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Biomedical subjects

J N Fiessinger

Publications and source records attributed to J N Fiessinger.

At least 19 recordsLinked to original sources
PubMed1992

Double-blind, randomized comparison of systemic continuous infusion of 0.25 versus 0.50 mg/kg/24 h of alteplase over 3 to 7 days for treatment of deep venous thrombosis in heparinized patients: results of the European Thrombolysis with rt-PA in Venous Thrombosis (ETTT) trial.

Thirty-two patients with acute, proximal-vein thrombosis were treated with heparin and alteplase (0.25 versus 0.5 mg/kg/24 h during 3-7 days) in a randomized, double-blind, multicenter, European (ETTT) trial. The treatment resulted in a decrease of the venographic Marder's score from 18 (6-25) to 13 (2-24) units (median, range) in Group I (0.25 mg/kg/24 h, n = 15, median decrease 3.0, p = 0.32) and from 17.5 (3-33) to 15.5 (0-27) in Group II (0.5 mg/kg/24 h, n = 16, median decrease 4.0, p = 0.23). Comparison of the sequential venograms could be performed in 14 cases of Group I and in 15 cases in Group II. A minority of patients showed substantial partial recanalization of the initially obstructed veins on the control venogram (one in each treatment group) and most of the control venograms showed either thrombus size reductions (5 in Group I, 7 in Group II) or no change or even deterioration (8 in Group I, 7 in Group II). Major bleedings were observed in 7 patients (7/32, 22%), 5 of them occurring in Group II (5/17, 29%). Thus, the results of the ETTT trial show that the used low dosages of alteplase administered intravenously over 3-7 days in heparinized patients cannot be recommended as a treatment for patients with deep venous thrombosis of lower limbs and/or pelvis. Further studies are needed to define a more suitable dosage regimen of alteplase in this indication.

Adolescent↗
PubMed1992

Partial characterization of an autoantibody recognizing the secondary binding site(s) of thrombin in a patient with recurrent spontaneous arterial thrombosis.

A patient with an 18 year history of recurrent arterial thrombosis and no evidence of atherosclerosis or embolism of cardiac origin presented with a prolonged thrombin clotting time when performed with human thrombin. The bovine thrombin clotting time was only slightly prolonged. During 30 months of follow-up, the thrombin time fluctuated, but remained prolonged. The patient has been treated with an oral anticoagulant for the past 8 years, with no thrombotic recurrence. The inhibitor activity was due to the presence of polyclonal IgGs which bound to thrombin-Sepharose. The influence of IgGs purified from the patient's serum was compared to the influence of normal IgGs in several systems exploring the catalytic activity of thrombin and the binding of the enzyme to macromolecular substrates through secondary binding site(s). We found that the IgGs did not impair the catalytic activity toward small synthetic substrates, but inhibited the binding of thrombin to fibrinogen, thrombomodulin and heparin cofactor II. Such proteins are known to require a secondary binding site of thrombin to interact with the enzyme. The anti-thrombin antibody might have resulted from an abnormal generation of thrombin. This would be the consequence of the process favouring thrombosis. Alternatively, the autoantibody might have favoured thrombosis primarily, by impairing natural antithrombotic mechanisms triggered by thrombin.

Adult↗
PubMed1992

[Treatment of venous thrombosis with low molecular weight heparin and fluindione].

Thirty-one consecutive patients with deep vein thrombosis were treated with Fraxiparine, a low molecular weight heparin, and fluindione, an oral anticoagulant prescribed at an early stage. Despite the weight/biological effectiveness ratio, the dose of Fraxiparine had to be adjusted in 46 percent of the patients to remain within the therapeutic range selected (0.5 to 1 antiXa/ml units). The early administration of fluindione reduced the duration of heparin therapy to 5.75 days. Using a prescription guide on days 2 and 4 might improve the safety of the fluindione induction.

Adult↗
PubMed1992

Two novel mutations responsible for hereditary type I protein C deficiency: characterization by denaturing gradient gel electrophoresis.

Hereditary protein C (PC) deficiency is usually associated with a high risk of thrombosis. We report the results of a study undertaken to screen for molecular defects in families with hereditary quantitative PC deficiency. Using a strategy combining polymerase chain reaction amplification of selected gene fragments, denaturing gradient gel electrophoresis of the amplification products, and direct sequencing of fragments with altered melting behavior, we studied the PC gene exons and exon/intron junctions of subjects with hereditary type I PC deficiency. Computer simulation of DNA melting was used to design several sets of primers, each containing a GC-clamp, permitting the complete analysis of each amplified exon sequence. Using this procedure, we identified two previously undescribed mutations located in exon VII: a C-to-T substitution generating a nonsense codon in place of Arg 157 in the mature PC and a G-to-A substitution converting Arg 178 to GIn. The two mutations were detected in, respectively, 3 and 2 apparently independent families. This strategy is therefore a valuable tool for screening patients, and the results emphasize its advantages over plasma assays in individuals with a family history of thrombosis.

Adult↗
PubMed1992

Femoropopliteal stent placement: long-term results.

Twenty-one patients who underwent percutaneous transluminal angioplasty (PTA) followed by attempted insertion of a self-expandable vascular endoprosthesis for femoropopliteal lesions were prospectively followed up for an average of 17.6 months with angiographic, Doppler ultrasound, and clinical examinations. Stents were placed bilaterally in one patient. Of the 22 lesions, 18 were total occlusions and four, stenoses. Stent placement was successful in 21 of 22 lesions. Nine occlusions occurred: four in the first 30 days and five 1-5 months after PTA. Three patients developed intrastent intimal hyperplasia that necessitated an additional percutaneous procedure. At 12 months, the patency rate without other interventions (the primary patency rate) was 49%. In patients who underwent secondary intervention (fibrinolysis, atherectomy, or PTA), the secondary patency rate was 67%, which fell to 56% after 18 months. At the end of the study, the overall rate of reocclusion was 43%. It is concluded that use of the self-expandable vascular endoprosthesis in the femoropopliteal region likely does not decrease the reocclusion rate after PTA alone. Its use is indicated for treatment of acute closures after femoropopliteal PTA.

Aged↗
PubMed1992

Met 358 to Arg mutation of alpha 1-antitrypsin associated with protein C deficiency in a patient with mild bleeding tendency.

The molecular defect responsible for a dramatic prolongation of all standard clotting tests discovered in a 15-yr-old boy has been identified. Initial investigations revealed the presence of an activated Factor X (Factor Xa) and thrombin inhibitor which copurified with alpha 1-antitrypsin (alpha 1-AT), thereby suggesting the occurrence of an alpha 1-AT variant similar to alpha 1-AT Pittsburgh. This was confirmed by dot-blot analysis and direct sequencing after amplification by the polymerase chain reaction. A G to T transition at nucleotide 10038 results in the substitution of Met to an Arg, converting alpha 1-AT into an Arg-Ser protease inhibitor (serpin) that inhibited thrombin and Factor Xa more effectively than antithrombin III. Surprisingly, there was no bleeding history in the proband. The common mutation Z, which may explain a reduced expression of the allele bearing the Arg 358 Met mutation, was not observed in the propositus' DNA. To exclude the presence of another mutation, the coding regions and intron/exon junctions were sequenced. No other mutation was found. Recently, the patient experienced his first hemorrhagic episode at the age of 17. The level of the abnormal inhibitor had increased twofold 2 mo before. The large decrease in protein C concentration may account for the mild bleeding tendency in this case, despite the presence of the alpha 1-AT Pittsburgh mutation. An abnormal protein C pattern was observed in patient's plasma, suggesting that the circulating deficiency might be due to a deleterious effect of the abnormal inhibitor on both intracellular processing and catabolism of protein C.

Base Sequence↗
PubMed1992

Molecular abnormalities responsible for thrombosis. Genetic aspects.

The association between congenital deficiencies and recurrent thrombosis strongly suggests that antithrombin III, protein C and protein S play a major role in inhibiting thrombin formation in vivo. Genetic analysis using DNA fragment amplification by polymerase chain reaction and direct gene sequencing has led to the identification of many novel mutations in qualitative and quantitative deficiencies. Elucidation of the molecular basis of these deficiencies is critical to our understanding of natural antithrombotic mechanisms. It not only provides information on the structural features governing protein function, but also permits a better classification, based on genomic abnormalities of hereditary deficiencies responsible for mild to severe phenotypes and may prove of further value to define the most pertinent plasma assays for routine diagnosis.

Antithrombin III Deficiency↗
PubMed1991

Molecular basis for hereditary antithrombin III quantitative deficiencies: a stop codon in exon IIIa and a frameshift in exon VI.

Antithrombin III (AT III) is an inhibitor of serine protease (serpin) comprising 432 amino acids. Quantitative AT III deficiencies are associated with a high risk of thrombotic disease. Although this risk is smaller in patients with qualitative AT III deficiencies, the molecular defects characterizing the latter have been the subject of many studies. However, in quantitative AT III deficiencies, only three mutations have been described: Pro 407 to Leu and A1a404 to Thr (both located in the C-terminal part of the AT III molecule) and also a frameshift in exon IIIa. Using the asymmetric polymerase chain reaction (PCR) and genomic DNA analysis by direct sequencing, we detected two mutations in three unrelated families: (i) a C----T transition in exon IIIa in two families, leading to the replacement of the codon corresponding to Arg 129 by a stop codon, and (ii) in the third family, insertion of an adenine in the codon corresponding to Phe 408, a highly conserved serpin amino acid. This insertion altered the reading frame and led to the appearance of a premature stop signal. Patients of all three families were heterozygous for their abnormality. These results show that asymmetric PCR and genomic DNA analysis by direct sequencing permit fast identification of the molecular basis of quantitative AT III deficiencies. It is concluded that in many cases the absence of AT III gene product probably results from point mutation, as previously observed for another serpin, alpha-1-antitrypsin.

Adolescent↗
PubMed1991

Percutaneous iliac artery stent: angiographic long-term follow-up.

The authors conducted a prospective study of 49 consecutive patients with 53 lesions in 52 iliac arteries. All were treated between October 1987 and April 1990 with percutaneous transluminal angioplasty (PTA) and insertion of either a self-expandable or balloon-expandable stent. Lesions included total occlusion (28%), dissection (42%), post-PTA restenosis (21%), and unsatisfactory PTA (9%). Complications included one aortic protrusion, one acute thrombosis of the stent (resolved with urokinase), and three distal embolizations (5.7%) (resolved with urokinase and aspiration). During 15 months of follow-up, two patients died (one after occlusion). Three other occlusions occurred; one of these was resolved with local thrombolysis. Hyperplasia occurred in seven cases (13.5%), and stenosis occurred at the end of the stent because of incomplete covering of the lesion in three (5.8%); a complementary procedure was performed in six of these cases. Primary patency was 85.3% at 12 months and 80.9% at 18 months; secondary patency rate was 96.1% at 12 and at 18 months. At the end of the study, excluding data for the two patients who died, 27 limbs (54%) were asymptomatic and improvement was achieved in 19 (38%); the clinical success rate was 92%. No amputations were required.

Adult↗
PubMed1991

Heparin cofactor II: an acute phase reactant in patients with deep vein thrombosis.

In human plasma, heparin cofactor II (HCII) is a thrombin inhibitor which displays similarities with antithrombin III (ATIII). As previously reported for hereditary ATIII deficiency, cases of recurrent thrombosis were reported in patients with hereditary HCII deficiency. Here, plasma HCII activity was studied in 372 patients with a history of thrombosis, classified according to their anticoagulant therapy. The mean plasma HCII level was significantly higher in patients with acute deep vein thrombosis (DVT) under heparin therapy than in patients with a history of thrombosis, who were studied more than 3 months after the acute event, and were either on, or had been on, oral anticoagulant therapy. HCII and fibrinogen were significantly correlated in all three groups of patients. These results were strengthened by those of a follow-up study in 23 patients with acute DVT. Changes in plasma HCII activity paralleled those of fibrinogen. This suggests that HCII might behave like an acute phase reactant in patients with thrombosis and that the measurement of its plasma level as a risk factor for thrombosis should be performed some time after the acute episode. In conclusion, the prevalence of HCII deficiency in patients with a history of thrombosis might have been underestimated in series which included patients with acute thrombosis.

Acute-Phase Proteins↗
PubMed1991

[Esophagitis in progressive systemic scleroderma. Prevalence and risk factors in forty-six patients].

Forty-six patients with progressive systemic sclerosis (37 women and 9 men) were successively evaluated by endoscopy, manometry, and esophageal pH monitoring. Fourteen patients (30.4 percent) had erosive esophagitis. Twenty-four patients were symptomatic; nineteen patients complained of dysplagia. Erosive esophagitis was significantly more frequent in symptomatic patients than in asymptomatic patients (50.0 percent vs 9 percent, P less than 0.01) and especially in patients complaining of dysphagia (57.9 percent vs 11.1 percent, P less than 0.01). Erosive esophagitis was not correlated with symptoms of gastroesophageal reflux. Abnormal esophageal motility was found in 34 patients (73.9 percent). Occurrence of erosive esophagitis was not linked with esophageal dysmotility. In patients with erosive esophagitis lower esophageal sphincter pressures were significantly lower than those in patients without erosive esophagitis. Twenty-four hr-pH monitoring showed pathological gastroesophageal reflux in 20 patients (43.5 percent). Erosive esophagitis was more frequent in patients with pathological gastroesophageal reflux than in patients with normal gastroesophageal reflux (50.0 percent vs 15.4 percent, P less than 0.02) especially in patients with pathological supine nighttime gastroesophageal reflux (61.5 percent vs 18.2 percent, P less than 0.01). Our data suggest that symptoms, dysphagia, diminished lower esophageal sphincter pressures, and pathologic nighttime gastroesophageal reflux are reliable predictors of the presence of erosive esophagitis in patients with progressive systemic sclerosis.

Adult↗
PubMed1990

[Echography and venous pathology].

When performed by a well-trained operator, ultrasonic exploration of the deep veins has a more than 90% sensitivity and specificity in the diagnosis of deep vein thrombosis. Despite technical problems in the ileal and sural regions, it is the first examination to be carried out in patients with clinical signs of venous thrombosis. In distal thrombosis of the leg and calf ultrasonography might even be more sensitive than phlebography. In superficial phlebitis ultrasounds can be used to evaluate the extent of thrombosis. In varicose vein disease, they are also a crucial element in the choice of treatment.

Humans↗