Impact of multidisciplinary team meetings on the management of venous thromboembolism. A clinical study of 142 cases.

OBJECTIVE: Numerous guidelines have been published on the management of venous thromboembolism (VTE). However, therapeutic decision-making may prove challenging in routine clinical practice. With this in mind, multidisciplinary team (MDT) meetings have been set up in Rennes University Hospital, France. This study sought to describe the situations discussed during MDT meetings and to assess whether the meetings bring about changes in the management of these patients. MATERIALS AND METHODS: A retrospective single-center study conducted at the Rennes University Hospital included cases presented from the beginning of the MDT meetings (February 2015) up to May 2017. RESULTS: In total, 142 cases were presented in 15 MDT meetings, corresponding to a mean of 10±4 cases per meeting. Of these, 129 related to VTE patients: 33 provoked VTEs, 22 unprovoked VTEs, 49 cancer-related VTEs, and 25 unspecified VTEs. MDT meetings led to significant changes in the anticoagulation type (therapeutic, prophylactic, or discontinuation) and duration, but not in the anticoagulant choice (direct oral anticoagulants, vitamin K antagonists, heparins, etc.). CONCLUSION: Requests for MDT meetings are made for all VTE types, and these meetings have an impact on VTE management.

[Biological monitoring of treatment with antivitamin K. Value of INR and definition of new therapeutic ranges. A study of 73 patients]. / Surveillance biologique des traitements par les antivitamines K. Intérêt de l'INR et définition des nouvelles zones thérapeutiques. Etude chez 73 malades.

The prothrombin time test (PT) is the most common method used for monitoring oral anticoagulant therapy. As a consequence of the variability in responsiveness of different thromboplastins, PT results obtained from patients on oral anticoagulant therapy may not be interchangeable between laboratories and as consequence could produce potential problems for anticoagulant control. The conversion of PT in INR (International Normalized Ratio) has been introduced recently to standardise the PT used for anticoagulant control. 127 determinations of prothrombin time and INR with 2 different thromboplastin reagents (Thromboplastin C Dade and Owren reagent) have been performed in 73 patients. This study confirm the usefulness of the INR (INR discrepancy in 10% of the cases) despite the imperfections concerning the choice of the control plasma and the need of a precise measurement of the ISI, International Sensitivity index. In parallel, changes in therapeutic ranges for anticoagulant therapy occurred, based on results of the international literature: less intense anticoagulant treatment (INR 2-3) is effective against recurrent venous thromboembolism with reduced bleeding. Different therapeutic ranges must be recommended for oral anticoagulant therapy according to the indication of the treatment.

[Follow-up of the treatment by direct thrombin inhibitors: activated partial thromboplastin time or ecarin clotting time]. / Surveillance du traitement par les inhibiteurs directs de la thrombine: temps de céphaline avec activateur ou temps d'écarine.

The clinical use of the direct inhibitors of thrombin requires a reliable test to monitor the treatment and to predict the hemorragic risk. The activated partial thromboplastin time (APTT) is the most common test used to monitor treatment with unfractionated heparin. Thus APTT has been first chosen to follow patients treated with direct thrombin inhibitors, but studies have shown that it was probably not the most appropriate test. Indeed, APTT values were not well correlated with the dose administered and were dependent on the type of the thrombin inhibitor used and on the APTT reagent. The ecarin clotting time (ECT), which converts prothrombin into meizothrombin has been then tested and seemed to be a better test. In vitro studies have shown a good correlation between ECT and the different concentrations of thrombin inhibitors. Furthermore, the ECT in contrast to APTT is not sensitive to heparin or oral anticoagulant and interindividual variations are low with ECT. ECT which is a reliable test and is easy to perform seems to be a more appropriate test to monitor treatment with direct thrombin inhibitors but further studies are needed to validate its use in a clinical setting.

[Myelodisplasic syndromes diagnosed in a geriatric hospital: morphological profile in 100 patients]. / Syndromes myélodysplasiques diagnostiqués dans un hôpital gériatrique: profil cytologique de 100 patients.

Myelodysplastic syndrome (MDS) is particularly common in geriatric practice. As few data are available in very elderly patients, we conducted a 54-month retrospective study in patients over 70 years with MDS diagnosed at Hôpital Charles Foix. Patients with cobalamine, folate or iron deficiency were excluded. Regarding biological and morphologic approaches, MDS patients were classified according to the FAB criteria. We then tempted to reclassify the patients according to the WHO criteria. The Bournemouth scoring system was used as a prognostic tool. During the study period, 100 patients were included, 29 males and 71 females, median age 86 +/- 7 years (70-103). At the time of bone marrow sampling, a peripheral blood cytopenia was documented in 64 patients, a bicytopenia in 27 patients and a pancytopenia in 9 patients. Isolated anaemia (Hb < 12 g/dL) was found in 60 patients and isolated thrombocytopenia (< 150 x 10(9)/L) in 4. Macrocytosis (MCV > 100 fL) was observed in 21 % of the cases. According to the FAB criteria, the 100 patients were classified as follows: refractory anaemia (RA): 79%; RA with ringed sideroblasts (RARS): 8%; RA with excess of blasts (RAEB): 8%; RAEB in transformation: 1%; chronic myelomonocytic leukaemia: 4%. According to the WHO classification, the patients were reclassified as follows: RA (unilineage) (with or without ringed sideroblasts): 10%; refractory cytopenia with multilineage dysplasia with or without ringed sideroblasts (RCMD): 73%; RAEB: 7% (RAEB-1 6%, RAEB-21%); MDS/Myeloproliferative disorder: 4%; unclassified (hypocellularity): 5%; acute leukaemia: 1%. In order to estimate prognosis at the time of the bone marrow aspirate, we calculated the Bournemouth'score: 8 patients scored 0,57 scored 1,25 scored 2,8 scored 3 and 2 scored 4. In this geriatric population, 83% cases of MDS are RA or RCMD (with or without sideroblasts); MDS with excess of blasts are uncommon. Thus, elderly patients under study with MDS were diagnosed at an earlier stage of the disease than younger ones from series published in the literature. Due to frequent comorbidities, geriatric patients may be symptomatic for a slight decrease of haemoglobin level. Therefore, elderly patients are investigated as soon as they present with moderate anaemia that may explain the early MDS diagnosis.

[ABO incompatibility and newborn haemolytic disease: two cases with major erythroblastosis]. / Incompatibilité foeto-maternelle ABO et maladie hémolytique du nouveau-né: à propos de deux observations avec érythroblastose majeure.

Two cases of newborn haemolytic disease because of ABO incompatibility are reported. In both cases, blood erythroblastosis exceeded 300 per 100 leukocytes at birth. Both newborns developed early jaundice and one presented with anaemia. Intensive phototherapy begun soon after birth was an effective treatment. The diagnosis of newborn jaundice and the patho-physiological basis of haemolytic disease because of ABO incompatibility are discussed.

[Evaluation of a new automatic hematological system: the Advia 70 (Bayer-Diagnostics)]. / Evaluation d'un nouvel automate de cytologie sanguine: l'Advia 70 (Bayer-Diagnostics).

The Advia 70 hematology system is a new automated analyser manufactured in Texas (USA) by MWI-DANAM and marketed by Bayer- Diagnostics in France. The throughput is 70 complete blood counts (CBC) with leukocyte differential counts (diff) per hour. Three sample modes are proposed: normal mode (180 muL of whole blood), sample saver mode (90 muL) or automatic sampler (180 muL). The principles used on Advia 70 are: 1) electrical impedance for cell counting (WBC, RBC, platelets, MCV) and RBC/plt sizing; 2) multi-dimensional optical system and absorbance for white cell differential. The Advia 70 has been evaluated in our laboratory over a three-week period. Within-run variations of blood counting (CBC & diff) were determined on normal and abnormal patient specimens whereas between run-variations were determined on normal controls. Linearity and detection limits were also tested. The Advia 70 system results were reproducible and reliable. The correlations between the various sample modes were very good. Contamination and store assays were performed. Thirty normal and abnormal samples were successively analysed on the Advia 70 system and on the Advia 120 system which methodologies are different (myeloperoxidase staining coupled with flow cytometry-nuclear lobularity analysis for WBC/Diff, flow cytometry and laser diffraction for RBC/platelets), and the results were compared: despite the different technologies used on both analysers, the correlations were very good (CBC and diff parameters). Finally, we evaluated the leukocyte differential flags on 72 patients samples with abnormal cells, using the blood smear examination as the reference method. In conclusion, the Advia 70 can be used in private and hospital laboratories.

[Cytochrome P450 2C9 polymorphisms (CYP2C9) and warfarin maintenance dose in elderly patients]. / Polymorphismes du cytochrome P450 2C9 (CYP2C9) et posologie à l'équilibre pour des patients âgés traités par warfarine.

PURPOSE: Allelic variants of the gene coding for cytochrome P450 isoform 2C9 (CYP2C9), 2C9*2 and 2C9*3, were shown to increase sensitivity to warfarin in adults. In the elderly, the maintenance dose is influenced by acquired factors including comorbidities and polymedication. The aim of our purpose was to investigate whether a genetic factor, such as cyp2c9 genotype, does influence the warfarin maintenance dose in very elderly patients. METHODS: In-patients treated with warfarin were recruited with the following inclusion criteria: i/ 75 years-old or over; ii/ a stable INR within the therapeutic range (INR 2.0-3.0). Genotypes were coded as numbers of alleles for each of the three polymorphisms, namely 2C9*1 (wild-type), 2C9*2, and 2C9*3. RESULTS: CYP2C9 genotype was performed in 126 patients, mean age 87 +/-6 years (75-103), 29 males-97 females. The mean daily dose of warfarin was 3.0 +/-1.4 mg, with 3.1 mg in patients with the wild-type *1/*1 genotype (n =80), 2.7 mg in *1/*2 heterozygotes (n =20), 2.9 mg in *1/*3 heterozygotes (n =18), 1.2 mg in *2/*2 homozygotes (n =2), 2.3 mg in compound heterozygotes *2/*3 (n =6). The relationships between dose and potential factors were assessed using the correlation coefficient test for age and Fischer exact tests for the categorical variables. The only factors significantly linked to the dose were the numbers of 2C9*1 and 2C9*2 alleles. CONCLUSION: In elderly patients, a genetic influence on response to warfarin does exist as in younger patients.

[Excess antivitamin K in elderly hospitalised patients aged over 70. A one-year prospective survey]. / Surdosages en antivitamine K dans une population de patients hospitalisés âgés de plus de 70 ans. Enquête prospective sur un an.

INTRODUCTION: Antivitamin K treatments (AVK) are related to increased morbidity and mortality, notably in elderly patients. The International Normalized Ratio (INR) should be well controlled and its stabilisation within the therapeutic range help to prevent the haemorrhagic complications. METHODS: A one-year prospective survey on all the cases of excess AVK was conducted in hospitalised patients aged over 70. RESULTS: During the study period, 225 hospitalised patients treated with AVK (mean age 84 years) were identified: 62% received warfarin, 19% fluindione, 8% acenocoumarol and 11% received several successive AVK. During this period, 1.904 INR measurements were recorded: 97 (5.1%) were > or =5.0 and 12 (0.63%) were > or =9.0. In all, 59 patients (23.1%) exhibited one or several episodes of excess AVK (INR > or =5.0) and 57 exhibited a target INR of 2.5. Three patients died of accidental haemorrhage--two of them due to intra-cerebral bleeding--among the 59 patients with excess AVK. In three cases, the INR was greater than 7.0 at the time of the accident. DISCUSSION: In half of the cases of excess, the episode occurred during the month following initiation of treatment with AVK. In nearly two thirds of cases, a change had been made in drug therapy in the 10 days preceding the excess, with the prescription of a drug enhancing the effect of the AVK: anti-infection agents (antibiotics and anti-fungals) and amiodarone were the drugs most frequently involved. Oral or intravenous vitamin K1 was administered in only 19% of cases. CONCLUSION: In very old patients treated with oral anticoagulants, certain risk factors must be identified: the initiation period of treatment, the occurrence of an intercurrent disease and the subsequent change in the drug therapy. INR monitoring should be intensified in order to detect any excess and, if detected, ensure the optimal management of the patient.

[Questions--answers on the use of rivaroxaban for the treatment of venous thromboembolic disease]. / Questions - réponses sur l'utilisation du rivaroxaban pour le traitement de la maladie thromboembolique veineuse.

Rivaroxaban is a direct oral anticoagulant targeting factor Xa. Efficacy and safety of rivaroxaban were evaluated through the phase 3 EINSTEIN program, consisting in three clinical trials regarding the treatment of deep vein thrombosis (EINSTEIN DVT), pulmonary embolism (EINSTEIN PE), and in secondary prevention after a first episode of venous thromboembolic disease (EISNTEIN EXT). Rivaroxaban was recently approved both by the European and the French Health agencies for the treatment of DVT and prevention of deep vein thrombosis recurrence. This report addresses the use of rivaroxaban in clinical practice in such indications.

In vitro effect of plasmin on human platelet function in plasma. Inhibition of aggregation caused by fibrinogenolysis.

BACKGROUND: Plasmin has been reported both to activate platelets and to inhibit platelet functions. The latter effect was thought to be caused by proteolysis of the main membrane glycoproteins. METHODS AND RESULTS: We found that incubation of citrated human platelet-rich plasma with streptokinase (SK) (300 IU/ml) does not produce any detectable activation but leads to a time-dependent inhibition of ADP-induced aggregation accompanied by substantial fibrinogenolysis. These effects were abrogated by previous addition of a plasmin inhibitor, aprotinin. Crossover experiments (SK-treated or control platelets mixed with SK-treated or control plasma) demonstrated that the platelets remained functional and that the aggregation defect was caused by fibrinogenolysis. Further experiments (addition of purified fibrinogen to fibrinogen-depleted plasma with either SK or thrombin) suggested that in addition to the low residual level of fibrinogen, fibrinogen degradation products had an inhibitory effect. Under the same conditions, tissue-type plasminogen activator (t-PA) (3,000 ng/ml) had no effect on platelet aggregation, and plasma fibrinogen was not significantly lowered. The effects on glycoproteins IIb-IIIa of incubation with SK, t-PA, or plasmin were assessed with immunoblots with murine monoclonal antibodies directed against either part of the complex, which is the receptor for fibrinogen. Proteolysis was detected only in the presence of EDTA, a potent chelator of divalent cations. CONCLUSIONS: The incubation of human platelets in citrated plasma with SK concentrations obtained during therapy leads to an aggregation defect that is related to the decrease in fibrinogen, the adhesive protein involved in this function, and to the impeding effect of fibrinogen degradation products on its binding onto platelets but not to an alteration of the corresponding platelet receptor, the heterodimer glycoproteins IIb-IIIa.