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Joseph Emmerich

Publications and source records attributed to Joseph Emmerich.

At least 19 recordsLinked to original sources
PubMed2006

Prothrombin 20210G>A is an ancestral prothrombotic mutation that occurred in whites approximately 24,000 years ago.

Prothrombin 20210G>A and factor V Leiden are common prothrombotic mutations in whites for which founder effects have been established. In this study, we analyzed the frequencies of 5 single nucleotide polymorphisms (SNPs) and 9 microsatellites flanking the prothrombin gene (F2) in 88 homozygotes for 20210A and 66 homozygotes for 20210G. For estimating the age of the prothrombin 20210G>A mutation, we used the DMLE+2.0 program, which analyzed linkage disequilibria between the mutation and the multiple markers that had been assessed. This analysis yielded an age estimate of 23,720 years (95% credible set, 19,080-31,340 years). A similar analysis by the DMLE+2.0 program was performed on 5 SNPs from previously studied homozygotes for factor V Leiden and controls that yielded an age estimate of 21,340 years (95% credible set, 16,880-29,480 years). The occurrence of the 2 mutations in whites toward the end of the last glaciation and their presently wide distribution in whites suggest selective evolutionary advantages for which some evidence was reported (diminished blood loss) or is controversial (protection against infections).

DNA Mutational Analysis↗
PubMed2006

[Coagulation factor mutations and thrombosis].

The coagulation system is governed by a subtle balance between clotting activators and inhibitors. Many genes can contribute to the overall phenotype, and polymorphisms may act to up regulate or down regulate the generation of thrombin, the coagulation-key enzyme. An increase in coagulation factor (gain function) or/and a decrease in coagulation inhibitors (loss of function) may favor venous thromboembolism (VTE). It has been observed since a long time that VTE may be a familial disease, but it was only in 1965 that Egeberg published the first case of inherited antithrombin (AT) deficiency. This was followed by similar reports of protein C (PC) and protein S (PS) deficiencies. Hereditary thrombophilia was thus initially considered as a rare monogenic disorder with incomplete penetrance. AT, PC and PS deficiencies are due to multiple and mostly private mutations of the corresponding genes. Most patients are heterozygous and experience VTE at adult age. Homozygosity associated with severe thrombosis at birth has been observed in newborns with undetectable PC or PS concentrations. The discovery of factor (F) V Leiden and F2 g.20210 G>A, two gain of function mutations, challenged the view of thrombophilia as a rare monogenic disorder. FV Leiden and F2 g.20210 G>A are due to a founder effect and affect populations of European descent with frequencies at 5% and 3% respectively. These two mutations are moderate of risk factor for thrombosis and paved the way for gene-gene and gene-environment interactions. Patients carrying more than one genetic risk factor are at higher risk to develop VTE. The exposition to acquired risk factors such as estrogen based oral contraception may also have a synergistic effect favoring thrombosis in patients with FV Leiden or other genetic risk factors.

Blood Coagulation Disorders↗
PubMed2006

Alpha1-antitrypsin gene polymorphisms are not associated with renal arterial fibromuscular dysplasia.

OBJECTIVE: We previously showed that fibromuscular dysplasia (FMD) of the renal artery may be familial. Case reports have associated alpha1-antitrypsin deficiency and FMD. The aim of this study was to test the implication of the alpha1-antitrypsin (AAT) gene in a large cohort of patients with renal FMD. MATERIALS AND METHODS: A case-control study comparing the genotype frequencies in 161 consecutive patients with angiographically proven renal FMD with those observed in three sets of controls (353 hypertensive patients, 288 normotensive patients, 444 normotensive women) was conducted. High-resolution echotracking of the carotid and radial arteries was performed in a subset of 77 FMD patients. Three functional polymorphisms of the AAT gene (PiM1, PiZ, PiS) were investigated. RESULTS: Clinical (age 44.3 +/- 13.8 years, 85.1% women) and radiological (77.1% of multifocal lesions) characteristics of the FMD population were consistent with those previously published. No differences were found in AAT genotype frequencies in the FMD subjects compared with the 1085 controls. We found no correlation between the AAT genotypes and the clinical and angiographical characteristics of the FMD patients. Echotracking results confirmed our previously published results in FMD patients with a specific pattern and a mean arterial phenotypic score greater than 3. However, no difference in the arterial score was observed across the genotypes. CONCLUSION: Polymorphisms PiM1, PiZ and PiS of the AAT gene are not associated with renal FMD or infraclinical carotid lesions detected by echotracking methods. As the true prevalence of renal FMD is not precisely known and alpha1-antitrypsin deficiency is not infrequent in the general population, the association of the two may occur by chance.

Adult↗
PubMed2006

Role of fibrinolysis and interventional therapy for acute venous thromboembolism.

The initial goals of treatment for venous thromboembolism (VTE) are usually achieved with anticoagulation. This review focuses on fibrinolysis and interventional therapy in VTE, treatments whose indications are much more controversial. The benefit-to-risk ratio of fibrinolysis in deep vein thrombosis (DVT) is dubious. Thrombolytic treatment is recommended for unstable patients with pulmonary embolism (PE), although these patients represent less than 5% of all patients hospitalized for PE. The use of thrombolytic treatment in patients with sub-massive PE remains controversial. Two indications are widely recognized for inferior vena cava filters: the first is a permanent or temporary contraindication to anticoagulation, in patients with proximal DVT or PE. The second is the occurrence of PE or propagation of the thrombus in patients treated for DVT or recurrence in patients with PE. The PREPIC study demonstrated that in acute VTE, vena cava filters reduced the risk of PE but increased that of DVT and had no effect on survival. The fact that prevention of PE is mainly observed during the short initial period following the diagnosis of an acute VTE event justifies a new randomized study with the use of retrievable filters as an adjuvant to anticoagulation in high risk patients with PE.

Acute Disease↗
PubMed2006

Initial treatment of venous thromboembolism.

Immediate anticoagulant treatment is essential to reduce morbidity and mortality in patients with acute venous thromboembolism (VTE). Currently, rapid anticoagulation can only be achieved with parenteral anticoagulants, such as heparin or low-molecular-weight heparin (LMWH). Weight-adjusted LMWH is the treatment of choice, because it produces predictable anticoagulation and does not require coagulation monitoring. If heparin is used, the activated partial thromboplastin time must be monitored and the heparin dose adjusted to ensure a therapeutic level of anticoagulation. Heparin is recommended for patients with renal impairment and for those at high risk of bleeding. The selective factor Xa inhibitor fondaparinux is a recently introduced alternative to heparin or LMWH for initial VTE treatment. Heparin, LMWH, or fondaparinux should be given for at least five to seven days. Vitamin K antagonists should be initiated on the first day, or as soon as possible, in patients who are candidates for an oral anticoagulant. An oral anticoagulant agent to be used without laboratory monitoring for both acute and long-term treatment of VTE remains an unsolved clinical need in the treatment of VTE.

Administration, Oral↗
PubMed2006

[Medical treatment of critical leg ischemia: current status and future perspectives of gene and cell therapy].

Critical limb ischemia (CLI) is associated with a high risk of amputation and death. For patients who cannot be surgically revascularized, medical options include prostanoids, spinal cord stimulation and lumbar sympathectomy, but none of these treatments has a demonstrated impact on the amputation rate at six months. Gene and cell therapy, aimed at stimulating angiogenesis, have mainly been tested in phase I and II clinical trials. These approaches appear to be feasible and safe in the short-term, but large randomized studies are necessary to demonstrate their clinical benefits and long-term safety.

Amputation, Surgical↗
PubMed2005

Prothrombotic mutations, hormone therapy, and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration.

BACKGROUND: Oral estrogen increases the risk of venous thromboembolism (VTE) in postmenopausal women, particularly in those with a prothrombotic mutation. Transdermal estrogen may be safe with respect to VTE. We investigated the impact of the route of estrogen administration on the association between a prothrombotic mutation (factor V Leiden or prothrombin G20210A mutation) and VTE risk. METHODS AND RESULTS: We performed a multicenter case-control study of VTE among postmenopausal women who were enrolled in 1999 through 2004 at 7 clinical centers in France. We recruited 235 consecutive patients with a first documented episode of idiopathic VTE and 554 controls. Factor V Leiden was associated with a 3.4-fold-increased risk of VTE (95% confidence interval [CI], 2.0 to 5.8), and a prothrombin mutation was associated with a 4.8-fold-increased risk of VTE (95% CI, 2.5 to 9.4). Oral but not transdermal estrogen was associated with an increased risk of VTE (odds ratio [OR], 4.3; 95% CI, 2.6 to 7.2; and OR, 1.2; 95% CI, 0.8 to 1.7, respectively). After adjustment for potential confounding factors, the combination of either factor V Leiden or prothrombin G20210A mutation and oral estrogen gave a 25-fold-increased risk of VTE compared with nonusers without mutation (95% CI, 6.9 to 95.0). However, the risk for women with prothrombotic mutation using transdermal estrogen was similar to that of women with a mutation who were not using estrogen (OR, 4.4; 95% CI, 2.0 to 9.9; and OR, 4.1; 95% CI, 2.3 to 7.4, respectively). CONCLUSIONS: In contrast to oral estrogen, transdermal estrogen does not confer additional risk on women who carry a prothrombotic mutation. The safety of transdermal estrogen has to be confirmed in randomized trials.

Aged↗
PubMed2005

Critical overexpression of thrombospondin 1 in chronic leg ischaemia.

The aim of this study was to identify gene expression governing the balance of angiogenic and angiostatic factors in human ischaemic leg tissues. In situ hybridization was used to screen for the expression of angiogenesis-related genes in tissues from 13 amputated limbs from patients suffering from critical leg ischaemia. The authors tested for mRNA of hypoxia-inducible transcription factors 1 alpha and 2 alpha, vascular endothelial growth factor, and its receptors VEGFR-1 and -2, the angiopoietin receptor Tie2, and the anti-angiogenic molecule thrombospondin 1. The expression levels of the genes in proximal, healthy muscles were compared with those in the distal, ischaemic counterparts. Surprisingly, only thrombospondin 1 was overexpressed in the ischaemic part of the leg of all patients studied. Thrombospondin 1 mRNA was assayed by real-time RT-PCR and the gene was overexpressed 20-fold. The presence of its encoded protein was confirmed by western blotting. The overproduction of this anti-angiogenic molecule was associated with a decrease in capillary density in the affected muscles. Thrombospondin 1 is thus a marker of chronic ischaemia and may affect angiogenesis in ischaemic tissues.

Aged↗
PubMed2005

Current state and perspective on medical treatment of critical leg ischemia: gene and cell therapy.

Critical limb ischemia (CLI) is a severe disease associated with a high risk of amputation and mortality. In patients who cannot be revascularized, several medical options have been tested, including the use of prostanoids, spinal cord stimulation, and lumbar sympathectomy. None of these treatments has demonstrated a benefit on the amputation rates after 6 months of follow-up; these treatments cannot therefore be recommended for CLI treatment in patients for whom surgery is not an option. In this setting, gene therapy and cell therapy to stimulate angiogenesis have been tested mainly in phase I and II clinical trials and are reviewed in this article. These studies demonstrated the short-term safety and feasibility of these new approaches, but larger randomized studies remain necessary to demonstrate their clinical benefits and longterm safety.

Critical Illness↗
PubMed2004

[Treatment of carotid stenosis: angioplasty, a well thought-out choice].

FOUR THERAPEUTIC CLASSES FOR SECONDARY PREVENTION: These are statins (benefit comparable to that obtained following myocardial infarction or stroke), antiplatelet drugs, basically aspirin, clopidogrel that currently has no place in first-line treatment, converting enzyme inhibitors and beta-blockers. There is currently insufficient data to recommend the routine use of vasoactive agents in patients presenting with claudication. IN THE CASE OF CRITICAL ISCHAEMIA: When faced with this serious situation, one must control the pain and the infection and, all cases, revascularisation should be attempted. Amputation should be proposed in the case of trophic disorders and gangrene. ANGIOGENESIS, A POSSIBLE ALTERNATIVE: This is defined by the budding, from existing vessels, of new vessels under the impact of growth and stabilising factors. It is possible to distinguish arteriogenesis with development of pre-existing collateral vessels, angiogenesis itself that corresponds to the development of small vessels from the large vessels and vasculogenesis, which is the formation of new vessels mediated by circulating endothelial progenitors.

Adrenergic beta-Antagonists↗
PubMed2004

Uptake of new treatment strategies for deep vein thrombosis: an international audit.

OBJECTIVE: Study of the uptake of new medical technologies provides useful information on the transfer of published evidence into usual practice. We conducted an audit of selected hospitals in three countries (Canada, France, and Switzerland) to identify clinical predictors of low-molecular-weight (LMW) heparin use and outpatient treatment, and to compare the pace of uptake of these new therapeutic approaches across hospitals. DESIGN: Historical review of medical records. SETTING AND PARTICIPANTS: We reviewed the medical records of 3043 patients diagnosed with deep vein thrombosis (DVT) in five Canadian, two French, and two Swiss teaching hospitals from 1994 to 1998. Measures. We explored independent clinical variables associated with LMW heparin use and outpatient treatment, and determined crude and adjusted rates of LMW heparin use and outpatient treatment across hospitals. RESULTS: For the years studied, the overall rates of LMW heparin use and outpatient treatment in the study sample were 34.1 and 15.8%, respectively, with higher rates of use in later years. Many comorbidities were negatively associated with outpatient treatment, and risk-adjusted rates of use of these new approaches varied significantly across hospitals. CONCLUSION: There has been a relatively rapid uptake of LMW heparins and outpatient treatment for DVT in their early years of availability, but the pace of uptake has varied considerably across hospitals and countries.

Aged↗
PubMed2004

The TF-603A/G gene promoter polymorphism and circulating monocyte tissue factor gene expression in healthy volunteers.

Three single nucleotide polymorphisms (-603A/G, -1322C/T, -1812C/T) and one deletion/insertion polymorphism (-1208D/I) are present in the tissue factor (TF) gene promoter sequence. These polymorphisms are in complete linkage disequilibrium, determining two haplotypes with almost equal frequency. The -603A/-1208D/-1322C/-1812C haplotype, presently defined as TF-603A, has been linked to venous thromboembolic disease, with a potentially protecting effect. The effects of the TF-603A/G gene polymorphism on monocyte gene expression and on a whole-blood clotting time (WBCT) are not known. We determined the WBCT in basal conditions (H0) and after 4 hours of LPS stimulation ex vivo (H4LPS) on blood samples from 100 young healthy caucasian male subjects on 2 visits, 7 days apart. Monocyte TF mRNA was quantified at H0 and H4LPS by real-time quantitative reverse-transcription PCR. The monocyte TF mRNA values determined at the first and second visits were concordant. In H4LPS samples, TF mRNA levels were increased 70-fold. The TF-603A haplotype was associated with 40%-lower TF mRNA levels at H0 (P=0.0002) and this association followed the same trend but was no longer significant at H4LPS. At H4LPS, TF mRNA levels were associated with WBCT shortening (P=0.0003). WBCT at H0 was not concordant over time, precluding any genotype-phenotype analysis. WBCT at H4LPS was concordant over time but was not related to the TF-603A/G polymorphism. The TF-603A/G gene promoter polymorphism thus significantly influences constitutive TF gene expression in human monocytes but has no major effect on TF gene expression or on WBCT in LPS stimulated conditions.

Adolescent↗
PubMed2003

P2Y12 H2 haplotype is associated with peripheral arterial disease: a case-control study.

BACKGROUND: We recently described a gain-of-function haplotype, called H2, of the adenosine diphosphate (ADP) receptor P2Y12 gene associated with increased ADP-induced platelet aggregation ex vivo in healthy volunteers. Because platelets play a key role in atherosclerosis and arterial thrombosis, we tested the possible link between the H2 haplotype and the risk of peripheral arterial disease (PAD) in a case-control study. METHODS AND RESULTS: We studied 184 consecutive male patients under 70 years of age with PAD and 330 age-matched control subjects free of symptomatic PAD and with no cardiovascular history. Mean age was 57.1+/-7.2 years (cases) and 56.7+/-7.6 years (control subjects). The H2 haplotype was more frequent in patients with PAD than in control subjects (30% and 21%, respectively; OR, 1.6; CI, 1.1 to 2.5; P=0.02 in univariate analysis). This association with PAD remained significant in multivariate regression analysis (OR, 2.3; CI, 1.4 to 3.9; P=0.002) after adjustment for diabetes, smoking, hypertension, hypercholesterolemia, and other selected platelet receptor gene polymorphisms. CONCLUSIONS: These data point to a role of the H2 haplotype in atherosclerosis and raise the possibility of relative thienopyridine resistance in carriers of the P2Y12 H2 haplotype.

Aged↗
PubMed2003

A haplotype of the EPCR gene is associated with increased plasma levels of sEPCR and is a candidate risk factor for thrombosis.

The endothelial cell protein C (PC) receptor (EPCR) facilitates PC activation by the thrombin-thrombomodulin complex. A soluble form of this receptor (sEPCR) found in plasma inhibits both activated PC (aPC) activity and PC activation by competing for PC with membrane-associated EPCR. Elevated sEPCR levels are found in approximately 20% of healthy subjects, but the mechanisms underlying this interindividual variability are unknown. We measured sEPCR levels in 100 healthy male volunteers, and observed 2 phenotypic groups of subjects. The temporal stability of sEPCR levels suggested genetic control. Extensive analysis of the EPCR gene in these subjects revealed 13 polymorphisms in complete linkage disequilibrium; these defined 3 haplotypes, 1 of which (A3) was strongly associated with high sEPCR levels. The high constitutive sEPCR levels observed in A3 haplotype carriers might reduce the efficiency of the PC system and predispose these subjects to venous thrombosis. By studying 338 patients with venous thrombosis and 338 age- and sex-matched healthy subjects, we found that the A3 haplotype was overrepresented in the patients. In multivariate analysis, subjects carrying the A3 haplotype had an increased risk of thrombosis (odds ratio [OR] = 1.8; P =.004). Thus, the A3 haplotype, which is associated with elevated plasma sEPCR levels, is a candidate risk factor for venous thrombosis.

Adolescent↗
PubMed2003

[Frequency and risk factors of thrombo-embolic venous disease].

Thromboembolic disease is a frequent pathology, responsible of around 10,000 deaths each year, in France. Post-thrombotic syndrome is also a health policy problem. Acquired and genetic causes of venous thrombo-embolism are better understood and have demonstrated that it is a multifactorial disease. The combination of several environmental and/or genetic risk factors and their understanding in the risk of the disease is important for prophylaxis and treatment after a first episode of the disease. Association between cancer and venous thromboembolism has been recently studied, and is most often associated with a bad prognosis of the underlying cancer.

Humans↗