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Evidence from patients with inflammatory bowel disease (IBD) and animal models suggests that inflammation alters blood flow to the mucosa, which precipitates mucosal barrier dysfunction. Impaired purinergic sympathetic regulation of submucosal arterioles, the resistance vessels of the splanchnic vasculature, is one of the defects identified during IBD and in mouse models of IBD. We hypothesized that this may be a consequence of upregulated catabolism of ATP during colitis. In vivo and in vitro video microscopy techniques were employed to measure the effects of purinergic agonists and inhibitors of CD39, an enzyme responsible for extracellular ATP catabolism, on the diameter of colonic submucosal arterioles from control mice and mice with dextran sodium sulfate [DSS, 5% (wt/vol)] colitis. Using a luciferase-based ATP assay, we examined the degradation of ATP and utilized real-time PCR, Western blotting, and immunohistochemistry to examine the expression and localization of CD39 during colitis. Arterioles from mice with DSS colitis did not constrict in response to ATP (10 [micro]M) but did constrict in the presence of its nonhydrolyzable analog [alpha],[beta]-methylene ATP (1 p[micro]M). [alpha],[beta]-Methylene ADP (100 [micro]M), an inhibitor of CD39, restored ATP-induced vasoconstriction in arterioles from mice with DSS-induced colitis. CD39 protein and mRNA expression was markedly increased during colitis. Immunohistochemical analysis demonstrated that, in addition to vascular CD39, F4/80-immunoreactive macrophages accounted for a large proportion of submucosal CD39 staining during colitis. These data implicate upregulation of CD39 in impaired sympathetic regulation of gastrointestinal blood flow during colitis. purinergic neurotransmission; ectonucleotidase; inflammation; sympathetic; vasoconstriction

Background: While bleeding around pregnancy is well described in von Willebrand disease (VWD), risk of pregnancy loss is less certain. We aimed to describe the frequency of pregnancy loss in females with VWD, compared with those with a similar mucocutaneous bleeding phenotype and no VWD, or compared with non-bleeding disorder controls., Methods: Female patients were consecutively approached in 8 specialty bleeding disorder clinics between 2014-2023. The VWD group was defined as having VWF:Antigen (Ag) and VWF:Activity (Act) levels, each <0.50 IU/mL on ≥2 occasions, and a Condensed MCMDM-1 score of ≥4. The non-VWD mucocutaneous bleeding disorder group had VWF levels ≥0.50 IU/mL on ≥2 occasions and a MCMDM-1 score ≥4. A non-bleeding disorder control group was recruited in pregnancy from a low-risk maternity clinic., Results: There were 150 females in the VWD group, 145 in the non-VWD mucocutaneous bleeding disorder group, and 137 in the control group. There was a similar frequency of individuals with ≥1 loss in the VWD group (45.3%, 68/150), the non-VWD group (56.6%, 82/145) (-11.2%, 97.5% CI -24.2, 1.8%), and the non-bleeding disorder control group (37.2%, 51/137) (8.1%, 97.5% CI -4.9%, 21.1%). Using a logistic regression, the odds ratio of pregnancy losses in the VWD group versus non-VWD group was 0.94 (95% CI 0.65, 1.36). All groups experienced more recurrent losses compared to the literature., Conclusions: There was no statistically significant difference in risk of pregnancy loss between females with VWD, females with a similar mucocutaneous bleeding phenotype, and with non-bleeding disorder controls., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Objective: Substantial morbidity and mortality affect those with antiphospholipid antibodies (aPLs) and antiphospholipid syndrome (APS), yet patient experiences remain poorly understood. This research investigated patient experiences of aPL/APS diagnosis; effects on daily life; and healthcare and treatment., Methods: Patients aged ≥18 years with APS per the Revised Sapporo criteria or with ≥1 positive aPL on ≥2 occasions were recruited from a Canadian multidisciplinary APS clinic to participate in semi-structured in-depth interviews. Interviews were conducted virtually and transcribed verbatim for subsequent thematic analysis., Results: Twenty-one patients with aPLs/APS participated; 95.2% were female, mean (SD) age was 45.6 (15.0) years. Most (71.4%) had APS, and 71.4% had aPLs/APS with SLE. Results are presented around patient experiences of aPL/APS diagnosis, effects on daily life, and healthcare and treatment. Participants described medical complications/physical symptoms and the healthcare, lifestyle, and emotional impacts experienced around the time of aPLs/APS diagnosis. In addition to the physical and psychosocial impacts of living with aPLs/APS, patients reported modified leisure activities, altered employment trajectories, and positive and negative impacts on relationships. Impacts on family planning were also a critical component of the aPL/APS lived experience; participants shared experiences of miscarriage, other pregnancy complications, and medication-related challenges (e.g., with low-molecular-weight heparin injections). Challenging aspects of aPL/APS healthcare and treatment were also discussed, particularly related to the lifestyle, physical, and emotional burden of medication use. Although a lack of resources was described, participants expressed trust in healthcare providers when making management decisions or when seeking information. Suggestions for resources included the need for additional medication-related information, examples to help contextualize management behaviours, and additional information for those with aPLs/APS without SLE., Conclusion: Patients highlighted how the diverse manifestations of aPLs/APS, accentuated by management-related challenges, impose considerable physical and psychosocial burdens. Results will inform the development of patient resources aligned with patient priorities., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: FSC, AOC, SJE, PSG and NS have no conflicts of interest to disclose. AEC has received grant/research support from GSK, and consulting fees from AstraZeneca, Bristol Myers Squibb, GSK, Otsuka, and Roche. LS has received grant/research support from CSL Behring, and honoraria from Leo Pharma and Sanofi. MRWB has received consulting fees from AbbVie, AstraZeneca, Janssen, GSK and Sanofi-Genzyme.

Background: Long-term anticoagulant therapy is generally recommended for thrombotic antiphospholipid syndrome (TAPS) patients, however it may be withdrawn or not introduced in routine practice., Objectives: To prospectively evaluate the risk of thrombosis recurrence and major bleeding in non-anticoagulated TAPS patients, compared to anticoagulated TAPS, and secondly, to identify different features between those two groups., Patients/methods: Using an international registry, we identified non-anticoagulated TAPS patients at baseline, and matched them with anticoagulated TAPS patients based on gender, age, type of previous thrombosis, and associated autoimmune disease. Thrombosis recurrence and major bleeding were prospectively analyzed using Kaplan-Meier method and compared using a marginal Cox's regression model., Results: As of June 2022, 94 (14 %) of the 662 TAPS patients were not anticoagulated; and 93 of them were matched with 181 anticoagulated TAPS patients (median follow-up 5 years [interquartile range 3 to 8]). The 5-year thrombosis recurrence and major bleeding rates were 12 % versus 10 %, and 6 % versus 7 %, respectively (hazard ratio [HR] 1.38, 95 % confidence interval [CI] 0.53 to 3.56, p = 0.50 and HR 0.53; 95 % CI 0.15 to 1.86; p = 0.32, respectively). Non-anticoagulated patients were more likely to receive antiplatelet therapy (p < 0.001), and less likely to have more than one previous thrombosis (p < 0.001) and lupus anticoagulant positivity (p = 0.01)., Conclusion: Fourteen percent of the TAPS patients were not anticoagulated at recruitment. Their recurrent thrombosis risk did not differ compared to matched anticoagulated TAPS patients, supporting the pressing need for risk-stratified secondary thrombosis prevention trials in APS investigating strategies other than anticoagulation., Competing Interests: Declaration of competing interest Authors had no conflict of interest to declare., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: The risk of venous thromboembolism (VTE) is increased postpartum and contributes to important morbidity and mortality. While there have been advances in evaluating diagnostic algorithms for suspected VTE during pregnancy, there is limited data for postpartum individuals., Objective: We conducted a scoping review to describe and evaluate diagnostic strategies used to investigate suspected VTE in postpartum individuals., Methods: A comprehensive search strategy was conducted in Ovid MEDLINE, Embase and the Cochrane Central Register of Controlled Trials (January 1, 2000-September 30, 2022) to identify original articles that reported on diagnostic strategies in postpartum individuals with suspected VTE. We extracted demographics, clinical decision rules used, D-dimer and imaging completed, including test performance and VTE outcomes., Results: A total of 13 studies conducted across 11 countries with separate postpartum data were included for 759 individuals with suspected PE (n = 634) or DVT (n = 125), including unpublished data (n = 251). Among those with suspected PE, computed tomography pulmonary angiography was conducted more commonly (n = 522) than ventilation-perfusion scans (n = 69), with PE positivity rates that ranged from 4 %-27.6 % and 0-50 % across studies, respectively. Among 131 postpartum individuals with suspected PE who had a D-dimer measured, only 4.6 % (6/131) had a negative D-dimer test. For postpartum individuals with suspected DVT, the most common diagnostic test was compression ultrasonography (positivity rate 12.2 %-18.6 %). There were limited retrospective data evaluating the clinical decision rules., Conclusions: There are heterogeneous approaches globally in the diagnosis of suspected postpartum VTE. Limited high-quality data available underscores the need for more robust evidence to inform clinical practice., Competing Interests: Declaration of competing interest Dr. Skeith holds unrelated research funding from CSL Behring and honoraria from Leo Pharma and Sanofi. The remaining authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background: Postpartum venous thromboembolism (VTE) incidence differs by race and ethnicity in the United States. However, it is unclear whether the eligibility criteria for postpartum VTE prophylaxis mirror this disparity., Objective: To characterize the prevalence of risk factors and eligibility for postpartum VTE prophylaxis, among US Birthing people, stratified by race and ethnicity., Methods: We analyzed the National Inpatient Sample from October 2015 to December 2019, using diagnosis and procedure codes to identify postpartum individuals and their VTE risk factors. We compared proportion of delivery hospitalizations meeting eligibility for thromboprophylaxis stratified by race or ethnicity, according to American College of Gynecology and Obstetrics, American College of Chest Physicians, Royal College of Obstetricians and Gynecologists (RCOG), and American Society for Hematology guidelines., Results: Among a national estimate of 14 967 861 delivery hospitalizations in the United States, the proportion of individuals eligible for thromboprophylaxis using the RCOG, American College of Chest Physicians, American College of Gynecology and Obstetrics, and American Society for Hematology guidelines were 32.9%, 8.0%, 0.2%, and 0.2%, respectively. Using the RCOG criteria, non-Hispanic Black individuals had the highest proportion of thromboprophylaxis eligibility (39.7%), whereas it was lowest among Hispanic individuals (30.8%). Racial disparities in thromboprophylaxis eligibility were driven by differences in clinical risk factors (38.8% non-Hispanic Black population vs 30.5% Hispanic population) and cesarean section rates (35.9% vs 32.2%), rather than history of VTE (0.3% vs 0.1%), inherited thrombophilia (0.2% vs 0.2%), or sickle cell disease (0.4% vs <0.1%)., Conclusion: Non-Hispanic Black individuals were most likely to qualify for postpartum thromboprophylaxis, attributable to clinical risk factors rather than inherited risk factors. An urgent need exists to better understand ethno-racial disparities in thromboprophylaxis use and to equitably address modifiable risk factors for postpartum VTE., Competing Interests: Declaration of competing interests J.F. was supported by the Eunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health under award K12HD103083. The content is solely the responsibility of the authors and does not represent the official views of the National Institutes of Health. A.I.K.C is a recipient of the Gertrude B. Elion Mentored Medical Student Research Award of Triangle Community Foundation. Y.X. and L.S. are members of the Canadian Venous Thromboembolism Research Network (CanVECTOR); the Network receives grant funding from the Canadian Institutes of Health Research (CDT-142654)., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

Background: Preeclampsia (PE) is a hypertensive disorder during pregnancy that results in significant adverse maternal and neonatal outcomes. Platelet activation is present in PE and contributes to the thrombo-hemorrhagic states of the disorder. However, the mechanisms that initiate and/or sustain platelet activation in PE are ill-defined., Objectives: We aimed to characterise this mechanism and the procoagulant potentials of platelets in PE., Methods: In this quantitative observational study, we analyzed platelet procoagulant membrane dynamics in patients with PE (n = 21) compared with age-matched normotensive pregnancies (n = 20), gestational hypertension (n = 10), and non-pregnant female controls (n = 19). We analyzed fluorescently labeled indicators of platelet activation, bioenergetics, and procoagulation (phosphatidylserine exposure and thrombin generation), coupled with high-resolution imaging and thrombelastography. We then validated our findings using flow cytometry, immunoassays, classical pharmacology, and convolutional neural network analysis., Results: PE platelets showed significant ultra-structural remodeling, are more extensively preactivated than in healthy pregnancies and can circulate as microaggregates. Preactivated platelets of PE externalized phosphatidylserine and thrombin formed on the platelet membranes. Platelets' expression of facilitative glucose transporter-1 increased in all pregnant groups. However, PE platelets additionally overexpress glucose transporter-3 to enhance glucose uptake and sustain activation and secretion events. Although preeclampsia platelets exposed to subendothelial collagen showed incremental activation, the absolute hemostatic response to collagen was diminished, and likely contributed to greater blood loss perioperatively., Conclusions: We revealed 2 bioenergetic mediators in the mechanism of sustained platelet procoagulation in preeclampsia. Although glucose transporter-1 and glucose transporter-3 remain elusive antiprocoagulant targets, they may be sensitive monitors of PE onset and progression., Competing Interests: Declaration of competing interests E.O.A. holds a patent “Facilitative Glucose Transporters 1 And 3 as an Anti-Thrombotic and Diagnostic Target” US Prov (US 63/275767); and Canadian Patent Applic #: (3,137,826). Other authors report no competing interests., (Copyright © 2023 International Society on Thrombosis and Haemostasis. Published by Elsevier Inc. All rights reserved.)

A state-of-the-art lecture titled "Preeclampsia and Platelet Procoagulant Membrane Dynamics" was presented at the International Society on Thrombosis and Haemostasis (ISTH) Congress in 2022. Platelet activation is involved in the pathophysiology of preeclampsia and contributes to the prothrombotic state of the disorder. Still, it remains unclear what mechanisms initiate and sustain platelet activation in preeclampsia and how platelets drive the thrombo-hemorrhagic abnormalities in preeclampsia. Here, we highlight our findings that platelets in preeclampsia are preactivated possibly by plasma procoagulant agonist(s) and overexpress facilitative glucose transporter-3 (GLUT3) in addition to GLUT1. Preeclampsia platelets are also partially degranulated, procoagulant, and proaggregatory and can circulate as microaggregates/microthrombi. However, in response to exposed subendothelial collagen, such as in injured vessels during cesarean sections, preeclampsia platelets are unable to mount a full procoagulant response, contributing to blood loss perioperatively. The overexpression of GLUT3 or GLUT1 may be monitored alone or in combination (GLUT1/GLUT3 ratio) as a biomarker for preeclampsia onset, phenotype, and progression. Studies to further understand the mediators of the platelet activation and procoagulant membrane dynamics in preeclampsia can reveal novel drug targets and suitable alternatives to aspirin for the management of prothrombotic tendencies in preeclampsia. Finally, we summarize relevant new data on this topic presented during the 2022 ISTH Congress., (© 2023 The Authors.)

Competing Interests: Intérêts concurrents: Megan Barber est cochercheuse au projet APSACTION (Antiphospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking) et a reçu des honoraires de GSK en tant que modératrice, de même que des honoraires pour sa participation à des comités consultatifs pour Janssen, Sanofi-Genzyme, AstraZeneca et Abbvie. Ann Clarke est membre d’APS-ACTION et fait état d’honoraires versés par AstraZeneca, Bristol Myers Squibb et GSK, de même que d’un financement de recherche de GSK. Leslie Skeith est membre d’APS-ACTION et du Réseau CanVECTOR (Canadian Venous Thromboembolism Research Network) et déclare des honoraires de Leo Pharma et de Sanofi. Aucun autre intérêt n’a été déclaré.

Background: Platelets play a role in venous thromboembolism (VTE) and in mediating colorectal cancer (CRC) progression. Still, platelets' role in hypercoagulability after surgical intervention for metastatic bone disease (MBD) is ill-defined., Methods: In this quantitative observational study, we utilized a high-resolution imaging approach to temporally examine platelet procoagulant membrane dynamics (PMD) in four patients with MBD from primary CRC (CRC/MBD), before and after surgical intervention, over a 6-month period. We coupled this investigation with thrombelastography, quantitative plasma shotgun proteomics, and biochemical analysis., Results: The plasma of CRC/MBD patients was enriched in ADAM1a, ADAMTS7, and physiological ligands for platelet glycoprotein-VI/spleen tyrosine kinase (GPVI/Syk) activation. Thromboprophylaxis attenuated procoagulation upon its initial prescription (post-operative day one, POD1); however, all patients experienced rebound procoagulation between POD3 and POD14, which was associated with Syk activation (Y525/Y526) in all patients, and a VTE event in two patients. Plasma levels of DNA-histone complexes increased steadily after surgery and remained elevated throughout the study period. Additionally, we increasingly sighted both homotypic and heterotypic platelet microaggregates after surgery in CRC/MBD patients, but not in healthy control participants' plasma., Conclusions: Our data elucidates the cell biology of a prothrombo-inflammatory state caused by disease and vascular injury, and recalcitrant to thromboprophylaxis. New mechanistic insights into hypercoagulability in CRC/MBD patients may identify novel drug targets for effective thromboprophylaxis type and duration after orthopaedic surgery.

Background and Objectives: Menstrual abnormalities and shortened reproductive lifespan are associated with shorter life expectancy and higher cardiovascular and osteoporosis risk in the general population, although the magnitude of these reproductive factor irregularities in females with CKD is unclear. This systematic review and meta-analysis aimed to summarize the current knowledge regarding menstrual abnormalities and reproductive lifespan among females with CKD., Design, Setting, Participants, & Measurements: A comprehensive bibliographic search (MEDLINE, Embase, and Cumulative Index to Nursing and Allied Health Literature [CINAHL]) was completed from database inception to February 2022 to identify all original articles reporting on females of reproductive age with nondialysis-dependent/nonkidney transplant CKD, dialysis-dependent CKD, or kidney transplantation and menstruation patterns, age of menarche, and/or menopause. Data extraction and study quality assessment were completed in duplicate. Random effects meta-analyses were used to derive pooled proportions estimates., Results: Forty-six studies were identified, and 35 were meta-analyzed, stratified by KRT modality and reported outcome. Menstrual abnormalities were present in 19%-47% of patients on hemodialysis and 75% of patients on peritoneal dialysis. Kidney transplantation was associated with a 7%-30% decrease in menstrual abnormalities. Reproductive lifespan was 32 years (95% confidence interval, 30 to 34 years). Although significant heterogeneity was present, study quality ranged from fair to good, and no evidence of publication bias was noted., Conclusions: Menstrual abnormalities and shorter reproductive lifespan are common in females with CKD, although kidney transplantation may improve menstrual health., (Copyright © 2022 by the American Society of Nephrology.)

Background: The development of a core outcome set (COS), defined as an agreed minimum set of outcome domains that should be measured and reported in all trials of a specific disease, aims to increase the relevance of study findings to stakeholder groups and improve standardization., Objectives: As the first step in developing a COS for venous thromboembolism (VTE) treatment studies, we aimed to generate an inclusive list of unique outcomes reported in previous VTE treatment studies and classify them into domains and core areas., Methods: MEDLINE, Embase and CENTRAL were searched for prospective studies reporting on interventions for VTE in non-pregnant adults. Study selection and data extraction were performed in blocks based on publication date, starting with 2015-2020 and subsequent 1-year periods, until no new outcome was identified. Outcomes were classified into domains, which are groups of closely related outcomes, and domains into four core areas including death, pathophysiological manifestations/abnormalities, life impact, and resource use., Results: Of 7100 records identified, 240 publications were included, representing 165 distinct studies. A total of 205 unique outcomes were identified that were grouped into 48 domains; 30 (13%) studies covered at least three core areas; death was included in 102 (43%), pathophysiological manifestations/abnormalities in 218 (91%), life impact in 41 (17%), and resource use in 25 (10%) studies., Conclusion: Most VTE treatment studies evaluated pathophysiological features of VTE, but few studies reported outcomes that measured life impact or resource use. The findings will inform next steps in the development of a COS for VTE treatment studies., (© 2022 International Society on Thrombosis and Haemostasis.)

Background: Venous thromboembolism (VTE) is a prevalent disease with high morbidity and mortality. VTE has well-documented physical sequelae; however, the psychological and emotional impacts are seldom evaluated in randomized controlled trials., Objective: We conducted a scoping review of published qualitative studies aiming to understand the physical, psychological, and emotional impact of VTE as reflected from patients' perspectives. This scoping review is part of a larger initiative to develop a core outcome set for VTE treatment studies., Methods: A systematic literature search was conducted to identify qualitative studies assessing patient experience of VTE. Two authors independently screened titles and abstracts using Covidence systematic review software. Full-text reviews were conducted independently by 2 study team members. A modified method of "thematic synthesis" was used to collate themes upon reading and rereading of the publications., Results: Our search strategy returned a total of 4944 citations; 28 were ultimately included in the analysis. The studies were conducted across 13 countries and representative of 436 participants including a spectrum of VTE subpopulations. There were seven major themes identified: Acute impacts: an unforeseen blow, Sustained psychological distress, Loss of self: life is changed, Challenges of thrombosis management, Balancing coping and control, Negative experience with the medical system, and VTE in the context of other conditions., Conclusions: The physical, psychological, and emotional impacts of VTE extend beyond objective outcomes typically evaluated in clinical trials. An improved understanding of the outcomes most important to patients will improve patient-centered care in VTE., (© 2022 International Society on Thrombosis and Haemostasis.)

The risk of recurrence after discontinuation of anticoagulation for a combined oral contraceptive (COC)-associated venous thromboembolism (VTE) is unclear. Therefore, we conducted a systematic review and meta-analysis to estimate the incidence of recurrent VTE among women with COC-associated VTE, unprovoked VTE and to compare the incidence of recurrent VTE between the two groups. The Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, Embase Classic +Embase and Medline ALL to July 2020 and citations from included studies were searched. Randomized controlled trials, prospective cohort studies and meta-analyses of these study types were selected. The analysis was conducted by random-effects model. Nineteen studies were identified including 1537 women [5828 person-years (PY)] with COC-associated VTE and 1974 women (7798 PY) with unprovoked VTE. Studies were at low risk of bias. The incidence rate of VTE recurrence was 1.22/100 PY [95% confidence interval (CI) 0.92-1.62, I 2  = 6%] in women with COC-associated VTE, 3.89/100 PY (95% CI 2.93-5.17, I 2  = 74%) in women with unprovoked VTE and the unadjusted incidence rate ratio was 0.34 (95% CI 0.26-0.46, I 2  = 3%). The recurrence risk in women after COC-associated VTE is low and lower than after an unprovoked VTE., (© 2022 British Society for Haematology and John Wiley & Sons Ltd.)

Competing Interests: Competing interests: Megan Barber is a coinvestigator of Antiphospholipid Syndrome Alliance for Clinical Trials and InternatiOnal Networking (APS-ACTION) and has received moderator fees from GSK, as well as advisory board fees from Janssen, Sanofi-Genzyme, AstraZeneca and Abbvie. Ann Clarke is a member of APS-ACTION and reports honoraria from AstraZeneca, Bristol Myers Squibb and GSK, as well as research funding from GSK. Leslie Skeith is a member of APS-ACTION and the Canadian Venous Thromboembolism Research Network (CanVECTOR), and reports honoraria from Leo Pharma and Sanofi. No other competing interests were declared.

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., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Blondon and Skeith.)

Introduction: Severe maternal morbidity (SMM)-an unexpected pregnancy-associated maternal outcome resulting in severe illness, prolonged hospitalisation or long-term disability-is recognised by many, as the preferred indicator of the quality of maternity care, especially in high-income countries. Obtaining comprehensive details on events and circumstances leading to SMM, obtained through maternity units, could complement data from large epidemiological studies and enable targeted interventions to improve maternal health. The aim of this study is to assess the feasibility of gathering such data from maternity units across Canadian provinces and territories, with the goal of establishing a national obstetric survey system for SMM in Canada., Methods and Analysis: We propose a sequential explanatory mixed-methods study. We will first distribute a cross-sectional survey to leads of all maternity units across Canada to gather information on (1) Whether the unit has a system for reviewing SMM and the nature and format of this system, (2) Willingness to share anonymised data on SMM by direct entry using a web-based platform and (3) Respondents' perception on the definition and leading causes of SMM at a local level. This will be followed by semistructured interviews with respondent groups defined a priori, to identify barriers and facilitators for data sharing. We will perform an integrated analysis to determine feasibility outcomes, a narrative description of barriers and facilitators for data-sharing and resource implications for data acquisition on an annual basis, and variations in top-5 causes of SMM., Ethics and Dissemination: The study has been approved by the Mount Sinai and Hamilton Integrated Research Ethics Boards. The study findings will be presented at annual scientific meetings of the Society of Obstetricians and Gynaecologists of Canada, North American Society of Obstetric Medicine, and International Network of Obstetric Survey Systems and published in an open-access peer-reviewed Obstetrics and Gynaecology or General Internal Medicine journal., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Competing Interests: None declared.

There is clinical practice variation in the area of prevention and management of venous thromboembolism (VTE) in pregnancy. There are limited data and differing recommendations across major clinical practice guidelines, especially relating to the role of postpartum low-molecular-weight heparin (LMWH) for patients with mild inherited thrombophilia and those with pregnancy-related VTE risk factors. This chapter explores the issues of practice variation and related data for postpartum VTE prevention. Controversial topics of VTE management in pregnancy are also reviewed and include LMWH dosing and the role of anti-Xa level monitoring, as well as peripartum anticoagulation management around labor and delivery., (Copyright © 2021 by The American Society of Hematology.)

Background: Antiphospholipid syndrome is associated with recurrent pregnancy loss. Low-molecular-weight heparin (LMWH) and/or aspirin (ASA) prophylaxis during pregnancy to prevent future loss is based on limited trial data with mixed results., Objectives: Given the clinical equipoise, we sought to understand how patients and physicians navigate the decision-making process for use of LMWH and/or ASA in pregnancy., Methods: We interviewed 10 patients and 10 thrombosis physicians in Ottawa, Canada from January 2017 to March 2018. Patients who had ≥1 late pregnancy loss or ≥2 early losses and persistently positive antiphospholipid antibodies based on the revised Sapporo/Sydney criteria were identified in the a Thrombosis Clinic. Patients were also identified by the TIPPS Study screening logs of excluded patients. Data collection and analysis occurred iteratively, in keeping with constructivist grounded theory methodology., Results: Our analysis generated three themes, present across both patient and physician interviews, which captured a patient-led decision-making experience: (1) managing high stakes, (2) accepting uncertainty, and (3) focusing on safety. Patients and physicians acknowledged the high emotional burden and what was at stake: avoiding further pregnancy loss. Patients responded to their situation by taking action (i.e., using LMWH injections became a "ritual"), whereas physicians reacted by removing themselves from the final decision by "[leaving] it up to the patient.", Conclusion: Our findings should be considered when designing future research on studying the role for LMWH/ASA in this population, as it suggests that the perceived benefits of treatment go beyond improving pregnancy rates. Rather, patients described potential benefit from the process of taking action, even in the absence of a guaranteed good outcome., Competing Interests: L.S.: honoraria from LEO Pharma; Research funding from CSL Behring. M.A.R.: no conflicts of interest to report. S.M.B.: honoraria from LEO Pharma. C.G.: no conflicts of interests to report. A.K.: no conflicts of interest to report. T.S.T.: no conflicts of interest to report. S.M.B. holds the Eli Lilly Canada/May Cohen Chair in Women's Health. M.R. is the McGill Harry Webster Thorp Professor of Medicine., (Thieme. All rights reserved.)

Background: Venous thromboembolism (VTE) is the second most common complication after hip fracture surgery. We used thrombelastography (TEG), a whole-blood, point-of-care test that can provide an overview of the clotting process, to determine the duration of hypercoagulability after hip fracture surgery., Methods: In this prospective study, consecutive patients aged 51 years or more with hip fractures (trochanteric region or neck) amenable to surgical treatment who presented to the emergency department were eligible for enrolment. Thrombelastography, including calculation of the coagulation index (CI) (combination of 4 TEG parameters for an overall assessment of coagulation) was performed daily from admission until 5 days postoperatively, and at 2 and 6 weeks postoperatively. All patients received 28 days of thromboprophylaxis. We used single-sample t tests to compare mean maximal amplitude (MA) values (a measure of clot strength) to the hypercoagulable threshold of greater than 65 mm, a predictor of in-hospital VTE., Results: Of the 35 patients enrolled, 11 (31%) were hypercoagulable on admission based on an MA value greater than 65 mm, and 29 (83%) were hypercoagulable based on a CI value greater than 3.0; the corresponding values at 6 weeks were 23 (66%) and 34 (97%). All patients had an MA value greater than 65 mm at 2 weeks. Patients demonstrated normal coagulation on admission (mean MA value 62.2 mm [standard deviation (SD) 6.3 mm], p = 0.01) but became significantly hypercoagulable at 2 weeks (mean 71.6 mm [SD 2.6 mm], p < 0.001). There was a trend toward persistent hypercoagulability at 6 weeks (mean MA value 66.2 mm [SD 3.8 mm], p = 0.06)., Conclusion: More than 50% of patients remained hypercoagulable 6 weeks after fracture despite thromboprophylaxis. Thrombelastography MA thresholds or a change in MA over time may help predict VTE risk; however, further study is needed., Competing Interests: Leslie Skeith reports research funding from CSL Behring and honoraria from LEO Pharma, outside the submitted work. Adrienne Lee reports research support from Bayer and speaker fees from Takeda, outside the submitted work. Ryan Martin consults for Smith & Nephew and DePuy Synthes. Prism Schneider reports honoraria from Amgen, Stryker and DePuy Synthes, outside the submitted work. No other competing interests were declared., (© 2021 CMA Joule Inc. or its licensors.)

Exogenous hormone therapies, such as combined oral contraceptives (COC) and hormone replacement therapy (HRT), cause blood hypercoagulability and are a risk factor for venous thromboembolism (VTE). There is controversy on how strong this "provoking" risk factor is, and how other risk factors may synergise VTE risk. We aim to review the latest literature on the risk of initial and recurrent VTE with COC and HRT use to provide guidance for decision-making about duration of anticoagulation, and guide future research efforts., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Introduction: The risk of recurrent venous thromboembolism (VTE) after combined oral contraceptive (COC) use is variably reported. We assessed the long-term risk of recurrent VTE in women on COC at the time of a first VTE, in comparison to women without COC use. Our secondary aim assessed the impact of COC use on the recurrent VTE risk in high-risk and low-risk hyperpigmentation, edema, or redness in either leg; D-dimer level ≥250 μg/L; obesity with body mass index ≥30; or older age, ≥65 years (HERDOO2) subgroups., Methods: The REVERSE cohort study derived the HERDOO2 clinical decision rule to predict recurrent VTE in patients who discontinued anticoagulation after 5-7 months for a first unprovoked VTE. Incidence rates of recurrent VTE among women with and without COC exposure were calculated as the number of recurrent VTE over the number of person-years of follow-up, and Cox proportional hazards model was used to compare risks between groups., Results: The risk of recurrent VTE among COC users was 1.1% (95% confidence interval [CI] 0.3-2.9) per patient-year as compared with 3.2% per patient-year (95% CI 2.4-4.3) among nonusers (hazard ratio 0.37; 95% CI 0.1-1.0). Women who were COC users and high risk by HERDOO2 score had a recurrence rate of 3.5% (95% CI 0.4-12.5) compared with 6.1% (95% CI 4.3-8.5) among women who were non-COC users and at high risk by HERDOO2 score (HR 0.6, 95% CI 0.1-2.5)., Conclusions: Women who were COC users at the time of an otherwise unprovoked VTE event had a lower VTE recurrence rate during long-term follow-up, compared with nonusers. The use of HERDOO2 rule may help identify higher risk women with COC use., (© 2021 International Society on Thrombosis and Haemostasis.)

Aims: Current guidelines recommend surgery within 48 hours among patients presenting with hip fractures; however, optimal surgical timing for patients on oral anticoagulants (OACs) remains unclear. Individual studies are limited by small sample sizes and heterogeneous outcomes. The aim of this study was to conduct a systematic review and meta-analysis to summarize the effect of pre-injury OACs on time-to-surgery (TTS) and all-cause mortality among older adults with hip fracture treated surgically., Methods: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL) from inception to 14 October 2019 to identify studies directly comparing outcomes among hip fracture patients receiving direct oral anticoagulants (DOACs) or vitamin K antagonists (VKAs) prior to hospital admission to hip fracture patients not on OACs. Random effects meta-analyses were used to pool all outcomes (TTS, in-hospital mortality, and 30-day mortality)., Results: A total of 34 studies (involving 39,446 patients) were included in our systematic review. TTS was 13.7 hours longer (95% confidence interval (CI) 9.8 to 17.5; p < 0.001) among hip fracture patients on OACs compared to those not on OACs. This translated to a three-fold higher odds of having surgery beyond the recommended 48 hours from admission (odds ratio (OR) 3.0 (95% CI 2.1 to 4.3); p = 0.001). In-hospital mortality was higher (OR 1.4 (95% CI 1.0 to 1.8); p < 0.03) among anticoagulated patients. Among studies comparing anticoagulants, there was no statistically significant difference in time-to-surgery between patients taking a DOAC compared to a VKA., Conclusion: Patients presenting with a hip fracture who were taking OACs prior to injury experience a delay in time-to-surgery and higher mortality than non-anticoagulated patients. Patients on DOACs may be at risk of further delays. Evaluating expedited surgical protocols in hip fracture patients on OACs is an urgent priority, with the potential to decrease morbidity and mortality in this group of high-risk patients. Cite this article: Bone Joint J 2021;103-B(2):222-233.

Thrombosis has emerged as an important complication of coronavirus disease 2019 (COVID-19), particularly among individuals with severe illness. However, the precise incidence of thrombotic events remains uncertain due to differences in study design, patient populations, outcome ascertainment, event definitions, and reporting. In an effort to overcome some of these challenges and promote standardized data collection and reporting in clinical studies, the American Society of Hematology Research Collaborative COVID-19 Non-Malignant Hematology Task Force, in collaboration with the International Society on Thrombosis and Haemostasis COVID-19 Task Force, developed sets of data elements in the following domains: venous thromboembolism, myocardial infarction, stroke/transient ischemic attack, peripheral arterial thrombosis, bleeding, laboratory investigations, and antithrombotic therapy. Data elements in each of these domains were developed with 3 levels of detail to facilitate their incorporation into studies evaluating a range of interventions and outcomes. Previously published data elements were included where possible. The use of standardized variables in a range of clinical studies can enhance the quality of data collection, create efficiency, enhance comparison of results across studies, and facilitate future pooling of data sets., (© 2020 by The American Society of Hematology.)

Introduction: Coronavirus disease (COVID-19) is associated with a high incidence of thrombosis and mortality despite standard anticoagulant thromboprophylaxis. There is equipoise regarding the optimal dose of anticoagulant intervention in hospitalized patients with COVID-19 and consequently, immediate answers from high-quality randomized trials are needed., Methods: The World Health Organization's International Clinical Trials Registry Platform was searched on June 17, 2020 for randomized controlled trials comparing increased dose to standard dose anticoagulant interventions in hospitalized COVID-19 patients. Two authors independently screened the full records for eligibility and extracted data in duplicate., Results: A total of 20 trials were included in the review. All trials are open label, 5 trials use an adaptive design, 1 trial uses a factorial design, 2 trials combine multi-arm parallel group and factorial designs in flexible platform trials, and at least 15 trials have multiple study sites. With individual target sample sizes ranging from 30 to 3000 participants, the pooled sample size of all included trials is 12 568 participants. Two trials include only intensive care unit patients, and 10 trials base patient eligibility on elevated D-dimer levels. Therapeutic intensity anticoagulation is evaluated in 14 trials. All-cause mortality is part of the primary outcome in 14 trials., Discussion: Several trials evaluate different dose regimens of anticoagulant interventions in hospitalized patients with COVID-19. Because these trials compete for sites and study participants, a collaborative effort is needed to complete trials faster, conduct pooled analyses and bring effective interventions to patients more quickly., (© 2020 International Society on Thrombosis and Haemostasis.)

Background: Hip fracture patients on oral anticoagulants (OACs) experience increased time-to-surgery and higher mortality compared to non-anticoagulated patients. However, it is unclear whether pre-injury OAC status and its associated operative delay are associated with worsening of peri-operative hemostasis or an increased risk of postoperative thromboembolism., Methods: We performed a systematic review to identify studies that directly compared hemostatic and thromboembolic outcomes among hip fracture patients on an OAC prior to admission with those not on anticoagulants. Random effects meta-analyses were used to pool all outcomes of interest (estimated blood loss, transfusion requirements, and postoperative thromboembolism)., Results: Twenty-one studies involving 21 417 patients were included. Estimated blood loss was higher among patients presenting with OACs compared to those not anticoagulated (mean difference 31.0 mL, 95% confidence interval [CI] 6.2-55.7). Anticoagulated patients also had a 1.3-fold higher risk of receiving red blood cell transfusions (odds ratio [OR] 1.34, 95% CI 1.20-1.51); however, rates of postoperative thromboembolism were similar regardless of anticoagulation status (OR 0.96, 95% CI 0.40-2.79 for venous thromboembolism; OR 0.58, 95% CI 0.25-1.36 for arterial thromboembolism). No subgroup effect was found based on anticoagulant type or degree of surgical delay., Conclusion: Hip fracture patients on OACs experience increased surgical blood loss and higher risk of red blood cell transfusions. However, the degree of surgical delay did not mitigate this risk, and there was no difference in postoperative thromboembolism. The impact of appropriate, timely OAC reversal on blood conservation and expedited surgery in anticoagulated hip fracture patients warrants urgent evaluation., (© 2020 International Society on Thrombosis and Haemostasis.)

Postpartum venous thromboembolism (VTE) is a leading cause of maternal mortality in developed countries and can carry significant long-term morbidity. Despite being able to identify postpartum VTE risk factors in a large proportion of the obstetrical population, there is little high-quality evidence available to guide practice on who should receive postpartum thromboprophylaxis. Based on epidemiological data, women with a prior history of VTE or known potent thrombophilia are likely to benefit from an extended duration of low-molecular-weight heparin (LMWH) prophylaxis. However, significant controversy exists around the benefit and harm of postpartum thromboprophylaxis in women with more modest risk factors, such as those with mild thrombophilias or transient situational risk factors around labor and delivery, such as cesarean delivery. We review the available data for postpartum VTE risk factors and thromboprophylaxis in these patients. This review highlights the latest evidence in the area of postpartum VTE prevention, and is a call to action for further research in this area to improve maternal morbidity and mortality., Competing Interests: Declaration of competing interest L.A.: No conflicts of interest to disclose; F.N.A: Unrestricted investigator-initiated research awards paid to institution (Leo Pharma, Actelion, Bayer); Advisory board membership (past 5 years): Bayer, BMS/Pfizer, Daiichi-Sankyo; M.B.: No conflicts of interest to disclose. M.A.R.: No conflicts of interest to disclose; L.S.: Research funding from CSL Behring; Honoraria from LEO Pharma., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Placenta-mediated pregnancy complications are clinically important conditions and include preeclampsia, placental abruption, intrauterine growth restriction, and late fetal loss. Pathophysiology is complex, and may be linked to prothrombotic disorders such as antiphospholipid syndrome, whose understanding is still evolving. In this narrative review, we will present the latest evidence to better understand hemostatic mechanisms of preeclampsia, as well as in women with placenta-mediated pregnancy complications and inherited thrombophilia or antiphospholipid antibodies. Using four clinical scenarios, the mixed results of preventive efforts through the use of antithrombotic drugs (aspirin, heparin) will be discussed. We will also review knowledge gaps and ongoing research., Competing Interests: L.S.: Honoraria from Leo Pharma; research funding from CSL Behring. M.B: no conflicts of interest. F.N.A.: Research funding (paid via an IIS to the host university) from Bayer, Leo Pharma, and Actelion., (Georg Thieme Verlag KG Stuttgart · New York.)

Background: The average risk of venous thromboembolism (VTE) in long haul travellers is approximately 2.8 per 1000 travellers, which is increased in the presence of other VTE risk factors. In pregnant long-haul travellers, little is known in terms of the absolute risk of VTE in these women and, therefore, there is limited consensus on appropriate thromboprophylaxis in this setting., Objective: This review will provide guidance to allow practitioners to safely minimize the risk of travel-related VTE in pregnant women. The suggestions provided are based on limited data, extrapolated risk estimates of VTE in pregnant travellers and recommendations from published guidelines., Results: We found that the absolute VTE risk per flight appears to be <1% for the average pregnant or postpartum traveller. In pregnant travellers with a prior history of VTE, a potent thrombophilia or strong antepartum risk factors (e.g. combination of obesity and immobility), the risk of VTE with travel appears to be >1%. Postpartum, the risk of VTE with travel may be >1% for women with thrombophilias (particularly in those with a family history) and other transient risk factors and in women with a prior VTE., Conclusions: Based on our findings, we recommend simple measures be taken by all pregnant travellers, such as frequent ambulation, hydration and calf exercises. In those at an intermediate risk, we suggest a consideration of 20-30 mmHg compression stockings. In the highest risk group, we suggest careful consideration for low-molecular-weight heparin thromboprophylaxis. If there are specific concerns, we advise consultation with a thrombosis expert at the nearest local centre., (© International Society of Travel Medicine 2019. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)