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International audience; Background Diagnosis of heparin-induced thrombocytopenia (HIT) requires pretest probability assessment and dedicated laboratory assays.Objective To develop a pretest score for HIT.Design Observational; analysis of prospectively collected data of hospitalized patients suspected with HIT (ClinicalTrials.gov NCT00748839).Setting Thirty-one tertiary hospitals in France, Switzerland, and Belgium.Patients Patients tested for HIT antibodies (2280 evaluable), randomly allocated to derivation and validation cohorts.Measurements Independent adjudicators diagnosed HIT based on the prospectively collected data and serotonin release assay results.Results Heparin-induced thrombocytopenia was diagnosed in 234 (14.7%) and 99 (14.5%) patients in the two cohorts. Eight features were associated with HIT (in brackets, points assigned for score calculation of the score): unfractionated heparin (1); therapeutic-dose heparin (1); cardiopulmonary bypass (cardiac surgery) (2); major trauma (3); 5- to 21-day interval from anticoagulation initiation to suspicion of HIT (4); >= 40% decrease in platelet count over

International audience

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., Inappropriate CHC prescriptions are prevalent among CHC users with a first venous thrombosis event. The appropriate way to take family history of VTE into account should be further clarified.

Samples transported by pneumatic tube system are submitted to forces of acceleration and deceleration which can affect laboratory parameters. At Cochin hospital, majority of samples of hemostasis, except for platelets tests, are transported by pneumatic tube system. The objective of this study was to evaluate the impact of a pneumatic tube system (PTS) transport compared to hand-delivered transport on samples and to qualify Cochin hospital PTS according to requirements of standard ISO 15189. A bibliographical study was made and showed that pneumatic tube system particularly influences platelets tests. Four citrate tubes were collected in 5 healthy volunteers in the maternity: 2 tubes were transported by PTS and 2 others were hand-delivered to the laboratory. Five coagulation tests were analyzed: prothrombine time (PT), activated partial thromboplastin time (aPTT), factor (F) V, FVIII and platelet closure time with PFA-100TM collagen/epinephrine. For each volunteer, the results obtained by PTS and by hand-delivered transport were compared with formula usually used for biological analysis retake: 2.8 x standard deviation of reproductibility variation coefficient (SH GTA 01, COFRAC). This study did not show an impact of PTS on PT, aPTT, FV and FVIII. For PFA-100TM collagen/epinephrine, we noted an impact on 2/5 volunteers. These results, in agreement with the literature, led to the conclusion that Cochin hospital PTS is in compliance to transport samples for usual coagulation tests except platelet tests. This study allowed to issue French recommendations for PTS transport of hemostasis tubes qualification available on "Groupe français d'hémostase et thrombose" Web site.

Background: Diagnosis of heparin-induced thrombocytopenia (HIT) is based on a composite of clinical likelihood and laboratory testing. We aimed to develop a diagnostic score derived from multivariate analysis of clinical features, including platelet count changes, prospectively recorded in patients with suspected HIT. Methods: This multinational observational study (ClinicalTrials.gov no. NCT00748839) included 2280 adult patients with suspected HIT: 1597 (derivation cohort) formed the basis for developing the scoring system, subsequently validated in 683 additional randomly selected patients (validation cohort). HIT was diagnosed by two independent adjudicators based on clinical features, local laboratory data, and the results of a centrally performed serotonin release assay (SRA). Findings: Overall, 56.7% of the patients were treated in an intensive care unit of whom 57.4% received unfractionated heparin; thromboembolism occurred in 12.3%. In the derivation and validation cohorts, 234 (14.7%) and 99 (14.5%) patients, respectively, were diagnosed with HIT. Eight features were positively associated with HIT diagnosis in a multivariate model (in brackets the value assigned for score calculation): unfractionated heparin use (1); therapeutic-dose heparin use (1); cardiac surgery with cardiopulmonary bypass (2); major trauma (3); 5- to 21-day interval from anticoagulant treatment initiation to suspicion of HIT (4); ≥ 40% decrease in platelet count over ≤ 6 days during the last 10 days of anticoagulation exposure (3); thrombotic event, either arterial (3) or venous (3). The C statistic of the model was 0.791 [0.76; 0.82] (p-value 0.70, Hosmer-Lemeshow test). In the validation cohort, the area under the ROC curve was 0.77 [95% CI 0.74-0.80], and HIT prevalence was 2.6% for a score ≤2; 6% for a score of 3–8; and 28.8% for a score >8: Interpretation: This study distinguishes validated clinical features of HIT, permitting improved estimation of its likelihood. Trial Registration: (ClinicalTrials.gov no. NCT00748839) Funding Statement: Programme Hospitalier de Recherche Clinique (French Health Ministry), Sanofi, LFB, Organon SA. Declaration of Interests: Dr. Mullier reports personal fees from Aspen, personal fees from Stago, grants from Werfen, outside the submitted work; Dr. Gruel reports personal fees from Sanofi, personal fees from LFB, other from Stago, personal fees from Aspen, outside the submitted work; . All other authors declare no conflict of interests. Ethics Approval Statement: The study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki, Good Clinical Practice, and relevant French, Swiss and Belgian legal and regulatory requirements regarding data protection. The protocol was approved by French, Swiss and Belgian independent ethics committees. All patients received written information about the study, emphasizing their right to refuse participation or to withdraw at any time. As no experimental interventions were induced from the protocol, no written informed consent was required for inclusion.

International audience; Reliable laboratory diagnosis of heparin-induced thrombocytopenia (HIT) remains a major clinical concern. Immunoassays are highly sensitive, while confirmatory functional tests (based on heparin-dependent platelet activation) lack standardization. We evaluated the diagnostic performance of a functional flow cytometric assay (FCA) based on the detection of heparin-dependent platelet activation with an anti-p-selectin. A total of 288 patients were included (131 HIT-positive and 157 HIT-negative) with a HIT diagnosis established by expert opinion adjudication (EOA) considering clinical data and local laboratory results. The FCA was centrally performed in a single laboratory on platelet-rich plasma, using a very simple four-color fluorometer. The results were standardized according to the Heparin Platelet Activation (HEPLA) index. The serotonin release assay (SRA) was performed in the four French reference laboratories. Based on the final HIT diagnosis established by EOA, the sensitivity and specificity of the FCA were 88 and 95%, respectively, values very similar to those of the SRA (88 and 97%, respectively). This study showed that the FCA, based on easily implementable technology, may be routinely used as a reliable confirmatory test for HIT diagnosis.

The proposals of the Working group on perioperative hemostasis (Groupe d'interet en hemostase peri-operatoire (GIHP)) concerning the perioperative management of patients receiving the direct oral anticoagulants (DOACs) are based on the measure of their anticoagulant activities (anti-Xa for rivaroxaban and anti-IIa for dabigatran) with a safety threshold ≤ 30 ng/mL. If the dosage of the drug is not available, proposals are based on the combination of a PT ≥80% and an aPTT ≤1.20. The aim of our study was to evaluate the performance of PT, aPTT and thrombin time to predict values above or below the safety threshold. The measurement of DOACs concentration was carried out in 64 samples from patients treated with rivaroxaban and 48 samples from patients treated with dabigatran. The PT and aPTT were measured for all samples, while the TT was measured only for patients receiving dabigatran. The absence of agreement between the global hemostasis tests and the DOACs concentrations was observed for 10% of patients receiving dabigatran and 27% of patients with rivaroxaban treatment. Apart from dabigatran for which the predictive negative value of PT and aPTT or TT allows to exclude a concentration >30 ng/mL in 100% of cases, our results highlight the risk of misinterpretation when using global coagulation tests (PT and aPPT) for determination of the safety threshold for patients receiving the DOACs.

Objective This article estimates the interaction between types of combined hormonal contraception (CHC) and factor V Leiden (FVL) mutation on the risk of venous thrombosis event (VTE). Subjects and Methods All premenopausal women with first incident VTE who were referred to our unit (Paris, France) between 2000 and 2009 were included in this case-only study. Differences in interactions by progestin type were assessed on a multiplicative scale, assuming the independence of genotype and prescription of type of CHC. Results Among 2,613 women with VTE, 15.9% had a FVL and 69% used CHC. The interaction between CHC use and presence of FVL on VTE risk was statistically significant (1.37, 1.06–1.77 95% confidence interval [CI]). This interaction appeared higher for drospirenone 1.99 (1.18–3.38 95% CI) (n = 98) or cyproterone acetate users 1.71 (1.20–2.45 95% CI) (n = 326), but not significant for 1st or 2nd or norgestimate CHC users. The results were similar when excluding women with a family history of VTE or with provoked VTE. In this sub-group of women, these interactions appeared higher for third generation, cyproterone acetate and drospirenone CHC users as compared with 1st or 2nd or norgestimate CHC users (odds ratio [OR], 1.68 [1.04–2.70; 95% CI], 2.91 [1.71–4.95 95% CI], 3.22 [1.54–6.73 95% CI], respectively). Conclusion Our results show that the interaction between FVL and CHC use differ by progestin type, which is higher in CHC containing third-generation progestin, drospirenone or cyproterone acetate, compared with second generation. Further studies are needed to assess the cost-effectiveness of biological thrombophilia screening (FVL) when such prescription of CHC is planned.

Peri-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.To 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.Patients 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.Sixty-five patients were enrolled. Duration of DOAC discontinuation ranged from 1-168h. Per-procedural [DOAC] ranged from30 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.A 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.

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.

SummaryWhile laboratory monitoring is not required in patients treated with apixaban, a direct factor-Xa inhibitor, assessment of its concentration is useful in some critical situations. However, few data are available on its effect on coagulation tests and on the suitability of anti-Xa assays for its quantification. It was the objective of this study to identify laboratory tests suitable for apixaban concentration assessment. Coagulation tests – PT and aPTT- and anti-Xa assays were performed in apixaban-spiked plasma samples. To evaluate the sensitivity of PT and aPTT to apixaban, we conducted a first monocenter part, with a wide range of concentrations (50–1,000 ng/ml), a large panel of reagents (20 reagents), and two coagulometers (STAR®, Stago and ACL TOP®, IL), and a second multicenter part involving 13 laboratories using either a common PT reagent (RecombiPlastin2G®) or the local PT and aPTT reagents. In the multicentre part, five blinded apixaban-spiked plasma samples (0/100/200/400/800 ng/ml – checked by HPLC-MS/MS) were used; apixaban concentrations were measured with three anti-Xa assays, apixaban calibrators and controls (Stago). PT and aPTT tests using a large panel of reagents displayed a low sensitivity to a wide range of apixaban concentrations. The concentrations to double PT ranged from 400 to >1,000 ng/ml with the 10 reagents. With the three anti-Xa assays, interlaboratory precision and accuracy were below 11% and 12%, respectively. In conclusion, whereas PT and aPTT tests were not sensitive enough to detect apixaban, the three anti-Xa assays tested using lyophilised apixaban calibrators and controls allowed to reliably quantify a wide range of apixaban concentrations.

Resume Propos Plusieurs donnees recentes montrent que la qualite de l’anticoagulation des patients traites par les antivitamines K (AVK) n’est pas optimale en France. Le but de cette etude retrospective etait d’evaluer les performances de six cliniques francaises gerant les traitements par AVK, sur une periode de trois ans, allant de 2009 a 2011. Methodes Toutes les cliniques ont utilise le meme logiciel d’aide a la prescription en fonction de l’INR. Le critere principal analyse est le temps passe dans la zone therapeutique. Resultats La duree globale de suivi est de 2755 patient-annees pour 2385 patients. Le temps passe dans la zone therapeutique 2 a 3, qui concerne 89 % des patients, est de 73 %. Le temps passe dans la zone therapeutique pour les deux autres zones (2,5 a 3,5 et 3 a 4,5) concernant 11 % des patients porteurs de protheses cardiaques est inferieur (63,7 % et 68,8 % respectivement) avec un desequilibre en faveur du temps passe au-dessous de la zone. Dans cette etude, warfarine (Coumadine ® ) et fluindione (Previscan ® ) permettent une qualite d’equilibre equivalente. Les 1728 patients des tranches d’âges 60 a 100 ans sont mieux equilibres que les 651 patients plus jeunes. Le pourcentage de temps passe avec un INR superieur a 5 est extremement reduit, ce qui est un gage de securite. Conclusion Ces resultats prouvent que les cliniques des anticoagulants en France, dont le developpement n’a ete que peu encourage, font aussi bien que leurs homologues a l’etranger. Il est probable que la qualite de l’anticoagulation obtenue contribue a diminuer les incidents hemorragiques ou thrombotiques lies a un desequilibre du traitement.

SummaryInherited quantitative (type I) or qualitative (type II) antithrombin deficiency (ATD) due to mutations in the SERPINC1 gene is a well-known risk factor for venous thromboembolism. ATD may also increase risk for arterial thrombosis. Few studies have investigated risk for thrombosis according to mutations. We addressed this topic in a large retrospective cohort study of 540 heterozygous carriers of SERPINC1 mutations and compared risk for first venous or arterial thrombosis associated with carrying of different type II or type I mutations. No clear difference in risk for first venous thrombotic event was observed among type I (missense or null), type IIRS or type IIPE mutation carriers except for a few variants that displayed lower risk [all events, adjusted relative risk: Cambridge II: 0.42 (95%CI 0.25–0.70), Dublin: 0.35 (95%CI 0.13–0.99)]. IIHBS mutation carrying was associated with a clearly lower risk than type I mutation carrying [0.28 (95%CI 0.20–0.40)]. These differences in risk were observed for both all venous thrombotic events and pulmonary embolism associated with deep venous thrombosis. The HBS group was also heterogeneous, with AT Budapest 3 carriers displaying a non-significantly different risk [0.61 (95%CI 0.31–1.20)] compared to type I mutation carriers. We also studied risk for arterial thrombosis and found no significant influence of mutation type. Altogether, our findings suggest a place for SERPINC1 genotyping in the diagnosis of ATD.Supplementary Material to this article is available online at www.thrombosis-online.com.

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.

The route of estrogen administration is an important determinant of the risk of the first venous thromboembolism (VTE) event in postmenopausal women using hormone therapy (HT). However, the impact of transdermal estrogens on VTE recurrence risk has not been investigated. The aim of our study was to assess the impact of HT by route of estrogen administration on the risk of recurrent VTE.A total of 1,023 consecutive postmenopausal women aged 45 to 70 years with a confirmed first VTE were recruited from an outpatient clinic of a hemostasis hospital unit between January 2000 and December 2008 and were followed for an average of 79 months after discontinuation of anticoagulation therapy.Recurrent VTE occurred in 77 women (1.1% per year). During the follow-up, 130 women used HT (12.7%), including 103 transdermal estrogen users (10.0%) and 10 oral estrogen users (1.0%). After adjustment for potential confounders, there was no significant association between recurrent VTE and use of transdermal estrogens (hazard ratio, 1.0; 95% CI, 0.4-2.4), with the nonusers as a reference group. In contrast, women using oral estrogens had an increased risk of recurrent VTE (hazard ratio, 6.4; 95% CI, 1.5-27.3). Consistently, no subgroup of women had evidence of a risk of recurrent VTE with transdermal HT that significantly differed from that observed for all women.Oral but not transdermal estrogens are associated with a higher risk of recurrent VTE among postmenopausal women. This result provides further epidemiological evidence that transdermal estrogens may be safe with respect to VTE risk.

Pour etre facteur de risque, un parametre doit etre lie a la survenue de l’evenement etudie. Seule l’experimentation authentifie le statut causal d’un facteur de risque : exposition au facteur determine de facon aleatoire, suivi prospectif avec definition et determination precise des evenements, force de l’association, relation dose-effet, chronologie pertinente, constance de l’association dans plusieurs etudes et dans plusieurs populations, hypothese physiopathologique, specificite de l’association. Dans le cas des pathologies veineuses thromboemboliques, bien que de nombreux facteurs aient ete decrits, seuls certains sont a l’evidence causals : l’immobilisation, le postoperatoire chirurgical, la pathologie cancereuse, certaines thrombophilies, l’obesite, les estrogenes, etc. En marge de ces facteurs de risque unanimement reconnus, l’homocysteine est candidate a entrer dans ce « club tres ferme ». Malheureusement, malgre un rationnel tres seduisant pour attribuer a l’homocysteine un role causal dans la maladie thromboembolique, deux essais cliniques recents ne confirment pas cette hypothese.

Congenital afibrinogenemia is a rare disorder characterized by the absence in circulating fibrinogen, a hexamer composed of two sets of three polypeptides (Aalpha, Bbeta and gamma). Although predisposition to thrombosis is a well known feature of dysfibrinogenemia, the relatively frequent thrombotic manifestations seen in congenital afibrinogenemia are puzzling. We herein report a mutational analysis of a young afibrinogenemic man from Turkey with multiple thrombo-embolic events involving both arteries and veins. Purified DNAs of the propositus was used for amplification by polymerase chain reaction of all the exons of the A subunit gene with primers allowing the analysis of the intron-exon boundaries. Analysis of the genes coding for the three fibrinogen chains of the propositus found a homozygous G to A transition in the exon 5 of the A alpha chain gene (g.g4277a; access number gi458553). The TGG to TGA codon change predicts a homozygous W315X in the A alpha chain (p.W334X when referring to the translation initiation codon). Both parents and his brother were found to carry this heterozygous mutation. This is the first report of a patient homozygous for this rare mutation associated with afibrinogenemia. Our patient was free of known risk factors as well as diseases associated with thrombosis including atherosclerosis, vasculitis, Buerger's disease, and it seems therefore probable that afibrinogenemia itself might have contributed to both arterial and venous thrombosis.

Resume Les evenements thromboemboliques veineux constituent un des effets deleteres les plus frequents de la contraception combinee estroprogestative. Ils sont potentiellement graves en raison de la possibilite de survenue d’une embolie pulmonaire parfois fatale. Il est donc fondamental d’ecarter de cette prescription les femmes a haut risque de maladie veineuse thromboembolique. Se pose alors le probleme de leur depistage, d’autant plus crucial que l’utilisation de la contraception hormonale est frequente chez les femmes en bonne sante et souvent pour de longues durees. Il est demontre que certaines anomalies de la coagulation, congenitales ou acquises, sont associees a une augmentation du risque d’evenement thromboembolique. Par ailleurs, la contraception combinee estroprogestative, quelle que soit la voie d’administration, modifie un certain nombre de parametres de l’hemostase. Afin d’optimiser la balance benefice–risque de la contraception orale, la recherche d’une thrombophilie biologique est, dans certaines situations cliniques, indispensable. C’est le cas des jeunes femmes ayant presente un episode thromboembolique veineux ou ayant des antecedents familiaux de thrombose a un âge relativement jeune, cas retrouves par un interrogatoire soigneux. En revanche, cette recherche biologique n’est pas recommandee de facon systematique avant toute prescription de contraception combinee estroprogestative chez les patientes n’ayant ni antecedent personnel, ni antecedents familiaux de thrombose veineuse.

Two consecutive severe prekallikrein deficiencies were investigated. The first was identified in a 63-year-old patient admitted for ischemic stroke. The second deficiency was identified in a 38-year-old patient admitted for a second-trimester pregnancy loss. A homozygous C529Y mutation was identified for both cases, whereas they are unrelated and no consanguineous marriage is known from the patients. These data point to a possible high frequency of this mutation as a cause of prekallikrein deficiency.

Non-VKA oral anticoagulants (NOACs), thanks to their ease of use and their similar or superior safety/efficacy profiles versus warfarin, have now widely reached the lucrative market of anticoagulation. However, while the marketing authorization holders always claim, in a quite unclear way that no monitoring is required, accumulative evidence and cases of major bleeding have been described in the literature and reported by spontaneous reporting systems at the regulator's level. These compounds are usually given at fixed doses without routine coagulation monitoring. However, new data suggests that an assessment of the response at the individual level could improve the benefit-risk ratio of, at least dabigatran. Therefore, in certain patient populations, i.e. acute or chronic renal impairment or multiple drug interactions, measurement of drug exposure may be useful to ensure an optimal treatment response. More specific circumstances such as patients experiencing a haemorrhagic or thromboembolic event during the treatment duration, patients who require urgent surgery or an invasive procedure, or patient with a suspected overdose could benefit from such a measurement. This article aims at providing guidance on how to best estimate the intensity of anticoagulation using laboratory assays in daily practice.

The frequency and risk factors for central venous catheter-related thrombosis (CRT) during prolonged intravenous (i.v.) antibiotic therapy have rarely been reported. The primary objective of this study was to evaluate the frequency, incidence, and risk factors for CRT among patients being treated with prolonged i.v. antibiotic therapy. The secondary objective was to describe the clinical manifestations, diagnostic evaluation, and clinical management. This cohort study was conducted between August 2004 and May 2010 in a French referral center for osteoarticular infections. All patients treated for bone and joint infections with i.v. antimicrobial therapy through a central venous catheter (CVC) for ≥2 weeks were included. Risk factors were identified using nonparametric tests and logistic regression. A case-control study investigated the role of vancomycin and catheter malposition. A total of 892 patients matched the inclusion criteria. CRT developed in 16 infections occurring in 16 patients (incidence, 0.39/1,000 catheter days). The median time to a CRT was 29 days (range, 12 to 48 days). Local clinical signs, fever, and secondary complications of CRT were present in 15, 8, and 4 patients, respectively. The median C-reactive protein level was 95 mg/liter. The treatment combined catheter removal and a median of 3 months (1.5 to 6 months) of anticoagulation therapy. The outcome was good in all patients, with no recurrence of CRT. Three risk factors were identified by multivariate analysis: male sex (odds ratio [OR], 5.4; 95% confidence interval [CI], 1.1 to 26.6), catheter malposition (OR, 5.3; 95% CI, 1.6 to 17.9), and use of vancomycin (OR, 22.9; 95% CI, 2.8 to 188). Catheter-related thrombosis is a rare but severe complication in patients treated with prolonged antimicrobial therapy. Vancomycin use was the most important risk factor identified.

RESUME Le risque d’evenements thromboemboliques chez la femme enceinte porteuse d’une thrombophilie hereditaire avec mutation heterozygote du FV Leiden, du FII 20210A ou des deux, est mal documente. Aussi, les protocoles prophylactiques sont-ils encore discutes. Une etude retrospective a ete conduite chez 208 femmes porteuses d’une thrombophilie hereditaire par mutation heterozygote du FV ou du FII ou des deux. Le nombre total de grossesses menees a terme etait de 406 dont 10 avec prophylaxie antithrombotique. La frequence des evenements thrombotiques ante- et post-partum etait significativement plus grande dans le groupe de femmes ayant les 2 alterations genetiques (17,8%) que dans le groupe ou seul le gene du FII etait mute (6,2%) p = 0.003. En revanche, il n’existait pas de difference significative entre le groupe FV+FII et le groupe FV seul (10%). Le risque veineux lie a l’association de ces 2 varietes les plus communes de thrombophilie constitutionnelle est donc plutot additif que multiplicatif. Neanmoins, la presence d’un antecedent thromboembolique avant la grossesse dans ce groupe FV+FII majorait considerablement le risque thromboembolique (50%). La frequence des accidents a ete plus grande dans le post-partum que dans l’ante-partum. Il n’a pas ete observe de difference significative sur la frequence des pertes foetales dans ces 3 groupes, mais cet evenement n’etait pas un critere de jugement primaire dans cette etude. Ces resultats, recueillis dans un seul centre, permettent de proposer une attitude pour la prophylaxie des accidents chez les 3 groupes de femmes. L’utilisation systematique d’une HBPM n’est pas indiquee pendant la grossesse chez les femmes asymptomatiques ayant une seule mutation. En revanche, elle est justifiee pendant toute la grossesse chez les femmes ayant les 2 mutations et des antecedents de thrombose. Chez celles qui n’ont pas d’antecedent, une prophylaxie pendant une partie ou toute la grossesse doit etre consideree et decidee au cas par cas. Dans la periode du post-partum, une attitude consensuelle recommande un traitement prophylactique systematique avec une HBPM pendant 6 semaines au moins, dans toutes les thrombophilies hereditaires : anomalies isolees et combinees.

New anticoagulants have been designed using advances in the biotechnology and the biochemistry of the clotting factors. They are classified according to their target or their mechanism of action (AT-dependent or AT-independent). Antithrombotic activity after oral administration is another important property. This abstract is restricted to the synthetic pentasaccharide and the ximelagatran/melagatran. Fondaparinux (Arixtra) is a chemically synthesized methoxy derivative of the natural pentasaccharide (MW=1728 Da). Fondaparinux has nearly complete bioavailabity after subcutaneous injection. The elimination half-life is about 17 hours. Fondaparinux is cleared from the kidneys. In contrast to heparin, fondaparinux does not interact with plasma proteins other than antithrombin and it does not cross-react in vitro with heparin induced thrombocytopenia antibodies. Fondaparinux inhibits specifically FXa, although some other targets are suspected (FIXa and FVIIa). Endogenous levels of AT are the rate limiting factor for its anti-Xa activity. Fondaparinux, in contrast to direct FXa inhibitors (i.e. DX-9065a) inhibits free FXa but not the FXa bound to prothrombinase, and it does not prolong PT and aPTT. Fondaparinux inhibits thrombin generation in human plasma. We have shown that the inhibition of thrombin generation by fondaparinux is inversely correlated with thromboplastin concentration. This original observation may explain the absence of any effect of fondaparinux on PT. Melagatran dipeptide (MW=430 Da) is a specific, reversible direct thrombin inhibitor. It inhibits free and clot bound thrombin. Its half-life is 1.7-2.5 hours after i.v. or s.c. administration. Ximelagatran (Exantas), is a pro-drug with a hydroxyamidino instead of amidino-group and an esterified carboxyl-group. It is the first clinically used direct orally acting thrombin inhibitor. Ximelagatran after intestinal absorption is metabolized to melagatran. Melagatran is not metabolized and is cleared through the kidney. Among the specific FXa inhibitors the synthetic pentasaccharide (Fondaparinux-Arixtra) has been approved by FDA and several European health organizations for the prophylaxis of VTE in major orthopedic surgery. No specific antidote has been described for the new antithrombotics. Encouraging results have been obtained from our group on the possible use of rFVIIa (Novoseven). The general opinion is that there is no need for laboratory monitoring of the new antithrombotic agents. Conclusion. The research for safer and more effective anticoagulants has been successful by targeting specific steps in coagulation. These single-targeted agents are challenging multi-targeted drugs (heparins and vitamin-K antagonists). Other drugs including orally active FXa direct inhibitors will probably enrich the armentarium of antithrombotic drugs.

Information on the clinical and biological characteristics of combined hormonal contraceptives (CHC) users experiencing a venous thromboembolism (VTE) event is scarce. Better knowledge of factors determining the VTE risk in CHC users could help identify women at high risk. Data were obtained from a large cohort of consecutive women with the first documented VTE event. Cross-sectional analysis of clinical and biological characteristics of the women was performed. Of the 3009 women with the first VTE included, 31% were nonusers and 69% CHC users at time of VTE. CHC users were significantly younger (29.0 ± 7.2) than nonusers (31.6 ± 7.1) (P

We conducted a study to evaluate a noninvasive strategy including spiral computed tomography (CT) in patients with suspected pulmonary embolism (PE). We systematically performed spiral CT, ventilation/perfusion lung scanning, and D-dimer (DD) measurement (VIDAS test), and in some cases (with a normal CT with nondiagnostic lung scan and increased DD) performed venous ultrasonography (US) on 247 consecutive patients with clinically suspected PE in our hospital. Patients in whom PE was deemed absent were not given anticoagulants. All patients were followed for 3 mo. The prevalence of PE in the 228 patients who could be evaluated was 42% (96 of 228). PE was confirmed by spiral CT in 73% of the patients, by a high-probability lung scan in 4%, and by findings on US in 23%. PE was ruled out by a normal lung scan in 14% of the patients, by a normal DD concentration (500 ng/ml) in 31%, by an obvious differential diagnosis on spiral CT in 18%, by a similar prior lung scan in 11%, and by the combination of normal spiral CT findings, a nondiagnostic lung scan, a DD concentration500 ng/ml, and normal US in 26%. Pulmonary angiography was performed in only two patients, both of whom had a normal spiral CT scan and a high-probability lung scan, and was normal. The 3-mo risk of thromboembolism in patients not given anticoagulants, based on the results of the diagnostic protocol, was 1.7% (95% confidence interval: 1.5 to 2.3%). There were no deaths. The noninvasive strategy of combining spiral CT, lung scanning, DD measurement, and in some cases US, in patients with suspected PE yielded a definite diagnosis in 99% of patients, and appeared to be safe.

BACKGROUND: Acquired hemophilia is a rare disease caused by the development of auto-antibodies against factor VIII. SUBJECTS AND METHODS: We studied the characteristics and outcomes of 34 patients (19 women and 15 men) with acquired hemophilia from 1980 to 1997. RESULTS: The mean age of the patients was 61 years (range, 22–93 years). An underlying disease was observed in 18 (53%) patients: 5 patients had cancer, 4 an autoimmune disorder, 2 a dermatologic disorder, 3 asthma, 3 were postpartum, and 1 had an adverse reaction to ampicillin. Factor VIII level was 10 Bethesda units) in 23 (69%) patients. Bleeding requiring transfusions was reported in 25 (75%) patients. Human factor VIII was given to 14 patients and porcine factor VIII to 5. Six patients received prothrombin complex concentrates and one desmopressin. Several immunosuppressive treatments were used, mainly corticosteroids, cyclophosphamide, and intravenous immunoglobulin. Bleeding stopped in all but one patient within 2 weeks. Most patients achieved complete remission, although two relapses were observed subsequently. CONCLUSION: This large study helps to clarify the presentation and clinical course of acquired hemophilia. Prospective studies are needed to determine the efficacy of treatment.

The polymorphism G20210A in the 3′ untranslated region of the prothrombin gene is associated with an increased level of factor II activity and confers a twofold to fivefold increase in the risk for venous thromboembolism. Among Caucasian populations, the prevalence of factor II G20210A heterozygotes is 1% to 6%, whereas in non-Caucasian populations it is very rare or absent. The aim of the present study was to discern whether factor II G20210A originated from a single or recurrent mutational events. Allele frequencies of four dimorphisms spanning 16 of 21 kb of the factor II gene were determined in 133 unrelated Caucasian subjects of Jewish, Austrian, and French origins who bore factor II G20210A (10 homozygotes and 123 heterozygotes) and 110 Caucasian controls. Remarkable differences in the allele frequencies for each dimorphism were observed between the study groups (P = .0007 or less), indicating strong linkage disequilibrium and suggesting a founder effect. Indeed, a founder haplotype was present in 68% of 20210A mutant alleles and only in 34% of 20210G normal alleles (P < .0001). These data strongly support a single origin for factor II G20210A that probably occurred after the divergence of Africans from non-Africans and of Caucasoid from Mongoloid subpopulations.© 1998 by The American Society of Hematology.

SummaryAPTT is widely used for laboratory monitoring of treatment with unfractionated heparin (UFH). However, since its sensitivity to heparin varies significantly from one reagent to another, the therapeutic range had to be defined for each brand of APTT reagent. As an example, SILIMAT (bio-Mérieux) is a new APTT reagent containing rabbit brain phospholipids and micronized silica as an activator. Since its high sensitivity to heparin has been previously reported, a multicenter trial was carried out in an attempt to define the therapeutic range of APTT performed using this new reagent. For that purpose, 170 blood samples drawn for routine coagulation testing from 170 different patients treated with UFH were analyzed. A single batch of two different APTT reagents were used on KC10 coagulometers: SILIMAT and Automated APTT (Organon-Teknika) whereas the anti-Xa activity was evaluated by a chromogenic substrate-based assay. The same methodology was used in all the centers. In order to obtain a plasma anti-Xa activity within the therapeutic range i.e. between 0.30 and 0.70 IU/ml, the APTT ratios were found between 1.90 and 5.40 for SILIMAT, which corresponded to clotting times of the patients plasma between 63 and 178 s. The APTT ratios were significantly lower when evaluated using Automated APTT (between 1.70 and 4.10), with clotting times between 53 and 127 s. In addition, a good correlation was found between the Anti-Xa activity and APTT for both reagents (r >0.65). However, it is not possible to make recommendations regarding the therapeutic ranges without restrictions. Although about 70% of the patients with an anti-Xa activity between 0.30 and 0.70 IU/ml had an APTT in the above defined ranges, the degree of concordance between the two assays is not absolute. Actually more than 30% of the patients had discordant anti-Xa activity and APTT and more than a quarter of the patients included in the above defined therapeutic range for APTT had an anti-Xa activity outside the 0.30-0.70 IU/ml range, whatever the reagent used. In conclusion, to define the therapeutic ranges of APTT using the recommended method is practicable but some critical points could be raised, suggesting that a better method is awaited in order to improve the standardization.

Clinical studies have shown that acetylsalicylic acid (ASA) or ticlopidine (T) bring a partial clinical benefit in a subset of patients threatened by thrombosis on atherosclerotic plaques. Acetylsalicylic acid and T have different impacts on platelet function and the combination of the drugs seems logical to achieve a greater antiplatelet effect. Healthy volunteers were randomly allocated to any of the three treatment groups: T 250-placebo; T 250-T 250; placebo-placebo (treatment was administered in a double blind manner). Acetylsalicylic acid 40 mg was openly administered once a day to the subjects of the three groups after the first week of treatment. Simplate I bleeding time and platelet aggregation testing were performed before treatment and at the end of the two treatment periods. We confirmed that T alone prolongs bleeding time and impairs, in a dose-dependent manner, ADP-induced aggregation; platelet responses that depend on released ADP were also affected. Inhibition of thromboxane-dependent aggregation, associated with a doubling of the bleeding time, was observed after one week of low-dose ASA inhibition of thromboxane synthesis. An additive effect of ASA 40 mg to T 250 mg on the bleeding time was evidenced. There was also a wider alteration of platelet aggregation, with a trend towards an inhibition of the response to a high concentration of collagen as compared to ASA or T used alone. Such a powerful, logical drug combination is in good agreement with preliminary encouraging results obtained after coronary stent implantation and deserves further studies in patients at high risk for arterial thrombosis to define its benefit-risk profile. Key Words: Aspirin—Ticlopidine— Drug combination—Bleeding time—Platelet aggregation.

Introduction Migraine, 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. Objective To assess the risk of migraine without or with aura related to inherited biological thrombophilia adjusted for the main potential confounders. Material and Methods A cross-sectional study was conducted in 1456 French women aged 18 to 56 years, 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. Results There 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. Conclusion FVL 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.

Background and Purpose Cerebral venous thrombosis (CVT) is an infrequent condition with a large variety of causes. However, in 20% to 35% of cases, no cause is found. We studied coagulation parameters, including activated protein C resistance associated with factor V gene mutation (factor V Leiden) and anticardiolipin antibodies, in a large series of patients with CVT with or without identified cause or risk factor. Methods Forty patients (30 women and 10 men) aged 19 to 71 years (mean age, 36.2 years) with CVT diagnosed by angiography and/or MRI were studied 1 to 18 years after thrombosis. No known cause was found in 10 idiopathic cases. Coagulation studies included the following tests: fibrinogen, antithrombin, protein C, protein S, plasminogen, anticardiolipin antibodies, activated protein C resistance, and factor V Leiden. Results Six cases of thrombophilia (15%) were found: 1 protein C deficiency, 1 protein S deficiency, and 4 activated protein C resistance with heterozygous factor V Leiden mutation (10%). Only 1 case (protein S deficiency) was found in the group of 10 patients with idiopathic CVT. In the other 5, there was another cause or risk factor. Three patients (8%) had increased anticardiolipin antibodies: 1 with systemic lupus and 2 with primary antiphospholipid syndrome; 2 of these 3 patients also had factor V Leiden mutation. Conclusions Although present in a number of CVT cases, acquired (anticardiolipin) or congenital varieties of thrombophilia (factor V Leiden being the most frequent) are almost invariably associated with other predisposing factors. This suggests that (1) these abnormalities should be looked for in patients with CVT, whether a cause is found or not, and (2) their presence should not deter the search for other potential causes. The detection of such abnormalities has major practical consequences on the long-term management of patients to prevent further thrombotic episodes.

We evaluated the effectiveness of desmopressin to control bleeding of patients with coagulation defects during dental surgery. Thirty-five patients, mainly with moderate and mild hemophilia and Willebrand disease, were undergoing dental extractions (over 80 extractions in total). Bleeding was successfully prevented in 28 patients with the use of a combined treatment incorporating IV desmopressin, an antifibrinolytic agent (tranexamic acid), and local methods (surgical glue and compression techniques). Seven patients had a bleeding episode after dental extraction, which was controlled in two cases by repeated injection of desmopressin and in another two by local methods; Factor VIII substitutive treatment was needed in only three patients. Desmopressin offers an alternative to blood products to control bleeding risk in patients with moderate and mild coagulation defects. Our experience tends to specify the mode of administration of both desmopressin and the associated treatments. Our findings suggest that desmopressin can be used in conjunction with other treatments to prevent bleeding in patients with coagulation defects who undergo dental surgery. This work highlights the concept of multifactorial medical care of these patients in which desmopressin plays a major role.

Homozygous or double heterozygous protein-C deficiency can present at birth with purpura fulminans or later in life with venous thrombosis. Two homozygous patients who had previously sustained thrombotic episodes were investigated at a time when they were asymptomatic and not receiving antithrombotic therapy. The plasma levels of protein-C antigen and activity in both individuals were approximately 20% of normal. We administered a highly purified plasma-derived protein C concentrate to these individuals and monitored levels of several markers of in vivo coagulation activation. Assays for protein-C activation (activated protein C and protein C activation peptide) showed a sustained increase from reduced baseline levels, whereas thrombin generation (as measured by prothrombin fragment F1 + 2) gradually decreased over about 24 hours into the normal range. These investigations provide direct evidence that protein C is converted to activated protein C in vivo, and that the protein-C anticoagulant pathway is a tonically active mechanism in the regulation of hemostatic system activation in humans.

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.Thirteen-month observational study.Acute care, extended care, and rehabilitation geriatric wards of a teaching hospital in Paris, France.Hospitalized patients (N=307, mean age 86.1 +/- 6.1) treated with warfarin with a therapeutic international normalized ratio range of 2.0 to 3.0.Patients were assigned according to care unit to the computer-generated dosing group (CGD) or the standard management group (SM; usual physician-based care).Relationships between anticoagulation quality criteria and covariates (age, sex, warfarin indication, treatment phase, follow-up duration, model of care).According to multivariate analysis, only model of care and follow-up duration independently influenced anticoagulation control; the proportion of time within therapeutic INR range 2.0 to 3.0 was significantly greater in the CGD group than in the SM group (59% vs 48%, P=.004). When a wider INR range was analyzed (1.8-3.2), the proportion of time within range was 73% versus 64% (P=.006). Use of the computer was associated with fewer days with INRs greater than 3, a smaller percentage of INRs of 4 or greater, a longer time to the first INR of 4.0 or greater, and a smaller mean number of INRs per month than SM (all P.01).Initiation regimen and long-term rules that have specifically been developed and included in a computerized dosage program improve quality of anticoagulation in elderly inpatients, allowing them to benefit from a quality of care as high as that of younger ambulatory patients.

Primary lymphoma of the spleen is characterized by predominant splenomegaly. Lymphoplasmacytic malignant lymphoma of the spleen, of low malignancy in the Kiel classification, low and intermediate grade in the National Cancer Institute Working Formulation (NCIWF), is rare. It is often associated with a monoclonal immunoglobulin M (IgM). Four patients presenting with primary splenic lymphoma of plasmacytic type associated with a high level of monoclonal IgM and a lupus anticoagulant (LA) are described. This association has not previously been reported. In contrast with the usual heterogeneity of LA, this LA is relatively homogeneous with an important prolongation of the prothrombin time (greater than 18 sec for a control of 12), more prolonged partial thromboplastin time (PTT) of the mixture patient + control plasma than PTT of the patient plasma. Despite the important coagulation abnormalities, none of these four patients has presented any hemorrhagic or thrombotic complications, even during major surgery such as splenectomy. The lupus-like anticoagulant effect ran parallel with the monoclonal IgM. Survival, after splenectomy and chemotherapy, appears to be favourable: three patients are alive with survivals of greater than or equal to 7 years. The follow-up is as yet too short for the last patient.

The risk of venous thromboembolism (VTE) in the absence of prophylaxis was evaluated in a retrospective study of 47 women (84 pregnancies) with combined thrombophilia [heterozygous factor V Leiden (FVL) plus prothrombin (FII) 20210A mutation (group I)] and in 82 women (193 pregnancies) with the FII alone (group II). VTE was more frequent in group I than in group II [17.8% versus 6.2%, P = 0.003, relative risk (RR) 2.9, 95% confidence interval (CI) 1.4-5.9], ante partum (7.1% and 2.1%) and post partum (11.5% and 4.2%). The risk was higher in index cases than in family members (RR 2.5, 95% CI 1.2-5.2 and RR 2.1, 95% CI 0.2-22.3 respectively) Even women who had no history of VTE before pregnancy had an increased risk (RR 2.2, 95% CI 1.0-4.8). Our results suggest that, during ante partum, prophylaxis is indicated in women with combined thrombophilia and with a VTE before pregnancy. In those without VTE before pregnancy, prophylaxis might be decided for each individual case, taking into consideration all risk factors. In women with the FII mutation alone, the low risk may not justify prophylaxis in the absence of previous VTE. In post partum, prophylaxis is indicated in all cases.

Large epidemiological studies have shown that nearly all risk factors for deep vein thromboses have a different impact on the manifestation of the disease, which aids in their differentiation into high, moderate and low risk. North American authors have introduced a fourth class of very high risk. The prophylactic measures available are numerous. They can be used in isolation or association depending on the significance of the risk. In France, prophylaxis by LMWH (low molecular weight heparin) is by far the most frequently used method. Recently, apart from compression stockings and intermittent mechanical compression, the use of footpumps, and a technique of electrical calf stimulation have been proposed. Each thrombosis center or service should put in place a well defined strategy for prescribing thromboprophylaxis, adapted to the level of the thromboembolic risk for each group of patients. A dose of LMWH higher than that used for a moderate risk is indicated for most LMWH, in the case of a high or very high risk. A few problems still exist: the pre or postoperative timing of the first injection, the duration of the prophylaxis particularly during the post-discharge period, and the evaluation of the risk in certain situations such as laparoscopic surgery or limb immobilization, for which the studies are too few to formulate recommendations from the level of evidence available. The socioeconomic realities of using LMWH should not be ignored.