VTE Risk Assessment and Prevention in Pregnancy.

Venous thromboembolism (VTE) remains the leading cause of maternal mortality in pregnancy and the postpartum period. In addition to the higher pregnancy-associated baseline VTE risk, there are several well-established risk factors that can further increase the risk of VTE. At present, a thorough interrogation of these risk factors remains our only tool for estimating which pregnant people may be at an increased risk of VTE, and thus potentially benefit from thromboprophylaxis. However, an important knowledge gap still exists surrounding the duration of increased risk and the interaction of risk factors with each other. Furthermore, up to now, once significant risk has been established, prevention strategies have been largely based on expert opinion rather than high-quality data. Recent trials have successfully bridged a proportion of this knowledge gap; however, the challenge of conducting high-quality clinical trials with pregnant people remains. In this article, we provide an update on the recent evidence surrounding VTE risk factors in pregnancy while concurrently outlining knowledge gaps and current approaches to VTE prevention.

[Angiology and hemostasis: what's new in 2023]. / Angiologie et hémostase: ce qui a changé en 2023.

We discuss four topics among the angiology and hemostasis studies of importance in 2023. The BASIL-2 study provides new data for the management of chronic limb-threatening ischemia by comparing surgical and endovascular treatment. The new classification of antiphospholipid antibody (aPL) syndrome integrates new clinical elements and gives a different weight among the isotype and titer of aPL. Concizumab, an antibody targeting the tissue factor pathway inhibitor, broadens the therapeutic arsenal for hemophilia A and B as evidenced by the results of the EXPLORER 7 study. The PREVENT-CLOT and CASTING study focus on the prevention of thrombosis after trauma, by testing the role of aspirin or the lack of thromboprophylaxis, respectively.

Parmi les sujets d'angiologie et d'hémostase qui ont marqué l'année 2023, quatre ont retenu notre attention. L'étude BASIL-2 apporte de nouvelles données pour la prise en charge de l'ischémie critique des membres inférieurs en comparant les traitements chirurgical et endovasculaire. La nouvelle classification du syndrome des anticorps antiphospholipides (aPL) intègre de nouveaux items cliniques et donne un poids différent aux isotypes et titres des aPL. Le concizumab, un anticorps ciblant l'inhibiteur de la voie du facteur tissulaire, vient élargir l'arsenal thérapeutique pour les hémophilies A et B comme en témoignent les résultats de l'étude EXPLORER 7. Les études PREVENT-CLOT et CASTING s'intéressent à la prévention de la thrombose après traumatisme, en testant la place de l'aspirine ou l'absence de thromboprophylaxie.

Longitudinal profile of estrogen-related thrombotic biomarkers after cessation of combined hormonal contraceptives.

ABSTRACT: The persistence of risk of venous thromboembolism (VTE) due to combined hormonal contraceptives (CHCs), after their cessation, is unknown but important to guide clinical practice. The objective of this prospective cohort study was to define the time until normalization of estrogen-related thrombotic biomarkers after CHC cessation. We enrolled women aged 18 to 50 years who had decided to stop their CHC, excluding those with a personal history of VTE, anticoagulation, or pregnancy. The study started before cessation of CHC, with 6 visits afterwards (at 1, 2, 4, 6, and 12 weeks after cessation). Primary outcomes were normalized sensitivity ratios to activated protein C (nAPCsr) and to thrombomodulin (nTMsr), with sex hormone-binding globulin (SHBG) as a secondary end point. We also included control women without CHC. Among 66 CHC users, from baseline until 12 weeks, average levels of nAPCsr, nTMsr, and SHBG decreased from 4.11 (standard deviation [SD], 2.06), 2.53 (SD, 1.03), and 167 nmol/L (SD, 103) to 1.27 (SD, 0.82), 1.11 (SD, 0.58), and 55.4 nmol/L (SD, 26.7), respectively. On a relative scale, 85.8%, 81.3%, and 76.2% of the decrease from baseline until 12 weeks was achieved at 2 weeks and 86.7%, 85.5%, and 87.8% at 4 weeks after CHC cessation, respectively. Levels were not meaningfully modified throughout the study period among 28 control women. In conclusion, CHC cessation is followed by a rapid decrease in estrogen-related thrombotic biomarkers. Two to 4 weeks of cessation before planned major surgery or withdrawal of anticoagulants in patients with VTE appears sufficient for the majority of women. The trial is registered at www.clinicaltrials.gov as #NCT03949985.

Contemporary adequacy of thromboprophylaxis in acutely ill medical patients in Switzerland: a bi-centric prospective cohort.

BACKGROUND: Venous thromboembolism is a dreaded complication of hospitalised patients, with associated morbidity, mortality and increased healthcare costs. Previous studies have shown that pharmacological thromboprophylaxis, though effective, is inadequately administered in a large proportion of medical inpatients. STUDY AIMS: Our primary aim was to evaluate the contemporary adequacy of thromboprophylaxis in medical inpatients admitted to two Swiss hospitals (a university hospital and a regional hospital). The secondary aim was to estimate the 90-day incidence of relevant thrombotic and bleeding events. METHODS: In this prospective cohort, patients were recruited at the University Hospital of Geneva and the Regional Hospital of Lugano between September 2020 and February 2021 and followed for 90 days for venous thromboembolism and bleeding events. The adequacy of thromboprophylaxis (pharmacological and/or mechanical) at 24h after hospital admission was evaluated according to the simplified Geneva risk score for hospital-associated venous thromboembolism. RESULTS: Among 200 participants (100 at each site, mean age of 65 years), 57.5% were deemed at high risk of venous thromboembolism at admission. Thromboprophylaxis was adequate in 59.5% (95% CI 52.3-66.4%). Among high-risk and low-risk inpatients, thromboprophylaxis was adequate in 71.3% and 43.5%, respectively, with differences between sites. At 90 days, risks of adjudicated venous thromboembolism, major bleeding and mortality were 1.5%, 1.5% and 6.0%, respectively. CONCLUSION: Despite the extensive literature on thromboprophylaxis, the adequacy of thromboprophylaxis has not improved and remains insufficient among medical inpatients. Implementation and evaluation of clinical decision support systems are critically needed in this field. CLINICALTRIALS: gov number: NCT05306821.

[Angiology and hemostasis : what's new in 2022]. / Angiologie et hémostase : ce qui a changé en 2022.

In this article, we have selected four topics that particularly caught our attention during the year 2022, and which are related to anticoagulation, its bleeding complications, and hemophilia. Thus, we discuss the issue of the treatment with rivaroxaban of atrial fibrillation associated with rheumatic valvulopathy, which has been studied in a randomized trial, the intensity of thromboprophylaxis in COVID outpatients and inpatients, and the bleeding risk of anticoagulation in patients with cerebral tumors. Finally, recent data on gene therapy in severe hemophilia A, an upcoming treatment, are discussed.

Dans cet article, nous avons sélectionné 4 sujets qui ont particulièrement retenu notre attention durant l'année 2022, en lien avec l'anticoagulation, ses complications hémorragiques et l'hémophilie. Ainsi, nous abordons le traitement par rivaroxaban de la fibrillation atriale associée à une valvulopathie rhumatismale qui a fait l'objet d'une étude randomisée, l'intensité de la thromboprophylaxie chez les patients hospitalisés ou traités en ambulatoire avec un Covid dont les données se sont bien étoffées, le risque associé à l'anticoagulation chez les patients avec une néoplasie cérébrale et, finalement, la thérapie génique dans l'hémophilie A sévère qui devrait apparaître sur le marché très prochainement.

[Direct oral anticoagulant for venous thrombosis in unusual sites]. / Place des anticoagulants oraux directs dans le traitement des thromboses veineuses de localisation inhabituelle.

Thrombosis in unusual sites account for approximately 4% of venous thromboembolic events. The safety of direct oral anticoagulants (DOACs) has led to the widespread use of these treatments. However, they have mainly been studied in deep vein thrombosis of the lower limbs and in pulmonary embolism. This review of the literature assesses the current knowledge of the use of DOACs for venous thrombosis in unusual sites (splanchnic, cerebral, ovarian, upper-extremity deep vein thrombosis). Numerous case reports or observational studies have been published, but very few randomized trials. Nevertheless, experts-based guidelines suggest that these anticoagulants may be considered in specific cases.

La maladie thromboembolique veineuse de localisation atypique (MTEV-LA) représente environ 4 % des événements thromboemboliques veineux. Les anticoagulants oraux directs (ACOD), faciles d'utilisation et sécuritaires, ont essentiellement été étudiés dans la MTEV classique (thrombose veineuse profonde des membres inférieurs et embolie pulmonaire). Dans cette revue de la littérature, nous dressons un état des lieux sur les connaissances actuelles concernant l'utilisation des ACOD dans la MTEV-LA, notamment les thromboses splanchnique, cérébrale, ovarienne et des membres supérieurs. De nombreuses descriptions de cas et études observationnelles ont été publiées mais très peu d'essais randomisés l'ont été. Malgré cela, plusieurs sociétés savantes proposent la prescription d'ACOD dans certains cas spécifiques de MTEV-LA.

[Hospital mechanical thromboprophylaxis]. / Thromboprophylaxie mécanique hospitalière.

Mechanical thromboprophylaxis is an important part of hospital prevention of venous thromboembolism. It comprises graduated compression stockings and intermittent pneumatic compression. In this review, we summarize its physiological effect on venous hemodynamics, recent clinical studies that offer contrasting results, and discuss its utility in contemporary clinical practice. Mechanical thromboprophylaxis is currently suggested in patients at high thrombotic and hemorrhagic risk, favoring intermittent pneumatic compression, but does not seem useful in addition to pharmacological thromboprophylaxis.

La thromboprophylaxie mécanique est une composante importante de la prévention hospitalière de la maladie thromboembolique veineuse. Elle comprend la compression graduée par bas ou chaussettes et la compression pneumatique intermittente (CPIn). Dans cet article, nous résumons son effet veineux physiologique et revenons sur les études cliniques récentes qui offrent des résultats contrastés. Enfin, nous discutons de sa place en clinique contemporaine. La thromboprophylaxie mécanique est actuellement suggérée chez des patients à hauts risques thrombotique et hémorragique, en privilégiant la compression pneumatique intermittente, mais ne semble pas utile en plus d'une thromboprophylaxie pharmacologique.

Incident thrombus location and predicting risk of recurrent venous thromboembolism.

Background: Understanding venous thromboembolism (VTE) recurrence risk is central to determining the appropriate treatment course. Whether this risk varies after discontinuing anticoagulation or overall by type of incident event (pulmonary embolism [PE] vs deep vein thrombosis [DVT]) and by the detailed location of the DVT needs further clarification. Methods: In this population-based inception cohort of incident VTE cases with follow-up by electronic health record review, incident DVT was categorized as distal, popliteal, or iliofemoral. We used the Fine-Gray regression model to describe the predictive association of the thrombus location with the risk of recurrence before death. Results: Among 2766 participants with an incident event from 2002 to 2010, 1713 (62%) ceased anticoagulation and were followed for recurrent events; 301 events were observed during the 4.5 years of follow-up. Relative to participants with an incident thrombus in an iliofemoral location and no PE, those with a thrombus in a popliteal location and no PE had a similar risk of recurrence (adjusted subdistribution hazard ratio [aSHR], 0.82 [95% confidence interval (CI), 0.57-1.19]), while those with a thrombus in a distal location and no PE and those with a thrombus that included a PE had lower risk of recurrence: aSHR, 0.34 (95% CI, 0.20-0.57); and aSHR, 0.58 (95% CI 0.45-0.76), respectively. Conclusions: The findings of this population-based inception cohort confirm that the risk of recurrent VTE after discontinuing anticoagulants is similar after iliofemoral and popliteal DVT but is lower after distal DVT. Recurrence may be lower after PE than proximal DVT.

Therapeutic anticoagulation to prevent thrombosis, coagulopathy, and mortality in severe COVID-19: The Swiss COVID-HEP randomized clinical trial.

Background: Hospitalized patients with COVID-19 suffered initially from high rates of venous thromboembolism (VTE), with possible associations between therapeutic anticoagulation and better clinical outcomes in observational studies. Objective: To test whether therapeutic anticoagulation improves clinical outcomes in severe COVID-19. Patients/Methods: In this multicenter, open-label, randomized controlled trial, we recruited acutely ill medical COVID-19 patients with D-dimer >1000 ng/ml or critically ill COVID-19 patients in four Swiss hospitals, from April 2020 until June 2021, with a 30-day follow-up. Participants were randomized to in-hospital therapeutic anticoagulation versus low-dose anticoagulation in acutely ill participants/intermediate-dose anticoagulation in critically ill participants, with enoxaparin or unfractionated heparins. The primary outcome was a centrally adjudicated composite of 30-day all-cause mortality, VTE, arterial thrombosis, and disseminated intravascular coagulopathy (DIC), with screening for proximal deep vein thrombosis. Results: Among 159 participants, 55.3% were critically ill and 94.3% received corticosteroids. Before study inclusion, pulmonary embolism had been excluded in 71.7%. The primary outcome occurred in 4/79 participants randomized to therapeutic anticoagulation and 4/80 to low/intermediate anticoagulation (5.4% vs. 5.0%; risk difference +0.4%; adjusted hazard ratio 0.76, 95% confidence interval 0.18-3.21), including three deaths in each group. All primary outcomes and major bleeding (n = 3) occurred in critically ill participants. There was no asymptomatic proximal deep vein thrombosis and no difference in major bleeding. Conclusions: Among patients with severe COVID-19 treated with corticosteroids and with exclusion of pulmonary embolism at hospital admission for most, risks of mortality, thrombotic outcomes, and DIC were low at 30 days. The lack of benefit of therapeutic anticoagulation was too imprecise for definite conclusions.

Preventing Postpartum Venous Thromboembolism in 2022: A Narrative Review.

The postpartum period represents the most critical time for pregnancy-associated venous thromboembolism (VTE), which is responsible for substantial morbidity and an important cause of maternal mortality. The estimated risk of postpartum VTE of about 1/1,000 deliveries can be modulated with the knowledge of maternal and obstetrical risk factors, although a precise estimate remains challenging in individuals. The use of postpartum low-dose low-molecular-weight heparins are tailored at intermediate and high-risk groups to reduce the thrombotic burden, despite the lack of dedicated randomized controlled trials. In this review, we will highlight the contemporary evidence on the risk of postpartum VTE, its stratification and its prevention. We will also discuss our knowledge on the values and preferences of women for postpartum thromboprophylaxis and their adherence to treatment.

Differential impact of tamoxifen and aromatase inhibitors on thrombin generation: the prospective HEMOBREAST cohort.

Tamoxifen and aromatase inhibitors (AIs) are potent antitumoral agents against breast cancer. Tamoxifen increases the risk of venous thromboembolism (VTE), but the influence of AIs on the risk of VTE remains unclear. To inform clinical decisions, we evaluated associations of tamoxifen or AIs with changes of surrogate hemostatic biomarkers. This prospective cohort included 107 women with localized breast cancer starting tamoxifen (n = 42) or an AI (n = 65). Thrombin generation (CAT) its sensitivity to thrombomodulin (TM) or activated protein C (APC), and specific coagulation parameters, were measured before and 10-16 weeks after initiation of treatmen Compared with baseline, endogenous thrombin potential and thrombin peak increased in tamoxifen users (+86 nM × min; 95% confidence interval [CI], 30-142; and +33 nM; 95% CI, 21-45) but not in AI users (n = 65; +44 nM × min; 95% CI, -4 to 93; and +7 nM; 95% CI, -3 to 17). Normalized TM sensitivity ratios increased with tamoxifen (+0.26; 95% CI, 0.19-0.33y) but not with AI (+0.02; 95% CI, -0.03 to 0.07). Plasma levels of fibrinogen, antithrombin, protein C, and Tissue Factor Pathway Inhibitor decreased, and free protein S increased with tamoxifen but not with AIs. The observed shift toward increased coagulability associated with tamoxifen is in line with its known increased risk of VTE. In contrast, AIs do not appear to impact hemostasis, suggesting a lack of associated VTE risk. The trial was registered at www.clinicaltrials.gov as #NCT03381963.

[COVID-19, anticoagulation and venous thromboembolism: what have we learned ?] / Covid-19, anticoagulation et maladie thromboembolique veineuse : qu'a-t-on appris ?

Severe COVID-19 is associated with venous thromboembolic events and and immuno-thrombotic phenomena, responsible for pulmonary vascular damage. This review summarizes the current knowledge on thrombotic risk in COVID-19 inpatients, the potential predictive factors (including D-dimer) and the randomized trials studying the effect of intermediate or therapeutic-dose anticoagulation on the clinical and thrombotic prognosis. Despite the initial hope, therapeutic anticoagulation does not improve the clinical prognosis in critically ill inpatients, and standard prophylactic anticoagulation is therefore recommended. In non-critical inpatients, the use of therapeutic anticoagulation may help reduce the risk of severe clinical deterioration, but its risk-benefit will be clarified in ongoing studies and meta-analyzes.

Le Covid-19 sévère se complique fréquemment d'événements thromboemboliques veineux et de phénomènes d'immunothrombose responsables d'altérations vasculaires pulmonaires. Cet article résume les connaissances actuelles du risque thrombotique lié au Covid-19 hospitalier, les facteurs prédictifs (dont les D-dimères) et les résultats des essais randomisés d'anticoagulation à doses intermédiaire ou thérapeutique. Malgré l'espoir initial, une anticoagulation thérapeutique n'améliore pas le pronostic clinique aux soins intensifs et une anticoagulation prophylactique standard est donc préconisée. En médecine, l'utilisation d'une anticoagulation thérapeutique pourrait contribuer à réduire le risque de détérioration clinique, mais le rapport bénéfice-risque d'une telle stratégie sera précisé dans les résultats des études et méta-analyses en cours.

Comparative venous thromboembolic safety of oral and transdermal postmenopausal hormone therapies among women Veterans.

OBJECTIVE: Hormone therapy (HT) is used by menopausal women to treat vasomotor symptoms. Venous thromboembolism (VTE) is an important risk of HT use, and more knowledge on the comparative safety of different estrogenic compounds is useful for women who use HT for these symptoms. The objective was to compare the risk of VTE among users of oral conjugated equine estrogen (CEE), oral estradiol (E2), and transdermal E2, in a cohort of women veterans. METHODS: This retrospective cohort study included all women veterans aged 40 to 89 years, using CEE or E2, without prior VTE, between 2003 and 2011. All incident VTE events were adjudicated. Time-to-event analyses using a time-varying HT exposure evaluated the relative VTE risk between estrogen subtypes, with adjustment for age, race, and body mass index, with stratification for prevalent versus incident use of HT. RESULTS: Among 51,571 users of HT (74.5% CEE, 12.6% oral, and 12.9% transdermal E2 at cohort entry), with a mean age of 54.0 years, the incidence of VTE was 1.9/1,000 person-years. Compared with CEE use, in the multivariable regression model, there was no difference in the risk of incident VTE associated with oral E2 use (hazard ratio 0.96, 95% CI 0.64-1.46) or with transdermal E2 use (hazard ratio 0.95, 95% CI 0.60-1.49). Results were unchanged when restricting to incident users of HT. CONCLUSIONS: Among women veterans, the risk of VTE was similar in users of oral CEE, oral E2, and transdermal E2. These findings do not confirm the previously observed greater safety of transdermal and oral E2 over CEE.

Thromboprophylaxis strategies to improve the prognosis of COVID-19.

The outbreak of 2019 novel coronavirus disease (Covid-19) has deeply challenged the world population, but also our medical knowledge. Special attention has been paid early to an activation of coagulation, then to an elevated rate of venous thromboembolism (VTE) in patients hospitalized with severe COVID-19. These data suggested that anticoagulant drugs should be evaluated in the treatment of patients with COVID-19. The publication of unexpected high rates of VTE in patients hospitalized with COVID-19, despite receiving thromboprophylaxis, open the way to dedicated trials, evaluating modified regimens of thromboprophylaxis. Moreover, the further improvement in our comprehension of the disease, particularly the pulmonary endothelial dysfunction increased the hope that anticoagulant drugs may also protect patients from pulmonary thrombosis. In this comprehensive review, we cover the different situations where thromboprophylaxis standard may be modified (medically-ill inpatients, ICU inpatients, outpatients), and describe some of the current randomized controls trials evaluating new regimens of thromboprophylaxis in patients with COVID-19, including the preliminary available results. We also discuss the potential of anticoagulant drugs to target the thromboinflammation described in patients with severe COVID-19.

Management of high-risk pulmonary embolism in pregnancy.

Pregnancy-associated high-risk pulmonary embolism (PE) is among the most frequent causes of maternal mortality in the Western world, by causing hemodynamic instability and circulatory failure through a large thrombotic pulmonary obstruction. The very challenging management of these dramatic situations comprises the need to quickly select a therapy of pulmonary reperfusion or hemodynamic replacement, while taking into account both maternal and fetal risks. In this review, we discuss the role of risk stratification in pregnancy-associated PE and the available evidence to support the use of thrombolysis, catheter-directed thrombectomy/thrombolysis, surgical embolectomy and extracorporeal membrane oxygenation. Despite the lack of comparative studies and solid evidence, most reported cases of high-risk pregnancy-associated PE have been treated with thrombolysis, with high maternal and fetal survivals, and thrombolysis is suggested by guidelines in life-threatening PE. For women in the peripartum and early post-partum period, non-fibrinolytic treatments may be preferred as a first-line treatment, if available, because of the particularly high bleeding risk. In all cases, pregnancy-associated high-risk PE requires a multidisciplinary approach involving PE response teams and obstetricians.

Proximal deep vein thrombosis and pulmonary embolism in COVID-19 patients: a systematic review and meta-analysis.

BACKGROUND: COVID-19 appears to be associated with a high risk of venous thromboembolism (VTE). We aimed to systematically review and meta-analyze the risk of clinically relevant VTE in patients hospitalized for COVID-19. METHODS: This meta-analysis included original articles in English published from January 1st, 2020 to June 15th, 2020 in Pubmed/MEDLINE, Embase, Web of science, and Cochrane. Outcomes were major VTE, defined as any objectively diagnosed pulmonary embolism (PE) and/or proximal deep vein thrombosis (DVT). Primary analysis estimated the risk of VTE, stratified by acutely and critically ill inpatients. Secondary analyses explored the separate risk of proximal DVT and of PE; the risk of major VTE stratified by screening and by type of anticoagulation. RESULTS: In 33 studies (n = 4009 inpatients) with heterogeneous thrombotic risk factors, VTE incidence was 9% (95%CI 5-13%, I2 = 92.5) overall, and 21% (95%CI 14-28%, I2 = 87.6%) for patients hospitalized in the ICU. Proximal lower limb DVT incidence was 3% (95%CI 1-5%, I2 = 87.0%) and 8% (95%CI 3-14%, I2 = 87.6%), respectively. PE incidence was 8% (95%CI 4-13%, I2 = 92.1%) and 17% (95%CI 11-25%, I2 = 89.3%), respectively. Screening and absence of anticoagulation were associated with a higher VTE incidence. When restricting to medically ill inpatients, the VTE incidence was 2% (95%CI 0-6%). CONCLUSIONS: The risk of major VTE among COVID-19 inpatients is high but varies greatly with severity of the disease. These findings reinforce the need for the use of thromboprophylaxis in all COVID-19 inpatients and for clinical trials testing different thromboprophylaxis regimens in subgroups of COVID-19 inpatients. TRIAL REGISTRATION: The review protocol was registered in PROSPERO International Prospective Register of Systematic Reviews ( CRD42020193369 ).