[Rare vascular diseases]. / Maladies vasculaires rares.

Scarce knowledge of vascular rare diseases, defined by prevalence lower than 1/2000, is accompanied by increased patients mis-management and impaired quality of life. Recent advances in clinical knowledge, molecular biology, and genetic evaluation of certain vascular rare diseases allows designing new management strategies. A tight coordinated collaboration between angiologists and other specialists is therefore necessary to optimize patient's care.

[Thrombotic risk in assisted reproductive technology]. / Risque thrombotique sous procréation médicalement assistée.

Use of assisted reproductive technology (ART) is increasing in many developed countries. Arterial and venous thromboembolic complications are reported during ART with an incidence of 0.1%. The development of these events has been mainly ascribed to the presence of ovarian hyperstimulation syndrome (OHSS). Precise mechanisms by which OHSS and exogenous hormonal stimulation used in ART induce thromboembolic events remain unclear. However, vascular endothelial growth factor secreted during OHSS, high estradiol concentrations, and blood hyperviscosity play a major role in inducing a prothrombotic state. Therefore, before planning an ART, individual thromboembolic risk should be assessed and thromboprophylaxis offered to high risk patients. Prophylaxis should be initiated in women who develop moderate-to-severe OHSS.

New versus established drugs in venous thromboprophylaxis: efficacy and safety considerations related to timing of administration.

European surgeons generally administer thromboprophylaxis with low-molecular-weight heparins (LMWHs) at high doses 12 hours preoperatively in response to findings that surgery-related deep-vein thrombosis typically originates at the time of major orthopedic surgery or shortly afterwards. North American surgeons, in contrast, generally administer LMWHs at an almost 50% higher dose than that given in Europe 12-24 hours postoperatively, even though both pre- and postoperative administration are considered suitable in current guidelines. This review therefore examines how close to major orthopedic surgery thromboprophylaxis is administered, and the subsequent effect of timing on clinically relevant efficacy and safety parameters. The trials examined involve fondaparinux sodium (fondaparinux) and (xi)melagatran, in comparison with the established LMWHs enoxaparin sodium (enoxaparin) and dalteparin. In key trials, fondaparinux reduced the risk of asymptomatic and clinical venous thromboembolism (VTE) by 55% compared with enoxaparin, at the expense of a 1.6-fold higher risk of bleeding. While the studies were not designed to compare efficacy endpoints based on clinical outcomes, no significant difference was demonstrated for symptomatic VTE. The fact that the enoxaparin regimen was started at the upper limits of its recommended initiation timeframe may have significantly influenced the results of comparative studies, given that several meta-analyses found that the timing of LMWH initiation significantly influenced its effectiveness on asymptomatic VTE and major bleedings. Compared with once-daily LMWH in European trials, early postoperative doses/regimens of twice-daily (xi)melagatran did not increase severe bleeding and was significantly less effective at preventing asymptomatic total VTE in patients who had undergone total hip-replacement surgery. When used according to the 'knife-to-skin' protocol, the melagatran regimen was superior to enoxaparin in preventing major asymptomatic VTE, but at the cost of a higher rate of major bleeding. In North America, the delayed postoperative administration of (xi)melagatran (oral only) was less effective than the postoperative twice-daily enoxaparin regimen with regard to asymptomatic total and major VTE. Our analysis highlights the fact that differences in efficacy and safety data in clinical trials of thromboprophylaxis might also be linked to differences in the timing of initiation. However, it is not possible to assess the importance of this 'time effect' among other factors considered as drug-specific properties (pharmacokinetics, mode of action, dosage) and evaluate their respective contribution in the observed differences. To avoid unbiased comparison in further studies, the possible effect of timing should be taken into account and, when feasible, both therapies started at the same time. For instance, harmonizing the initiation of thromboprophylaxis 6-8 or 12 hours postoperatively could be two acceptable harmonized options for scheduling in clinical trials.

Antineutrophil cytoplasmic antibody-associated neutropenia.

BACKGROUND: Antineutrophil cytoplasmic antibodies (ANCA) can be associated with various disorders. However, their association with neutropenia has never been reported. METHODS: Nine patients with chronic unexplained neutropenia and ANCA were studied. Clinical charts were extensively analyzed and all patients underwent hematological and immunological investigations. RESULTS: All patients (6 women and 3 men) were Caucasian and had a mean age of 49 years (range 16-67 years). All presented with a neutropenia below 1.5x10(9)/L for more than 6 months. The neutropenia was <0.5x10(9)/L in six cases and moderate in three. There was no evidence of toxic- or drug-related neutropenia or of a hematological malignancy. Autoimmune anemia and/or thrombocytopenia were present in five patients. ANCA, with various specificities, were present in all patients. ANCA were associated with various other autoantibodies in eight patients, including antisurface-neutrophil antibodies in three cases. Four of the six patients with severe neutropenia experienced infections. Five patients were treated with hematopoietic growth factors, steroids, intravenous immunoglobulins, splenectomy, methotrexate and/or cyclophosphamide, allowing the neutrophil count to be restored transiently or permanently. CONCLUSIONS: A subset of patients with neutropenia of possible autoimmune origin may develop ANCA. Their detection would provide strong evidence of an autoimmune mechanism. Neutropenia should be added to the list of ANCA-associated diseases.

Hyperhomocysteinaemia, folate and vitamin B12 in unsupplemented haemodialysis patients: effect of oral therapy with folic acid and vitamin B12.

BACKGROUND: Hyperhomocysteinaemia, a risk factor for atherosclerosis, is common in dialysis patients and particularly in those homozygous for a common polymorphism in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene (C677T transition). B-complex vitamin supplements have been shown to lower plasma total homocysteine (tHcy) concentrations, but the respective effectiveness of folate and oral vitamin B12 is not yet known. Our objectives were: (i) to determine the status of folate and vitamin B12 in a cohort of unsupplemented dialysis patients (ii) to assess the homocysteine-lowering effect of a folate supplement and then of a folate supplement with added vitamin B12. The responses were analysed for the C677T genotypes of MTHFR. METHODS: Plasma tHcy, folate and vitamin B12 were measured in 51 haemodialysis patients genotyped for the C677T MTHFR mutation (homozygotes, TT; heterozygotes, CT; without mutation, CC). All patients were then given daily supplements of 15 mg of folic acid for 2 months. They were given daily supplements of 1 mg of vitamin B12 in addition to the folate supplements for a further 2 months. Plasma tHcy, folate and vitamin B12 were monitored after each intervention. RESULTS: At baseline folate and vitamin B12 deficiencies were found in 10% and 6% of the patients. Initial plasma tHcy concentrations were high in all patients (mean 38.1+/-15 micromol/l). CC patients tended to have a lower tHcy concentration than pooled CT and TT patients. After 2 months of folate therapy, tHcy concentration decreased significantly to 20.2+/-7 micromol/l (P<0.001) and no significant differences were observed between the different genotype subgroups (19.4+/-6 for CC, 21.3+/-8 for CT, 18.5+/-4 for TT). A significant positive relationship was found between the reduction of tHcy and its initial value (rho=0.615, P<0.0001). The impact of the added vitamin B12 was negligible since tHcy concentrations did not change for the patients as a whole (19.8+/-7 micromol/l, NS) or in any subgroup (19.1+/-5 for CC, 20.3+/-9 for CT and 20+/-7 micromol/l for TT). CONCLUSIONS: (i) Folate and vitamin B12 deficiencies were observed in 10% and 6% respectively of our unsupplemented dialysis patients. (ii) After folate therapy, tHcy levels decreased significantly in all patients and were identical between the three C677T MTHFR genotype subgroups. (iii) Vitamin B12 supplements are useful in folate treated patients to prevent cobalamin deficiency and its neurological consequences but they did not lower tHcy plasma levels for the patients as a group or for any of the MTHFR subgroups.