[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.

[Management of major bleeding complications and emergency surgery in patients on long-term treatment with direct oral anticoagulants, thrombin or factor-Xa inhibitors. Proposals of the Working Group on Perioperative Haemostasis (GIHP) - March 2013]. / Prise en charge des complications hémorragiques graves et de la chirurgie en urgence chez les patients recevant un anticoagulant oral anti-IIa ou anti-Xa direct. Propositions du Groupe d'intérêt en Hémostase Périopératoire (GIHP) - mars 2013.

New direct oral anticoagulants (NOAC), inhibitors of factor IIa or Xa, are expected to be widely used for the treatment of venous thromboembolic disease, or in case of atrial fibrillation. Such anticoagulant treatments are known to be associated with haemorrhagic complications. Moreover, it is likely that such patients on long-term treatment with NOAC will be exposed to emergency surgery or invasive procedures. Due to the present lack of experience in such conditions, we cannot make recommendations, but only propose management for optimal safety as regards the risk of bleeding in such emergency conditions. In this article, only dabigatran and rivaroxaban were discussed. For emergency surgery at risk of bleeding, we propose to dose the plasmatic concentration of drug. Levels inferior or equal to 30ng/mL for both dabigatran and rivaroxaban, should enable the realization of a high bleeding risk surgery. For higher concentration, it was proposed to postpone surgery by monitoring the evolution of the drug concentration. Action is then defined by the kind of NOAC and its concentration. If the dosage of the drug is not immediately available, proposals only based on the usual tests, PT and aPTT, also are presented. However, these tests do not really assess drug concentration or bleeding risk. In case of severe haemorrhage in a critical organ, it is proposed to reduce the effect of anticoagulant therapy using a nonspecific procoagulant drug (activated prothrombin concentrate, FEIBA, 30-50U/kg, or non-activated 4-factors prothrombin concentrates 50U/kg). For any other type of severe haemorrhage, the administration of such a procoagulant drug, potentially thrombogenic in these patients, will be discussed regarding concentration of NACO and possibilities for mechanical haemostasis.

[Hemorrhagic accidents of the new oral anticoagulants and coagulation assays]. / Accidents hémorragiques des nouveaux anticoagulants oraux et examens de la coagulation.

New oral anticoagulants which specifically inhibit factor Xa (FXa) or thrombin (FIIa) do not require routine laboratory monitoring. However, they induce a state of hypocoagulation and increase the risk of bleeding. In some clinical situations, such as emergency surgery, hemorrhagic episodes, or recurrent stroke, coagulation monitoring may be useful. A significant number of publications have reported uncontrollable hemorrhagic complications and deaths in patients treated with these new anticoagulants. The selection of the most appropriate clotting assay is based on the drug used and the availability of the test. The new anticoagulants influence all global clot-based tests. Prothrombin time and partial thromboplastin time measured before and after treatment are considered as qualitative tests since they are not specific. Specific anti-Xa and anti-IIa assays are available and results can be expressed in nanogram per milliliter of plasma using calibrated plasmas containing well-established amounts of drug. The fact that there is no specific antidote to reverse the anticoagulant action of the new anticoagulants can impair management of hemorrhagic complications; clinical experience is still limited. Pro-hemostatic treatment with non-activated or activated prothrombin complexes (FEIBA(®)), or as a last recourse with FVIIa concentrates (NovoSeven(®)), has been used with variable results. Some suggestions for the management of patients with bleeding have been published but there is still little clinical evidence for these interventions.

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.

Effect of edoxaban on markers of coagulation in venous and shed blood compared with fondaparinux.

Edoxaban, an oral direct factor Xa (FXa) inhibitor, is in phase III clinical development for stroke prevention in atrial fibrillation and treatment of venous thromboembolism. The shed blood model allows for study of activated coagulation at a site of standardised tissue injury due to local release of tissue factor. The objective of this study was to evaluate the effect of three doses of edoxaban on markers of coagulation in shed and venous blood versus placebo and a standard prophylactic dose of fondaparinux. A total of 100 healthy male subjects were randomised to receive single doses of one of five treatments: subcutaneously administered fondaparinux 2.5 mg; orally administered edoxaban 30, 60, or 120 mg; or placebo. The primary objective was measurement of blood coagulation markers prothrombin fragment 1+2 (F1+2) and thrombin-antithrombin (TAT) complex, and platelet activation marker ß-thromboglobulin (ß-TG), in venous and shed blood. Secondary objectives included pharmacokinetics, shed blood volume, and safety of edoxaban. Single doses of edoxaban caused rapid and significant decreases of F1+2, TAT, and ß-TG in the shed blood model, indicating inhibition of thrombin generation and platelet activation. Inhibition was significantly less for fondaparinux versus edoxaban. Baseline-corrected F1+2, TAT, and ß-TG values demonstrated sustained inhibition up to 24 hours for shed blood in the edoxaban groups but no significant inhibition in venous blood. Overall, edoxaban treatments were well tolerated. In conclusion, single oral doses of edoxaban 30, 60, or 120 mg caused rapid and sustained inhibition of coagulation up to 24 hours in the shed blood model.

[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.

[Direct inhibitors of thrombin, hirudin, bivalirudin, and dabigatran etexilate]. / Les inhibiteurs directs de la thrombine, l'hirudine, la bivalirudine, l'argatroban, et le dabigatran etexilate.

Thrombin inhibition is an important objective in the prevention and treatment of thrombosis. A new molecule, dabigatran etexilate or Pradaxa(®), has been recently licensed for thromboprophylaxis in major orthopedic surgery in several countries but not in the USA. In contrast, the FDA has approved it for prevention in patients with non-valvular atrial fibrillation. This new orally active anticoagulant is being developed for the treatment of venous thromboembolism and acute coronary syndromes in patients with non-valvular atrial fibrillation. Dabigatran is a reversible inhibitor of free thrombin and clot-bound thrombin. An oral thrombin inhibitor melagatran is no longer available due to hepatic toxicity. Several other thrombin inhibitors are used via parenteral administration: lepirudine and desirudine, bivalirudine and argatroban. They are mostly given to patients with heparin-induced thrombocytopenia (HIT). Bivalirudine is used for acute coronary syndrome in patients undergoing percutaneous interventions. The main pharmacologic characteristics of thrombin inhibitor agents are presented focusing on dabigatran etexilate and including the main results of clinical trials.

[Perioperative use of antithrombotic agents: recommendations of the American College of Chest Physicians (ACCP) and the French Superior Health Authority (HAS)]. / La prise en charge périopératoire des traitements antithrombotiques. Des recommandations de l'American College of Chest Physicians (ACCP) à celles de la Haute Autorité de santé (HAS).

The purpose of this work was to analyse management practices for patients given anticoagulants or antiplatelet agents such as aspirin, clopidogrel and who are to undergo an invasive procedure or surgery. The modalities for the transition from oral agents to low-molecular-weight-heparin (LMWH) or unfractionated heparin (UFH) are studied. The recommendations or suggestions using the ACCP score: grade 1 recommendations are strongly motivated and indicate whether the benefit overbalances or not the risk, the burden, and the cost of the treatment. Grade 2 recommendations are considered to be suggestions. They imply that the individual physician chooses between different therapeutic strategies. For the purpose of this work, the most important recommendations are the following:

[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.

[Pregnancy and venous thromboembolism. North-American and European guidelines. American College of Chest Physicians]. / Grossesse et maladie thromboembolique veineuse. A propos des recommandations nord-américaines eteuropéennes.

Guidelines concerning the prevention and treatment of pregnancy-associated venous thromboembolism (VTE) have been elaborated by the American College of Chest Physicians and published in Chest in 2008. In this review, they have been compared with European guidelines and discussed taking into account the papers published since 2008.Most recommendations are of low grade of evidence because randomized studies are lacking during pregnancy and many reflect guidelines proposed by experts. The decisions on the most appropriate prophylaxis, dose to be administered and moment of pregnancy for starting prophylaxis are often decided case by case after careful assessment of the risk of pregnancy-associated VTE, on one hand, and the risk for the mother, on the other.Risk factors (age >or= 35, obesity, history of VTE with or without sequellae, in vitro fertilization)or thrombophilia have to be taken into account. Scores have been proposed to improve standardisation and evaluation of the risk of VTE and they should be validated.

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.

Effect of the anti-factor Xa and anti-factor IIa activities of low-molecular-weight heparins upon the phases of thrombin generation.

BACKGROUND: Low-molecular-weight heparins (LMWHs), derived from unfractionated heparin (UFH) by different depolymerization procedures, vary in both their relative abilities to enhance the inhibition of FXa (anti-FXa) and thrombin (anti-FIIa), and in their physicochemical properties. OBJECTIVE: We aimed to profile the inhibition of thrombin generation induced by bemiparin, enoxaparin, nadroparin, dalteparin and tinzaparin in platelet-rich plasma (PRP), and to compare them with UFH and fondaparinux (a synthetic pentasaccharide that specifically enhances FXa inhibition). METHODS: Different LMWHs, UFH or fondaparinux were added to normal PRP. Thereafter, tissue factor-triggered thrombin generation was assessed using the Thrombogram-Thrombinoscope assay. RESULTS: At equivalent anti-FIIa activity concentrations, LMWHs and UFH exhibited similar inhibitory effects upon thrombin generation. However, when used at equivalent anti-FXa activity concentrations, tinzaparin was significantly more active than the other LMWHs at inhibiting thrombin generation, and had similar activity to that of UFH. Enoxaparin, nadroparin and dalteparin all showed similar inhibitory activities. In these experiments, bemiparin exhibited the lowest inhibitory effect on thrombin generation of all the LMWHs. At 0.1 microg mL(-1) (0.093 anti-FXa IU mL(-1)), fondaparinux inhibited the rate of thrombin generation by 50%. A 7-fold higher concentration of fondaparinux was required to inhibit the endogenous thrombin potential by 50%. CONCLUSIONS: LMWHs have a variable inhibitory effect on thrombin generation in vitro when compared by anti-FXa activity, but are similar when compared by their anti-FIIa activities. The rate of thrombin generation during the propagation phase, rather than the endogenous thrombin potential, is more sensitive to the anticoagulant activity of fondaparinux and the polysaccharide chains of LMWHs possessing only anti-FXa activity.