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Biomedical subjects

J N Fiessinger

Publications and source records attributed to J N Fiessinger.

At least 91 records · Page 5Linked to original sources
PubMed1995

Mechanism of protein C deficiency in a patient with arginine 358 alpha 1-antitrypsin (Pittsburgh mutation): role in the maintenance of hemostatic balance.

We recently described a new case of alpha 1-antithrombin (alpha 1-AT) Pittsburgh, a mutation that transforms alpha 1-AT into a potent inhibitor of thrombin. In contrast to the originally described patient, who had a severe hemorrhagic diathesis, our proband had only a mild bleeding tendency. The current article explores possible mechanisms for the relative hemostatic competence of our patient. The levels of both normal and mutant alpha 1-AT were similar to those of the previously reported case, as was the rise in plasma antithrombin level during an acute phase reaction. The level of protein C, however, was found on several occasions to be approximately 20% of normal. Family studies and examination of the patient's protein C gene on a denaturing gel failed to identify an abnormality. Moreover, the patient's protein C showed no abnormalities suggestive of faulty intracellular processing. However, the protein C in his plasma was for the most part in the activated form and bound to the mutant alpha 1-AT. Thus it is likely that the strong affinity of mutant alpha 1-AT for protein C leads to an increased turnover and thus to a low circulating level. A seeming flaw in that scenario is that the mutant alpha 1-AT also has a very high affinity for thrombin and might be expected therefore to block the activation of protein C. When thrombin was complexed with thrombomodulin (as it is when protein C is physiologically activated at the endothelial surface), mutant alpha 1-AT was far less able to inhibit thrombin than was the case for the free enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗
PubMed1995

Comparison of biological activities of two low molecular weight heparins in 10 healthy volunteers.

1. Low molecular weight heparins (LMWHs) are produced by different depolymerization processes and may therefore differ with respect to their pharmacokinetic properties. 2. We designed a single dose, randomized cross-over study in 10 healthy volunteers to compare the 24 h pharmacokinetics of two LMWHs, reviparin and enoxaparin, which have been previously shown to be clinically equivalent in terms of post-operative deep vein thrombosis prevention, despite significant differences in their in vivo biological activity. The two LMWHs were subcutaneously administered at the same dosages that are used in clinical studies: 4250 anti-Xa iu for reviparin and 40 mg for enoxaparin which have similar in vitro anti-Xa activities. 3. The overall 24 h profiles of the plasma anti-Xa and anti-thrombin activities were similar for reviparin and enoxaparin. The Amax and the AUC(0, 24h) of plasma anti-Xa activity after reviparin administration were both slightly but significantly lower than those observed after enoxaparin administration (difference between treatments of 0.03 95% CI[0.01-0.05] iu ml-1 h and 0.56 95% CI[0.22-0.90] iu ml-1 for Amax and AUC(0, 24h) respectively). After adjustment for in vitro anti-Xa activity, the statistical difference between the two LMWHs persisted for the AUC(0, 24h) but not for the Amax of plasma anti-Xa activity. The tmax and the MRT values for plasma anti-Xa activity did not significantly differ between the two drugs. The t1/2 for reviparin did not significantly differ from that of enoxaparin (2.7 +/- 0.7 h vs 3.5 +/- 0.9 h respectively, NS). The Amax of the plasma anti-thrombin activity after reviparin administration was also slightly but significantly lower than that observed after enoxaparin administration, (difference between treatments of 0.018 95% CI[0.01-0.025] iu ml-1) whereas the AUC(0, 24h) of anti-thrombin activity vs time was not. A slight but significant increase of the activated partial thromboplastin time of a similar magnitude was observed after both reviparin and enoxaparin injections. 4. The calculated surface under the thrombin generation curve vs time (or thrombin potential) at peak was significantly higher after reviparin than after enoxaparin (367 +/- 53 UA vs 305 +/- 48 UA respectively, P < 0.05). Four hours after injection, thrombin potential was significantly correlated to plasma anti-Xa activity after reviparin but not after enoxaparin injection (r = 0.65, n = 10, P = 0.05 and r = -0.38, n = 10, P = 0.25 respectively). 5. After a single-dose injection in healthy subjects, two LMWHs with comparable in vitro activities differed slightly kinetically. Such minor differences are probably of little importance in the prevention of post-operative deep vein thrombosis, since these two LMWHs were previously shown to be comparable in this setting.

Adult↗
PubMed1994

A phenylalanine 402 to leucine mutation is responsible for a stable inactive conformation of antithrombin.

In a South African family with antithrombin deficiency and unexplained thrombosis, genomic DNA analysis revealed a substitution of Phe 402 by Leu. This mutation involves an amino acid located in the carboxyterminal side of the antithrombin reactive loop and has already been observed in a French family (antithrombin Maisons-Laffitte). In both cases, the expression of the mutation is pleiotropic, i.e. results in a reduction in the circulating concentration of antithrombin and impairs both its anti-thrombin activity and its ability to bind heparin. The effect of a denaturing agent (sodium dodecyl sulfate) on the recognition of the plasma antithrombin by a polyclonal antibody was studied in an immuno-enzymatic assay. The Phe to Leu mutation decreased the sensitivity to denaturation, suggesting that the mutation increases the stability of the protein. Whether this stable conformation is due to a partial insertion of the amino-terminal side of the reactive loop, which would explain how both protease binding and heparin binding are affected, remains to be determined.

Adolescent↗
PubMed1994

[A new cause of familial thrombophilia: resistance to the effect of activated protein C].

An examination of the cascade of events leading to coagulation emphasizes the importance of protein inhibitors. Deficiencies in these proteins have been implicated as playing a possible causal role in familial thrombo-embolic diseases. Recently the discovery of a probable deficiency in protein C cofactor, different from protein S, stimulated much research in this area. Protein C is a 461 amino acid vitamin K-dependent protein with a molar mass of 62,000 Daltons. After transduction the precursor protein is modified into an active form. Circulating protein C is then activated by proteolysis on the endothelial surface under the control of thrombomodulin-bound thrombin. Thus thrombin affects both procoagulation by activating factors V and VIII (and XI) and anticoagulation after being bound to thrombomodulin. Inactivation of factors V and VIII requires calcium, phospholipids and a C-protein cofactor, protein S. On the basis of clinical observations, it was hypothesized then confirmed that deficiency in a non-identified cofactor of protein C could explain resistance to the anticoagulating action of activated protein C. Purification of the plasma fraction carrying the cofactor activity led to the isolation of a protein which has all the biochemical properties of factor V. In addition, adding factor V to affected plasma has been shown to correct for resistance to activated protein C. But paradoxically, patients with resistance to the action of activated protein C have a normal level of factor V. The mutation responsible for activated protein C resistance was found to be a Gln for Arg mutation at position 506 of factor V. The implication of this mutation has been very recently confirmed and led rapidly to the development of molecular biology methods allowing its identification. At present, this new cause of familial hypercoagulable states can thus be identified with polymerase chain reaction and denaturing gradient gel electrophoresis. These advances have increased the number of identifiable hypercoagulable states, yet further work is needed since currently less than 10% of these diseases can be explained by deficiencies in one of the inhibitor proteins, antithrombin III, protein C or protein S.

Factor V↗
PubMed1994

[Measurement of quality of life in intermittent claudication. Clinical validation of a questionnaire].

OBJECTIVES: Functional limitation in patients with intermittent claudication impairs their quality of life. In order to measure this new evaluation parameter, we developed a self-administered questionnaire: Artemis. METHODS: The questionnaire was composed of a general instrument (SF-36) and a specific one. A cross sectional study was performed in 177 patients with intermittent claudication (mean age 68 +/- 10 years, 77% males) who stated their walking distance was limited within 50 to + 2000 meters. The acceptability, reliability and sensitivity of the questionnaire were tested. RESULTS: In patients who had a walking distance greater than 500 m (n = 96), the scores obtained were significantly higher (better quality of life) than in patients whose walking distance was limited to less than 500 m (n = 81) (p < 0.05). Intermittent claudication had a global effect on the different parameters of the quality of life evaluated by the questionnaire including physical performance and psychological and social aspects. CONCLUSION: The Artemis questionnaire as shown its ability to describe patients with intermittent claudication. It can be used in clinical trials as a tool for measuring quality of life.

Activities of Daily Living↗
PubMed1994

[Which antithrombotic agents should be prescribed in deep venous thrombosis of the limbs?].

Anticoagulants are generally prescribed for the treatment of thrombosis occurring in deep veins. Recent progress in both heparin therapy and in antivitamin K agents require a new look at the therapeutic choice. Due to its immediate anticoagulant action heparin is essential as first intention therapy. Indeed, initial oral anticoagulants are less effective, both in terms of clinical extension and in radiological outcome, than an initial heparin/antivitamin K combination. Non-fractionated heparin administered with an automatic syringe after a priming bolus is the reference treatment for venous thrombosis since it has now been established that 2 subcutaneous injections of heparin are less effective than the intravenous route. Both the effect and safety of low molecular weight heparin have been shown to be comparable with that of non-fractionated heparin. When the dose is adapted to patient weight, 70% are within therapeutic limits after the first injection. Two daily injections of 100 IU per kg body weight can be recommended as initial treatment for deep vein thrombosis. Anticoagulation must be continued for several days but the risk of induced thrombocytopenia persists with low molecular weight heparin. Long-term use should be retained essentially for pregnant women with deep vein thrombosis due to the foetal risk of oral antivitamin K. Antivitamin K oral agents may be initiated early without hindering the anticoagulant effect of heparin. With oral agents, anticoagulant equilibrium is reached, on the average, after 6 days and is a function of vitamin K-dependent half-lives. Since antivitamin K agents affect the stability of prothrombin times during the day/night cycle, it has been recommended to favour long half-life molecules. Standardized prescription protocols can improve safety and anticoagulant equilibrium. To date, the recommended management of deep vein thrombosis includes combining low molecular weight heparin and long half-life antivitamin K. Further progress may be forthcoming with the development of new antithrombotic agents such as hirudine or sulfated heparanes.

4-Hydroxycoumarins↗
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

Adjusted versus fixed doses of the low-molecular-weight heparin fragmin in the treatment of deep vein thrombosis. Fragmin-Study Group.

Treatment monitoring based on a laboratory parameter increases the efficacy and safety of standard heparin therapy, but it is not known if this also applies to low-molecular-weight heparin (LMWH) therapy of acute deep vein thrombosis (DVT). In a prospective randomized trial involving 122 consecutive patients, group A (58 patients) received a weight adjusted dose of Fragmin (100 IU/kg) subcutaneously twice a day throughout the treatment period (10 days +/- 1), while in group B (64 patients) the dosage was based on the results of an anti factor Xa (anti Xa) amidolytic assay to obtain a target concentration from 0.5 to 1 IU/ml. AntiXa and antithrombin activities were also measured retrospectively on frozen plasma from all patients. The two regimens were comparable in terms of hemorrhagic complications (4 in group A and 3 in group B). Bilateral ascending phlebography was performed before inclusion and at the end of LMWH treatment. Treatment efficacy, based on Marder's score, did not differ between the two groups (p = 0.3). Dosage adjustment to between 0.5 to 1 IU anti-Xa/ml does not therefore appear to improve the efficacy or safety of LMWH treatment. However, correlations between the change in Marder's score and both anti-Xa (p < 0.001) and antithrombin activity (p < 0.001) were observed, suggesting a relationship between the degree of FXa or thrombin inhibition and antithrombotic activity.

Acute Disease↗
PubMed1994

Thrombotic complications of polycythemia. The venous and arterial risk factors.

Arterial and venous thrombotic complications have being increasingly recognized as a major cause of mortality and morbidity in polycythemia vera. The risk can be increased with the treatment. Actually, we can not precisely evaluate the risk of previous venous and arterial lesions, however we have non invasive techniques that permit an accurate evaluation of the vascular bed in patients without recent thrombotic events. The ratio cost-efficacy of the vascular explorations has to be discussed according to the risk factors. In patients with a recent arterial thrombotic event, extensive vascular investigations are mandatory.

Arterial Occlusive Diseases↗
PubMed1994

[Short occlusion of the superficial femoral artery: argument for medical treatment].

In cases of superficial femoral artery occlusion, the choice between endovascular therapy and medical rehabilitation is only relevant in the presence of an occlusion shorter than 10 cm. Thirty to fifty per cent of patients who had an endovascular procedure will have their artery patent for one year. The true benefit of this result can only be assessed by taking into account the efficiency of the medical treatment, the costs and the risks of the endovascular treatments. Endovascular techniques should be reserved for selected patients: psychologically or socially incapable of accepting the slowness and the restraints of the medical treatment.

Arterial Occlusive Diseases↗
PubMed1993

[Buerger disease, clinical and prognostic aspects. 83 cases].

A retrospective analysis of 83 records of patients with Buerger's disease is presented. There were 71 men and 12 (14.5 percent) women. Compared with men, women with Buerger's disease had a significantly more frequent vasomotor disorder, but they had less trophic disorders and a lower risk of amputation. After a 42-month follow-up, it appeared that tobacco plays a major role in the prognosis: patients who continued to smoke had significantly more numerous acute episodes than those who ceased smoking. The degree of intoxication is an element of prognosis, but good medical management contributes to reduction in the number of major amputations: only 5 patients (6 percent), all male, had a leg (4 cases) or a thigh (1 case) amputated.

Adult↗