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PubMed1977

Antithrombin III deficiency causing postsplenectomy mesenteric venous thrombosis coincident with thrombocytopenia.

The most commonly recognized cause of mesenteric venous thrombosis following splenectomy is hypercoagulation secondary to reactive thrombocytosis. A case is reviewed in which hypercoagulation followed splenectomy for idiopathic thrombocytopenic purpura (ITP) in spite of persistent thrombocytopenia. Episodic mesenteric venous occlusion occurred due to antithrombin III deficiency. This hypercoagulable state may be the cause of primary acute mesenteric venous occlusive disease. Symptoms and signs suggesting thrombosis in the portal circulation demand immediate coagulation studies since even in the thrombocytopenic patient thrombotic proglems can occur. Surgical intervention is the treatment of choice for segmental small bowel ischemia; warfarin therapy is indicated when there is evidence of antithrombin III deficiency.

Adult↗

PubMed1992

A microtitre plate ELISA to measure thrombin-antithrombin complex using pan-specific antibodies.

A sandwich enzyme-linked immunosorbent assay (ELISA) has been developed to measure plasma levels of thrombin-antithrombin complex (TAT). The assay is performed in a microtitre plate using polyclonal antibodies specific for antigenic determinants on prothrombin and antithrombin. Antibody to prothrombin was immobilized on a solid phase, using a titre predetermined to optimize capture of TAT. The performance of the microtitre plate ELISA for TAT has been extensively investigated and compared with the performance characteristics of a tube-based ELISA for TAT which is available commercially (Enzygnost-TAT, from Behringwerke, Marburg, Germany). Studies with plasma containing various levels of prothrombin showed that the zymogen competed with TAT for capture antibody in both assays. Variations in prothrombin levels between plasma samples present a potential source of artifact, but one which does not critically affect the performance of either assay in detecting large elevations in TAT. A high correlation (r = 0.88) was established between the results of plasma samples assayed by both assays, whether citrate or EDTA anticoagulant was used to prepare plasma. High correlations (r > 0.90) were also established for each assay between the results of plasma prepared with EDTA as compared to citrate anticoagulant. Both assays were able to discriminate completely between a group of 16 normal controls and a group of 31 patients with disseminated intravascular coagulation (DIC).

Antibody Specificity↗

PubMed1992

Comparison of prothrombin fragment 1 + 2 with thrombin-antithrombin III complex in plasma of patients with disseminated intravascular coagulation.

Plasma levels of prothrombin fragment 1 + 2 (F1 + 2) and thrombin-antithrombin III complex (TAT) are thought to be specific indicators of thrombin generation. To assess whether these two parameters behave similarly in vivo, we compared the plasma levels of F1 + 2 with TAT in 41 patients with disseminated intravascular coagulation (DIC). Both F1 + 2 and TAT were markedly elevated in patients with DIC compared to healthy subjects. Although a positive correlation was found between F1 + 2 and TAT (r = 0.585, P < 0.001) there was a large scatter among individuals. In addition, plasma concentrations of TAT were much lower than F1 + 2. The correlation between the TAT/F1 + 2 ratio and antithrombin III was weak (r = -0.268, P = 0.09). The TAT/F1 + 2 ratio was positively correlated with TAT (r = 0.481, P = 0.002), indicating that the difference in molar concentrations between F1 + 2 and TAT decreased as the TAT value increased. Serial determinations of these parameters showed that plasma TAT values changed roughly in parallel with F1 + 2 in the majority of patients. Although further studies are required to further clarify the observed differences between F1 + 2 and TAT, both parameters would be equally useful for the precise detection of haemostatic activation in patients with DIC.

Antithrombin III↗

PubMed1995

Functional analysis of an unusual length polymorphism in the human antithrombin III (AT3) gene promoter.

The prevalence of the alternative alleles of an unusual length polymorphism in the promoter of the human antithrombin III (AT3) gene was determined in a sample of 155 unrelated individuals from the Northern Irish population. The 108bp L allele and the 32bp S allele occurred at frequencies of 0.21 and 0.79 respectively. Some homology was noted between the L-specific sequence and the region immediately downstream. Residual homology was also evident between the L and S sequences, suggesting that the S allele was derived from the L allele during evolution by partial deletion followed by sequence divergence. The functional significance of the polymorphism was investigated by transient transfection of AT3 promoter/luciferase reporter gene constructs into two human hepatoma cell lines in vitro. The promoter strength of the L allele was found to be 1.6-fold higher than the S allele in HepG2 cells whereas in Hep3B cells, the strength of the S allele was 1.7-fold higher than that of the L allele. In order to evaluate the phenotypic consequences of the AT3 promoter polymorphism in vivo, plasma samples from the 155 control individuals were assayed for antithrombin III (ATIII) activity. Mean activities of the different promoter polymorphism genotypes (SS, LL, SL) were not significantly different. These results suggest that the AT3 promoter polymorphism does not contribute to the variation in plasma ATIII activity that occurs in the general population.

Alleles↗

PubMed1997

Five antithrombin variants, four associated with thrombosis.

We have identified five mutations in antithrombin by direct sequencing of exons amplified using polymerase chain reaction. Four of these mutations are associated with thrombosis, three cause type I antithrombin deficiency and one has features of a type II deficiency. The fifth variant appears to have no functional consequences. The type I mutations are in exon 2, exon 3b and exon 4. The first of these is a nonsense mutation causing substitution of a Tyr-->stop at position -16 within the secretion signal sequence. The second is a missense mutation resulting in the substitution Cys-->Ser at position 247. This disrupts the disulphide bond with Cys 430 leaving a free cysteine residue and the C-terminus unconstrained. The third type I mutation is an in-frame deletion resulting in the loss of Ile 186. This is a highly conserved residue in the serpin superfamily and will predictably result in the disruption of the F-helix. The fourth mutation, in exon 3a, results in the substitution of Ser 162 by Asn. This residue is sited in the E-helix and the replacement of the buried side chain of serine by the larger asparagine side chain will predictably cause structural perturbation. The last example, Val 415-->Asp, was an incidental finding as a follow up investigation of a nephrotic patient. Although one other member of the family also had the mutation there was no linked history of thrombotic disease.

Adult↗

PubMed1991

Association and linkage analyses of restriction fragment length polymorphisms for the human renin and antithrombin III genes in essential hypertension.

Essential hypertension is a highly hereditable disorder in which genetic influences predominate over environmental factors. The molecular genetic profiles which predispose to essential hypertension are not known. In rats with genetic hypertension, there is some recent evidence pointing to linkage of renin gene alleles with blood pressure. The genes for renin and antithrombin III belong to a conserved synteny group which, in humans, spans the q21.3-32.3 region of chromosome I and, in rats, is linkage group X on chromosome 13. The present study examined the association of particular human renin gene (REN) and antithrombin III gene (AT3) polymorphisms with essential hypertension by comparing the frequency of specific alleles for each of these genes in 50 hypertensive offspring of hypertensive parents and 91 normotensive offspring of normotensive parents. In addition, linkage relationships were examined in hypertensive pedigrees with multiple affected individuals. Alleles of a REN HindIII restriction fragment length polymorphism (RFLP) were detected using a genomic clone, lambda HR5, to probe Southern blots of HindIII-cut leucocyte DNA, and those for an AT3 PstI RFLP were detected by phATIII 113 complementary DNA probe. The frequencies of each REN allele in the hypertensive group were 0.76 and 0.24 compared with 0.74 and 0.26 in the normotensive group. For AT3, hypertensive allele frequencies were 0.49 and 0.51 compared with normotensive values of 0.54 and 0.46. These differences were not significant by chi 2 analysis (P greater than 0.2).(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1983

Arterial thromboembolism and associated antithrombin III deficiency.

A patient with antithrombin III (ATT) deficiency after arterial embolism manifested an increasing requirement for heparin to adjust a partial thromboplastin time. This was corrected by dramatically increasing doses of heparin and by conversion to warfarin sodium. "Heparin-resistance" should direct the physician to examine antithrombin III levels, and ATT levels should be determined as a baseline before anticoagulation therapy.

Antithrombin III Deficiency↗

PubMed2005

Low normal level of protein C or of antithrombin increases risk for recurrent cardiovascular events.

The relationship between haemostatic factors and recurrent cardiovascular events was investigated in patients enrolled with acute coronary syndrome (acute non-Q myocardial infarction or unstable angina pectoris). One hundred and fifteen patients, aged 64 +/- 10 years, were included in the study. Haemostatic parameters [prothrombin time, activities of factor VII, factor VIII, factor X, antithrombin (AT) and protein C (PC), and concentrations of free protein S, fibrinogen, D-dimer, prothrombin fragment 1+2, and thrombin-antithrombin complex] were measured four times: within 48 h of hospitalization, at discharge (days 5-8), at 3 months and after 1 year. Screening for factor V Leiden mutation was also performed. Patients were followed for cardiovascular endpoints (new or refractory unstable angina pectoris, non-fatal myocardial infarction, stroke, or death) for an average of 555 days. Of all patients, 35 had an endpoint during the follow-up ("endpoint" group) and 80 patients did not ("no endpoint" group). Analysing the whole follow-up period, PC (P < 0.01) and AT (P < 0.01) were lower in the "endpoint" than in the "no endpoint" group. With 50% percentiles at enrollment, the odds ratio for getting an endpoint in the low (cut-off value < 100%) versus high PC group was 2.72 (95% confidence interval, 1.18-6.29; P < 0.05). Lower levels of AT (P < 0.05) and PC (P < 0.05) during the whole follow-up were associated with a shorter event-free time. In conclusion, lower PC and AT values, even within the normal range, seem to be associated with elevated risk for recurrent cardiovascular events and shorter event-free time in acute coronary syndrome patients.

Aged↗

PubMed2005

Hyperproduction of fibrin and inefficacy of antithrombin III and alpha2 macroglobulin in the presence of bacterial porins.

Bacterial porins enhance the thrombin activity upon chromogen substrate chromozym. Should porin-dependent enhancement of thrombin activity take place also upon fibrinogen in vivo, this might greatly increase the fibrin production which, in turn, might lead to blood vessel obstruction. In this study, we demonstrate fibrin hyperproduction in a simplified coagulative system, consisting of fibrinogen and thrombin-pure molecules, in the presence of bacterial porins. In particular, bacterial porins, in the presence of thrombin, significantly increased the fibrin production compared with thrombin alone. Also, fibrin hyperproduction took place even in the presence of the thrombin inhibitors antithrombin III (AT III) or alpha2 macroglobulin (alpha2M). However, the thrombin-fibrinogen reaction in the presence of AT III or alpha2M did not generate fibrin, unless porins were present. In conclusion, porins not only enhance thrombin activity but also inhibit the antithrombin activity exerted by AT III or alpha2M. We hypothesize that, because of porins activity, fibrin is largely generated due to thrombin hyperactivation. Moreover, further fibrin is produced by thrombin, which is not blocked by two serpins for the presence of porins. These results might be relevant as to the occurrence of disseminated intravascular coagulation in sepsis by gram-negative bacteria, which are known to produce porins.

Antithrombin III↗

PubMed1983

Studies of the heterogeneity of antithrombin III concentrates.

The biological activities of antithrombin III (At III) concentrates, prepared by several manufacturers for clinical use, have been compared by three assay methods, and their heparin-binding properties studied by crossed immunoelectrophoresis and heparin affinity chromatography. Concentrates from two of the four manufacturers showed discrepancies between assay methods, with concentrations by heparin co-factor assays significantly lower than those by immunological and progressive antithrombin methods. Heterogeneity was also found by heparin binding studies, with about half the total At III antigen in these concentrates being unable to bind to heparin. These results confirm previous findings of heterogeneity in At III concentrates and show that some concentrates contain substantial amounts of altered At III molecules in which the heparin-binding site has been denatured but the thrombin-neutralizing site left largely intact.

Antigens↗

PubMed1987

Comparative effect of heparin and heparan sulphate on two abnormal antithrombin III type 3 variants.

Two families were found with an antithrombin III that was unresponsive towards heparin (type 3 AT III variants). The abnormal species were purified using affinity chromatography on Sepharose bound anti-AT III antibodies. This yielded active proteins, as judged by their progressive antithrombin activities. In an attempt to explain the thrombotic tendency observed in this abnormality we compared the effect of heparin and heparan sulphate on these abnormal AT III, since, unlike heparin, heparan sulphate is a naturally occurring anticoagulant in the human. In normal plasma the heparan sulphate used in this study had a heparin-like activity of 50 U/mg by anti-F.XA and anti-F.IIa amidolytic assays. Full expression of the heparin cofactor activity in normal plasma could be obtained at a final concentration of 0.024 mg/ml of heparan sulphate (equivalent to 0.007 mg/ml of heparin). At this concentration of heparan sulphate the two abnormal AT III still exhibit a heparin cofactor activity below 10%. This absence of binding of heparan sulphate to abnormal AT III of type 3 could explain why some patients with this abnormality suffer from thrombo-embolic episodes while their AT III acts normally in the absence of heparin.

Adult↗

PubMed1990

Clinical and biochemical characterization of antithrombin III Franconville, a variant with Pro 41 Leu mutation.

We describe a familial study of AT III, a type III antithrombin III variant which was identified in the propositus by gene analysis as Pro 41 Leu heterozygous mutation. None of the four members of the family who presented with defective heparin cofactor (hep-cofactor) activity, and therefore probably carried the mutation, had experienced deep venous thrombosis. The abnormal AT III was purified from the propositus' plasma, taking advantage of the difference in NaCl concentrations required to elute variant and normal AT III from heparin-Sepharose. The antithrombin and anti-Xa activities of the purified variant AT III were comparable to those observed for normal AT III, but hep-cofactor activity was strikingly reduced. The enhancement by heparin of thrombin and F Xa inhibition by normal and variant AT III was compared in the absence of NaCl and in the presence of normal NaCl concentrations. The difference between the degrees of inhibition by normal and variant AT III was maximal at physiological ionic strength (i.e. at a concentration of 0.15 M). The quantification of heparin AT III interaction with both normal and variant purified proteins in a double reciprocal plot yielded similar dissociation constants but a 9-fold decrease in the maximal pseudo-first order constant. This suggests that Pro 41 is more involved in the molecular changes induced by heparin than in the primary binding of the activator.

Adult↗

PubMed1991

Antithrombin Vicenza, Ala 384 to Pro (GCA to CCA) mutation, transforming the inhibitor into a substrate.

Antithrombin (AT) Vicenza has been previously identified as a functionally abnormal antithrombin associated with familial thrombosis (Finazzi et al, 1985). It binds normally to heparin, but loses its affinity following interaction with thrombin: it is a poor inhibitor of thrombin. AT Vicenza was isolated from plasma by heparin-Sepharose and thrombin-Sepharose chromatography, fragmented with cyanogen bromide (CNBr) and its tryptic peptides were analysed by fast atom bombardment mass spectrometry mapping. An abnormal peptide mass 1112 was identified. Edman degradation confirmed a substitution of Ala to Pro in the sequence Ala 383-Arg 393. Polymerase chain reaction amplification of exon 6 of the gene followed by genomic sequencing, localized the mutation to codon 384, GCA to CCA. The same mutation has recently been reported in AT Charleville (Mohlo-Sabatier et al, 1989). Sodium dodecyl-sulphate polyacrylamide gel electrophoresis of AT Vicenza (/Charleville) under non-reducing conditions revealed an apparent increase in mol. wt following interaction with thrombin: under reducing conditions the mol. wt was less than that of normal AT. This indicated cleavage and unfolding of the molecule. The site of cleavage was determined by incubation of AT Vicenza (/Charleville) with thrombin-Sepharose, reduction and S-carboxymethylation and reverse phase FPLC. A peptide was identified with the NH2-terminal sequence beginning Ser-Leu-Asn, demonstrating the cleavage had occurred at the reactive site of the variant. It is concluded that the Ala 384 to Pro substitution transforms AT Vicenza (/Charleville) from an inhibitor into a substrate.

Amino Acid Sequence↗

PubMed1993

Identification of nine novel mutations in type I antithrombin deficiency by heteroduplex screening.

We have utilized DNA heteroduplex detection as a method for screening sequences of the antithrombin (AT) gene for the presence of mutations. Affected individuals from 41 kindreds with type Ia antithrombin deficiency were investigated. Heteroduplexes were detected in 12 cases; direct sequencing of the appropriate exons revealed nine cases with novel mutations, and two with previously described mutations. In addition, a new polymorphism in the 5' untranslated region was characterized. The defects included minor insertions and deletions which lead to the removal of intact codons or premature termination, and single base substitutions leading to premature termination or amino acid substitution. In all cases, the affected individuals were heterozygous for the defect and variant AT protein was not detected. In keeping with previous reports the defects associated with type Ia AT deficiency are extremely heterogeneous, the vast majority being point mutations. This study also demonstrates the efficiency of hydrolink gel electrophoresis as a method of screening for unknown mutations by heteroduplex detection.

Antithrombins↗

PubMed1994

Protein C, antithrombin III and plasminogen: effect of age, sex and blood group.

We conducted a cross-sectional study of antithrombin III (ATIII), protein C (PC) and plasminogen (Plg) concentrations in a population of healthy plasma donors in the Trent Region. The distribution of values for protein C was log normal whereas for ATIII and Plg the distributions were positively skewed and differed significantly from normal and log normal. Males had higher antithrombin III concentrations (mean 1.10 iu/ml, range 0.72-1.65) than females (mean 1.07 iu/ml, range 0.75-1.69) (P = 0.001) and levels increased with age in women. Younger women aged 25-34 had significantly lower plasma concentrations of ATIII compared to males of similar age. For protein C, concentrations were higher in males (mean 1.07 u/ml, range 0.37-2.11) than in females (mean 1.01 u/ml, range 0.59-1.61) (P < 0.001) and levels increased with age in both sexes P < 0.001). In women, a novel difference in protein C concentration between ABO blood groups was noted. There was no significant difference in plasminogen concentration between males and females, and in women plasminogen decreased with age (r = -0.205, P < 0.001). We conclude that these variations in ATIII and protein C with age and sex are important considerations in the determination of reference ranges for these proteins.

ABO Blood-Group System↗

PubMed1995

Coronary artery bypass surgery in patients with inherited antithrombin deficiency.

Antithrombin (AT) replacement in coronary artery bypass grafting procedures in three individuals with inherited antithrombin deficiency is described. All three had a significant personal or family history of thrombotic disease. All patients achieved satisfactory AT levels throughout bypass and in the postoperative period. All received heparin prophylaxis in the postoperative period. None suffered thrombotic or bleeding complications.

Aged↗

PubMed2007

Reduction of high fetal loss rate by anticoagulant treatment during pregnancy in antithrombin, protein C or protein S deficient women.

Hereditary thrombophilia is associated with an increased risk of fetal loss. Assuming that fetal loss is due to placental thrombosis, anticoagulant treatment might improve pregnancy outcome. In an observational family cohort study, we prospectively assessed the effects of anticoagulant drugs on fetal loss rates in women with hereditary deficiencies of antithrombin, protein C or protein S. The cohort contained 376 women (50 probands and 326 deficient or non-deficient relatives). Probands were consecutive deficient patients with venous tromboembolism. Thromboprophylaxis during pregnancy was recommended in deficient women, irrespective of prior venous thromboembolism, and in non-deficient women with prior venous thromboembolism. Outcome of first pregnancy was analysed in 55 eligible women. Of 37 deficient women, 26 (70%) received thromboprophylaxis during pregnancy, compared with three of 18 (17%) non-deficient women. Fetal loss rates were 0% in deficient women with thromboprophylaxis versus 45% in deficient women without (P = 0.001) and 7% in non-deficient women without thromboprophylaxis (P = 0.37). The adjusted relative risk of fetal loss in women who received thromboprophylaxis versus women who did not was 0.07 (95% confidence interval 0.001-0.7; P = 0.02). Our data suggest that anticoagulant treatment during pregnancy reduces the high fetal loss rate in women with hereditary deficiencies of antithrombin, protein C or protein S.

Adolescent↗

PubMed1989

Abnormal proteolysis (DIC)--successful treatment with antithrombin III concentrate and a concentrate containing F XIII and native von Willebrand factor.

Two patients with life-threatening disseminated intravascular coagulation (DIC) syndrome, one caused by Gram-negative bacteria and one by premature separation of the placenta, are described. Specific substitution was given by antithrombin III concentrate and AHF-Kabi, a low purity factor VIII concentrate containing native von Willebrand factor and factor XIII. The treatment quickly returned the extremely low levels of antithrombin III, factor VIII:C, fibrinogen and factor XIII, initially found, to normal, and also returned the multimeric pattern of von Willebrand factor to normal. This resulted in diminished bleeding, enabling surgical treatment of the underlying disease.

Adult↗