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PubMed1985

[Cerebral venous thrombosis with familial antithrombin III deficiency].

A case of cerebral venous thrombosis with familial antithrombin III (AT III) deficiency was reported and we discussed the anticoagulant therapy of cerebral venous thrombosis from the viewpoint of AT III. The patient, a 17-year-old boy, was admitted to our clinic with severe bifrontal headache, generalized convulsions and progressive disturbance of consciousness. He developed deep vein thrombosis in his right leg and pulmonary emboli two years earlier when he was placed on heparin and so forth, followed by warfarin sodium. Warfarin was terminated 9 months prior to his recent illness. On neurological examination on admission, he was semicomatous with blurred disc margins, roving eye movements with right abducens nerve palsy, nuchal stiffness and right flaccid hemiplegia. Left carotid angiogram and CT scan revealed extensive superior sagittal sinus thrombosis, complicated with hemorrhagic infarcts in bilateral frontal lobes. When examined for coagulation studies, the patient and his father had decrease in AT III activity and antigen levels. He was treated successfully with antiedematous agents and anticonvulsants during acute phase of illness. He was thereafter placed on warfarin 5-6 mg/day with no further clinical thromboembolic event for 2 years 9 months. There was no neurological abnormality when he was last examined, although he was treated with valproic acid 1,200 mg/day and phenytoin 250 mg/day to control occasional adversive seizures. A coagulation study following infusion of 5,000 units of AT III was carried out. Warfarin was discontinued the day before the study. 0.64 U/kg of AT III administration resulted in a 1% increase in AT III level after the infusion. The biological half life of AT III was 14.4 hours.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1983

[Experiences with the substitution of antithrombin III concentrates in congenital and acquired deficiency disorders].

Antithrombin III (AT III) is the most important inhibitor for factor X and thrombin. Hence, it essentielly influences the regulation of haemostasis. In the aetiology of AT III decreases, hereditary as well as acquired deficiencies can be differentiated. With the exception of patients with hereditary AT III deficiency it is not possible to define the heavy tendency of thrombosis clearly on a biochemical basis. Acquired AT III decreases lead much often to clinical relevant problems than the congenital ones. Since 1974 we substitute AT III using AT III concentrates. The evaluation of the clinical success was often impeded due to the polypragmatic additional therapy. Well-founded and strict indications for the substitution of AT III with a therapeutical concentrate are acute macro- and microthrombosis with decreased AT III levels, e.g. in severe thromboembolic diseases and in hereditary AT III deficiencies. Concerning other clinical pictures with acquired AT III deficiency, a substitution may be indicated very reasonably, however, further studies are necessary to prove this.

Aged↗
PubMed1984

Heparin cofactor II determination--levels in normals and patients with hereditary antithrombin III deficiency and disseminated intravascular coagulation.

A technique is described to completely remove antithrombin III (AT) from small amounts of human plasma by immunoaffinity chromatography on antibodies against human AT linked to Sepharose 4B. The level of heparin cofactor II (HCII) was not affected by the immunoadsorption. HCII activity was then determined by measuring the rate of human thrombin inhibition by 3 ways: a) activation with heparin in AT-free plasma, b) activation with dermatan sulfate in normal plasma and c) activation with dermatan sulfate in AT-free plasma. The normal range of HCII varied between 0.7-1.5 U/ml, as compared to a normal plasma pool containing by definition 1 U/ml. Highly significant correlations between assays as obtained from 40 normal plasmas proved the suitability of the 3 assays, although the progressive thrombin inhibition by AT, when not removed, contributed about one fifth to the thrombin inhibition by HCII in the presence of dermatan sulfate. There were also highly significant correlations between HCII activity and antigen, as determined by rocket immunoelectrophoresis using specific antibodies against HCII. Levels of HCII and AT were examined in 7 patients with hereditary AT deficiency and 7 patients with disseminated intravascular coagulation (DIC). In hereditary AT deficiency, whereas the AT activity was reduced by half, levels of HCII activity and antigen were in the normal range. In DIC, a parallel decrease of HCII and AT suggests that HCII may participate in the inhibition of thrombin released during DIC and thus provides an inhibitor reserve, once the AT level becomes subnormally low.

Antigens↗
PubMedDate not supplied

Antithrombin III in systemic lupus erythematosus.

Plasma antithrombin III (AT III) was studied in 39 patients with systemic lupus erythematosus (SLE) and in 12 patients with other connective tissue disorders. AT III was measured immunologically by the Mancini method as well as by functional assay using thrombin and the chromogenic substrate, chromozyn TH (Boehringer). Reduced AT III activity was found in 17 patients; 8 had thrombosis. In 6 patients low AT III correlated with disease exacerbations and 2 had systemic vasculitis. No significant correlation could be demonstrated between low AT III levels and thromboembolic disease. A marked variation of functional AT III activity was observed in 30 patients in whom the presence of the lupus anticoagulant was demonstrated. The significance of this association is discussed.

Adolescent↗
PubMed1984

Acquired deficiency and urinary excretion of antithrombin III in nephrotic syndrome.

The published data concerning changes of antithrombin III (ATIII) in nephrotic syndrome (NS) are contradictory. While increased ATIII activity has been reported by some investigators, decreased concentration has been shown by others and normal values by yet another group of authors. We determined plasma and urine concentrations of ATIII in a group of 20 patients with NS using an immunologic assay. In addition, plasma ATIII activity was determined. The results were compared with those obtained in a group of normal volunteers. Plasma concentration and activity of ATIII were both greatly reduced in the patients with NS. In addition, substantial quantities of ATIII were recovered in the urine of all tested patients. The present study, therefore, substantiates the low plasma concentrations of ATIII and its urinary losses in NS. In addition, a parallel reduction in plasma ATIII activity is demonstrated providing functional evidence of acquired ATIII deficiency in this condition.

Adolescent↗
PubMed1984

Antithrombin III deficiency as a reflection of dynamic protein metabolism in patients undergoing vascular reconstruction.

Antithrombin III (AT-III) deficiency has been associated with increased risk of venous and arterial thromboses and arterial graft failure. Deficiency of this circulating glycoprotein may be congenital; however, acquired deficiencies may develop in protein-losing or protein-wasting states. In the present study, AT-III levels of 108 patients undergoing vascular surgical procedures were determined preoperatively and at intervals (third, fifth, and seventh days) postoperatively. The mean AT-III level was then compared to the patient's protein status. The effect of reduced AT-III activity on early graft failure was also noted. A low preoperative AT-III level (less than 80%) was found in 16.3% of the patients studied. Among 83 patients with serum albumin levels greater than 3.0 gm/dl or transferrin levels greater than 180 mg/dl, reduced AT-III activity was present in only 10 (12%). In contrast, when serum albumin levels were less than 3.0 gm/dl, AT-III deficiency was found in 12 of 25 patients (48%) (p less than 0.01). Early thrombosis of a femorodistal graft occurred in 5 of 15 patients (33%) with reduced AT-III levels. When AT-III levels were normal, early bypass failure occurred in only 9 of 67 grafts (13.4%). However, this difference was not statistically significant. An additional 15 patients had sequential pre- and postoperative measurements (up to 3 weeks) of serum protein and AT-III levels to illustrate the relationship between the dynamics of protein metabolism and AT-III levels. There was a clear temporal relationship between albumin, transferrin, and AT-III levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗
PubMed1980

Severe antithrombin III deficiency in a patient with pre-eclampsia. Observations on the effect of human AT III concentrate transfusion.

Severe acquired antithrombin III (AT III) deficiency was observed in a patient with severe pre-eclamptic toxaemia. Plasma AT III concentration of 0.25 U/ml was found in both functional and immunological assays. The patient was treated with human AT III concentrate as a result of the development of progressive disseminated intravascular coagulation (DIC), the further deterioration of renal function, the risk for thromboembolic complications and the possible adverse effects of heparin therapy. The selective correction of AT III activity resulted in a rapid disappearance of coagulation abnormalities. The patient underwent uncomplicated caesarian section. This observation indicates that acquired severe AT III deficiency may occur as an early feature of DIC in severe pre-eclamptic toxaemia.

Antithrombin III↗
PubMed1980

Reliability of amidolytic assays for progressive antithrombin and heparin cofactor activities on capillary blood.

Amidolytic assay of antithrombin III on capillary blood can validly substitute for similar assays performed on venous blood, as an excellent correlation exists (r = 0.95). For the amidolytic assays of heparin cofactor activity, a much less satisfactory correlation is found (r = 0.81). Results are far more dispersed and a decrease is observed in late capillary samples. Using a low heparin concentration to assay heparin cofactor activity leads to surprisingly high activities for capillary blood. The same type of discrepancy is observed during the earliest stages of clotting of venous blood.

Amides↗
PubMedDate not supplied

Deficient antithrombin III activity and enhanced fibrinolysis in patients with liver disease: evidence against a cause-effect relationship.

To investigate the pathogenesis of fibrinolysis in liver disease, antithrombin III (AT III) activity, prothrombin fragment (F1 + 2) and d-dimer (D-DI) were measured in 50 patients with liver disease and in 17 healthy controls. Moreover, 4 patients with cirrhosis were randomly assigned to receive either an intravenous infusion of AT III (at two different dosages) or placebo, with a crossover design. Increased levels of D-DI were detected in patients with cirrhosis and hepatocellular carcinoma in comparison both with control subjects and with patients with acute hepatitis or mild chronic liver disease. An inverse correlation was observed between AT III and D-DI (r = -0.755, P < 0.001, simple linear regression), while no correlation was found between D-DI or AT III and F1 + 2. The correlation of the deficiency of AT III activity by infusion of human AT III did not result in any significant change (P0.10, analysis of variance for repeated measures) of the plasma concentration of either D-DI or F1 + 2, in comparison to placebo. Thus, advanced forms of chronic liver disease, but not acute hepatitis and mild forms of chronic liver disease, are associated with increased plasma concentrations of markers of fibrinolysis, which are inversely correlated with AT III activity. However, the correction of the deficient AT III activity does not affect the plasma concentration of either D-DI or F1 + 2, thence not supporting the hypothesis that enhanced fibrinolysis in advanced liver disease is the result of low-grade disseminated intravascular coagulation.

Adult↗
PubMed1994

Molecular basis of antithrombin type I deficiency: the first large in-frame deletion and two novel mutations in exon 6.

We report three novel mutations accounting for cases of inherited type I antithrombin (AT) deficiency. Using the polymerase chain reaction (PCR) and direct sequencing of the coding sequences of the AT gene, we found one mutation in exon 4 and two in exon 6. A deletion of 105 bp causing an in-frame deletion of 35 amino acids between Tyr 240 and Gly 276 was found in exon 4. In a second kindred, deletion of two adenines in codon 412-413 introduced a frameshift and a stop codon at position 431. The last mutation was an insertion of ACCG in codon 387, generating a frameshift with a stop codon located at the normal position. The finding of a sequence repeat of nine residues located at the 5' and 3' ends of the deleted fragment might explain the 105 bp deletion by slippage and mispairing at the replication fork during DNA synthesis. The second mutation is the fourth described within a region of six amino acids (between Phe 408 and Arg 413), which seems to be a cluster of mutations. In this case, the presence of a double repeat sequence--TTCCT and AACA--flanking this region could be particularly favorable for slipped mispairing. These results confirm that human gene mutations are not random events but are strongly influenced by DNA flanking sequences.

Amino Acid Sequence↗
PubMed1994

Effects of recombinant human soluble thrombomodulin (rhs-TM) on a rat model of disseminated intravascular coagulation with decreased levels of plasma antithrombin III.

We reported that recombinant human soluble thrombomodulin (rhs-TM) is effective for disseminated intravascular coagulation (DIC) in vivo, in mice and rats. In the present work, we investigated the effects of decreased plasma antithrombin III (ATIII) levels on anticoagulant effects of rhs-TM, as compared to findings with heparin, of which effect is lowered by the decreased plasma ATIII levels in patients with DIC. Rat plasma ATIII levels decreased when we mixed plasma with anti-rat ATIII antibody and the potential of heparin to prolong APTT or PT was markedly diminished. The potential of rhs-TM to prolong APTT and PT was not affected. In rats injected with anti-rat ATIII antibody, plasma ATIII levels decreased immediately. When the rats were infused with tissue factor (TF), DIC was induced. At doses of rhs-TM and heparin which were equally effective at inhibiting the decrease in platelet count and fibrinogen level in control rats treated with TF, only rhs-TM remained effective in preventing DIC in rats with reduced ATIII levels. Heparin was not effective when administered to these rats with reduced ATIII levels. Therefore, rhs-TM effectively inhibits coagulation independent of ATIII levels, in contrast to heparin, which depends on the ATIII level.

Animals↗
PubMed1994

Thrombotic risk of women with hereditary antithrombin III-, protein C- and protein S-deficiency taking oral contraceptive medication. The GTH Study Group on Natural Inhibitors.

The thrombotic risk of women with a heterozygous natural clotting inhibitor deficiency taking oral contraceptives (OC) has not been evaluated. Therefore, a retrospective collaborative controlled cohort-study was carried out in 8 coagulation laboratories and thrombosis units in Austria, Germany and Switzerland. The incidence of thromboembolism in 48 females heterozygous for hereditary type I deficiency of antithrombin III (n = 15), protein C (n = 16) or protein S (n = 17), who had taken OC at least once in their life were compared with that of 48 deficient women, who had never taken OC (controls). Diagnosis of the deficiency state was made in the participating centers. Data on the onset and duration of OC intake and the date and site of thrombotic events were obtained from a questionnaire filled in by the patient or a physician during a visit at a participating center. The observation period in the OC patients was started with onset of OC intake and was terminated when a thromboembolic event had occurred or when OC medication were discontinued. In the patients without OC, the observation period began at an age matched to that of the OC patient and ended when a thromboembolic event had occurred or was continued as long as the corresponding OC patient was on treatment. In AT III-deficient females the probability for thrombosis was significantly higher for patients taking OC compared to the non-OC-patients (Wilcoxon test p = 0.004, Log Rank test p = 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Antithrombin III↗
PubMed1993

Venous thrombosis: antithrombin III deficiency.

Antithrombin (ATIII) is believed to be one of the body's most powerful natural anticoagulants, so individuals with a deficiency of this protein exhibit a marked propensity to venous thrombosis. This article will focus on the pathophysiology of this disorder, including clinical presentation, diagnosis, and treatment.

Adult↗
PubMed1995

A review of mutations causing deficiencies of antithrombin, protein C and protein S.

The mutations observed in patients with antithrombin and protein C deficiencies are mostly substitutions of one nucleotide, or deletions/insertions of fewer than 10 nucleotides in the exons and intron-exon junctions. These genomic abnormalities result in missense changes (involving aminoacids important for protein folding), aberrant polypeptide chains and/or premature termination codons, or abnormal splicing precluding DNA transcription. The number of mutations so far identified is such that it is difficult to use genomic DNA analysis for diagnostic purpose. However, identification of the gene defect can be useful in well-defined situations, such as the risk of homozygosity, and complex or ambiguous plasma phenotypes, which frequently occur in protein C deficiency. Protein S deficiency, the molecular bases of which have been less extensively studied, is due to micromodifications of the coding sequence in only half the cases investigated so far. The mechanisms involved in the remaining cases remain to be identified.

Alleles↗
PubMed1997

Antithrombin III-independent effect of depolymerized holothurian glycosaminoglycan (DHG) on acute thromboembolism in mice.

A previous study in this laboratory showed that depolymerized holothurian glycosaminoglycan (DHG) has two different antithrombin III (ATIII)-independent inhibitory effects on the in vitro blood coagulation system: heparin cofactor II (HCII)-dependent inhibition of thrombin, and ATIII- and HCII-independent inhibition of factor X activation by factor IXa-factor VIIIa complex (Nagase et al. Blood 85, 1527-1534, 1995). In the present study, we compared the antithrombotic effects of DHG in normal and in ATIII-deficient mice with those of unfractionated heparin (UFH) and low molecular weight heparin (LMWH). DHG, unlike UFH and LMWH, exerted an in vivo antithrombotic effect even in mice with decreased plasma ATIII activity (about 30% of normal). We then compared the anticoagulant and antithrombotic effects of DHG in mice with those of high molecular weight (HMW)-DHG, low molecular weight (LMW)-DHG, and dermatan sulfate (DS). In terms of in vitro anticoagulant activity assessed by use of purified human components, DHGs (DHG, HMW-DHG, and LMW-DHG) had different anti-thrombin activity in the presence of HCII and anti-factor Xase activities, which differences were dependent on the molecular weight. With respect to in vivo antithrombotic activity, DHG, HMW-DHG, and LMW-DHG showed almost the same inhibitory effect on acute thromboembolism in mice (minimum effective dose [MED]: > 0.3 mg/kg). Since the antithrombotic activities of DHGs were not correlated with the anticoagulant-specific activities, the contribution of the two anticoagulant activities to the in vivo antithrombotic effect of DHGs remains unknown. However, DHG was more effective against acute thromboembolism in mice than DS (MED > 1 or > 3 mg/kg), which showed no inhibitory activity toward factor Xase. Therefore, it seems that factor Xase inhibition contributes greatly to the antithrombotic effect of DHG and that DHG exerts this effect in mice mainly by inhibiting factor Xase.

Animals↗
PubMed1997

[Congenital antithrombin III deficiency associated with pulmonary thromboembolism].

A 42-year-old man was admitted to the hospital because of sudden left-lateral chest pain and dyspnea. The chest roentgenogram on admission showed a string-like shadow and pleural effusion, and analysis of arterial blood gases revealed hypoxemia. Many bilateral segmental defects were seen on a radioisotope perfusion scan of the lungs, and the chest CT scan showed a low-density area in the trunk of the pulmonary artery. From these findings, pulmonary thromboembolism was diagnosed. The serum antithrombin III (ATIII) activity and the antigen value were low, and the patient's son's serum ATIII level was also low. Both the patient and his son were given the diagnosis of congenital ATIII deficiency. Gene analysis revealed two point mutations in exon 6 of the ATIII gene, so we classified this case as type IIc. The patient was treated with intravenous urokinase and heparin, and was then given warfarin. The arterial blood gas tensions improved, and the low-density area of the pulmonary artery on the CT scan disappeared, as did the pulmonary perfusion defect on the radioisotope scan. The clinical manifestations of members of 28 families with congenital ATIII deficiency reported in Japan were reviewed. Patients in whom many point mutations were detected in the ATIII gene were rare.

Adult↗
PubMed1986

Diagnostic efficacy of six plasma proteins in evaluating consumptive coagulopathies. Use of receiver operating characteristic curves to compare antithrombin III, plasminogen, alpha 2-plasmin inhibitor, fibronectin, prothrombin, and protein C.

Six coagulation proteins were measured in 79 consecutive patients referred to the coagulation service for suspected disseminated intravascular coagulation. Antithrombin III, plasminogen, and alpha 2-plasmin inhibitor were measured with fluorescent substrate assays. Fibronectin, prothrombin, and protein C were measured with electroimmunoassays. Using history and physical findings and the results of a coagulation screen (prothrombin time, partial thromboplastin time, fibrinogen, fibrin[ogen] degradation products, platelet count, and peripheral smear), the 79 patients were classified into five categories: no disseminated intravascular coagulation (n = 21), elevated fibrin(ogen) degradation products without other evidence of coagulopathy (n = 44), defibrination syndrome (n = 9), microangiopathic thrombocytopenic purpura (n = 4), and primary fibrinolysis (n = 1). Because the sensitivity and specificity of each of the proteins could not easily be compared, receiver operating characteristic (ROC) curves and areas under the ROC curves were calculated for each of the six proteins as well as for the tests of the coagulation screen. The ROC curves indicated that, apart from plasminogen, the other coagulation proteins provided little additional information about the classification of the coagulopathy.

Antithrombin III↗
PubMed1994

Inherited antithrombin III deficiency in the neonate.

OBJECTIVE: To describe two cases of inherited antithrombin III (AT-III) deficiency presenting at less than or equal to 28 days of age, and to review other neonatal reports. RESEARCH DESIGN: Clinical descriptions of two patients and literature review of known references to the neonatal presentation of this disorder. SETTING: Academic neonatal intensive care unit. PATIENTS: Case reports--two patients with thrombosis and family history of AT-III deficiency. Literature review--neonatal patients with thrombosis and diagnosis of AT-III deficiency or parental diagnosis of AT-III deficiency or diagnosis of AT-III deficiency alone. SELECTION PROCEDURES: Random observation (case reports) and literature search for cases of AT-III deficiency diagnosed in the neonatal period or presenting with thrombosis and a positive family history of the disorder. INTERVENTIONS: Fresh frozen plasma, heparin, and AT-III concentrate were employed in the current case reports. The cases from the literature used combinations of the above or no intervention. MEASUREMENTS/MAIN RESULTS: Twenty-three cases, including the current reports, of suspected or proved AT-III deficiency were found, with at least 11 cases of thrombosis and at least 10 deaths. CONCLUSIONS: Significant morbidity and mortality from inherited AT-III deficiency can occur in the neonatal period, and the incidence of affected neonatal patients is probably underestimated. Careful family history, early recognition, diagnosis, and specific treatment are important for management of this disorder.

Antithrombin III Deficiency↗