Haematological parameters associated with postpartum haemorrhage after vaginal delivery: Results from a French cohort study.

BACKGROUND: Immediate postpartum haemorrhage (PPH) is a major, feared and often unpredictable issue. Besides many clinical risk factors, some biological parameters could also be predictive of PPH. OBJECTIVE: To study simple and easily accessible haematological parameters as potential risk factors for PPH after vaginal delivery. METHODS: All women who had a vaginal delivery between April 1, 2013 and May 29, 2015 in the maternity ward of Brest University Hospital (France) were included, after oral informed consent obtained. Clinical data were collected by obstetricians or midwives during antenatal care visits, labour and delivery, and recorded by trained research assistants. Haematological variables, including immature platelet fraction, were measured from a blood sample systematically collected at the entrance in the delivery room. PPH, measured with a graduated collector bag, was defined as blood loss of at least 500 ml. RESULTS: 2742 women were included. PPH occurred in 141 (5%) women. Seven clinical factors were independently associated with PPH: pre-eclampsia (OR 5.85, 95%CI 2.02, 16.90), multiple pregnancy (OR 3.28, 95%CI 1.21, 8.91), assisted reproduction (OR 2.75, 95%CI 1.45, 5.20), antepartum bleeding (OR 2.15, 95%CI 1.24,3.73), post-term delivery (OR 1.93, 95%CI 1.17, 3.17), obesity (OR 2.95, 95%CI 1.76, 4.93) and episiotomy (OR 2.51, 95%CI 1.63, 3.74). Three haematological factors were additionally identified as independent risk factors for PPH: platelets < 150 Giga/L (OR 2.98, 95%CI 1.63, 5.46), fibrinogen < 4.5 g/l (OR 1.86, 95%CI 1.21, 2.87) and APTT ratio ≥ 1.1 (OR 2.16, 95%CI 1.31, 3.57). Immature platelet fraction was not associated with PPH. CONCLUSION: Besides classical clinical risk factors, this study identifies simple haematological parameters as risk factors for PPH.

[Patient expectations in asthma care]. / Attentes des patients asthmatiques vis-à-vis de leur prise en charge.

Asthma, a common chronic disease characterized by variable levels of severity, requires patient-centered management to achieve the best health outcomes. Studies have highlighted the gap between consensus management recommendations and patient goals, which represent a potential source of therapeutic wandering and of poor compliance. Patient expectations are continually evolving and are dependent on knowledge, feelings and individual experience. From this perspective, listening carefully to patients and caregivers makes it easier to exchange views and define common goals. The active participation of patients at all levels of decision-making and transmission of information may improve asthma control and other quality of life parameters.

Outcomes in patients with acute pulmonary embolism and patent foramen ovale: Findings from the RIETE registry.

INTRODUCTION: An increased risk of ischemic stroke in patients with acute pulmonary embolism (PE) and patent foramen ovale (PFO) was reported but few data exist regarding prognostic outcomes of those patients. MATERIAL AND METHODS: Using data in the RIETE registry, we compared the characteristics, therapeutic approaches and outcomes of patients with PE according to the presence or absence of PFO. RESULTS: From August 2016 to January 2020, 4148 patients with acute PE were enrolled. Of these, 2775 (67%) had no transthoracic echocardiogram (TTE), 993 (24%) underwent TTE but had no reported results on PFO. Among the remaining 380 patients, 287 (74%) did not have PFO and 93 (26%) had PFO. Patients with PFO were more likely to have chronic heart failure, prior myocardial infarction or ischemic stroke than those without PFO. Patients with PFO had a higher rate of subsequent ischemic stroke than those without PFO (hazard ratio (HR): 9.28; 95% CI: 1.83-69.1), than those with TTE but no data on PFO (HR: 10.1; 95% CI: 2.56-42.4) or without TTE (HR: 9.78; 95% CI: 3.02-28.4). On multivariable analysis, patients with PFO were at increased risk for subsequent ischemic stroke than those without PFO (HR: 8.96; 95% CI: 1.68-47.7). CONCLUSIONS: PFO was searched in a minority of patients with an acute PE in real life setting. Subject to possible selection and measurement biases, our results confirmed a higher risk of ischemic stroke in PE patients with PFO compared to those without PFO. This association warrants further investigation before determining the best therapeutic option in patients with acute PE and concomitant PFO.

[Direct oral anticoagulants: In which indications? Which one to prescribe? For or against their use in frail patients and in atypical cases? Which monitoring and management haemorrhage complications?] / Anticoagulants oraux directs : dans quelles indications ? Lequel prescrire ? Pour ou contre chez les personnes fragiles et dans les situations atypiques ? Quelle surveillance et gestion des accidents hémorragiques ?

Since their approval, the direct oral anticoagulants have been widely used in the management of venous thromboembolism, for stroke and systemic embolism prevention in non valvular atrial fibrillation, and in venous thromboembolism prophylaxis after surgical hip or knee replacement. Because they are easy to use, with oral fixed doses and no biological monitoring need, they are more and more prescribed. New indications are rising in cancer associated thrombosis in France beyond the 6 first months of treatment, and to prevent cardiovascular events after an acute coronary syndrome, or in stable coronary or peripheral arterial disease in Europe. The efficacity and safety of direct oral anticoagulants in frail patients or in unusual pathological contexts are not entirely known, but further data are coming and will probably bring new answers.

[Diagnostic and therapeutic management of venous thromboembolic disease in obese patients]. / Prise en charge diagnostique et thérapeutique de la maladie veineuse thromboembolique chez le patient obèse.

Despite the high proportion of obese patients this population remains understudied in the field of venous thromboembolic disease (VTE). Obesity is a risk factor for pulmonary embolism and/or deep vein thrombosis, especially when it is associated with other risk factors for VTE. Currently there is no validated diagnostic algorithm for VTE in the population of obese patients. Moreover, imaging examinations can be of poor quality and inconclusive. In the prevention of VTE, data concerning obese patients are mainly based on low-level studies. Apart from the context of bariatric surgery, an adjustment of heparin doses according to the weight of the patient is proposed only on a case-by-case basis. According to the current guidelines, therapeutic fixed dose oral anticoagulants should not be prescribed for patients with weights exceeding 120kg or a body mass index>40kg/m2. Heparin doses should be weight adjusted and monitored with anti-Xa activity. Anti vitamin K can be prescribed but require INR monitoring. Therefore, new studies specifically dedicated to obese patients are required in the field of VTE for better diagnostic and therapeutic management.

[Pre-eclampsia prevention in 2018 in general population and in lupic women: At the dawn of a personalized medicine?] / Prévention de la pré-éclampsie en 2018 en population générale et chez la femme lupique : à l'aube d'une médecine personnalisée ?

Pre-eclampsia prevention represents a major public health issue, as this vasculo-placental disorder generates a great burden of foeto-maternal morbi-mortality. Aspirin has proved its efficacy in primary and secondary pre-eclampsia prevention, especially when it is given at 150mg per day bedtime before 15 weeks of gestation to high-risk women. In the English trial ASPRE, high-risk women were identified by an algorithm taking into account angiogenic biomarkers ascertained at the end of first trimester of pregnancy. This article focuses on physiopathological mechanisms and risk factors of pre-eclampsia and on the interest of early angiogenic biomarkers dosing during pregnancy, for the assessment of pre-eclampsia risk. Unlike Great Britain or Israel, cost-effectiveness of this algorithm in general population has not been assessed in France. Finally, systemic lupus erythematous is at high risk of vasculo-placental disorders. Although few studies of angiogenic biomarkers dosing during lupus pregnancies identified a correlation between high sFlt1 levels at the end of first trimester and subsequent onset of severe vasculo-placental disorders, with a very good negative predictive value of sFtl1. Angiogenic biomarkers ascertainment for screening of vasculo-placental disorders in pregnant women with systemic lupus erythematous could allow targeting at best women needing an aspirin treatment and a closer monitoring.

Antipsychotic drugs and the risk of recurrent venous thromboembolism: A prospective cohort study.

BACKGROUND: Numerous studies have suggested that antipsychotic drugs are associated with an increased risk for a first episode of venous thromboembolism (VTE). However, after anticoagulation discontinuation, the impact of antipsychotic drugs on the risk of recurrent VTE (rVTE) remains unknown. OBJECTIVE: To estimate the risk of rVTE in association with antipsychotic drugs. METHODS: Between May 2000 and December 2012, we included all consecutive patients with a first unprovoked symptomatic VTE and who discontinued anticoagulation. During follow-up, exposure to antipsychotic drugs was systematically assessed. RESULTS: A total of 736 patients with a first unprovoked symptomatic VTE were followed-up during a median period of 27.0 months (interquartile range (IQR) 6.2-60.0). Patients' median age was 66.0 years (IQR 49.0-76.0), 404 (54.9%) were men, and 61 (8.3%) were exposed to antipsychotics during follow-up. The incidence rate of r VTE was 12.1% person-year (95% CI 7.2-20.5) in antipsychotics users compared with 8.3% person-year (95% CI 7.1-9.8) in non-users (p = 0.20). Multivariate analysis showed a significant increased risk of recurrence associated with antipsychotic exposure (adjusted hazard ratio 1.9, 95% CI 1.1-3.3). CONCLUSIONS: In this cohort study, exposure to antipsychotic drugs was found to be associated with an increased risk of rVTE among patients with a previous first unprovoked symptomatic VTE and who discontinued anticoagulation. Larger studies are needed to confirm and further explore this association.

Body mass index, a major confounder to insulin resistance association with unprovoked venous thromboembolism. Results from the EDITH case-control study.

Shared risk factors help explain the association between venous thromboembolism (VTE) and atherothrombosis. The potential association between insulin resistance and VTE has been poorly evaluated. Thus, we aimed to assess the association between insulin resistance and VTE in the EDITH hospital-based case-control study. Between May 2000 and December 2004, 677 patients with unprovoked VTE and their age- and sex-matched controls were included. Fasting glycaemia and insulinaemia were measured and insulin resistance was estimated with the homeostasis model assessment of insulin resistance (HOMA-IR) equation. The association between HOMA-IR and VTE was determined in non-diabetic patients in a quintile-based analysis. A total of 590 non-diabetic cases (median age 73.0 years, 255 men) and 581 non-diabetic controls (median age 72.0 years, 247 men) were analysed. There was a trend for a higher median level of HOMA-IR index in cases than in controls (1.21 [interquartile range 0.84-2.10] vs1.19 [interquartile range 0.72-2.02], p=0.08). The unadjusted analysis showed an increased risk of unprovoked VTE associated with increasing HOMA-IR (odds ratio [OR] 1.53; 95% confidence interval [CI] 1.00-2.34 for the highest quintile of HOMA-IR compared with the first quintile). Adjustment for lipid lowering drugs and antiplatelet agents use slightly modified the association (OR 1.51; 95% CI 0.97-2.34). When body mass index was added in the adjusted model, HOMA-IR was no longer associated with VTE (OR 1.08; 95% CI 0.67-1.73). Our results highlight the role of body mass index in the association between cardiovascular risk factors and VTE.

Antipsychotics: a real or confounding risk factor for venous thromboembolism?

In a meta-analysis of case-control studies, Zhang et al. (2011) found an increased risk of venous thromboembolic events (VTE) in patients exposed to antipsychotics (OR=2.39 [1.71-3.35]). Our updated meta-analysis including the 2 available cohort studies, recognized as a more relevant type of observational study, showed a weaker, but still strong association (OR=1.84 [1.39; 2.44]). In view of the lack of data on the confirmed risk factors for VTE in existing studies, prospective studies including adjustment for these risk factors are warranted to confirm this association and to assess the benefit/risk ratio of antipsychotics in high-risk patients.

Serum lipoprotein (a) levels in patients with first unprovoked venous thromboembolism is not associated with subsequent risk of recurrent VTE.

INTRODUCTION: Case-control studies suggest that elevated lipoprotein (a) (Lp(a)) is a risk factor for first venous thromboembolism (VTE). Lp(a) has not been prospectively investigated as a possible risk factor for recurrent VTE in first unprovoked VTE patients. We sought to determine if serum Lp(a) levels in patients with unprovoked VTE who discontinue anticoagulants after 5 to 7 months of therapy predict VTE recurrence in a prospective cohort study. MATERIALS AND METHODS: Serum Lp(a) measurements were obtained from 510 first unprovoked VTE patients treated for 5 -7 months with anticoagulants in a 12 center study. Patients were subsequently followed for a mean of 16.9 months (SD+/-11.2) for symptomatic VTE recurrence which was independently adjudicated with reference to baseline imaging. RESULTS: There was no significant association between Lp(a) as a continuous variable and recurrent VTE nor in gender stratified subgroups. No statistically significant differences were observed in the median Lp(a) concentrations between patients who recurred and those who did not recur (median (interquartile range): 0.09 g/L (0.17) versus 0.06 g/L (0.11) respectively; p=0.15). The Lp(a) cut-off point of 0.3g/L was not significantly associated with recurrent VTE for the overall population nor in gender stratified subgroups. CONCLUSIONS: Elevated serum Lp(a) does not appear to be associated with recurrent VTE in patients with history of first unprovoked VTE and may not play a role in identifying patients with unprovoked VTE at high risk of recurrence. There was no optimal predictive threshold for the overall population or for sex sub-groups and Lp(a)>or=0.3 g/L was not a significant predictor of recurrent VTE.

Antihypertensive drugs and risk of venous thromboembolism: results from the EDITH case-control study.

Previous studies evaluating the association between arterial blood pressure and venous thromboembolism (VTE) reported conflicting results. The relationship between antihypertensive therapy and VTE has never been specifically evaluated. This report from a hospital-based case-control study included 785 cases with confirmed unprovoked VTE and their 785 age- and sex-matched controls. Cases and controls were asked for drug exposure in a one-to-one standardized interview using the same questionnaire. Drug exposure was defined as current use of drugs at admission with onset at least 1 week ago. Three hundred and eighty-four out of 785 cases (48.9%) and 379 out 785 controls (48.3%) reported that they were currently using at least one antihypertensive drug. Among all antihypertensive therapies, only angiotensin II receptor blockers were significantly associated with a reduced risk for VTE: adjusted conditional odds ratio (OR) 0.45 (95% CI, 0.29-0.70). In this hospital-based case-control study, a preventive role for angiotensin II receptor blockers as regards VTE risk was suggested. More studies are needed in order to further elucidate the biological mechanisms involved.

[Drugs and venous thromboembolism]. / Médicaments et maladie veineuse thromboembolique.

Among the many factors likely to favour the occurrence of venous thromboembolism (VTE), exposure to certain drugs has to be taken into account. Although hormone treatments, oral contraception and hormone replacement therapy (HRT) for menopause have been studied, these are not the only drugs associated with an increased risk of VTE. The antipsychotics have also been incriminated in the occurrence of venous thromboembolism. The association of thalidomide and dexamethasone, used in the treatment of multiple myeloma, is responsible for a major increase in the risk of VTE. The physiopathological mechanisms accounting for the possible prothrombotic effect of most of these drugs is still not fully understood. Further observational and interventional clinical studies should provide a better understanding of VTE, potentially associated with drugs. However, certain drugs may be associated with a reduced risk of VTE. Although several studies indicate that aspirin and statins may favourably influence the risk of VTE, it is still not possible to draw up any practical recommendations.

[Prolongation of anti vitamin K treatment for 18 months versus placebo after 6 months treatment of a first episode of ideopathic pulmonary embolism: a mutlicentre, randomised double blind trail. The PADIS-EP Trial]. / Prolongation d'un traitement par antivitamine K pendant dix-huit mois versus placebo au décours d'un premier épisode d'embolie pulmonaire idiopathique traité six mois: un essai randomisé multicentrique en double aveugle. Essai "PADIS-EP".

BACKGROUND: After stopping a 3 to 6 months course of oral anticoagulation for a first episode of idiopathic venous thromboembolism (VTE), the risk of recurrent VTE is high (10% per year). In this setting, international guidelines recommend at least 6 months treatment. However, this recommendation is not satisfactory for the following reasons: (1) no randomized trial has compared 6 months to extended duration (2 years) anticoagulation; and (2), even though the frequency of recurrent VTE is similar after pulmonary embolism (PE) and deep vein thrombosis (DVT), the fatality rate of recurrent VTE after PE is higher than that after DVT. METHODS: A French multicentre double blind randomized trial. The main objective is to demonstrate, after a first episode of symptomatic idiopathic PE treated for 6 months using a vitamin K antagonist, that extended anticoagulation for 18 months (INR between 2 and 3) is associated with an increased benefit / risk ratio (recurrent VTE and severe anticoagulant-related bleeding) compared to placebo. The double blind evaluation is ensured using by active warfarin and placebo, and blinded INR. The protocol was approved by the ethics board of the Brest Hospital on the 7th of March 2006. For an alpha risk of 5% and a beta risk of 20%, the estimated sample size is 374 patients. EXPECTED RESULTS: This study has the potential to: (1) demonstrate that the benefit / risk ratio of extended anticoagulation for 18 months is higher than that observed with placebo in patients with a first episode of idiopathic PE initially treated for 6 months, during and after the treatment period; and (2) to validate or invalidate the contribution of isotope lung scans, lower limb Doppler ultrasound and D-Dimer at 6 months of treatment as predictors of recurrent VTE (medico-economic analysis included).

Association between antipsychotic drugs, antidepressant drugs and venous thromboembolism: results from the EDITH case-control study.

Cohort studies suggest that exposure to antipsychotic agents may be associated with an increased risk of venous thromboembolism (VTE). Few data concerning antidepressant drugs are available. Using a different methodological approach, the aim of this study was to estimate the association between neuroleptic and antidepressant drug use and the risk of VTE. We report the results of a case-control study designed to evaluate interactions between acquired and inherited risk factors of VTE. We included 677 cases hospitalized with deep vein thrombosis and or pulmonary embolism with no major acquired risk factor for VTE, and 677 controls matched for gender and age. Drug exposure was defined as current use of drugs at admission. Neuroleptic exposure was associated with an increased risk of VTE (OR = 2.1, 95% CI 1.4-3.2). Among neuroleptics, antipsychotic agent use was associated with a 3.5-fold increased risk of VTE (OR = 3.5, 95% CI 2.0-6.2). No association was found between antidepressant drug exposure and the risk of VTE (OR = 1.1, 95% CI 0.9-1.5). In this hospital-based case-control study, exposure to antipsychotic drugs was associated with an increased risk of VTE. These results, added to previous results, suggest that clinicians should consider antipsychotic drug exposure as a potential risk factor of VTE. More studies are needed in order to further elucidate this adverse effect, and to determine the possible predisposing factors and the biological mechanisms involved.

Vitamin K epoxide reductase genetic polymorphism is associated with venous thromboembolism: results from the EDITH Study.

BACKGROUND: The vitamin K epoxide reductase complex subunit 1 (VKORC1) recycles endogenous vitamin K, a cofactor for vitamin K-dependent coagulation factor synthesis. Common polymorphisms in VKORC1, the gene coding for VKORC1, have been found to affect the dose response to vitamin K antagonists, and to confer an increased risk of vascular diseases in a Chinese population. The aim of this study was to evaluate the association between the VKORC1 1173C > T polymorphism and venous thromboembolism (VTE). METHODS: We report the results of a case-control study designed to evaluate interactions between acquired and inherited risk factors of VTE. We studied 439 cases hospitalized with a first venous thromboembolic event that was not related to a major acquired risk factor for VTE, and 439 matched controls. The VKORC1 1173C > T polymorphism was selected for genotyping as the tagging single-nucleotide polymorphism for previously identified VKORC1 haplotypes. RESULTS: The relationship between VTE and the VKORCI 1173C > T polymorphism was consistent with a recessive model. The frequency of the VKORCI TT genotype was lower in cases than in controls. The odds ratio (OR) (95% CI) was 0.62 (0.41-0.94) for the TT genotype as compared to CT/CC genotypes. Adjustment on cardiovascular diseases, body mass index, factor V (FV) and prothrombin gene mutations did not alter the results. CONCLUSIONS: In this case-control study, the frequency of the VKORCI TT genotype was lower in patients with VTE than in matched controls. The clinical consequence of these results remains to be determined, but gives new perspectives for exploration of the role of VKORCI polymorphism in the pathogenesis of VTE.

Hyperhomocysteinemia and low B vitamin levels are independently associated with venous thromboembolism: results from the EDITH study: a hospital-based case-control study.

BACKGROUND: Moderate hyperhomocysteinemia and B vitamins deficiency are thought to be risk factors for venous thromboembolism (VTE). The causality and independence of those associations are still questioned. METHODS: We measured fasting serum total homocysteine, folates, and vitamin B12 levels as well as 5,10-methylenetetrahydrofolate reductase (MTHFR) C677T genotypes in 467 patients hospitalized with a first well-documented deep vein thrombosis and/or pulmonary embolism not related to a major acquired risk factor and 467 controls matched for gender and age. RESULTS: Mild hyperhomocysteinemia, low serum folates, and vitamin B12 were associated with VTE independently of each other. In multivariate analysis, odds ratios (OR) (95% CI) for VTE associated with mild hyperhomocysteinemia (>15 micromol L(-1)), low serum folates (< or = 4.9 nmol L(-1)), and vitamin B12 (< or = 253 pmol L(-1)) were 1.48 (1.05-2.08), 3.14 (1.35-7.32) and 1.42 (1.03-1.98), respectively. An MTHFRC677T genotype was not significantly associated with VTE; OR (95% CI): 1.13 (0.70-1.81) CONCLUSIONS: The current data provides further knowledge in the complex relationship between hyperhomocysteinemia, low vitamin levels, and VTE.

Prevention of venous thrombosis in patients with acute intracerebral hemorrhage.

OBJECTIVE: To assess intermittent pneumatic compression (IPC) in the prevention of venous thromboembolism (VTE). METHODS: The authors randomly allocated patients with a documented intracerebral hemorrhage (ICH) to elastic stockings (ES) alone or combined with IPC. The primary outcome was a combined criteria assessed at day 10: a symptomatic and well-documented VTE, or a death arising before day 10 and related to pulmonary embolism (PE), or an asymptomatic deep vein thrombosis (DVT) of the lower limbs detected by compression ultrasonography (CUS). Outcome assessment was blinded. RESULTS: One hundred fifty-one patients were randomized; 133 (88%) patients were evaluated at day 10. No clinical suspicion of VTE arose before day 10. Fourteen patients died before having a CUS but no death was definitely related to PE. Fourteen asymptomatic DVT were detected by CUS: three (4.7%) in the ES + IPC group (all distal) and 11 (15.9%) in the ES group (three proximal and eight distal). ES combined with IPC is associated with a reduced risk of asymptomatic DVT compared to ES alone: relative risk, 0.29 (95% CI 0.08 to 1.00). CONCLUSIONS: Asymptomatic deep vein thrombosis (DVT) was detected at day 10 in 15.9% of patients wearing elastic stockings alone. Intermittent pneumatic compression significantly decreased the occurrence of asymptomatic DVT for patients with intracerebral hemorrhage.