[Two new anticoagulants available in 2010--Dabigatran Etexilate and Rivaroxaban: expected progresses--raised problems]. / Deux nouveaux anticoagulants disponibles en 2010--Dabigatran Etexilate et Rivaroxaban: progrès attendus--problèmes posés.

After having been used for decades, heparins (unfractionated heparin [UFH] or low molecular weight heparins [LMWH]) and vitamin K antagonists (VKA), which are only parenterally active or which are responsible for frequent iatrogenicity respectively, have to face the competition of new anticoagulant drugs targeting either factor Xa or factor IIa (thrombin). Rivaroxaban (Xarelto(®)) and Dabigatran Etexilate (Pradaxa(®)) are the two leading components. They are more convenient to use and do not require routine coagulation monitoring. They are already marketed for venous thromboembolism prevention in major orthopaedic surgery. Although manufacturers claim that no biological monitoring is required, these two compounds may interfere in routine coagulation tests such as PT or aPTT, and in esoteric assays such as anti-Xa activity (the results of which are usually expressed in international anti-Xa units either UFH or LMWH unit) for Rivaroxaban or anti-IIa activity for Dabigatran Etexilate. Noteworthy is the fact that, in the case of these new anticoagulant drugs, results should be expressed in active product units (nanogram per millilitre of Rivaroxaban or Dabigatran). The new anticoagulants are associated with a bleeding risk comparable to that of VKA and heparins.

The adolescent and adult form of cobalamin C disease: clinical and molecular spectrum.

BACKGROUND: Cobalamin C disease is the most common inborn error of cobalamin metabolism with an autosomal recessive mode of inheritance and mutations within the MMACHC gene. Clinical features, including systemic, haematological and neurological abnormalities, usually occur in the first year of life. Adolescent and adult onset presentations are rare. METHODS: We report on the clinical, molecular and imaging features in three patients aged 40, 42 and 42 years at the last follow-up. We examine these cases together with eight previously described cases to determine the clinical and molecular features of the disease in adults. RESULTS: Mean age at onset of clinical symptoms was 26 years; clinical features included predominant neurological disturbances and thromboembolic complications. White matter abnormalities on brain MRI were sometimes observed. Most patients (eight of nine patients investigated) were compound heterozygotes for the 271dupA mutation and a missense mutation. Intramuscular or intravenous hydroxycobalamin therapy stopped the progression of the disease and resulted in a better clinical outcome and favourable biological status in 7/9 treated cases, while the two untreated patients died quickly. CONCLUSIONS: As cobalamin C disease and related disorders of homocysteine metabolism are treatable conditions, homocysteinaemia should be included in the investigations of patients with progressive neurological deterioration, unexplained psychiatric disturbances or recurrent thromboembolic events.

[Hormonal contraception and risk of venous thromboembolism: When to ask for an assessment of hemostasis? Which parameters?]. / Contraception hormonale et risque thromboembolique veineux : quand demander une étude de l'hémostase ? Et laquelle ?

One of the deleterious effects of the combined oral contraceptives is venous thromboembolism (VTE) and it is the most frequent. VTE is potentially serious because it is sometimes responsible for fatal pulmonary embolism. Because of the large use of hormonal contraception among healthy women and often for long durations, it is fundamental to target the prescriptions and detect women at high risk of VTE. It has been demonstrated that some congenital or acquired coagulation anomalies are associated with an increase of thromboembolic risk. In addition, combined oral contraceptives modify some parameters of the hemostasis, whatever the route of administration. In order to optimize the benefit-risk balance of oral contraception, the search for a biological thrombophilia is essential in some clinical situations such as in young women with a history of venous thromboembolic event or with a family history of thrombosis at a relatively young age. A thorough questioning must be performed. On the other hand, this biological research is not systematically recommended before any prescription of hormonal contraception in patients having neither previous personal nor family history of venous thrombosis.

[Therapeutic management of menometrorrhagia in hemostasis disorders]. / Prise en charge thérapeutique des ménométrorragies liées aux coagulopathies et traitement anticoagulant.

Numerous epidemiological studies have confirmed an association between disorder of hemostasis and menorrhagia with an incidence of von Willebrand factor deficiency of 13%, the most common underlying bleeding disorder. In this context, a multidisciplinary approach is the best model. Similarly, women using anticoagulant treatment are exposed to menorrhagia or metrorraghia. The research of both gynaecological disease and therapeutic overdose is necessary.

[Venous thromboembolism and pregnancy]. / Maladie thrombo-embolique veineuse et grossesse.

Venous thromboembolism (VTE) is a major cause of maternal morbidity and mortality during or early after pregnancy. Prior VTE or family history of VTE, clinical or biological risk factors increased the risk of pregnancy-related VTE. Defining the risk of VTE before or at the beginning of pregnancy is necessary to propose the best prevention. However, the management is not standardized between physicians, centres and countries. Current guidelines for prophylaxis and treatment of VTE are discussed in this review.

[Thrombosis and assisted reproductive techniques (ART)]. / Thrombose et assistance médicale à la procréation (AMP).

Assisted reproductive techniques (ART) concern procedures designed to increase fertility of couples: artificial insemination, in vitro fertilization (IVF), either classical or after intracytoplasmic sperm injection (ICSI), transfer of frozen embryos, or gamete intrafallopian transfer. Their use has greatly increased these last years. They may be associated with severe ovarian hyperstimulation syndrome and one possible major complication is venous or arterial thrombosis. Thromboses are rare but potentially serious with important sequellae. They are mostly observed in unusual sites such as head and neck vessels and the mechanism is still unknown although hypotheses have been proposed. This review is an update of our knowledge and an attempt to consider guidelines for the prevention and treatment of ART-associated thromboses, which frequently occur when the woman is pregnant. Prevention of severe ovarian hyperstimulation by appropriate stimulation procedures, detection of women at risk of hyperstimulation and of women at high risk of thrombosis should allow reduction of the risk of thrombosis, possibly by administration of a thromboprophylaxis at a timing and dose which can be only determined by extrapolation.

[Pharmacologic heterogeneity of new anticoagulants]. / Hétérogénéité pharmacologique des nouveaux anticoagulants.

Amongst numerous promising anticoagulant molecules, rivaroxaban (Xarelto(®)), dabigatran (Pradaxa(®)) and apixaban (Eliquis(®)) have been registered outside the USA in the prevention of thromboembolic events in patients undergoing total hip or knee prosthetic replacement. Rivaroxaban however has been granted authorisation by the FDA for the thromboprophylaxis after surgery for total hip or knee surgery. Dabigatran has been granted authorisation by the FDA in non-valvular atrial fibrillation (RE-LY trial) while rivaroxaban is expecting approval in this same indication (ROCKET trial). Phase III results in the treatment and in the secondary prevention of established venous thrombosis and pulmonary embolism are encouraging. These small molecules are obtained by chemical synthesis, their molecular weight is lower than 500 daltons. Many coagulation tests may be affected by these molecules. Those modifications should be known in order to avoid misinterpretation of the tests but could also be used to measure plasma concentrations of these products. The choice of a non specific global and readily available test has been documented (Quick time for rivaroxaban and aPTT for dabigatran). Anti-Xa (for rivaroxaban) and anti-IIa (for dabigatran) activities should however be preferred, expressed in ng/ml with calibrated plasmas (containing predetermined concentration of the tested drug). The half-life is around 8 to 12 hours, with a peak activity 2 to 4 hours after ingestion. Dabigatran is mainly eliminated via the kidney, hence requiring dose-adjustment in case of moderate renal insufficiency, and contra-indicated in case of severe renal insufficiency. Rivaroxaban being excreted via kidney and liver, some precautions should apply in case of liver insufficiency. No data are available in pregnancy or pediatrics, clinical trials are ongoing. There are few interactions with concomitant drugs, which should not be ignored. The short half-life of these new agents compensates for the lack of any specific antidote in many instances. Their oral administration, without the need for dose adjustment, and without requirement for a laboratory monitoring will increase their use in a large number of patients, in those indications for which an approval has been granted by health authorities.

Rituximab alone or in association with corticosteroids in the treatment of acquired factor VIII inhibitors: report of two cases.

Acquired haemophilia is a factor VIII (FVIII) deficiency due to autoantibodies directed against FVIII that can be responsible for severe haemorrhage. The therapeutic approach, in addition to the treatment of bleeding episodes with clotting factor infusion, relies on corticosteroids (CS), cyclophosphamide (CYC), and/or high-dose intravenous immunoglobulins (IVIg). However, the efficacy of IVIg is limited, and CS and CYC may cause a number of adverse effects. Recently, rituximab has been proposed, alone or in combination with CS and immunosuppressants in a small number of patients with acquired anti-FVIII antibodies with a good efficacy. We report here on two patients, aged 74 and 81, respectively, who developed acquired haemophilia, with high titre FVIII inhibitors and severe haemorrhage, in the absence of a detectable cause. Both of them received rituximab as a first line therapy with a marked and prolonged efficacy.