Biomedical subjects
Publications and source records attributed to J N Fiessinger.
Stringent conditions have been applied to set up an "enzyme-linked immunosorbent assay" to detect anti-endothelial cell autoantibodies. These predominated in Sneddon's syndrome.
We describe an unusual presentation of bacterial endocarditis due to Staphylococcus aureus in a 50 year-old woman with mitral insufficiency. The disease began by a vascular purpura without fever and a digital embolism. The source of infection was anal ulcerations. Diagnosis of endocarditis was made possible by trans-oesophagus echocardiography but not by trans-thoracic echocardiography. The patient was successfully treated by surgery associated with antibiotherapy. This observation emphasizes the indications of surgery at the acute phase of endocarditis. The anal source of endocarditis is original, no other case has been found in the literature.
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The authors report the case of a 34-year-old woman, of North African origin, with mitral valve disease and abdominal aortitis. The differential diagnosis between Takayasu' disease, embolism of cardiac origin and rheumatic aortitis is discussed. Treatment of these lesions was by combined cardiac and vascular surgery in a single-stage operation.
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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.
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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.
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.
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.
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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.
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.
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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.
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