Relationship between plasma tissue Factor Pathway Inhibitor (TFPI) levels, thrombin generation and clinical risk of bleeding in patients with severe haemophilia A or B.

INTRODUCTION: Bleeding severity in severe haemophilic patients, with low thrombin generation (TG) capacity, can vary widely between patients, possibly reflecting differences in tissue factor pathway inhibitor (TFPI) level. AIM: To compare free TFPI (fTFPI) levels in patients with severe haemophilia A (sHA) and severe haemophilia B (sHB) and to investigate in these patients as a whole the relationships between bleeding and TG potential, between TG potential and fTFPI level and between fTFPI level and bleeding tendency. METHODS: Data on bleeding episodes retrospectively recorded during follow-up visits over 5-10 years were collected and used to calculate the annualised joint bleeding rate (AJBR). fTFPI levels and basal TG parameters were determined in platelet-poor plasma (PPP) and platelet-rich plasma (PRP) using calibrated automated tomography (CAT). RESULTS: Mean fTFPI levels did not differ significantly between sHA (n = 34) and sHB (n = 19) patients. Mean values of endogenous thrombin potential (ETP) and thrombin peak (peak) in PPP and PRP were two-fold higher when fTFPI levels < 9.4 versus > 14.3 ng/mL. In patients treated on demand, ETP and peak in PRP were doubled when AJBR was ≤ 4.9 $ \le 4.9$ , AJBR being halved in patients with a low fTFPI level (9.4 ng/mL). In patients on factor prophylaxis, no association was found between TG parameters and either fTFPI level or AJBR. CONCLUSION: In patients treated on demand, bleeding tendency was influenced by fTFPI levels, which in turn affected basal TG potential. In patients on prophylaxis, bleeding tendency is probably determined primarily by the intensity of this treatment.

Intermediate-dose versus low-dose low-molecular-weight heparin in pregnant and post-partum women with a history of venous thromboembolism (Highlow study): an open-label, multicentre, randomised, controlled trial.

BACKGROUND: Pregnancy-related venous thromboembolism is a leading cause of maternal morbidity and mortality, and thromboprophylaxis is indicated in pregnant and post-partum women with a history of venous thromboembolism. The optimal dose of low-molecular-weight heparin to prevent recurrent venous thromboembolism in pregnancy and the post-partum period is uncertain. METHODS: In this open-label, randomised, controlled trial (Highlow), pregnant women with a history of venous thromboembolism were recruited from 70 hospitals in nine countries (the Netherlands, France, Ireland, Belgium, Norway, Denmark, Canada, the USA, and Russia). Women were eligible if they were aged 18 years or older with a history of objectively confirmed venous thromboembolism, and with a gestational age of 14 weeks or less. Eligible women were randomly assigned (1:1), before 14 weeks of gestational age, using a web-based system and permuted block randomisation (block size of six), stratified by centre, to either weight-adjusted intermediate-dose or fixed low-dose low-molecular-weight heparin subcutaneously once daily until 6 weeks post partum. The primary efficacy outcome was objectively confirmed venous thromboembolism (ie, deep-vein thrombosis, pulmonary embolism, or unusual site venous thrombosis), as determined by an independent central adjudication committee, in the intention-to-treat (ITT) population (ie, all women randomly assigned to treatment). The primary safety outcome was major bleeding which included antepartum, early post-partum (within 24 h after delivery), and late post-partum major bleeding (24 h or longer after delivery until 6 weeks post partum), assessed in all women who received at least one dose of assigned treatment and had a known end of treatment date. This study is registered with ClinicalTrials.gov, NCT01828697, and is now complete. FINDINGS: Between April 24, 2013, and Oct 31, 2020, 1339 pregnant women were screened for eligibility, of whom 1110 were randomly assigned to weight-adjusted intermediate-dose (n=555) or fixed low-dose (n=555) low-molecular-weight heparin (ITT population). Venous thromboembolism occurred in 11 (2%) of 555 women in the weight-adjusted intermediate-dose group and in 16 (3%) of 555 in the fixed low-dose group (relative risk [RR] 0·69 [95% CI 0·32-1·47]; p=0·33). Venous thromboembolism occurred antepartum in five (1%) women in the intermediate-dose group and in five (1%) women in the low-dose group, and post partum in six (1%) women and 11 (2%) women. On-treatment major bleeding in the safety population (N=1045) occurred in 23 (4%) of 520 women in the intermediate-dose group and in 20 (4%) of 525 in the low-dose group (RR 1·16 [95% CI 0·65-2·09]). INTERPRETATION: In women with a history of venous thromboembolism, weight-adjusted intermediate-dose low-molecular-weight heparin during the combined antepartum and post-partum periods was not associated with a lower risk of recurrence than fixed low-dose low-molecular-weight heparin. These results indicate that low-dose low-molecular-weight heparin for thromboprophylaxis during pregnancy is the appropriate dose for the prevention of pregnancy-related recurrent venous thromboembolism. FUNDING: French Ministry of Health, Health Research Board Ireland, GSK/Aspen, and Pfizer.

Slope analysis for the prediction of fluid responsiveness by a stepwise PEEP elevation recruitment maneuver in mechanically ventilated patients.

OBJECTIVE: Assessment of fluid responsiveness is problematic in intensive care unit patients. Lung recruitment maneuvers (LRM) can be used as a functional test to predict fluid responsiveness. We propose a new test to predict fluid responsiveness in mechanically ventilated patients by analyzing the variations in central venous pressure (CVP) and systemic arterial parameters during a prolonged sigh breath LRM without the use of a cardiac output measuring device. DESIGN: Prospective observational cohort study. SETTING: Intensive Care Unit, Saint-Etienne University Central Hospital. PATIENTS: Patients under mechanical ventilation, equipped with invasive arterial blood pressure, CVP, pulse contour analysis (PICCO™), requiring volume expansion, with no right ventricular dysfunction. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: CVP, systemic arterial parameters and stroke volume (SV) were recorded during prolonged LRM followed by a 500 mL fluid expansion to asses fluid responsiveness. 25 patients were screened and 18 patients analyzed. 9 patients were responders to volume expansion and 9 were not. Evaluation of hemodynamic parameters suggested the use of a linear regression model. Slopes for systolic arterial pressure, pulse pressure (PP), CVP and SV were all significantly different between responders and non-responders during the pressure increase phase of LRM (STEP-UP) (p = 0.022, p = 0.014, p = 0.006 and p = 0.038, respectively). PP and CVP slopes during STEP-UP were strongly predictive of fluid responsiveness with an AUC of 0.926 (95% CI, 0.78 to 1.00), sensitivity = 100%, specificity = 89% and an AUC = 0.901 (95% CI, 0.76 to 1.00), sensibility = 78%, specificity = 100%, respectively. Combining sensitivity of PP and specificity of CVP, prediction of fluid responsiveness can be achieved with 100% sensitivity and 100% specificity (AUC = 0.96; 95% CI, 0.90 to 1.00). One patient showed inconclusive values using the grey zone approach (5.5%). CONCLUSIONS: In patients under mechanical ventilation with no right heart dysfunction, the association of PP and CVP slope analysis during a prolonged sigh breath LRM seems to offer a very promising method for prediction of fluid responsiveness without the use and associated cost of a cardiac output measurement device. TRIAL REGISTRATION: NCT04304521 , IRBN902018/CHUSTE. Registered 11 March 2020, Fluid responsiveness predicted by a stepwise PEEP elevation recruitment maneuver in mechanically ventilated patients (STEP-PEEP).

Impact of take-home messages written into slide presentations delivered during lectures on the retention of messages and the residents' knowledge: a randomized controlled study.

BACKGROUND: Lectures with slide presentations are widely used to teach evidence-based medicine to large groups. Take-home messages (THMs) are poorly identified and recollected by students. We investigated whether an instruction to list THMs in written form on slides would improve the retention thereof by residents, and the residents' level of knowledge, 1 month after lectures. METHODS: Prospective blinded randomized controlled study was conducted. Twelve lectures (6 control and 6 intervention lectures) were delivered to 73 residents. For the intervention lectures, the lecturers were instructed to incorporate clear written THMs into their slide presentations. The outcomes were ability of resident to recollect THMs delivered during a lecture (as assessed by accordance rate between the lecturers' and residents' THMs) and knowledge (as assessed by multiple choice questions (MCQs)). RESULTS: Data for 3738 residents' THMs and 3410 MCQs were analyzed. The intervention did not significantly increase the number of THMs written on slides (77% (n = 20/26), 95% CI 56-91 vs 64% (n = 18/28), 95% CI 44-81, p = 0.31) nor THMs retention (13% (n = 238/1791), 95% CI 12-15 vs 17% (n = 326/1947), 95% 15-18, p = 0.40) nor knowledge (63.8 ± 26.2 vs 61.1 ± 31.4 /100 points, p = 0.75). In multivariable analyses performed with all THMs written on slides from the two groups, a superior knowledge was associated with notetaking during lectures (OR 1.88, 95% CI 1.41-2.51) and THMs retention (OR 2.17, 95% CI 1.54-3.04); and THMs retention was associated with written THMs (OR 2.94, 95% CI 2.20-3.93). CONCLUSIONS: In lectures delivered to residents, a third of the THMs were not in written form. An intervention based on an explicit instruction to lecturers to provide THMs in written form in their slide presentations did not result in increased use of written THMs into the slide presentation or improvement of the THMs retention or level of knowledge. However, we showed that there was a strong positive association between writing THMs on a slide, retention of THMs and residents' knowledge. Further researches are needed to assess interventions to increase written THMs in lectures by faculty. TRIAL REGISTRATION: ClinicalTrials.gov NCT01795651 (Fev 21, 2013).

Drug Management in End-of-Life Hospitalized Palliative Care Cancer Patients: The RHESO Cohort Study.

OBJECTIVE: Little data about the management of drugs in terminally ill palliative care cancer patients is available. The present study aimed at describing the evolution of anticancer and non-anticancer treatments (NACTs) in cancer patients in palliative care units. The second objective was to identify factors leading to the medical decision to withdraw or not NACTs. METHODS: Data from 1,091 cancer patients hospitalized in palliative care units were prospectively collected in 2010-2011, through a multicenter, observational French cohort. RESULTS: The median overall survival after admittance in palliative care units was 15 days. Specific anticancer treatments were systematically stopped in the first 24 h in palliative care units, but for 4.5% of patients. Regarding NACTs, patients were heavily treated with strong opioids (74%), corticosteroids (51%), and antidepressants (21.8%) until death. Antiulcer agents (63.4%), antibiotics (25.7%), thrombosis prevention (21.8%), antidiabetics (7.6%), and transfusions (4%) were often also continuously prescribed. In multivariate analysis, ECOG PS 4 was an independent predictor of continuous prescription of morphine and an independent predictor of discontinuation of corticosteroids, proton-pump inhibitors, antidiabetics, and preventive anticoagulant therapy. Infection symptoms independently predicted continuous prescription of paracetamol. Paralysis and cancer palpable mass independently predicted corticosteroid withdrawal. Brain metastases independently predicted antiulcer withdrawal. Hemorrhage independently predicted preventive anticoagulant withdrawal. Availability to a venous access independently predicted paracetamol and antiulcer continuous prescriptions. Co-prescriptions independently predicted continuous prescriptions (antibiotics with antiulcer, antifungals with antibiotics) or withdrawal (preventive anticoagulant with antiplatelets and antifungals). CONCLUSIONS: NACT prescription remained commonplace in terminally ill palliative cancer patients, although their benefit is questionable.

Platelet toll-like receptors are crucial sensors of infectious danger moieties.

In addition to their haemostatic role and function in the repair of damaged vascular epithelium, platelets play a defensive role in innate immunity, having the capacity to produce and secrete various anti-infectious factors, as well as cytokines, chemokines and related products, to interact with other immune cells to modulate immune responses to pathogens. Thus, it is now widely acknowledged that platelets participate in inflammatory processes and infection resolution, most notably by expressing and using receptors to bind infectious pathogen moieties and contributing to pathogen clearance. The ability of platelets to sense external danger signals relates to the expression of certain innate immunity receptors, such as toll-like receptors (TLRs), and the activation of efficient cell signalling machinery. TLR engagement triggers platelet response, which results in adapted degranulation according to: the type of TLR engaged, the nature of the ligand and the milieu; together, the TLR-mediated event and other signalling events may be followed by aggregation. Platelets thus use complex tools to mediate a whole range of functions upon sensing danger. By linking the inflammatory and haemostatic platelet response to infection, TLRs play a central role. The extent of the inflammatory response to pathogen clearance is still a debatable issue and is discussed in this short review.

Antithrombotic therapy and platelet transfusions in hematologic malignancy patients presenting chemotherapy-induced thrombocytopenia: a French survey.

BACKGROUND: Patients with hematologic malignancies are at high risk for both thrombosis and bleeding. During the prolonged periods of thrombocytopenia experienced by patients who are receiving intensive chemotherapy, clinicians often hesitate to prescribe any protection against thrombosis. In case of anticoagulant prescription, it is the prescribers' responsibility to weigh risks and benefits for each patient. Current guidelines exist but do not take into account types of thrombosis, patients' comorbidities, or previous bleeding events. STUDY DESIGN AND METHODS: We proposed to gain insight into hematologists' beliefs about antithrombotic prescription in hematologic malignancy patients, to design future clinical trials. Therefore, we conducted a survey in France to evaluate the practices among a panel of hematologists. RESULTS: We found that more than 92% of the respondents prescribed therapeutic anticoagulation in case of pulmonary embolism or deep venous thrombosis. In the case of therapeutic anticoagulation, only 64% of the physicians reconsidered treatment under a platelet threshold of 50 × 109 /L. None of the respondents decided to renounce treatment, nor to discontinue it because of thrombocytopenia, except in distal venous thrombosis or superficial vein thrombosis. One-fifth of clinicians proposed the insertion of a vena cava filter. CONCLUSION: As observed in the United States and Canada, we noticed discrepancies between recommendations and current practices in France. This highlights the urgent need to conduct studies to evaluate both efficacy and safety of antithrombotics in patients with hematologic cancer and thrombocytopenia.

Limited screening with versus without (18)F-fluorodeoxyglucose PET/CT for occult malignancy in unprovoked venous thromboembolism: an open-label randomised controlled trial.

BACKGROUND: Clear guidelines for the investigation of occult malignancy after unprovoked venous thromboembolism are not yet available. (18)F-fluorodeoxyglucose ((18)F-FDG) PET/CT could serve as a comprehensive screening strategy for occult malignancy in this context. We aimed to compare a screening strategy based on (18)F-FDG PET/CT with a limited screening strategy for detection of malignant disease in patients with unprovoked venous thromboembolism. METHODS: In an open-label, multicentre, randomised study we enrolled patients from four French university hospitals. Patients aged 18 years or older, diagnosed with unprovoked venous thromboembolism (not provoked by a major inherited or acquired risk factor) were invited to participate. Patients were randomly assigned in a 1:1 ratio to a limited screening strategy (physical examination, usual laboratory tests, and basic radiographs) or a screening strategy consisting of the limited strategy plus an (18)F-FDG PET/CT scan. Randomisation was done with a dedicated central web-based randomisation system, in block sizes of six, stratified by centre, and concealed from the investigators. Patients and investigators were not masked to study group assignment. Patients were followed up for 2 years. The primary outcome was the proportion of patients with a cancer diagnosis in each group after the initial screening assessment. Analyses were conducted in modified intention-to-test and per-protocol populations. This trial is completed and registered with ClinicalTrials.gov, number NCT00964275. FINDINGS: Between March 3, 2009, and Aug 18, 2012, we enrolled and randomly assigned 399 patients; five withdrew consent, leaving 197 in each group for the modified intention-to-test analysis. After initial screening assessment, cancer was diagnosed in 11 (5·6%) patients in the (18)F-FDG PET/CT group and four (2·0%) patients in the limited screening group (absolute risk difference 3·6%, 95% CI -0·4 to 7·9; p=0·07). At the initial screening assessment, seven (64%) of the 11 cancers diagnosed in the (18)F-FDG PET/CT group were early-stage compared with two of four cancers diagnosed in the limited screening group (p=1·00). One (0·5%) occult malignancy was detected in 186 patients who had negative initial screening in the (18)F-FDG PET/CT group, compared with nine (4·7%) in 193 patients in the limited screening group (absolute risk difference 4·1%, 95% CI 0·8 to 8·4, p=0·01). Overall, five (42%) of the 12 cancers diagnosed in the (18)F-FDG PET/CT group were advanced stage, compared with seven (54%) of the 13 cancers diagnosed in the limited screening group (p=0·70). 16 patients died during follow-up, eight (4·1%) in each group. Two (1·0%) patients in the (18)F-FDG PET/CT group and five (2·5%) in the limited screening group had cancer-related deaths. INTERPRETATION: A strategy including limited screening and a (18)F-FDG PET/CT was not associated with a significantly higher rate of cancer diagnosis after unprovoked venous thromboembolism. The risk of subsequent cancer diagnosis was, however, lower in patients who had negative initial screening that included (18)F-FDG PET/CT than in patients who had negative initial limited screening. Whether or not (18)F-FDG PET/CT might be useful in a more selected population of patients with a high risk of cancer remains to be determined. FUNDING: Programme Hospitalier de Recherche Clinique (French Department of Health).

Transient and Persistent Acute Kidney Injury and the Risk of Hospital Mortality in Critically Ill Patients: Results of a Multicenter Cohort Study.

OBJECTIVE: To assess the prognostic impact of transient and persistent acute kidney injury in critically ill patients. DESIGN: Retrospective analysis of prospectively collected patient data SETTING: : Six hospital ICUs. PATIENTS: Critically-ill patients with ICU stay longer than three days. INTERVENTION: None. MEASUREMENTS AND MAIN RESULTS: Assessment of hospital survival with respect to acute kidney injury duration. A total of 447 patients were included in this study, including 283 patients (63.3%) with an acute kidney injury at admission (175 and 108 patients with persistent and transient acute kidney injury, respectively). Patients with persistent acute kidney injury more frequently had stage 3 acute kidney injury (42.9% vs 30.6%; p = 0.04). Hospital survival was 76.2% (n = 125) in patients without acute kidney injury, 70.4% (n = 76) in patients with transient acute kidney injury, and 61.1% (n = 107) in patients with persistent acute kidney injury. After adjustment for confounding factors, the factors associated with lower hospital survival were the need for vasopressors (odds ratio, 0.65; 95% CI, 0.43-0.98) and the presence of persistent acute kidney injury (odds ratio, 0.58; 95% CI, 0.36-0.95). When included in the final model, stage 3 acute kidney injury was independently associated with a lower hospital survival (odds ratio, 0.83; 95% CI, 0.70-0.98), and persistent acute kidney injury was no longer associated with outcome. CONCLUSION: Two thirds of the critically ill patients with acute kidney injury have persistent acute kidney injury. Although mortality increased progressively with the duration of acute kidney injury, we found no independent association between this duration and patient outcome when the acute kidney injury severity is taken into account. Our results suggest that the classical "prerenal acute kidney injury" and "acute tubular necrosis" paradigm might be of limited interest from a pathophysiological or prognostic point of view.

Effect of a retrievable inferior vena cava filter plus anticoagulation vs anticoagulation alone on risk of recurrent pulmonary embolism: a randomized clinical trial.

IMPORTANCE: Although retrievable inferior vena cava filters are frequently used in addition to anticoagulation in patients with acute venous thromboembolism, their benefit-risk ratio is unclear. OBJECTIVE: To evaluate the efficacy and safety of retrievable vena cava filters plus anticoagulation vs anticoagulation alone for preventing pulmonary embolism recurrence in patients presenting with acute pulmonary embolism and a high risk of recurrence. DESIGN, SETTING, AND PARTICIPANTS: Randomized, open-label, blinded end point trial (PREPIC2) with 6-month follow-up conducted from August 2006 to January 2013. Hospitalized patients with acute, symptomatic pulmonary embolism associated with lower-limb vein thrombosis and at least 1 criterion for severity were assigned to retrievable inferior vena cava filter implantation plus anticoagulation (filter group; n = 200) or anticoagulation alone with no filter implantation (control group; n = 199). Initial hospitalization with ambulatory follow-up occurred in 17 French centers. INTERVENTIONS: Full-dose anticoagulation for at least 6 months in all patients. Insertion of a retrievable inferior vena cava filter in patients randomized to the filter group. Filter retrieval was planned at 3 months from placement. MAIN OUTCOMES AND MEASURES: Primary efficacy outcome was symptomatic recurrent pulmonary embolism at 3 months. Secondary outcomes were recurrent pulmonary embolism at 6 months, symptomatic deep vein thrombosis, major bleeding, death at 3 and 6 months, and filter complications. RESULTS: In the filter group, the filter was successfully inserted in 193 patients and was retrieved as planned in 153 of the 164 patients in whom retrieval was attempted. By 3 months, recurrent pulmonary embolism had occurred in 6 patients (3.0%; all fatal) in the filter group and in 3 patients (1.5%; 2 fatal) in the control group (relative risk with filter, 2.00 [95% CI, 0.51-7.89]; P = .50). Results were similar at 6 months. No difference was observed between the 2 groups regarding the other outcomes. Filter thrombosis occurred in 3 patients. CONCLUSIONS AND RELEVANCE: Among hospitalized patients with severe acute pulmonary embolism, the use of a retrievable inferior vena cava filter plus anticoagulation compared with anticoagulation alone did not reduce the risk of symptomatic recurrent pulmonary embolism at 3 months. These findings do not support the use of this type of filter in patients who can be treated with anticoagulation. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00457158.

Diagnostic accuracy of early urinary index changes in differentiating transient from persistent acute kidney injury in critically ill patients: multicenter cohort study.

INTRODUCTION: Urinary indices have limited effectiveness in separating transient acute kidney injury (AKI) from persistent AKI in ICU patients. Their time-course may vary with the mechanism of AKI. The primary objective of this study was to evaluate the diagnostic value of changes over time of the usual urinary indices in separating transient AKI from persistent AKI. METHODS: An observational prospective multicenter study was performed in six ICUs involving 244 consecutive patients, including 97 without AKI, 54 with transient AKI, and 93 with persistent AKI. Urinary sodium, urea and creatinine were measured at ICU admission (H0) and on 6-hour urine samples during the first 24 ICU hours (H6, H12, H18, and H24). Transient AKI was defined as AKI with a cause for renal hypoperfusion and reversal within 3 days. RESULTS: Significant increases from H0 to H24 were noted in fractional excretion of urea (median, 31% (22 to 41%) and 39% (29 to 48%) at H24, P<0.0001), urinary urea/plasma urea ratio (15 (7 to 28) and 20 (9 to 40), P<0.0001), and urinary creatinine/plasma creatinine ratio (50 (24 to 101) and 57 (29 to 104), P=0.01). Fractional excretion of sodium did not change significantly during the first 24 hours in the ICU (P=0.13). Neither urinary index values at ICU admission nor changes in urinary indices between H0 and H24 performed sufficiently well to recommend their use in clinical setting (area under the receiver-operating characteristic curve≤0.65). CONCLUSION: Although urinary indices at H24 performed slightly better than those at H0 in differentiating transient AKI from persistent AKI, they remain insufficiently reliable to be clinically relevant.

Inferior vena cava filters in pregnancy: Safe or sorry?

Background: Potential hazards of vena cava filters include migration, tilt, perforation, fracture, and in-filter thrombosis. Due to physiological changes during pregnancy, the incidence of these complications might be different in pregnant women. Aim: To evaluate the use and safety of inferior vena cava filters in both women who had an inferior vena cava filter inserted during pregnancy, and in women who became pregnant with an inferior vena cava filter in situ. Methods: We performed two searches in the literature using the keywords "vena cava filter", "pregnancy" and "obstetrics". Results: The literature search on women who had a filter inserted during pregnancy yielded 11 articles compiling data on 199 women. At least one filter complication was reported in 33/177 (19%) women and included in-filter thrombosis (n = 14), tilt (n = 6), migration (n = 5), perforation (n = 2), fracture (n = 3), misplacement (n = 1), air embolism (n = 1) and allergic reaction (n = 1). Two (1%) filter complications led to maternal deaths, of which at least one was directly associated with a filter insertion. Filter retrieval failed in 9/149 (6%) women. The search on women who became pregnant with a filter in situ resulted in data on 21 pregnancies in 14 women, of which one (6%) was complicated by uterine trauma, intraperitoneal hemorrhage and fetal death caused by perforation of the inferior vena cava filter. Conclusion: The risks of filter complications in pregnancy are comparable to the nonpregnant population, but could lead to fetal or maternal death. Therefore, only in limited situations such as extensive thrombosis with a contraindication for anticoagulants, inferior vena filters should be considered in pregnant women.

External validation of the MidiCAT variant of thrombography: Comparison with calibrated automated thrombography and study of the centrifugation scheme.

Introduction: To perform Calibrated Automated Thrombography (CAT), the use of reduced plasma volumes (referred to as "MidiCAT") makes it possible to more efficiently use limited volumes of valuable biobanked plasma samples and decreases expenses for reagents. It is, however, unclear whether the MidiCAT procedure is suitable when thrombin generation (TG) is studied in the presence of added thrombomodulin (TG-TM). Moreover, a simplified centrifugation scheme would facilitate biobanking, if appropriate, for more sensitive coagulation studies. We aimed to compare the results of "MidiCAT" (halved plasma and reagent volumes) with those from regular CAT, in the absence or presence of TM, as well as to study the impact of a single-centrifugation scheme for plasma preparation before freezing. Materials and methods: Plasma samples were prepared from the citrated blood from 20 Geneva hospital diverse patients without gross coagulation abnormalities with a single- or double-centrifugation scheme. Samples were kept frozen at -80°C and thawed just before the TG assay in duplicate under two conditions: 1 pM tissue factor (TF) or 5 pM TF + TM. Results and discussion: (1) We externally validated "MidiCAT" and also extended the validation to TG-TM. Whatever the method (CAT or MidiCAT), intra-assay (assessed with duplicates) CV was below 6% (1 pM TF) or below 10% (5 pM TF + TM) for ETP. Agreement between the MidiCAT and CAT results was satisfactory; the p coefficients were above 0.95 for ETP and above 0.90 for most other parameters; biases for ETP were +10.0% (1 pM FT) and +13.5% (5 pM + TM). (2) The centrifugation scheme markedly affected the results obtained in the presence of TM, whereas the bias and limit of agreement (difference plots) were low for the no TM condition. The bias in the presence of TM was obvious, more marked with plasma samples sensitive to TM when double centrifuged: the lower the ETP-TM, the greater the relative difference between the ETP-TM of plasma samples prepared with just single centrifugation and the reference plasma samples. Thus, a single-centrifugation procedure, as is often used for plasma biobanking, is suitable for TG study only if it is not performed in the presence of TM.

Prediction of venous thromboembolism in patients with multiple myeloma treated with lenalidomide, bortezomib, dexamethasone, and transplantation: Lessons from the substudy of IFM/DFCI 2009 cohort.

BACKGROUND: Venous thromboembolism (VTE) is a concern for patients with newly diagnosed multiple myeloma. OBJECTIVES: We aimed to evaluate VTE incidence, risk factors, and risk score. PATIENTS/METHODS: We performed a substudy of the "Intergroupe Francophone du Myelome 2009" randomized controlled trial. RESULTS: We assessed 700 patients receiving lenalidomide/bortezomib/dexamethasone, followed or not by autologous hematopoietic stem cell transplantation. VTE incidence at 6 months was 4.8% (95% confidence interval [CI]: 3.3-6.9%) and 1.5% (95% CI: 0.8-2.9%) from 6 to 12 months. Using multivariate analysis we confirmed history of VTE (odds ratio 5.1 [1.6-16.7], P = .007) as a strong VTE-related risk factor, invalidated erythropoietin exposure (0.6 [0.2-1.7], P = .3) as risk factor, and added two new risk factors: fracture at diagnosis (2.6 [1.3-5.5], P = .01), and serum gamma globulin level > 27 g/L (2.8 [1.2-6.8,] P = .02). Moreover, we noticed that VTE occurred earlier in patients with gamma globulin levels >27 g/L, suggesting a need to revisit the thromboprophylaxis timeframe. Heparin administration was associated with a decreased risk (0.3 [0.1-0.7], P = .005) but failed to erase the risk regardless of dose. The area under the receiver operating characteristic curve of the IMPEDE VTE score was 0.67, as previously reported, confirming our cohort was well representative. CONCLUSIONS: Prospective studies are warranted in light of these results to improve VTE risk stratification and to design adapted thromboprophylaxis in terms of timing and dose.

Diuretic vs. placebo in intermediate-risk acute pulmonary embolism: a randomized clinical trial.

AIMS: The role of diuretics in patients with intermediate-risk pulmonary embolism (PE) is controversial. In this multicentre, double-blind trial, we randomly assigned normotensive patients with intermediate-risk PE to receive either a single 80 mg bolus of furosemide or a placebo. METHODS AND RESULTS: Eligible patients had at least a simplified PE Severity Index (sPESI) ≥1 with right ventricular dysfunction. The primary efficacy endpoint assessed 24 h after randomization included (i) absence of oligo-anuria and (ii) normalization of all sPESI items. Safety outcomes were worsening renal function and major adverse outcomes at 48 hours defined by death, cardiac arrest, mechanical ventilation, or need of catecholamine. A total of 276 patients underwent randomization; 135 were assigned to receive the diuretic, and 141 to receive the placebo. The primary outcome occurred in 68/132 patients (51.5%) in the diuretic and in 49/132 (37.1%) in the placebo group (relative risk = 1.30, 95% confidence interval 1.04-1.61; P = 0.021). Major adverse outcome at 48 h occurred in 1 (0.8%) patients in the diuretic group and 4 patients (2.9%) in the placebo group (P = 0.19). Increase in serum creatinine level was greater in diuretic than placebo group [+4 µM/L (-2; 14) vs. -1 µM/L (-11; 6), P < 0.001]. CONCLUSION: In normotensive patients with intermediate-risk PE, a single bolus of furosemide improved the primary efficacy outcome at 24 h and maintained stable renal function. In the furosemide group, urine output increased, without a demonstrable improvement in heart rate, systolic blood pressure, or arterial oxygenation.ClinicalTrials.gov identifier NCT02268903.

Prognostic factors for pulmonary embolism: the prep study, a prospective multicenter cohort study.

RATIONALE: The short-term prognosis of pulmonary embolism (PE) depends on hemodynamic status and underlying disease. The prognostic value of right ventricular dysfunction and injury is less well established. OBJECTIVES: To evaluate prognostic factors of PE in a multicenter prospective cohort study. METHODS: Echocardiography, brain natriuretic peptide (BNP), N-terminal-proBNP and cardiac troponin I measurements were done on admission of 570 consecutive patients with an acute PE. A predictive model was based on independent predictors of 30-day adverse events defined as death, secondary cardiogenic shock, or recurrent venous thromboembolism. MEASUREMENTS AND MAIN RESULTS: At 30 days, 42 patients (7.4%; 95% confidence interval [CI], 5.5-9.8%) had adverse events. On multivariate analysis, altered mental state (odds ratio [OR] 6.8; 95% confidence interval [CI], 2.0-23.3), shock on admission (OR 2.8; 95% CI, 1.1-7.5), cancer (OR 2.9; 95% CI, 1.2-6.9), BNP (OR 1.3 for an increase of 250 ng/L; 95% CI, 1.1-1.6) and right to left ventricle diameter ratio (OR 1.2 for an increase of 0.1; 95% CI, 1.1-1.4) were associated with 30-days of adverse events. The predictive performance of the model was good (area under receiver operating characteristics curve 0.84 [95% CI, 0.78-0.90]), making it possible to develop a bedside prognostic score. CONCLUSIONS: BNP and echocardiography may be useful determinants of the short-term outcome for patients with PE, together with clinical findings. Patients with PE can be stratified according to the initial risk of adverse outcome, using a simple score based on clinical, echocardiographic, and biochemical variables.

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

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.