[Pharmacologic and clinical characteristics of direct inhibitors of factor Xa: rivaroxaban, apixaban, edoxaban and betrixaban]. / Caractéristiques pharmacologiques et cliniques des inhibiteurs directs du facteur Xa : rivaroxaban, apixaban, edoxaban et betrixaban.

Heparins and vitamin K antagonists (VKA) used commonly are the standard treatment of venous and arterial thromboses. They are very efficient and safe, but have some limitations: iatrogenicity, laboratory monitoring, parenteral use for heparins and fondaparinux. Nowadays, four new inhibitors of factor Xa are used orally (rivaroxaban, apixaban, edoxaban, betrixaban), and they are at least as efficient as heparins and vitamin K antagonists. The objective is to substitute these indirect inhibitors of factor Xa (heparins, low molecular weight heparins and fondaparinux) in the prevention of venous and arterial thromboembolic episodes. The new direct inhibitors do not require routine laboratory monitoring of blood coagulation. They inhibit the extrinsic and the intrinsic pathways of blood coagulation. Rivaroxaban and apixaban are efficacious and safe in the prevention of cerebral infarcts in patients with non-valvular fibrillation. Apixaban is another direct inhibitor of factor Xa used orally which is developed in the same indications as rivaroxaban. Edoxaban and betrixaban are also in development. The objective of this work is to study the pharmacodynamic, pharmacokinetic, the efficacy and safety of these four oral direct factor Xa inhibitors.

Pro- and anti-angiogenic agents.

The vascular endothelium has been characterized in every organ system, and is described as a selective permeable barrier and as a dynamic and disseminated organ with endocrine function. These activities have been shown to result from the interactions of ligands with membrane-bound receptors as well as through specific junctional proteins and receptors that govern cell-cell interactions. The endothelial cells' movement (e.g., angiogenesis) has been hypothesized to occur following the release of stimuli that could promote the formation of new blood vessels. Angiogenesis has also been reported to be the continued expansion of the vascular tree in avascular regions, as a result of the sprouting of endothelial cells from existing vessels. Most commonly, angiogenesis has been characterized during wound healing and tumour growth. Herein we summarize and discuss the latest results from fundamental laboratory research aimed at proving a link between the proliferation of cancer and angiogenesis, as well as the new rationale around novel pro- and anti-angiogenic molecules.

[Skin necrosis during long-term fluindione treatment revealing protein C deficiency]. / Nécroses cutanées tardives sous fluindione révélant un déficit en protéine C.

BACKGROUND: Cutaneous necrosis is a rare complication of vitamin K antagonist therapy. It presents as cutaneous hemorrhagic necrosis and usually occurs at the start of treatment. We describe an atypical case of recurrent skin necrosis after two years of treatment with fluindione. CASE REPORT: A 70-year old woman with a history of venous thromboembolism and obesity presented with a large haemorrhagic necrosis of the abdominal wall. She had been treated with fluindione for two years. Genetic protein C deficiency was discovered. Resumption of vitamin K antagonist therapy was followed by recurrence of skin necrosis despite concomitant administration of heparin. Treatment with vitamin K antagonists could not be continued. DISCUSSION: This observation is unusual due to the late onset of skin necrosis. The condition usually begins shortly after initiation of vitamin K antagonist therapy, generally between the third and the sixth day of treatment. It is due to a transient hypercoagulable state in patients with protein C deficiency or, in rare cases, protein S deficiency. This late-onset skin necrosis, occurring many years after initiation of anticoagulant therapy, may be explained by a sudden worsening of pre-existing protein C deficiency due to infectious and iatrogenic factors.

[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.

[From old to new anticoagulants: the role of the biologist]. / Des anciens aux nouveaux anticoagulants : le rôle du biologiste.

Anticoagulant drugs are of great interest to patients and clinical physicians, as well as research scientists. The latter two groups combine their efforts to unravel the related mechanisms of action, as well as means of monitoring and proper dosing. Unfractionated heparin and low molecular weight heparins and vitamin K antagonists have been on board for several decades by now. They act on several clotting factors in certain sequences. Newer drugs, produced by chemical synthesis, act on a more specific target, often factor Xa or factor IIa. These newer anticoagulants have a great convenience in being orally administered and not needing routing laboratory monitoring - which is their main advantage. Hirudine and fondaparinux have been registered for a few years. This year, that is 2008 + 2009, two of these new anticoagulants have been registered and approved for use in Europe and Canada - these are dabigatran etexilate (Pradaxa) and rivaroxaban (Xarelto). Both do not require routine laboratory monitoring. However, coagulation assays for measuring their activity have been studied. A small number of standardized tests should be perfected.

[Study of variability in response to aspirin and clopidogrel: clinical and/or biological resistance?]. / Etude de la variabilité de réponse à l'aspirine et au clopidogrel: résistance clinique et/ou biologique?

Millions of people in France are taking long-term treatments with the two main antiplatelet drugs, aspirin and/or clopidogrel. Most of these people are on a secondary preventive regimen after arterial thrombotic events such as myocardial infarction, stroke, or ischemic complications of lower limb arteriopathy. The term resistance is often a source of confusion. When used, its definition should be explicit. It would be probably be wiser to use a term such as "variable response" which is more widely accepted by specialists and researchers. It would be better to use the term variable platelet response since true pharmacological resistance is rare. The distinction may have clinical pertinence in terms of prognosis. An abundant amount of biological and clinical work in the literature has improved our understanding of the topic. Diverse tests for exploring platelet functions can be used to evaluate the biological impact of treatment. They should, in the near future, contribute to the implementation of guidelines or suggestions for optimal therapeutic modalities. Upcoming results of ongoing large-scale prospective studies will be needed before confirming the potential usefulness and clinical pertinence of these tests.

Circulating platelet-leukocyte aggregates: a marker of microvascular injury in diabetic patients.

Diabetes is associated with multiple disorders including metabolic, cellular and blood disturbances leading to vascular complications. Increased circulating levels of platelet-leukocyte aggregates (PLA) have been described in several thrombotic diseases. In this study, we have evaluated circulating PLA in diabetic patients and we have investigated whether they may be a marker of vascular complications. Using flow cytometry assay, we have quantified PLA percentages in 65 diabetics including 20 patients with type I and 45 with type II diabetes, and 25 healthy subjects. Specific labelling identified platelet-polymorphonuclear aggregates (PPA) and platelet-monocyte aggregates (PMA). We have observed a significant increase of PPA and PMA levels in diabetics (22+/-12% and 45+/-18%, respectively) compared to controls (7+/-4% and 19+/-10%, respectively) (p<0.01). However, both PPA and PMA values were similar in the two diabetes types. Circulating PPA and PMA were significantly enhanced in diabetics with vascular lesions (PPA: 24+/-13%; PMA: 50+/-18%) than in diabetics without vascular lesions (PPA: 18+/-8%; PMA: 38+/-15%) (p<0.05 and p<0.01). Patients with PPA>18% and/or PMA>38% showed a more important vascular injury (OR: 6; 95% CI: 1.6-23). Increased PMA circulating rate is particularly correlated to retinopathic injury (OR: 19; 95% CI: 2.3-154). Our findings established a relationship between increased circulating PLA levels, particularly PMA, and the incidence of microvascular complications in diabetes. They reinforce the concept of pro-inflammatory cells involvement in diabetic retinopathy pathogenesis and their link with thrombotic process.

[New antitoagulants]. / Les nouveaux anticoagulants.

In contrast to older anticoagulant agents vitamin K antagonists and heparins, the new ones are directed towards a single target in general. The main characteristics of the new agents are: their site of action in the coagulation cascade and their mechanism of action which is indirect, antithrombin dependent, most often such as Fondaparinux and Idraparinux or direct such as Dabigatran, Rivaroxaban; the specificity of the new molecules, since they must not interact with other enzymes: trypsin, kallikrein, t-PA, etc...; their mode of administration parenteral and/or oral; their pharmacokinetics and their clearance frequently by the kidney (Hirudin, fondaparinux) or through hepatic metabolism (argatroban); tolerance including for all compounds the bleeding risk or an unexpected hepatic intolerance for Ximelagatran; the availability of a specific antidote and the cost of the drug; one compound is registered in France Arixtra Fondaparinux in major orthopedic surgery and in the treatment of venous thromboembolism and in prophylactic treatment in medical patients. However, the main indications of interest for these new drugs is atrial fibrillation. There is a real need in this indication and the number of patients to treat is growing with the longer life expectancy.

[Prevention of thrombosis and vascular inflammation: importance of combined cyclooxygenase and 5-lipoxygenase inhibitors]. / Prévention de la thrombose et de l'inflammation vasculaire: place des inhibiteurs mixtes des cyclooxygénases et de la 5-lipoxygénase.

Aspirin, a standard non-steroidal anti-inflammatory drug (NSAID) is currently used in antithrombotic treatment. However, its use is limited by largely recognized gastrotoxicity and recommended doses are low. The major side effect of aspirin is related to its ability to suppress prostaglandin (PG) synthesis by constitutive cyclooxygenase-1 (COX-1). Specific inhibitors of COX-2, the inducible isoform of COX which was more recently described, have potent antiinflammatory effects. They are associated with minor risk of gastric tractus toxicity and reduced inflammatory leukocyte components known for their proatherothrombotic properties. Nevertheless, recent findings attributed a significant cardiovascular risk to some of them. 5-lipoxygenase (5-LOX), an enzyme mainly expressed by leukocytes, is responsible for the generation of leukotrienes, the major lipidic proinflammatory mediators. Development of combined inhibitors of 5-LOX and COX isoforms 1 and 2 inaugurate an interesting new therapeutic pathway. Indeed, such inhibitors suppress not only the activation of platelets, leukocytes and endothelial cells but also prevent their metabolic and functional interactions. In addition to their broad spectrum inhibition, they may be associated with the minor gastrotoxic effect. Thus, platelet-leukocyte interactions which dominate the underlying inflammatory process particularly in atherosclerosis, might reinforce the benefits of such inhibitors.

[Prevention of venous thromboembolism after major orthopedic surgery: update and contribution of a specific synthetic inhibitor of factor Xa]. / Prévention de la maladie thrombo-embolique veineuse après chirurgie orthopédique majeure: état des lieux et place d'un inhibiteur synthétique et spécifique du facteur Xa.

Despite widespread use of antithrombotic agents, major orthopedic surgery (total hip arthroplasty, major knee surgery, fracture of the femoral neck) still raises a high risk of deep vein thrombosis and pulmonary embolism. Proper understanding of thromboprophylaxis in orthopedic surgery requires good knowledge of the mechanisms of coagulation and the point of action of different antithrombotic agents. Sodium fondaparinux is the first synthetic inhibitor selective for factor Xa. It is composed of five saccharide units obtained by chemical synthesis, thus eliminating the risk of contamination by a pathogenic agent of animal origin and batch variability. Clinical trials using sodium fondaparinux for the prevention of venous thromboembolism after major orthopedic surgery have demonstrated its superiority over low-molecular-weight heparin without increased risk of clinically pertinent bleeding if the first injection is given at the proper time. We present the main results of clinical trials.