Publications by authors named "Brigitte Tardy-Poncet"

21 Publications

  • Page 1 of 1

Heparin-induced thrombocytopenia: construction of a pre-test diagnostic score derived from the analysis of a prospective multinational database, with internal validation.

J Thromb Haemost 2021 Apr 19. Epub 2021 Apr 19.

F-Crin INNOVTE, Université de Lyon, CIC 1408, Inserm U1059 SAINBIOSE, Saint-Etienne, France.

Background: Diagnosis of heparin-induced thrombocytopenia (HIT) requires pre-test probability assessment and dedicated laboratory assays.

Objective: To develop a pre-test 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 (2,280 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: HIT 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 ≤ six days (3); thrombotic event, arterial (3) or venous (3). The C-statistic was 0.79 [95% CI, 0.76-0.82]. In the validation cohort, the area under the receiver operating characteristic curve was 0.77 [95% CI, 0.74-0.80]. Three groups of scores were defined; HIT prevalence reached almost 30% in the high-probability group.

Limitation: The performance of the score may depend on settings and practices.

Conclusion: The objective, easy-to-collect, clinical features of HIT we evidenced were incorporated into a pre-test score, which may guide clinical decisions regarding diagnostic testing and anticoagulation.
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http://dx.doi.org/10.1111/jth.15344DOI Listing
April 2021

Surgery with emicizumab prophylaxis for two paediatric patients with severe haemophilia A with inhibitors.

Pediatr Blood Cancer 2021 Apr 13:e29041. Epub 2021 Apr 13.

Hematology and Oncology Pediatric Unit, Haemophilia CRC Hospital of Saint-Etienne, Saint-Etienne, France.

Emicizumab is a prophylaxis for patients with severe haemophilia A with and without inhibitor. Despite weekly administration of emicizumab, coagulation states stay below normal value and cannot be assessed by standard haemostasis tests. In our two patients, we used the thrombin-generation assay (endogenous thrombin potential and Peak) to monitor the patient's clotting status. Under emicizumab, it is necessary to add a bypassing agent (BPA) such as rFVIIa (Novoseven) to avoid bleeding before surgery. The BPA dosage was based on a thrombin-generation assay and collegial consultation.
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http://dx.doi.org/10.1002/pbc.29041DOI Listing
April 2021

Use of population PK/PD approach to model the thrombin generation assay: assessment in haemophilia A plasma samples spiked by a TFPI antibody.

J Pharmacokinet Pharmacodyn 2021 Apr 12. Epub 2021 Apr 12.

School of Pharmacy, University of Waterloo, Kitchener, ON, Canada.

The thrombin generation (TG) assay is a well-established tool to capture the clotting potential of any healthy or haemophiliac subject. It measures ex vivo the kinetics of thrombin activation throughout the coagulation. Clinical studies allowed to create two databases gathering the coagulation factor levels and the thrombin generation profile of 40 healthy and 40 haemophiliac A (HA) subjects. Besides, portions of all HA samples were spiked with increasing levels of a TFPI antibody (considered as a possible therapeutic target) and corresponding TG profiles were determined. The non-linear mixed-effect (NLME) modelling aims at describing and explaining the experimentally observed important variability of the TG curves between subjects and the individual effects of spiking with a TFPI antibody. The models consist of an empirical description of the TG kinetics, accounting for an additive residual error and between-subject variability on its parameters. Factor VIII and TFPI were found to significantly explain and reduce the variability of the TG of haemophilia A samples. Besides, the model is shown to correctly reproduce the variability in the response to the ex vivo spiking with the TFPI antibody, by combining the empirical description of TG to a simple Hill equation that accounts for the binding between TFPI and different doses of its antibody. Such models can be useful for clinical practice, with the analysis and comparison of the distributions of TG profiles in healthy and haemophilia populations; and also for research, with the analysis of the effect of TFPI and its neutralization on individual TG profiles.
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http://dx.doi.org/10.1007/s10928-021-09752-1DOI Listing
April 2021

Functional Flow Cytometric Assay for Reliable and Convenient Heparin-Induced Thrombocytopenia Diagnosis in Daily Practice.

Biomedicines 2021 Mar 25;9(4). Epub 2021 Mar 25.

Inserm U1059 Sainbiose, Université de Lyon, 42055 Saint-Etienne, France.

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.
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http://dx.doi.org/10.3390/biomedicines9040332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8064483PMC
March 2021

PHILEOS () Study: protocol of a multicentre prospective case-control study.

BMJ Open 2021 01 13;11(1):e042283. Epub 2021 Jan 13.

Inserm CIC 1408, Saint-Etienne University Hospital Center, Saint-Etienne, Rhône-Alpes, France.

Introduction: Two meta-analyses showed lower bone mineral density (BMD) in patients with haemophilia (haemophilia type and severity were often not specified) compared with healthy controls. This finding could be related to reduced mobility and sedentary lifestyle, and/or hepatitis C or HIV infection. The aim of this study is to determine osteoporosis prevalence in patients with haemophilia classified in function of the disease type (A or B) and severity, and to evaluate the potential role of regular prophylactic factor replacement (early vs delayed initiation) in preserving or restoring BMD.

Methods And Analysis: The haemoPHILia and ostEoporOSis Study is a prospective, controlled, multicentre study that will include patients in France (13 haemophilia treatment centres), Belgium (1 centre) and Romania (1 centre). In total, 240 patients with haemophilia and 240 matched healthy controls will be recruited (1:1). The primary objective is to determine osteoporosis prevalence in patients with severe haemophilia A and B (HA and HB) without prophylaxis, compared with healthy controls. Secondary outcomes include: prevalence of osteoporosis and osteopenia in patients with mild, moderate and severe HA or HB with prophylaxis (grouped in function of their age at prophylaxis initiation), compared with healthy subjects; BMD in patients with HA and HB of comparable severity; correlation between BMD and basal factor VIII/IX levels and thrombin potential; and quantification of plasmatic markers of bone remodelling (formation and resorption) in patients with haemophilia.

Ethics And Dissemination: The protocol was approved by the French Ethics Committee and by the French National Agency for Medicines and Health Products Safety (number: 2019-A03358-49). The results of this study will be actively disseminated through scientific publications and conference presentations.

Trial Registration Number: NCT04384341.
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http://dx.doi.org/10.1136/bmjopen-2020-042283DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7812091PMC
January 2021

Comparative Analysis of a French Prospective Series of 144 Patients with Heparin-Induced Thrombocytopenia (FRIGTIH) and the Literature.

Thromb Haemost 2020 Jul 22;120(7):1096-1107. Epub 2020 Jun 22.

EA 7501, GICC, Université de Tours, Tours, France.

Background:  Heparin-induced thrombocytopenia (HIT) is a rare complication of heparin treatments, and only a few large patient cohorts have been reported. In this study, biological and clinical data from 144 French patients with HIT were analyzed in comparison with the literature.

Methods:  The diagnosis of HIT was confirmed in all patients by an immunoassay combined with serotonin release assay. In the literature, only cohorts of at least 20 HIT patients published from 1992 were selected for a comparative analysis.

Results:  Two-thirds of patients were hospitalized in surgery and most were treated with unfractionated heparin (83.2% vs. 16.8% with low molecular weight heparin only). Thrombotic events in 54 patients (39.7%) were mainly venous (41/54). However, arterial thrombosis was more frequent after cardiac surgery (13.2% vs. 2.4% in other surgeries,  = 0.042) with a shorter recovery time (median = 3 vs. 5 days,  < 0.001). The mortality rate was lower in our series than in the 22 selected published studies (median = 6.3% vs. 15.9%). Three genetic polymorphisms were also studied and homozygous subjects FcγRIIA RR were more frequent in patients with thrombosis (37.8 vs. 18.2% in those without thrombosis,  = 0.03).

Conclusion:  This study shows that the mortality rate due to HIT has recently decreased in France, possibly due to earlier diagnosis and improved medical care. It also confirms the strong association between polymorphism FcγRIIA H131R and thrombosis in HIT.
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http://dx.doi.org/10.1055/s-0040-1712957DOI Listing
July 2020

Effect of heparin thromboprophylaxis on thrombin generation in multiple myeloma patients.

Br J Haematol 2019 07 21;186(2):337-339. Epub 2019 Feb 21.

Centre d'Investigation Clinique Inserm CIC 1408, CHU Saint Etienne, Saint Etienne, France.

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http://dx.doi.org/10.1111/bjh.15815DOI Listing
July 2019

Tissue factor pathway inhibitor is the main determinant of thrombin generation in haemophilic patients.

Haemophilia 2019 Mar 28;25(2):343-348. Epub 2019 Jan 28.

INSERM, U1059, SAINBIOSE, Université de Lyon, UJM-Saint-Etienne, Saint-Etienne, France.

The thrombin generation (TG) assay evaluates haemostatic balance, which is influenced by the levels of many coagulation factors and inhibitors. Our objective was to identify the determinant factors of TG in haemophilia A (HA) and haemophilia B (HB) patients and to compare them to those in healthy controls. Coagulation factor and inhibitor levels, and TG, were measured in platelet-poor plasma from 40 patients with HA, 32 patients with HB and 40 healthy subjects. Data were analysed using multiple regression models. In HA patients, factor VIII was a positive determinant of endogenous thrombin potential (ETP) and peak, whereas tissue factor pathway inhibitor (TFPI) and factor V were negative determinants of ETP and peak. In HB patients, FIX was a positive determinant of ETP and peak, FVII being a positive determinant of peak. Antithrombin and protein S (PS) were negative determinants of ETP while FX was a negative determinant of peak. Above all, in HB patients, TFPI was a negative determinant of ETP and peak. In healthy subjects, FVIII was a positive determinant of ETP and peak, whereas FX and protein S were negative determinants of these parameters. TFPI was not a negative determinant of either peak or ETP. In haemophilic patients, the determinant factors of TG are all implicated in FXa generation and inhibition, the crucial determinant factor being TFPI whatever the type of haemophilia, A or B. These findings contribute to the rationale that recently place TFPI as a target for innovative therapies of haemophilia.
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http://dx.doi.org/10.1111/hae.13679DOI Listing
March 2019

Thrombin generation in newly diagnosed multiple myeloma during the first three cycles of treatment: An observational cohort study.

Res Pract Thromb Haemost 2019 Jan 13;3(1):89-98. Epub 2018 Dec 13.

Centre d'Investigation Clinique Inserm CIC 1408 CHU de Saint-Etienne Saint-Etienne France.

Background: Multiple myeloma (MM) is associated with a high risk of thrombosis, particularly during the first months of treatment including immunomodulatory drugs (IMiDs). There is no consensus on prevention of thromboembolic risk in patients with de novo MM, and identification of patients requiring anticoagulant thromboprophylaxis remains challenging. Evaluating coagulability by an in vitro thrombin generation (TG) test might be a way of identifying such patients.

Objective: To determine whether TG assessment could reveal an increase in coagulability during the first three chemotherapy cycles.

Methods: This prospective and longitudinal observational study included patients newly diagnosed with MM. TG was determined in platelet-rich and platelet-poor plasma using calibrated automated thrombography with a low tissue factor (TF) concentration.

Results: Seventy-one patients were enrolled, allowing TG analysis during 213 chemotherapy cycles. TG remained unchanged throughout follow-up irrespective of treatment regimen, but values determined before cycles 2 and 3 were significantly higher in patients receiving iMiDs-containing regimens. No association was found between TG and its changes and thrombosis occurrence during follow-up: venous thrombosis in eight patients; no cardiovascular event. A significantly (87%) lower risk of venous thrombosis was observed in patients receiving prophylaxis with a low-molecular-weight heparin (LMWH; OR: 0.13 (95% CI: 0.02-0.76). Neither bortezomib- nor dexamethasone-containing regimens were associated with thrombotic risk. Changes in TG, as studied, were not associated with thrombotic events.

Conclusions: The only factor associated with a reduction in early thrombotic risk was prophylaxis with LMWH. The issue of how to identify patients requiring prophylactic anticoagulation remains unresolved.
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http://dx.doi.org/10.1002/rth2.12161DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6332829PMC
January 2019

Evaluation and Calibration of In Silico Models of Thrombin Generation Using Experimental Data from Healthy and Haemophilic Subjects.

Bull Math Biol 2018 08 13;80(8):1989-2025. Epub 2018 Jun 13.

INSERM, U1059, SAINBIOSE, F-42000, Saint Etienne, Univ Lyon, Univ Jean Monnet, INSERM, 42023, Saint-Étienne, France.

The coagulation cascade comprises numerous chemical reactions between many proteins, that finally lead to the formation of a clot to stop bleeding. Many numerical models have attempted to translate understanding of this cascade into mathematical equations that simulate the chain reactions. However, their predictions have not been validated against clinical data stemming from patients. In this paper, we propose an extensive validation of five available models, by comparing in healthy and haemophilic subjects, thrombin generation measured in vitro to thrombin generation predicted by the models in silico. In order to render the models more predictive, we calibrated the models to have an acceptable agreement between the experimental and estimated data. Optimization processes based on genetic algorithms were developed to search for those calibrated kinetic parameters. Our results show that the thrombin generation kinetics are so complex that they cannot be predicted by a unique set of kinetic parameters for all patients: the calibration of only three parameters in a subject-specific way allows reaching good model estimations for different experimental conditions realized on the same patient.
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http://dx.doi.org/10.1007/s11538-018-0440-4DOI Listing
August 2018

Anticoagulant properties of enoxaparin 400 IU/mL-40 % ethanol catheter lock solution.

Springerplus 2015 1;4:746. Epub 2015 Dec 1.

Université de Lyon, 42023 Saint-Etienne, France ; Groupe de Recherche sur la Thrombose, EA 3065, 42023 Saint-Etienne, France ; Laboratoire d'Hématologie, CHU Saint-Etienne, Hôpital Nord, 42055 Saint-Etienne, France.

Unfractionated heparin (UFH) is the most widely used interdialytic lock solution but has no anti-infectious properties. Ethanol at a content ≥40 %v/v eradicates experimental biofilm but has no anticoagulant properties. In contrast to UFH, enoxaparin (Enox) can be combined with 40 % ethanol without precipitation. Enoxaparin 400 UI/mL-40 % ethanol (Enox/Eth) has antibiofilm properties and therefore has promise as an alternative lock solution. This study assessed the anticoagulant properties of Enox/Eth. Enox and Enox/Eth were diluted in whole blood at a final Enox concentration of 0.5, 1 (N = 6 samples), 1.5 (N = 4) and 2 (N = 6) IU/mL. Anti-Xa activity was determined by chromogenic assay and the inhibition of endogenous thrombin potential (ETP) by thrombinography. Quantitative data were compared by the Mann-Withney U test. For Enox concentrations of 0.5, 1, 1.5 and 2 UI/mL in whole blood samples, the mean ± SD values of the anti-Xa activity were 0.68 ± 0.09, 1.26 ± 0.14, 1.73 ± 0.30, 2.35 ± 0.32 UI/mL for Enox/Eth and 0.94 ± 0.15, 1.80 ± 0.22, 2.74 ± 0.23, 3.54 ± 0.44 UI/mL for Enox (P = 0.03, P = 0.03, P = 0.13, P = 0.03); and of the percentage of ETP inhibition was 17.36 ± 9.65, 30.27 ± 17.06, 36.5 ± 17.06, 57.82 ± 15.42 for Enox/Eth, and 42.96 ± 15.68, 68.93 ± 10.01, 83.5 ± 8.81, 91.19 ± 4.67 for Enox (P = 0.03, P = 0.03, P = 0.13, P = 0.03), respectively. The median and IQR values of Enox concentration inhibiting 50 % of ETP (IC50 ETP) were 1.8 [1.1-2.4] IU/mL for Enox/Eth and 0.7 [0.3-0.9] IU/mL for Enox, P = 0.03. Enox/Eth has strong anticoagulant activity, albeit lower than that of Enox, but with an extremely low IC50 ETP compared to the Enox concentration of non-diluted Enox/Eth.
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http://dx.doi.org/10.1186/s40064-015-1533-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4666847PMC
December 2015

Argatroban in the management of heparin-induced thrombocytopenia: a multicenter clinical trial.

Crit Care 2015 Nov 11;19:396. Epub 2015 Nov 11.

Laboratory of Hematology, University Hospital of Dijon, Dijon, France.

Introduction: The aim of this study was to collect data in France in patients with heparin-induced thrombocytopenia who required parenteral anticoagulation and for whom other non-heparin anticoagulant therapies were contraindicated including patients with renal failure, cross-reactivity to danaparoid or at high hemorrhagic risk.

Methods: A total of 20 patients, of mean age 72 ± 10 years, were enrolled in this open-label, multicenter clinical study. Exploratory statistical data analysis was performed with descriptive interpretation of intra-individual comparisons using simple univariate statistics.

Results: The diagnosis of HIT was confirmed in 16 subjects by an independent scientific committee. Fourteen patients (70 %) were in an intensive care unit during the course of the study. Patients were treated with argatroban for a mean duration of 8.5 ± 6.1 days. The mean starting dose of argatroban was 0.77 ± 0.45 μg/kg/min. Platelet recovery was rapid. aPTT and anti-IIa activity assays were used to monitor the dose of argatroban. The mean baseline aPTT value was 45.0 ± 9.8 sec and increased to 78.2 ± 35.8 sec two hours after initiating argatroban. At this time mean argatroban concentration was 0.34 ± 0.16 and 0.61 ± 0.28 μg/ml using ECT and TT measurements, respectively. New and/or extended thromboses were reported in 25 % of patients and major bleedings were documented in 15 %. Six patients died due to their underlying medical condition.

Conclusion: Considering its hepatic elimination and its short half-life, argatroban can be considered as a safe therapeutic option in HIT patients at high hemorrhagic risk and with renal failure, particularly in an ICU setting.
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http://dx.doi.org/10.1186/s13054-015-1109-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4641392PMC
November 2015

Delayed-onset heparin-induced thrombocytopenia without thrombosis in a patient receiving postoperative thromboprophylaxis with rivaroxaban.

Thromb Haemost 2015 Aug 11;114(3):652-4. Epub 2015 Jun 11.

Bernard Tardy, CHU - Intensive care, InsermCIE3, CHU Saint Etienne, Saint Etienne, Loire 42055, France, Tel.: +33 4 77 12 07 97, Fax: +33 4 77 12 78 20, E-mail:

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http://dx.doi.org/10.1160/TH14-07-0593DOI Listing
August 2015

Effects of argatroban, danaparoid, and fondaparinux on trombin generation in heparin-induced thrombocytopenia.

Thromb Haemost 2013 Mar 17;109(3):504-9. Epub 2013 Jan 17.

Laboratoire d'Hématologie, Groupe de Recherche sur la Thrombose, EA 3065, Université J Monet, Inserm CIE 3, CHU Saint Etienne, 42055 Saint Etienne cedex 2, France.

There is no in vitro data on the comparison of the effects of danaparoid, argatroban and fondaparinux on thrombin generation in patients with heparin-induced thrombocytopenia. It was the study objective to compare the in vitro anticoagulant potential of argatroban, danaparoid and fondaparinux using a thrombin generation assay TGA on a mixture of control platelet-rich plasma (PRP) and HIT patient platelet-poor plasma (PPP). The plasma of seven patients with a clear HIT diagnosed at our institution was selected. Mixtures of donor PRP and patient PPP were incubated with unfractionated heparin 0.2 U.mL⁻¹, argatroban at 600 ng.mL⁻¹, argatroban at 400 ng.mL⁻¹, danaparoid at 0.65 IU.mL⁻¹ and fondaparinux at 1 μg.mL⁻¹. Thrombin generation was assessed by calibrated thrombinography. The percentage of inhibition of the endogenous thrombin potential observed with argatroban at 600 ng.mL⁻¹ was statistically significantly higher compared with those observed with fondaparinux (median: 53.6% vs. 3.9%; p=0.031) but not compared with argatroban at 400 ng.mL⁻¹ and danaparoid. The percentage of inhibition of the thrombin peak observed with argatroban at 600 ng.mL⁻¹ was statistically significantly higher compared with those observed with danaparoid (median: 71.2 vs. 56.8; p=0.031) and fondaparinux (mean: 71.2 vs. 30; p=0.031) but not with argatroban at 400 ng.mL⁻¹. In conclusion, the in vitro effect of argatroban and danaparoid on thrombin generation seems to corroborate the results of clinical studies of these drugs in the treatment of HIT in term of efficiency. Fondaparinux showed a very small effect on thrombin generation evaluated by calibrated thrombinography.
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http://dx.doi.org/10.1160/TH12-05-0321DOI Listing
March 2013

TFPI resistance related to inherited or acquired protein S deficiency.

Thromb Res 2012 Dec 15;130(6):925-8. Epub 2012 Oct 15.

Université de Lyon, F-42023, Saint-Etienne, France.

Background: Protein S (PS) is an essential component of the protein C pathway and PS deficiency can explain a poor response to activated protein C. It has recently been shown that PS also acts as a cofactor of Tissue Factor Pathway Inhibitor (TFPI).

Objectives: In the present study, we investigated whether PS deficiency could be responsible for a poor response to TFPI.

Patients/methods: Thirty-one patients with inherited PS deficiency, seven pregnant women and 36 controls were enrolled in the study. We measured the plasma response to added TFPI using a two-step diluted prothrombin time (dPT) assay. The response of the different plasmas to the anticoagulant activity of TFPI was expressed as TFPI Normalised Ratio (TFPI NR).

Results: The median TFPI NR was statistically significantly lower in patients with inherited PS deficiency (0.5) than in controls (1.0) (p<0.0001). It was statistically significantly lower in patients with type I inherited PS deficiency (0.47) compared to patients with type III inherited PS deficiency (0.58) (p=0.018). In contrast, it did not differ between patients with and without thrombosis. Median TFPI NR values were statistically significantly lower during pregnancy (0.54) than 3 months after delivery (0.71) (p=0.016). TFPI NR values correlated well with PS activity values (R(2)=0.681) whatever the nature of the PS deficiency.

Conclusions: Our findings confirm that PS deficiency results in a poor anticoagulant response to TFPI, demonstrating again the cofactor role of PS in TFPI activity.
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http://dx.doi.org/10.1016/j.thromres.2012.07.025DOI Listing
December 2012

Clinical characteristics and laboratory testing of patients with suspected HIT: a survey on current practice in 11 university hospitals in France.

Thromb Res 2010 Jun 23;125(6):e294-9. Epub 2010 Feb 23.

Laboratory of Hematology, Hôpital Cardiologique-Haut Lévêque, CHU Bordeaux, France.

Unlabelled: We undertook a survey of French university hospital hematological laboratories to ascertain the clinical characteristics of patients with suspected HIT, the laboratory tests performed, and the therapeutic strategy adopted in current practice.

Methods: A standardized medical records database for patients with suspected HIT was sent to 19 laboratories. During two months, all consecutive patients for whom a biological test was performed were included.

Results: 169 patients were included, 27 (16%) patients having a final diagnosis of HIT. At the time HIT was suspected, the heparin duration and the level of thrombocytopenia were similar in HIT- positive and HIT-negative groups. The use of unfractionated heparin, a therapeutic heparin dose regimen and the presence of thrombotic complications were significantly more frequent in HIT-positive patients. When the heparin dose regimen was taken into account, only thrombotic complications under a therapeutic dose regimen were significantly increased in HIT-positive patients. Eighty-six percent of patients presented at least one alternative diagnosis of thrombocytopenia without significant difference between the two groups. Laboratory tests were performed after a mean of 0.3days and mainly consisted of antigen assays. At the time HIT was suspected, heparin was stopped in 56 (33%) patients, being replaced mainly by danaparoid. Only three laboratories declared they usually received all the necessary clinical information to establish the likelihood of HIT.

Conclusion: In current practice in France, the clinical probability of HIT is rarely established, leading to systematic requests for laboratory HIT tests.
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http://dx.doi.org/10.1016/j.thromres.2010.02.003DOI Listing
June 2010

Risk factors for unfavorable clinical outcome in patients with documented heparin-induced thrombocytopenia.

Thromb Res 2009 Nov 1;124(5):554-9. Epub 2009 May 1.

University Hospital Tenon, ER2 UPMC Paris.

Background: Prognostic factors for unfavorable clinical outcome in patients with heparin-induced thrombocytopenia (HIT) are largely unknown.

Design And Methods: In this multicenter, retrospective, case-control study, all HIT patients were treated with danaparoid. Study cases were HIT patients with an unfavorable clinical outcome. Controls were HIT patients who were not study cases. Unfavorable clinical outcome was defined as the occurrence of at least one of the following clinical events: death within 60 days after HIT start date, or venous or arterial thromboembolism, amputation, major bleeding, or disseminated intra-vascular coagulation between 48 hours and 60 days after HIT start date.

Results: Compared with controls (n=65), thrombotic episodes within 48 hours of HIT start date were more frequent (59.2% versus 32.3%; p=0.004), the median time between HIT start date and initiation of danaparoid infusion was longer (3.0 versus 1.0 days; p=0.001), and this treatment was more frequently underdosed (43.8% versus 18.8%; p=0.004) in study cases (n=49). Upon multivariate analysis, all these three parameters were significant predictive factors for unfavorable clinical outcome. The adjusted odds ratios [95% confidence interval] were 6.6 [2.5-17.3] for time between HIT start date and danaparoid initiation over 48 hours, 4.3 [1.5-12.0] for danaparoid underdosing, and 3.2 [1.3-8.0] for presence of a thromboembolic episode at HIT start date.

Conclusions: This study supports the recommendations concerning the management of HIT patients, namely discontinuation of all heparin administration once the diagnosis is suspected and prompt initiation of an alternative anticoagulant drug with a strict adherence to doses specifically recommended for these patients.
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http://dx.doi.org/10.1016/j.thromres.2009.04.002DOI Listing
November 2009

Predictive factors for thrombosis and major bleeding in an observational study in 181 patients with heparin-induced thrombocytopenia treated with lepirudin.

Blood 2006 Sep 11;108(5):1492-6. Epub 2006 May 11.

Institut National de la Santé et de la Recherche Médicale (Inserm) Centre d'Investigation Clinique Epidémiologique 3 (CIC E3), Service d'Urgence et de Réanimation Médicales Hôpital Bellevue, Saint-Etienne, France.

The antithrombotic efficacy of lepirudin in patients with heparin-induced thrombocytopenia (HIT) is compromised by an increased risk for bleeding. A retrospective observational analysis in 181 patients (median age, 67 years) with confirmed HIT treated in routine practice with lepirudin was performed to identify predictive factors for thrombotic and bleeding complications. Lepirudin was administered at a mean (+/- SD) dose of 0.06 +/- 0.04 mg/kg/h (compared with a recommended initial dose of 0.15 mg/kg/h). Mean activated partial thromboplastin time was greater than 1.5 times baseline value in 99.4% of patients. Median treatment duration was 7.7 days. Until discharge from the hospital, 13.8% and 20.4% of patients experienced a thrombotic or a major bleeding event, respectively. On multivariate analysis, mean lepirudin dose was not a significant predictive factor for thrombosis. In contrast, mean lepirudin dose greater than 0.07 mg/kg/h, long duration of lepirudin treatment, and moderate to severe renal impairment were significant positive factors for major bleeding. Overall, these results suggest that the recommended dose of lepirudin in patients with HIT is too high; the use of reduced doses may be safer with regard to bleeding risk and does not compromise antithrombotic efficacy.
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http://dx.doi.org/10.1182/blood-2006-02-001057DOI Listing
September 2006

Compliance and stability of INR of two oral anticoagulants with different half-lives: a randomised trial.

Thromb Haemost 2003 Mar;89(3):458-67

Thrombosis Research Group, Clinical Pharmacological Department, University Hospital, Pavillon 5, F-42055 Saint-Etienne Cedex 2, France.

The aim of the study was to assess the respective roles of the half-life of elimination of oral anticoagulants and patient education as causes of instability of anticoagulation level in patients on oral anticoagulant therapy. Patients were randomised to receive either warfarin (long half-life) or acenocoumarol (short half-life) and either intensive or standard education, according to a factorial design. Instability of oral anticoagulant therapy was evaluated by the percentage of INRs and the time within the target range, and the variability between successive measurements. Compliance was assessed by means of electronic pill bottles. Eighty-six patients were included. Apart from the variability index, instability was similar between groups. Correlations between compliance and instability were observed only in the acenocoumarol group. No difference was found between the education groups. In patients starting oral anticoagulant therapy, dose determination may be the most important factor contributing to instability.
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March 2003

D-dimer levels in patients with suspected acute cerebral venous thrombosis.

Am J Med 2002 Aug;113(3):238-41

Department of Emergency Medicine, Centre Hospitalier et Universitaire de Saint-Etienne, Saint-Etienne, France.

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http://dx.doi.org/10.1016/s0002-9343(02)01151-8DOI Listing
August 2002