ISTH Research Articles

MO123USE OF RIVAROXABAN VERSUS WARFARIN IN PATIENTS WITH ATRIAL FIBRILLATION AND ADVANCED CHRONIC KIDNEY DISEASE*

Abstract Background and Aims Patients with chronic kidney disease (CKD) develop bleeding and thromboembolic tendencies, so the indication for the use of anticoagulants for atrial fibrillation (AF) is difficult. AF is the most common chronic cardiac arrhythmia, and thromboembolism and ischemic stroke in particular are the main complications. In recent years, new oral anticoagulants (rivaroxaban) have been developed and have shown superiority over classic anti-vitamin K anticoagulants in preventing the risk of stroke, systemic embolism and bleeding. Aim is to evaluate the safety parameters of rivaroxaban in patients with stage 4 chronic kidney disease (CKD) or a transient sustained decrease in glomerular filtration rate (GFR) to 15–29 ml/min/1,73 m2 in the presence of atrial fibrillation (AF). Method Multicenter prospective randomized study that included patients from cardiology departments in 2019. Of 5448 hospitalized patients, 109 (2%) patients with AF and CKD stage 4 or a sustained decrease in GFR to 15-29 ml/min/1.73 m2 were randomized in a 2:1 ratio to rivaroxaban 15 mg/day (n=73) or warfarin (n=36). Primary endpoint: development of large, small and small clinically significant bleeding according to the BARC (Bleeding Academic Research Consortium) and ISTH (International Society on Thrombosis and Hemostasis) scales. The average follow-up period is 12 months. Results Patients taking warfarin were significantly more likely to develop minor bleeding according to BARC scales (n=26 (72.2%) versus n=31 (42.4%), p<0.01) and ISTH (n=22 (61.1%) versus n=27 (36.9%), p<0.01) and all clinically significant (minor clinically significant and major) bleeding according to the ISTH scale [n=10 (27.7%) versus n=8 (10.9%), p=0.03]. The number of readmissions was 32 (43.8% of patients) in the rivaroxaban group, 17 (47.2% of patients) in the warfarin group (p=0.57), of which 12 (37.5%) and 7 (41.1%) (in the rivaroxaban and warfarin groups, respectively) - for urgent reasons (p=0.96). A significant improvement in the dynamics of creatinine levels, GFR (according to CKD-EPI) in the rivaroxaban group was revealed. Conclusion The study provides evidence of a favorable safety profile for rivaroxaban compared with warfarin in patients with AF and advanced CKD.

The effect of sex on the efficacy and safety of dual antithrombotic therapy with dabigatran versus triple therapy with warfarin after PCI in patients with atrial fibrillation (a RE-DUAL PCI subgroup analysis and comparison to other dual antithrombotic therapy trials).

BackgroundThe RE‐DUAL PCI trial demonstrated that in patients with nonvalvular atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI), dual therapy with dabigatran and a P2Y12 inhibitor, either clopidogrel or ticagrelor, reduced the risk of bleeding without an increased risk of thromboembolic events as compared to triple therapy with warfarin in addition to a P2Y12 inhibitor and aspirin. What remains unclear is whether this effect is consistent between males and females undergoing PCI.HypothesisThe reduction in risk of bleeding without increased risk of thromboembolic events with dual therapy with dabigatran and a P2Y12 inhibitor in comparison to triple therapy with warfarin, a P2Y12 inhibitor and aspirin is consistent in females and males.MethodsThe primary safety endpoint was the first International Society on Thrombosis and Hemostasis (ISTH) major bleeding event (MBE) or clinically relevant non‐major bleeding event (CRNMBE). The efficacy endpoint was the composite of death, thromboembolic event (stroke, myocardial infarction, and systemic embolism) or unplanned revascularization. Cox proportional hazard regression analyses were applied to calculate corresponding hazard ratios and interaction p values for each endpoint.ResultsA total of 655 women and 2070 men were enrolled. The risk of major or CRNM bleeding was lower with both dabigatran 110 mg dual therapy and dabigatran 150 mg dual therapy compared with warfarin triple therapy in female and male patients (for 110 mg: females: HR 0.69, 95% CI 0.47–1.01, males: HR 0.46, 95% CI 0.37–0.59, interaction p value: 0.084 and for 150 mg: females HR 0.74, 95% CI 0.48–1.16, males HR 0.71, 95% CI 0.56–0.90, interaction p value: 0.83). There was also no detectable difference in the composite efficacy endpoint of death, thromboembolic events or unplanned revascularization between dabigatran dual therapy and warfarin triple therapy, with no statistically significant interaction between sex and treatment (interaction p values: 0.73 and 0.72, respectively).ConclusionsConsistent with the overall study results, the risk of bleeding was lower with dabigatran 110 mg and 150 mg dual therapy compared with warfarin triple therapy, and risk of thromboembolic events was comparable with warfarin triple therapy independent of the patient's sex.

CAVA (Ultrasound-Accelerated Catheter-Directed Thrombolysis on Preventing Post-Thrombotic Syndrome) Trial: Long-Term Follow-Up Results.

BackgroundThe CAVA (Ultrasound‐Accelerated Catheter‐Directed Thrombolysis Versus Anticoagulation for the Prevention of Post‐Thrombotic Syndrome) trial did not show a reduction of post‐thrombotic syndrome (PTS) after additional ultrasound‐accelerated catheter‐directed thrombolysis in patients with acute iliofemoral deep vein thrombosis at 1‐year follow‐up. This prespecified analysis of the CAVA trial aimed to determine the impact of additional thrombolysis on outcomes of PTS at long‐term follow‐up.Methods and ResultsPatients aged 18 to 85 years with a first‐time acute iliofemoral deep vein thrombosis were included and randomly assigned (1:1) to either standard treatment plus ultrasound‐accelerated catheter‐directed thrombolysis or standard treatment alone. The primary outcome was the proportion of PTS (Villalta score ≥5 on 2 occasions ≥3 months apart or venous ulceration) at the final follow‐up visit. Additionally, PTS according to the International Society on Thrombosis and Haemostasis (ISTH) consensus definition was assessed to allow external comparability. Major bleedings were the main safety outcome. At a median follow‐up of 39.0 months (interquartile range, 23.3–63.8), 120 patients (79.8%) participated in the final follow‐up visit: 62 from the intervention group and 58 from the standard treatment group. PTS developed in 19 (30.6%) versus 26 (44.8%) patients, respectively (odds ratio [OR], 0.54; 95% CI, 0.26 to 1.15 [P=0.11]), with an absolute difference between groups of −14.2% (95% CI, −32.0% to 4.8%). Using the ISTH consensus definition, a significant reduction in PTS was observed (29 [46.8%] versus 40 [69.0%]) (OR, 0.40; 95% CI, 0.19–0.84 [P=0.01]) with an absolute difference between groups of −22.2% (95% CI, −39.8% to −2.8%). No new major bleedings occurred following the 12‐month follow‐up.ConclusionsThe impact of additional ultrasound‐accelerated catheter‐directed thrombolysis on the prevention of PTS was found to increase with time. Although this study was limited by its sample size, the overall findings indicate a reduction of mild PTS without impact on quality of life.RegistrationURL: https://www.clinicaltrials.gov; Unique identifier: NCT00970619.

Preoperative patient blood management during the SARS-CoV-2 pandemic.

Preoperative patient blood management during the SARS-CoV-2 pandemic.

Significance and future of anticoagulant therapy for sepsis

Sepsis is caused by the imbalance of the host body's response to infection, which causes life-threatening organ dysfunction. Disorders of blood coagulation play a very important role in the development of sepsis. In sepsis, the body's coagulation system is activated, leading to hypercoagulability, while the anticoagulation mechanism is significantly inhibited, causing a large number of microthrombi to form, and disseminated intravascular coagulation (DIC) may occur. Although there are obvious controversies about the anticoagulation treatment of sepsis at home and abroad, we cannot deny the significance of anticoagulation treatment in sepsis. Only appropriate anticoagulation can effectively reduce the mortality in septic DIC, septic shock and high-risk population, and ultimately effectively reduce the occurrence of multiple organ dysfunction syndrome. The sepsis-induced coagulation dysfunction (SIC) score is currently used internationally to guide anticoagulation. SIC score is optimized based on the International Society on Thrombosis and Haemostasis (ISTH) overt DIC score and Sepsis-3, including platelet, international normalized ratio (INR) and sequential organ failure assessment (SOFA). The SIC score can sensitively monitor sepsis-induced coagulation dysfunction. When the SIC score is ≥ 4, it is the best timing to initiate anticoagulation therapy. At present, the internationally recommended anticoagulant drugs include antithrombin (AT), thrombomodulin (TM), tissue factor pathway inhibitor (TFPI), heparin, etc., while the domestically recommended anticoagulant drugs are only unfractionated heparin and low molecular weight heparin. Before using anticoagulant drugs, it is necessary to evaluate the possibility of bleeding and thrombosis in the patients. At the same time, it is necessary to pay attention to the patient's primary disease. Try to adopt the treatment strategy of transitioning from unfractionated heparin to low molecular weight heparin without obvious anticoagulation contraindications.

Coagulopathy After Viper Snakebite in Vietnam and Relationship with Time of Admission

BackgroundSnakebite envenoming is a potentially life-threatening condition and causes many serious consequences.Subjects and MethodsTherefore, this study aimed to throw some light on coagulopathy after Viperidae envenomations at Vietnam Poison Control Center and the relationship between coagulopathy and time of admission. A prospective, descriptive study was conducted from October 2016 to April 2018. The survey questionnaire included socio-economic characteristics, characteristics of snakebite, signs and clinical symptoms and blood test. Disseminated intravascular coagulation (DIC) condition was diagnosed using the International Society on Thrombosis and Haemostasis (ISTH) criteria. Rotational thromboelastometry was evaluated using ROTEM® delta system.ResultsA total of 41 cases of viper snakebite with the mean age of snakebite victims were 41.27 ± 14.72 years old. Mean hospital stay of the patients was 5.63± 3.29 days. The association between coagulation disorder and clotting time (CT) EXTEM prolonged, CT INTEM prolonged, CT FIBTEM prolonged remained significant (multivariable odds ratio MOR=5.81, 95% CI: 1.20–28.06; MOR= 9.32, 95% CI: 1.001–84.48; MOR=5.55, 95% CI: 1.12–27.50, respectively).ConclusionThis study indicates a hypocoagulation status in ROTEM, elevated international normalised ratio (INR), activated partial thromboplastin time (APTT) and D-dimer, decreased fibrinogen concentration and platelet count following envenoming by Viperidae.

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Evolution of haemophilia integrated care in the era of gene therapy: Treatment centre's readiness in United States and EU.

Evolution of haemophilia integrated care in the era of gene therapy: Treatment centre's readiness in United States and EU.

Efficacy and Safety of Direct Oral Anticoagulants in Venous Thromboembolism Compared to Traditional Anticoagulants in Morbidly Obese Patients: A Systematic Review and Meta-Analysis.

BackgroundRandomized clinical trials comparing the efficacy and safety of direct oral anticoagulants (DOAC) with vitamin K antagonist (VKA) or low molecular weight heparin (LMWH) for the treatment of venous thromboembolism (VTE) generally exclude patients who are morbidly obese (body mass index ≥ 40 kg/m2 or weight ≥ 120 kg). Recently, smaller studies have compared DOACs with warfarin or low molecular weight heparin (LMWH) in morbidly obese patients with VTE. We aim to systematically review and do a meta-analysis of the studies that directly compared DOACs with VKAs or LMWH in morbidly obese patients.MethodsStudies comparing DOAC with warfarin or LMWH in patients with acute VTE were identified through electronic literature searches of MEDLINE, EMBASE, Scopus, clinicaltrials.gov, and the Cochrane Library up to March 2020. The primary efficacy outcome was recurrent VTE and the primary safety outcome was major bleeding as defined by the International Society on Thrombosis and Haemostasis (ISTH) guidelines. Study-specific odds ratios (OR) were calculated and combined using a random-effects model meta-analysis.ResultFive studies were identified. Recurrent VTE occurred in 95 of 3207 (2.96%) patients in the DOAC group and 81 of 3181 (2.54%) patients in the VKA and LMWH group (OR: 1.17; 95% CI 0.87 to 1.59, p=.30). Major bleeding occurred in 63 of 3316 (1.89%) patients in the DOAC group, and 83 of 3259(2.54%) patients in the VKA or LMWH group (OR: 0.74; 95% CI: 0.53 to 1.03, p=.08). Sensitivity analysis comparing factor Xa inhibitors apixaban and rivaroxaban to warfarin also yielded consistent findings.ConclusionDOACs showed similar efficacy and safety in the prevention of recurrent VTE risk and major bleeding events in morbidly obese patients when compared to warfarin/LMWH. Our study underscores the need for further modifications of therapy to reduce the high VTE recurrence rate irrespective of whether the patient is on a DOAC or VKA. This might be possible through a very large multi-institutional randomized clinical trial.

Can disseminated intravascular coagulation scores predict mortality in COVID-19 patients?

ObjectivesComplications related to coronavirus disease 2019 (COVID-19) may lead to disseminated intravascular coagulation (DIC), which has been reported to be among the known causes of mortality in such patients. This study aims to analyse the incidence of DIC in COVID-19 non-survivors and to assess the association between DIC and its comorbidities. MethodsThe medical records of 154 non-survivors of COVID-19, hospitalised between April 2020 and July 2020, were retrospectively analysed. The International Society on Thrombosis and Haemostasis (ISTH) criteria for DIC were applied to identify the occurrence of coagulopathy. The receiver-operating characteristic (ROC) analysis was used to assess the association between DIC and its comorbidities. ResultsOut of 154 non-survivors, non-overt DIC was observed in 94.8% of the patients, whereas only 5.2% fulfilled the overt criteria of DIC with a mean age 64.6 years. The mortality rate was 4.5 times higher among men than women. The D-dimer level was >250 ng/ml in 68.8% of the patients including 88.9% of the non-overt and 100% of the overt DIC patients. Prothrombin time (PT) in non-overt and overt DIC cases was 17.3 s and 24.4 s, respectively. Thrombotic event and chronic kidney disease were found to be the main predictors of DIC (p < 0.0001 and 0.03, respectively) followed by diabetes mellitus (DM) and hypertension (statistically insignificant). ConclusionsOur study concludes that the ISTH DIC score cannot predict mortality as the COVID-19 related DIC differs from the sepsis-induced DIC. Among the seriously ill, older patients with comorbidities, increased levels of D-dimer and prolonged PT are more reliable parameters among COVID-19 non-survivors.

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Effectiveness and Safety of Direct Oral Anticoagulants in Patients with Nonvalvular Atrial Fibrillation and Weighing ≥ 120 Kilograms versus 60-120 Kilograms.

Direct oral anticoagulants (DOACs) have become favorable choices for anticoagulation due to their fixed-dose schedule, limited need for monitoring, and non-inferiority or superiority to warfarin. DOACs are currently not recommended in patients with a body weight ≥120 kg or body mass index ≥40 kg/m2 due to limited data regarding safety and efficacy. The aim of this study was to compare the safety and efficacy of DOACs in patients with nonvalvular atrial fibrillation (NVAF) and weighing ≥120 kg with those weighing <120 kg. A single-center, retrospective study was conducted in patients weighing ≥120 kg who received either apixaban, dabigatran, or rivaroxaban for stroke risk reduction in NVAF, and matched to patients who weighed <120kg. The primary outcome was the incidence of stroke, deep vein thrombosis, pulmonary embolism, or myocardial infarction, while the safety outcome was the incidence of major or clinically relevant non-major bleeding based on the International Society on Thrombosis and Haemostasis (ISTH) definitions. A total of 318 patients weighing ≥120 kg with NVAF and meeting the inclusion criteria were evaluated and matched with 318 patients weighing <120 kg. The primary outcome occurred in 2.5% of patients in the ≥120 kg group and in 3.1% of patients in the <120 kg group (p=0.632). The safety outcome occurred in 5.3% and 6.6% of patients in these respective groups (p=0.503). Apixaban, dabigatran, or rivaroxaban may be well-tolerated and effective anticoagulant options in patients with NVAF weighing ≥120 kg.

Safety of direct oral anticoagulants in patients with mild to moderate cirrhosis: a systematic review and meta-analysis.

To evaluate major bleeding in cirrhosis with use of traditional anticoagulation or direct oral anticoagulants (DOACs), using a standardized definition. Anticoagulation in patients with cirrhosis is often a clinical conundrum for providers as the necessary balance between thrombotic and bleeding risk is complicated by end organ damage. Recent meta-analyses have sought to evaluate the safety and efficacy of direct oral anticoagulants in patients with liver disease. These recent analyses are limited by various bleeding definitions, broad inclusion criteria, and few indications for anticoagulation. We sought to conduct a meta-analysis using a validated definition for major bleeding and compare rates between traditional anticoagulation and DOACs in patients with cirrhosis. Articles were eligible for inclusion if the international society on thrombosis and hemostasis (ISTH) definition of a major bleed was the primary safety outcome. Additionally, only articles including patients with cirrhosis and receiving treatment with anticoagulation for an indication for stroke prevention or venous thromboembolism were eligible. Eligible articles needed a DOAC comparator group against traditional anticoagulant medication. Seven studies met inclusion criteria and compiled data for 683 patients in the meta-analysis. Pooled trial analysis demonstrated no statistically significant difference in the primary outcome of ISTH major bleeding (OR 0.55, 95%CI 0.28-1.07, I2 0%). Individual secondary outcomes of all bleeding, intracerebral hemorrhage, or gastrointestinal bleeding also demonstrated no significant difference between DOACs and traditional anticoagulation. Use of DOACs in patients with mild to moderate cirrhosis carries similar risk to use of traditional anticoagulation.

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Autopsy and statistical evidence of disturbed hemostasis progress in COVID-19: medical records from 407 patients

BackgroundThe progression of coagulation in COVID-19 patients with confirmed discharge status and the combination of autopsy with complete hemostasis parameters have not been well studied.ObjectiveTo clarify the thrombotic phenomena and hemostasis state in COVID-19 patients based on epidemiological statistics combining autopsy and statistical analysis.MethodsUsing autopsy results from 9 patients with COVID-19 pneumonia and the medical records of 407 patients, including 39 deceased patients whose discharge status was certain, time-sequential changes in 11 relevant indices within mild, severe and critical infection throughout hospitalization according to the Chinese National Health Commission (NHC) guidelines were evaluated. Statistical tools were applied to calculate the importance of 11 indices and the correlation between those indices and the severity of COVID-19.ResultsAt the beginning of hospitalization, platelet (PLT) counts were significantly reduced in critically ill patients compared with severely or mildly ill patients. Blood glucose (GLU), prothrombin time (PT), activated partial thromboplastin time (APTT), and D-dimer levels in critical patients were increased compared with mild and severe patients during the entire admission period. The International Society on Thrombosis and Haemostasis (ISTH) disseminated intravascular coagulation (DIC) score was also high in critical patients. In the relatively late stage of nonsurvivors, the temporal changes in PLT count, PT, and D-dimer levels were significantly different from those in survivors. A random forest model indicated that the most important feature was PT followed by D-dimer, indicating their positive associations with disease severity. Autopsy of deceased patients fulfilling diagnostic criteria for DIC revealed microthromboses in multiple organs.ConclusionsCombining autopsy data, time-sequential changes and statistical methods to explore hemostasis-relevant indices among the different severities of the disease helps guide therapy and detect prognosis in COVID-19 infection.

Diagnosis and management of von Willebrand disease: A community-wide effort to deliver evidence-based clinical practice guidelines.

Diagnosis and management of von Willebrand disease: A community-wide effort to deliver evidence-based clinical practice guidelines.

Low Dose Rivaroxaban for Atherosclerotic Cardiovascular Diseases: A Systematic Review and Meta-analysis.

Background: This study aims to explore the role of low-dose rivaroxaban (≤10 mg daily) for the treatment of atherosclerotic cardiovascular disease (ASCVD). Methods: PubMed, Embase and the Cochrane Library were searched for randomized controlled trials (RCTs) of low-dose rivaroxaban in patients with ASCVD including coronary artery disease (CAD) and peripheral artery disease (PAD). Literature screening, data extraction, and risk of bias assessment were carried out independently by two researchers. Hazard ratio (HR) and 95% confidence interval (CI) were calculated using random-effect models to determine risks of outcomes in ASCVD patients treated with rivaroxaban and comparators, and meta-analysis was conducted via Review Manager 5.3.5 software. Results: 3,768 records were obtained through literature search, and 9 articles representing 6 RCTs ultimately qualified for this study. The meta-analysis indicated that for patients with CAD, the addition of rivaroxaban (5 mg daily) to aspirin could significantly reduce the risk of major adverse cardiovascular events (MACEs) compared with aspirin alone (HR 0.81, 95% CI, 0.72 to 0.91, p = 0.0004, I2 = 60%, 4 studies). For PAD patients receiving rivaroxaban (5 mg daily) plus aspirin, there was no significant reduction in the risk of MACEs (HR 0.84, 95% CI, 0.63 to 1.13, p = 0.25, I2 = 74%, 2 studies); however, there was significant reduction in major adverse limb events (MALEs) (HR 0.54, 95% CI, 0.35 to 0.83, p = 0.005, one studies) and in the composite of MACEs or MALEs (HR 0.78, 95% CI, 0.64 to 0.95, p = 0.02, I2 = 66%, 2 studies) when compared with patients receiving aspirin alone. Meanwhile, rivaroxaban combined with aspirin significantly increased the risk of International Society on Thrombosis and Haemostasis (ISTH) major bleeding compared with aspirin alone in patients with CAD (HR 1.74, 95% CI, 1.43 to 2.13, p < 0.00001, I2 = 0%, 2 studies) and PAD (HR 1.47, 95% CI, 1.19 to 1.83, p = 0.0004, I2 = 0%, 2 studies). Conclusions: Compared with standard antiplatelet therapy, the addition of a 5 mg daily dose of rivaroxaban to standard antiplatelet therapy may improve cardiovascular or limb outcomes of patients with ASCVD, with an increase in major bleeding. Patients who would benefit from the addition of low-dose rivaroxaban to antiplatelet agents and appropriate dual-pathway antithrombotic strategies should be identified in clinical practice to individualize antithrombotic therapy.

Diagnosis and treatment of disseminated intravascular coagulation in COVID-19 patients: a scoping review.

BackgroundDisseminated intravascular coagulation (DIC) is noted in severe cases of coronavirus disease 2019 (COVID-19). Recently, a number of studies evaluating the diagnosis and treatment of DIC in COVID-19 patients have been reported.ObjectiveThe aim of this study is to identify existing gaps where further research is needed on the diagnosis and treatment of DIC complicated by COVID-19.MethodsWe used the PRISMA Extension for Scoping Reviews. MEDLINE, CENTRAL, WHO-ICTRP, ClinicalTrial.gov and PROSPERO were searched from their inception to 6 October 2020.ResultsSeven studies were selected; five were already published and two are ongoing. DIC was diagnosed using the International Society on Thrombosis and Hemostasis (ISTH) DIC score (n = 4) and the sepsis-induced coagulopathy (SIC) DIC score (n = 5). Seven studies examined the effectiveness of low molecular weight heparin (LMWH); of these, four studies used a prophylactic dose and five used a therapeutic dose of LMWH. A prophylactic dose of unfractionated heparin (UFH) was investigated in two studies.ConclusionStudies on DIC diagnostic criteria and anticoagulants were limited to the ISTH or SIC scores and heparinoids, particularly LMWH. Further studies are needed to compare these with other available DIC scoring systems and anticoagulants.

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ASH ISTH NHF WFH 2021 guidelines on the management of von Willebrand disease.

von Willebrand disease (VWD) is a common inherited bleeding disorder. Significant variability exists in management options offered to patients. These evidence-based guidelines from the American Society of Hematology (ASH), the International Society on Thrombosis and Haemostasis (ISTH), the National Hemophilia Foundation (NHF), and the World Federation of Hemophilia (WFH) are intended to support patients, clinicians, and health care professionals in their decisions about management of VWD. ASH, ISTH, NHF, and WFH formed a multidisciplinary guideline panel. Three patient representatives were included. The panel was balanced to minimize potential bias from conflicts of interest. The University of Kansas Outcomes and Implementation Research Unit and the McMaster Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline development process, including performing and updating systematic evidence reviews (through November 2019). The panel prioritized clinical questions and outcomes according to their importance to clinicians and patients. The panel used the GRADE approach, including GRADE Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. The panel agreed on 12 recommendations and outlined future research priorities. These guidelines make key recommendations regarding prophylaxis for frequent recurrent bleeding, desmopressin trials to determine therapy, use of antiplatelet agents and anticoagulant therapy, target VWF and factor VIII activity levels for major surgery, strategies to reduce bleeding during minor surgery or invasive procedures, management options for heavy menstrual bleeding, management of VWD in the context of neuraxial anesthesia during labor and delivery, and management in the postpartum setting.