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Biomedical subjects

J Amiral

Publications and source records attributed to J Amiral.

At least 19 recordsLinked to original sources
PubMed2003

Poor anticoagulant response to tissue factor pathway inhibitor in patients with venous thrombosis.

Tissue factor pathway inhibitor (TFPI) is of major importance in regulating the coagulation triggering effects of tissue factor. An association between TFPI deficiency and thrombosis has still not been clearly demonstrated. We evaluated the anticoagulant activity of exogenous TFPI added either to the plasma of patients with venous thrombosis (n = 118) or to the plasma of healthy controls similar in terms of mean age and sex ratio (n = 107). A poor anticoagulant response to TFPI, defined as TFPI resistance, was observed in 4.7% of controls and in 11.0% of patients. TFPI resistance was associated with an almost threefold increase in the risk of thrombosis and could therefore represent a novel hemostatic risk factor for venous thrombosis.

Adult↗
PubMed2001

Induction of monocyte tissue factor expression by antibodies to heparin-platelet factor 4 complexes developed in heparin-induced thrombocytopenia.

The pathogenesis of thrombosis in heparin-induced thrombocytopenia (HIT) was studied by investigating whether antibodies to heparin-platelet factor 4 (H-PF4) induced tissue factor (TF) synthesis by monocytes. Plasma from 5 patients with HIT containing IgG to H-PF4 was incubated with peripheral blood mononuclear cells without or with purified PF4 and heparin. Significant TF-dependent procoagulant activity (PCA) expressed by monocytes, measured with a factor Xa-based chromogenic assay, was induced after incubation of each HIT plasma sample. This monocyte PCA required the presence of PF4 and was inhibited by high concentrations of heparin. Furthermore, purified HIT IgG added to whole blood with PF4 and heparin also provoked significant synthesis of TF mRNA by monocytes, demonstrated by RT-PCR, and this effect was not observed with normal IgG. These findings strongly support the hypothesis that antibodies to PF4 developed in HIT trigger the production of tissue factor by monocytes, and this effect could account in vivo for hypercoagulability and thrombotic complications in affected patients.

Blood Coagulation↗
PubMed2001

Effect of alpha-lipoic acid on the progression of endothelial cell damage and albuminuria in patients with diabetes mellitus: an exploratory study.

Oxidative stress plays a central role in the pathogenesis and progression of late microangiopathic complications (diabetic nephropathy) in diabetes mellitus. Previous studies suggested that treatment of diabetic patients with the antioxidant alpha-lipoic acid reduce oxidative stress and urinary albumin excretion. In this prospective, open and non-randomized study, the effect of alpha-lipoic acid on the progression of endothelial cell damage and the course of diabetic nephropathy, as assessed by measurement of plasma thrombomodulin and urinary albumin concentration (UAC), was evaluated in 84 patients with diabetes mellitus over 18 months. Forty-nine patients (34 with Type 1 diabetes, 15 with Type 2 diabetes) had no antioxidant treatment and served as a control group. Thirty-five patients (20 with Type 1 diabetes, 15 with Type 2 diabetes) were treated with 600 mg alpha-lipoic acid per day. Only patients with an urinary albumin concentration <200 mg/l were included into the study. After 18 months of follow up, the plasma thrombomodulin level increased from 35.9+/-9.5 to 39.7+/-9.9 ng/ml (P<0.05) in the control group. In the alpha-lipoic acid treated group the plasma thrombomodulin level decreased from 37.5+/-16.2 to 30.9+/-14.5 ng/ml (P<0.01). The UAC increased in patients without alpha-lipoic acid treatment from 21.2+/-29.5 to 36.9+/-60.6 ng/l (P<0.05), but was unchanged with alpha-lipoic acid. It is postulated that the significant decrease in plasma thrombomodulin and failure of UAC to increase observed in the alpha-lipoic acid treated group is due to antioxidative effects of alpha-lipoic acid, and if so that oxidative stress plays a central role in the pathogenesis of diabetic nephropathy. Furthermore, progression of the disease might be inhibited by antioxidant drugs. A placebo-controlled study is needed.

Albuminuria↗
PubMed2001

A cross sectional study of antiphospholipid-protein antibodies in patients with venous thromboembolism.

OBJECTIVE: To look for an association between venous thromboembolism (VTE) and antiphospholipid antibodies (aPL) in patients without Systemic Lupus Erythematosus (SLE) when implementing, beside conventional assays, new tests for aPL screening directed towards purified proteic targets. METHODS: We conducted a cross-sectional, hospital-based study of consecutive unselected outpatients. We compared VTE+ patients to VTE- among 398 consecutive unselected outpatients referred for clinical suspicion of VTE. To detect aPL, the following ELISAs were performed: 1) a conventional standardized ELISA 2) an improved APA assay, 3) an anti-Beta2GPI ELISA, 4) an anti-Annexin V ELISA, 5) an anti-Prothrombin ELISA. We sought an association between VTE and aPL through a quantitative (t-test) and a qualitative comparison (chi-square test, according to the cut-off values set as the 95th percentile of aPL distribution). First we conducted an analysis of all patients. Then we stratified them into 2 subgroups, with or without a wellknown risk factor for VTE (prolonged immobilization >72h, surgery or trauma within the past three months, current malignancy). RESULTS: 61% of patients were classified as VTE-positive. Before stratification, we did not find any significant association between the VTE status and aPL. However, after stratification, in the subgroup without risk factors for VTE, the frequency of positive values as regards the anti Prothrombin antibodies detection was significantly higher in VTE+ patients (p = 0,04). CONCLUSION: The presence of anti Prothrombin antibodies might be an independent risk factor of VTE. However systematic screening for aPL in non SLE patients referred for VTE suspicion at the time of the thrombo-embolic event has little clinical relevance.

Adult↗
PubMed2000

Differences in free and total tissue factor pathway inhibitor, and tissue factor in peripheral artery disease compared to healthy controls.

Tissue factor (TF) is one of the major initiators of coagulation and raised plasma levels have been found in various cardiovascular diseases. TF activity is, however, regulated by tissue factor pathway inhibitor (TFPI), and alteration in levels of TF and/or TFPI may thus relate to thrombogenesis and atherogenesis. To investigate possible abnormalities in TF and free TFPI (i.e. unbound to TF) and total TFPI among patients with peripheral artery disease (PAD), we studied 42 patients (mean age 57, 35 men) with objectively proven (by ABPI/Doppler) disease and 42 age- and sex- matched healthy controls. TF, free TFPI and total TFPI were measured in citrated plasma by ELISA. TF was higher in the patients with PAD compared to controls (275+/-122 pg/ml versus 158+/-60, P<0.0001) but levels of total TFPI were lower in the patients (43+/-10 ng/ml versus 50+/-15, P=0.021). There was no significant difference in levels of free TFPI between patients and controls (7.2+/-1.5 ng/ml in controls, 7.5+/-1. 6 among patients, P=0.39). Within the control patients, levels of free and total TFPI were significantly correlated (Spearman r=0.51, P=0.001) but in the patients with PAD this correlation was poor (r=0. 21, P=0.178). We suggest that reduced levels of total TFPI and raised levels of TF may contribute to the process of atherogenesis and the increased risk of thrombosis among patients with cardiovascular disease.

Adult↗
PubMed2000

Affinity purification of heparin-dependent antibodies to platelet factor 4 developed in heparin-induced thrombocytopenia: biological characteristics and effects on platelet activation.

Antibodies to heparin platelet factor 4 (H-PF4) complexes were purified from the plasma of three patients with heparin-induced thrombocytopenia (HIT) using affinity chromatography. From each plasma, the largest amount of antibodies was eluted with 2 M NaCl at pH 7.5 (peak 1) and the remainder was obtained using 0.1 M glycine/0. 5 M NaCl at pH 2.5 (peak 2). In an enzyme-linked immunosorbent assay (ELISA), we then showed that each patient had developed antibodies to PF4 displaying different characteristics. In patient 1, peak 1 IgG reacted almost exclusively with H-PF4 complexes, whereas peak 2 IgG had similar reactivity with PF4 whether or not heparin was present. Patient 2 expressed a mixture of IgA, IgM and IgG and both fractions bound to PF4 alone or to H-PF4 complexes. Finally, IgG in patient 3 only bound to H-PF4 and was unreactive with PF4 alone. Using [14C]-serotonin release assays, the antibodies developed in the three patients and exhibiting the strongest ability to activate platelets with heparin were those having the highest affinity to H-PF4. These results strongly support the hypothesis that HIT antibodies to PF4 are heterogeneous regarding their affinity and specificity for target antigens and this may greatly influence their ability to activate platelets and their pathogenicity.

Anticoagulants↗
PubMed2000

Antiphospholipid and antiprotein syndromes in non-thrombotic, non-autoimmune women with unexplained recurrent primary early foetal loss. The Nîmes Obstetricians and Haematologists Study--NOHA.

Various antiphospholipid and/or antiprotein antibodies have been suspected to be associated with recurrent early foetal loss in absence of any habitual aetiology. We conducted a hospital-based case control study on women with no antecedent of thromboembolic or autoimmune disease. We studied 3 groups of 518 women: patients with unexplained primary recurrent early foetal loss, patients with explained episodes and mothers with no previous obstetrical accident. Matching the 3 groups was carried out on the basis of age, number or pregnancies and time elapsed since the end of the last pregnancy. Significant biological markers were then prospectively tested. The various antibodies were shown to be dependent on parity and on the presence of previous foetal loss: cut-off values were thus calculated using data obtained from the group of explained accidents, and adjusted for parity. Only anti-phosphatidylethanolamine IgM [odds ratio: 6.0, 95% confidence interval (2.3-15.7), p = 0.0003], anti-beta2-glycoprotein I IgG [4.4, (1.6-11.7), p = 0.0035] anti-annexin V IgG antibodies [3.2 (1.2-8.1), p = 0.015] and lupus anticoagulant [3.0, (1.3-6.8), p = 0.009], were found to be independent retrospective risk factors for unexplained early foetal loss. These four markers were subsequently found to be, during the following pregnancy, associated with a significant risk of foetal loss despite a low-dose aspirin treatment. In non-thrombotic, non-auto-immune women with unexplained primary recurrent early foetal loss, subgroups of patients with positive anti-phosphatidylethanolamine IgM antibodies, or positive anti-beta2-glycoprotein-I IgG antibodies, or positive anti-annexin V IgG antibodies or lupus anticoagulant must be particularised. This should allow therapeutic trials to be carried in well-defined patients.

Abortion, Spontaneous↗
PubMed1999

Antibodies to platelet factor 4-heparin after cardiopulmonary bypass in patients anticoagulated with unfractionated heparin or a low-molecular-weight heparin : clinical implications for heparin-induced thrombocytopenia.

BACKGROUND: Cardiopulmonary bypass (CPB) induces platelet activation with release of platelet factor 4 (PF4), and patients are exposed to high doses of heparin (H). We investigated whether this contributes to the development of antibodies to H-PF4 and heparin-induced thrombocytopenia (HIT). METHODS AND RESULTS: CPB was performed with unfractionated heparin (UFH) in 328 patients. After surgery, patients received UFH (calcium heparin, 200 IU. kg-1. d-1) (group 1, n=157) or low-molecular-weight heparin (LMWH, Dalteparin, 5000 IU once daily) (group 2, n=171). Eight days after surgery, antibodies to H-PF4 were present in 83 patients (25.3%), 46 in group 1 and 37 in group 2 (P=0.12). Most patients (61%) had IgG1 to H-PF4, but only 8 samples with antibodies induced platelet activation with positive results on serotonin release assay. HIT occurred in 6 patients in group 1, but no thrombocytopenia was observed in subjects receiving LMWH, although 2 had high levels of antibodies with positive serotonin release assay results. When antibodies to H-PF4 were present, mean platelet counts were lower only in patients with FcgammaRIIA R/R131 platelets. CONCLUSIONS: These results provide evidence that the development of antibodies to H-PF4 after CPB performed with UFH is not influenced by the postoperative heparin treatment. The antibodies associated with high risk of HIT are mainly IgG1, which is present at high titers in the plasma of patients continuously treated with UFH.

Adolescent↗
PubMed1999

Peripheral blood mononuclear cells isolated from patients with diabetic nephropathy show increased activation of the oxidative-stress sensitive transcription factor NF-kappaB.

Increased oxidative stress and subsequent activation of the transcription factor NF-kappaB has been linked to the development of late diabetic complications. To determine whether oxidative stress dependent NF-kappaB activation is evident in patients with diabetic nephropathy we used an Electrophoretic Mobility Shift Assay based semiquantitative detection system which enabled us to determine NF-kappaB activation in ex vivo isolated peripheral blood mononuclear cells. We examined 33 patients with diabetes mellitus (Type I and Type II). Patients with diabetic nephropathy showed higher NF-kappaB binding activity in Electrophoretic Mobility Shift Assays and stronger immunohistological staining for activated NF-kappaBp65 than patients without renal complications. NF-kappaB binding activity correlated with the degree of albuminuria (r = 0.316) and with thrombomodulin plasma concentrations (r = 0.33), indicative for albuminuria associated endothelial dysfunction. In a 3 day intervention study in which 600 mg of the antioxidant thioctic acid (alpha-lipoic acid) per day were given to nine patients with diabetic nephropathy oxidative stress in plasma samples was decreased by 48% and NF-kappaB binding activity in ex vivo isolated peripheral blood mononuclear cells by 38%. In conclusion, activation of the transcription factor NF-kappaB in ex vivo isolated peripheral blood mononuclear cells of patients with diabetes mellitus correlates with the degree of diabetic nephropathy. NF-kappaB activation is at least in part dependent on oxidative stress since thioctic acid (alpha-lipoic acid) reduced NF-kappaB binding activity.

Adult↗
PubMed1999

Endothelial dysfunction during acute methionine load in hyperhomocysteinaemic patients.

Hyperhomocysteinaemia has been associated with arterial and venous thrombosis possibly by causing damage to the endothelium. We hypothesised that an oral load in methionine, that increases plasma homocysteine, would also result in an increase in biological markers of endothelial or platelet dysfunction. Then we investigated two groups of patients with arterial or venous occlusive disease: 17 with hyperhomocysteinemia and 12 without hyperhomocysteinemia. We measured in both groups plasma soluble thrombomodulin, von Willebrand factor, P-selectin and tissue factor plasma inhibitor before and 6 hours after a load with 100 mg/kg oral methionine. Methionine load resulted in a significant increase in von Willebrand factor in both groups (P<0.02), suggesting that endothelial dysfunction occurs during the load.

Administration, Oral↗
PubMed1999

Preoperative screening for von Willebrand disease type 1: low yield and limited ability to predict bleeding.

Type 1 von Willebrand disease (vWd) is the most common hereditary bleeding disorder. The objective of this study was to measure the von Willebrand factor antigen (vWf:Ag) in a large cohort of patients who underwent surgery to assess the role of a new rapid immunoassay in a screening procedure for vWd in preoperative conditions. We studied 832 consecutive patients (540 children, 292 adults) referred to the surgical departments. For each patient we determined the vWf:Ag level with two different assays, an enzyme-linked immunosorbent assay (ELISA)(Asserachrom vWf:Ag; Diagnostica Stago, France) and a rapid immunoassay (Liatest vWf:Ag; Diagnostica Stago). Using the reference test, we found 30 of 832 patients with a vWf:Ag value below the lower limits (21 U/dL to 46 U/dL). The coefficient of correlation between the two tests was 0.77 (P = .001). When receiver operating characteristic curves were used, the cutoff value calculated to detect vWf:Ag defect with the rapid assay was 68.5 U/dL, leading to 0.36% false negatives and 9.7% false positives. Thus the rapid immunoassay appears to be a useful and easy method that is adaptable to urgent situations. Among the 30 patients with low values in ELISA, 8 had personal or familial bleeding history. Repeat blood samples confirmed the diagnosis of vWd in 5 cases, leading to a prevalence of vWd type 1 of 0.6%. However, in our series the absence of severe bleeding complications raises the question of the screening and the management of patients bearing a type 1 Willebrand disease during surgery.

Adolescent↗
PubMed1999

Octreotide (somatostatin analog) treatment reduces endothelial cell dysfunction in patients with diabetes mellitus.

Octreotide is a long-acting somatostatin analog that has been shown to have various effects in diabetes. This study was performed to evaluate whether octreotide affects the vascular complications of diabetes mellitus. Albuminuria and serum thrombomodulin were used as markers of vascular and renal dysfunction. We studied the effect of octreotide in 27 patients with insulin-dependent diabetes mellitus (IDDM). They received 200 microg octreotide per day over a period of 6 months. As a marker of endothelial cell damage, we measured the serum thrombomodulin level. We also measured urinary albumin excretion, hemoglobin A1c (HbA1c), insulin-like growth factor-1 (IGF-1), and other parameters. IGF-1 decreased from 123 ng/mL before treatment to 114 ng/mL after 6 months of octreotide treatment (P = .009), while no significant change was observed in the unblinded control group (from 103 ng/mL to 102 ng/mL after 6 months of treatment). Urinary albumin excretion in patients with macroalbuminuria declined from 1,124 mg/L before octreotide treatment to 556 mg/L after 6 months of treatment (P < .05), whereas no change was observed in the control group. There was also a reduction of the plasma thrombomodulin level from 61.8 ng/mL to 46.1 ng/mL (P < .07) after 6 months of treatment. Furthermore, HbA1c decreased from 8.75% +/- 1.27% to 8.12% +/- 1.23% (P < .07) after octreotide treatment.

Adult↗
PubMed1999

[Low prevalence of anti-annexin V antibodies in antiphospholipid syndrome with fetal loss].

PURPOSE: Annexin V, a protein with potent anticoagulant activity has a calcium-dependent binding affinity for phospholipids. Annexin V is distributed in many organs, especially in the placenta and endothelium. Various studies have shown that placental annexin V is decreased in women with anti-phospholipid syndrome. It has been suggested that annexin V might be a target of anti-phospholipid antibodies and that the subsequent decrease in annexin V might be associated with obstetrical complications. We investigated the presence of anti-annexin V antibodies in the plasma of women with anti-phospholipid syndrome and obstetrical complications. METHODS: Twenty-three patients with at least one spontaneous abortion were included in the study. Anti-cardiolipin antibodies and lupus anticoagulant were present in 87% and 30% of the patients, respectively. A group of 40 healthy women were included in the control group. Anti-annexin V IgG and IgM antibodies were measured by ELISA. RESULTS: The IgG mean OD was 0.07 +/- 0.013 in patients and 0.042 +/- 0.06 in the control group. There was no significant difference between the two groups (P = NS). Only two out of the 23 patients and two out of the 40 healthy women were positive for IgG (OD > 0.25). The sensitivity of the assay was poor (8.7%). Even when the threshold was adjusted according to the mean OD in control subjects +2 SD, the sensitivity was still poor, reaching only 13%. CONCLUSION: The prevalence of anti-annexin V was low in patients with anti-phospholipid syndrome and repetitive spontaneous abortions. Anti-annexin V assay does not appear to be sensitive enough for the identification of anti-phospholipid antibodies that might be involved in the decrease in annexin V leading subsequently to thrombosis risk.

Abortion, Spontaneous↗
PubMed1999

Influence of ramipril on the course of plasma thrombomodulin in patients with diabetes mellitus.

BACKGROUND: In diabetic patients endothelial dysfunction is reflected by an increased urinary albumine excretion, which can be reduced by ACE-inhibitors. No data are available showing a endothelial-protective effect by determining a marker reflecting endothelial cell-damage. PATIENTS AND METHODS: The effect of angiotensin converting enzyme inhibitor (ACEI) (ramipril) treatment on the progression of endothelial cell damage,--assessed by measurement of plasma-thrombomodulin (TM),--was investigated in an open, non randomized, prospective pilot study over a period of 18 months in diabetic patients. 87 patients with an urinary albumin concentration (UAC) below 100 mg/l at baseline were included. 46 patients were treated without ACEI and served as a control group, 41 patients were treated with ACEI. Participation in this study did not affect intensity in the treatment of blood glucose, blood pressure or diet. At study entry both groups were comparable with respect to duration of diabetes, diabetic complications, vascular risk factors, body mass index, medications used to treat diabetes, presence of hypertension, glycemic control, tryglycerides, HDL cholesterol, creatinine, UAC and plasma-TM. Age, blood pressure, and total cholesterol were significantly higher in the ACEI group, compared with the control group. RESULTS: After a follow up of 18 months a significant increase in UAC (delta UAC = 10.48 mg/l, p = 0.03) and plasma-TM (delta TM = 3.06 ng/l, p = 0.009) was observed in the control group, while in the ACEI treated group a decrease in albuminuria (delta UAC = -7.44 mg/l, p = 0.01) and plasma-TM (delta TM = -4.78 ng/l, p = 0.001) was seen. Despite a similar approach in hypertension and diabetes control in both groups, UAC and plasma-TM decreased after 18 months only in the ACEI treated group. Treatment with ACEI was the strongest predictor (p = 0.0001) indicating decrease of UAC and plasma-TM (multi regression analysis). CONCLUSION: Plasma-thrombomodulin might be a useful marker for assessing the efficacy of drugs potentially protecting the vessel wall. While the present study was a open, non randomized study, further investigation is necessary to proof the hypothesis in a randomized, placebo-controlled, double-blind study.

Adult↗