in 63 members of a large family with type 2 antithrombin III deficiency and individuals were classified as antithrombin III deficient or non-deficient according to the results. F1 + 2 and TAT complexes were measured using an ELISA and FPA levels were measured by radioimmunoassay. Thirty subjects (48%) were classified as antithrombin III deficient and 33 (52%) as antithrombin III non-deficient. The mean level of F1 + 2 was significantly higher in the deficient adults (0.87 +/- 0.26) compared to both the non-deficient adults (0.70 +/- 0.21) (p = 0.03) and the deficient adults receiving warfarin (0.16 +/- 0.01) (p less than 0.001). The differences in the mean values of TAT complexes and FPA between deficient and non-deficient individuals were not statistically significant. These findings suggest that untreated antithrombin III deficient subjects generate more thrombin than their non-deficient family members and that warfarin inhibits this thrombin formation. In this cross-sectional study, it is not possible to correlate the levels of the surrogate makers with future clinical outcome.

Adolescent↗

PubMed2005

Inherited antithrombin deficiency and end stage renal disease.

Antithrombin is a potent inhibitor of the coagulant effect of thrombin. In the latter half of 20th century, many families have been described in which an autosomaly dominant inherited antithrombin deficiency has caused severe venous thromboembolic disease in successive generations. The important complication is severe venoocclusive disease by deep venous thrombus. Some inherited antithrombin deficient patients developed renal failure because of fibrin deposition in the kidney glomeruli or renal vein thrombus, and therefore the need for replacement therapy for end stage renal disease (ESRD). Although an inherited antithrombin deficiency with renal failure is rare, prevention against renal failure in such patients, and their renal replacement therapy for ESRD are important. Proteinuria decreases plasma antithrombin level leading to more severe hyper-coagulation state. Therefore early in renal disease, it may be prudent for adaptation of anti-coagulation therapy even if recurrent thrombosis has not occurred. All replacement therapy (hemodialysis, transplantation or peritoneal dialysis) for ESRD are available for such thrombophilic disorders. Anticoagulation agents working without aggravation of antithrombin effects (Argatroban, Nafamostat mesilate etc.) are useful for hemodialysis. The renal allograft recipients with thrombophilia seem to be at risk of developing an acute rejection or other vascular event. Peritoneal dialysis is potentially a good adaptation for such thrombophilic disorders. However which therapy has the best mortality and morbidity outcomes is not clear. Physicians and Surgeons must pay attention to the coagulation state and thrombophilia in ESRD patients, give strong consideration for adequate anti-coagulation therapy and review the best renal replacement modality for each patient.

Animals↗