M.-H. Horellou

Improving Anticoagulation Control in Hospitalized Elderly Patients on Warfarin

OBJECTIVES: To determine the effect of patient characteristics and of specific guidelines that were developed for managing warfarin therapy in older adults and included in an in‐house computer program on anticoagulation quality.

Peri-procedural management of dabigatran and rivaroxaban: Duration of anticoagulant discontinuation and drug concentrations

BACKGROUNDnPeri-procedural management of direct oral anticoagulants (DOAC) is challenging. The optimal duration of pre-procedural discontinuation that guarantees a minimal DOAC concentration ([DOAC]) at surgery is unknown. The usual 48-hour discontinuation might not be sufficient for all patients.nnnOBJECTIVESnTo test the hypothesis that a 48-hour DOAC discontinuation is not sufficient to ensure a minimal per-procedural [DOAC], defined as [DOAC]<30ng/mL. To investigate the factors associated with per-procedural [DOAC]. To evaluate the ability of normal PT and aPTT to predict [DOAC]<30ng/mL.nnnMETHODSnPatients treated with dabigatran or rivaroxaban, and requiring any invasive procedure were included in this multicentre, prospective, observational study. [DOAC], PT and aPTT were measured during invasive procedure.nnnRESULTSnSixty-five patients were enrolled. Duration of DOAC discontinuation ranged from 1-168h. Per-procedural [DOAC] ranged from <30 to 466ng/mL. [DOAC]<30ng/mL occurred more frequently after 48-hour discontinuation than after a shorter delay. [DOAC] remained ≥30ng/mL in 36% and 14% of measurements performed 24-48h and 48h-120h after discontinuation, respectively. According to ROC curve, a cut-off value of 120hours for DOAC discontinuation had a better specificity than a cut-off value of 48hours to predict [DOAC]<30ng/mL. Normal PT and aPTT ratios had good specificity and positive predictive value, but limited sensitivity (74%) and negative predictive value (73%) to predict [DOAC]<30ng/mL.nnnCONCLUSIONSnA 48-hour discontinuation does not guarantee a [DOAC]<30ng/mL in all patients. Normal PT and aPTT are flawed to predict this threshold and could not replace specific assays. Further studies are needed to define the relationship between per-procedural [DOAC] and clinical outcomes.

Should women suffering from migraine with aura be screened for biological thrombophilia?: Results from a cross-sectional French study

INTRODUCTIONnMigraine, particularly migraine with aura (MA), is associated with a higher risk for ischemic stroke (IS). A procoagulant state may predispose to IS. Whether inherited biological thrombophilia are associated with migraine risk remains controversial.nnnOBJECTIVEnTo assess the risk of migraine without or with aura related to inherited biological thrombophilia adjusted for the main potential confounders.nnnMATERIAL AND METHODSnA cross-sectional study was conducted in 1456 French women aged 18 to 56years, referred for biological coagulation check-up because of personal or familial venous thrombosis history. Between April 2007 and December 2008, all women answered a self-administered questionnaire to determine whether they had headache.nnnRESULTSnThere were 294 (20%) migrainous sufferers (including 71 [5%] with MA), 975 (67%) non migrainous women and 187 (13%) non migrainous headache women. Inherited thrombophilia were detected in 576 (40%) women, including 389 (40%) non migrainous women, 90 (40%) migraine without aura (MWA), 33 (46%) MA women and 64 (34%) non migrainous headache women. Factor V Leiden (FVL) i.e. F5rs6025 or Factor II G20210A (FIIL) i.e. F2rs1799963 mutation was detected in 296 (30%) non migrainous women and in 100 (34%) migrainous women of which 27 had MA. There was a significant association between MA and FVL or FIIL mutations (adjusted OR=1.76 [95% CI 1.02-3.06] p=0.04) whereas this association in MWA and in non migrainous headache women was not significant. There was no significant association between migraine and other biological thrombophilia.nnnCONCLUSIONnFVL or FIIL mutations were more likely among patients suffering from MA. Whether biological thrombophilia screening should be systematically performed in women suffering from MA remains to be determined.

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.

Hétérogénéité pharmacologique des nouveaux anticoagulants

Resume Parmi de nombreuses molecules anticoagulantes prometteuses, trois nouveaux agents le rivaroxaban ou Xarelto®, dabigatran ou Pradaxa® et l’apixaban ou Eliquis® ont deja ete enregistres dans une centaine de pays a l’exception des Etats-Unis (pour le dabigatran et l’apixaban) dans la prevention des accidents thrombo-emboliques apres prothese totale de hanche ou de genou. Le rivaroxaban vient d’etre enregistre par la FDA dans la prevention des accidents thrombo-emboliques apres prothese totale de hanche ou de genou. Le dabigatran vient d’etre enregistre par la FDA dans la fibrillation auriculaire non valvulaire (etude RE-LY) tandis que le rivaroxaban espere l’etre (etude ROCKET). Les resultats des etudes de phase III dans le traitement de la thrombose veineuse et de l’embolie pulmonaire et dans la prevention des recidives sont favorables. Il s’agit de petites molecules obtenues par synthese chimique, de poids moleculaire (PM) legerement inferieur a 500 daltons. Mecanisme d’action anti Xa et Anti IIa. La demi-vie est de l’ordre de 8 a 12 heures, avec un pic d’activite 2 a 4 heures apres la prise medicamenteuse. Le dabigatran etant principalement elimine par le rein, sa posologie doit etre adaptee en cas d’insuffisance renale moderee et son utilisation contre-indiquee en cas d’insuffisance renale severe. Le rivaroxaban est elimine par le rein (33% sous forme active) et par le foie, il necessite donc des precautions d’emploi en cas de troubles hepatiques. De nombreux examens de la coagulation peuvent etre modifies par l’action anticoagulante de ces deux molecules. Ces modifications doivent etre bien connues pour eviter des erreurs d’interpretation mais pourraient aussi etre utilisees pour mesurer les concentrations plasmatiques de ces produits. Le choix d’un test global non specifique mais disponible d’une maniere permanente (temps de Quick pour le rivaroxaban et TCA pour le dabigatran) a ete documente. La tendance est de preferer le dosage de l’activite anti-Xa et anti-IIa respectivement qui sont specifiques avec une expression des resultats en ng/ml a l’aide de plasmas calibres (a teneur predeterminee en medicament). Il n’existe pas de donnees chez la femme enceinte ni en pediatrie, mais des etudes sont en cours. Les interferences medicamenteuses ne doivent pas etre negligees. Elles sont peu nombreuses. La courte demi-vie rend acceptable l’absence d’antidote specifique dans de nombreux cas. Enfin, l’absence de necessite d’un controle regulier de l’hemostase et leur administration par voie orale ne necessitant pas d’ajustement, devraient entrainer a preferer leur utilisation chez un grand nombre de patients dans les indications accordees par les autorites de sante.

Argatroban and renal replacement therapy in a morbidly obese patient with heparin-induced thrombocytopenia: a case report.

Continuous veno-venous hemofiltration (CVVH) is widely used for renal replacement therapy (RRT) in intensive careunits (ICUs).However, because patients undergoing CVVH often receive unfractionated heparin (UFH), there is a risk of Heparin-Induced Thrombocytopenia (HIT) and also of repeated hemofilter thrombosis [1,2]. Administration of a reversible direct thrombin inhibitor, such as argatroban or lepirudin, or of the heparinoid, danaparoid, is an alternative anti-coagulation strategy for RRT in patients with HIT. However, information on the use of argatroban in obese patients is relatively scarce. We report the case of a morbidly obese patient who received dose-adjusted argatroban for RRT with monitoring of anti-IIa activity.

Combined Hormonal Contraceptives and First Venous Thrombosis in Young French Women: Impact of Thrombotic Family History

Context: In UK and French, but not World Health Organization (WHO), guidelines for combined hormonal contraception (CHC), family history of a venous thromboembolism (VTE) is a condition for which the theoretical risks usually outweigh the advantages of using CHC. Objective: We estimated the prevalence of inappropriate prescriptions of CHC according to several international guidelines and their impact on VTE. Design: A single-center observational study. Setting: Hemostasis unit outpatient clinic (Paris, France). Population: A total of 2088 French CHC users of childbearing age with a first documented VTE who were referred to our unit between 2000 and 2009. Methods: Data were collected by a standardized questionnaire during a medical consultation. Family history of VTE was analyzed according to definitions from international recommendations (VTE before age 45 years, United Kingdom; before age 50 years, France). A CHC prescription was considered inappropriate for women with vascular contraindications and/or a family history of VTE. Cross-sectional analysis of the clinical and biological characteristics was performed. Main Outcome Measures: Prevalence of inappropriate prescription of CHC and potentially preventable events were estimated. Results: According to the WHO, UK, or French guidelines, 8.8%, 18.9%, and 25.9%, respectively, of CHC prescriptions were considered inappropriate. Compliance with these guidelines could reduce the corresponding number of VTEs by 6.3%, 13.5%, and 18.5%, respectively. Characteristics of the women were similar. Conclusion: Our results suggest inappropriate CHC prescriptions are prevalent among CHC users with first VTE. The appropriate way to take family history of VTE into account should be further clarified.

Concordance entre les tests globaux (TP, TCA et TT) et les activités anticoagulantes spécifiques du rivaroxaban et du dabigatran

Patients et méthodes.— Une étude épidémiologique descriptive longitudinale multicentrique par suivi d’une cohorte a été menée. De mai 2009 à décembre 2010, les patients ont bénéficié d’un programme d’éducation thérapeutique par un réseau ville-hôpital isérois. Les variables de sept scores prédictifs du risque hémorragique des patients sous AVK publiées dans la littérature ont été renseignées et complétées par d’autres variables d’intérêt. La survenue d’une hémorragie grave constituait le critère de jugement principal. Les scores existants ont été comparés par leurs courbes ROC, leurs valeurs prédictives et leurs rapports de vraisemblances. Un modèle de cox a été utilisé pour sélectionner les facteurs de risque d’hémorragie grave les plus pertinents. Résultats.— Sur les 968 patients qui ont été inclus et suivis pendant un an en médecine générale, 949 ont pu être analysés. L’âge médian était à 70 ans (54—81). Le taux d’incidence d’hémorragies graves à un an était de 2,4 % (IC95 = 1,54—3,61). Les scores avaient une valeur prédictive négative assez similaire allant de 97,7—98,4 %. ATRIA qui comprend l’anémie avait une aire sous la courbe à 0,71 (IC95 = 0,60—0,80) et la meilleure sensibilité (39,1 %), le rapport de vraisemblance positif (RVP) était à 4. L’anémie sévère (HR à 6,8 ; IC95 = 2,81—16,63), l’âge > 65 ans (HR à 2,4 ; IC95 = 0,66—8,67) et la présence d’une chute dans l’année ayant nécessité un recours à un médecin (HR à 2 ; IC95 = 0,80—4,83) étaient les trois facteurs de risques retenus après analyse multivariée pour modéliser un nouveau score. L’anémie sévère à l’inclusion, prise seule, suffisait à déterminer un risque élevé d’hémorragie grave. Conclusion.— Aucun score publié ne répond aux critères de validation pour prédire le risque de survenue d’hémorragie grave à un an dans une population ambulatoire éduquée à la gestion des AVK de tous types. Nous proposons uniquement l’anémie sévère (hémoglobinémie < 10 g/L ou hématocrite < 30 %) pour prédire un risque élevée d’hémorragie grave à un an.