Illustrated State-of-the-Art Capsules of the ISTH 2023 Congress.

This year's Congress of the International Society of Thrombosis and Haemostasis (ISTH) took place in person in Montréal, Canada, from June 24-28, 2023. The conference, held annually, highlighted cutting-edge advances in basic, translational, population and clinical sciences relevant to the Society. As for all ISTH congresses, we offered a special, congress-specific scientific theme; this year, the special theme was immunothrombosis. Certainly, over the last few years, COVID-19 infection and its related thrombotic and other complications have renewed interest in the concepts of thromboinflammation and immunothrombosis; namely, the relationship between inflammation, infection and clotting. Other main scientific themes of the Congress included Arterial Thromboembolism, Coagulation and Natural Anticoagulants, Diagnostics and Omics, Fibrinolysis and Proteolysis, Hemophilia and Rare Bleeding Disorders, Hemostatic System in Cancer, Inflammation and Immunity, Pediatrics, Platelet Disorders, von Willebrand Disease and Thrombotic Microangiopathies, Platelets and Megakaryocytes, Vascular Biology, Venous Thromboembolism and Women's Health. Among other sessions, the program included 28 State-of-the-Art (SOA) sessions with a total of 84 talks given by internationally recognized leaders in the field. SOA speakers were invited to prepare brief illustrated reviews of their talks that were peer reviewed and are included in this article. These illustrated capsules highlight the major scientific advances with potential to impact clinical practice. Readers are invited to take advantage of the excellent educational resource provided by these illustrated capsules. They are also encouraged to use the image in social media to draw attention to the high quality and impact of the science presented at the Congress.

Colorectal cancer screening in patients with inherited bleeding disorders: high cancer detection rate in hemophilia patients.

BACKGROUND: The population-based colorectal cancer (CRC) screening program in individuals aged 55 to 75 years in the Netherlands uses fecal immunochemical testing (FIT), to detect hemoglobin in feces, followed by colonoscopy in individuals with a positive FIT. OBJECTIVES: The objectives of this study are to assess the false-positive rate, detection rate, and positive predictive value of FIT for CRC and advanced adenoma (AA) in patients with Von Willebrand disease (VWD) or hemophilia. METHODS: We performed a multicenter, nationwide cross-sectional study embedded in 2 nationwide studies on VWD and hemophilia in the Netherlands. RESULTS: In total, 493 patients with hemophilia (n = 329) or VWD (n = 164) were included, of whom 351 patients participated in the CRC screening program (71.2%). FIT positivity and false-positive rate in patients with hemophilia and VWD were significantly higher than those in the general population (14.8% vs. 4.3%, p < .001 and 10.3% vs. 2.3%, p <.001, respectively). In patients with hemophilia, the detection rate of CRC/AA was significantly higher than that in the general male population (4.5% vs. 1.8%, p = .02), and the positive predictive value of FIT for CRC/AA was comparable (32.3% vs. 39.7%, n.s.). In patients with VWD, the detection rate was similar to that of the general population (0.8% vs. 1.4%, n.s.), whereas the positive predictive value was significantly lower than that in the general population (6.3% vs. 36.8%, p = .02). CONCLUSION: This study indicates that despite a high false-positive rate of FIT in patients with inherited bleeding disorders, the detection rate of CRC and/or AA in hemophilia patients is high. FIT performs different in patients with hemophilia or VWD compared with the general population.

Patient-Centered Digital Health Records and Their Effects on Health Outcomes: Systematic Review.

BACKGROUND: eHealth tools such as patient portals and personal health records, also known as patient-centered digital health records, can engage and empower individuals with chronic health conditions. Patients who are highly engaged in their care have improved disease knowledge, self-management skills, and clinical outcomes. OBJECTIVE: We aimed to systematically review the effects of patient-centered digital health records on clinical and patient-reported outcomes, health care utilization, and satisfaction among patients with chronic conditions and to assess the feasibility and acceptability of their use. METHODS: We searched MEDLINE, Cochrane, CINAHL, Embase, and PsycINFO databases between January 2000 and December 2021. PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines were followed. Eligible studies were those evaluating digital health records intended for nonhospitalized adult or pediatric patients with a chronic condition. Patients with a high disease burden were a subgroup of interest. Primary outcomes included clinical and patient-reported health outcomes and health care utilization. Secondary outcomes included satisfaction, feasibility, and acceptability. Joanna Briggs Institute critical appraisal tools were used for quality assessment. Two reviewers screened titles, abstracts, and full texts. Associations between health record use and outcomes were categorized as beneficial, neutral or clinically nonrelevant, or undesired. RESULTS: Of the 7716 unique publications examined, 81 (1%) met the eligibility criteria, with a total of 1,639,556 participants across all studies. The most commonly studied diseases included diabetes mellitus (37/81, 46%), cardiopulmonary conditions (21/81, 26%), and hematology-oncology conditions (14/81, 17%). One-third (24/81, 30%) of the studies were randomized controlled trials. Of the 81 studies that met the eligibility criteria, 16 (20%) were of high methodological quality. Reported outcomes varied across studies. The benefits of patient-centered digital health records were most frequently reported in the category health care utilization on the "use of recommended care services" (10/13, 77%), on the patient-reported outcomes "disease knowledge" (7/10, 70%), "patient engagement" (13/28, 56%), "treatment adherence" (10/18, 56%), and "self-management and self-efficacy" (10/19, 53%), and on the clinical outcome "laboratory parameters," including HbA1c and low-density lipoprotein (LDL; 16/33, 48%). Beneficial effects on "health-related quality of life" were seen in only 27% (4/15) of studies. Patient satisfaction (28/30, 93%), feasibility (15/19, 97%), and acceptability (23/26, 88%) were positively evaluated. More beneficial effects were reported for digital health records that predominantly focus on active features. Beneficial effects were less frequently observed among patients with a high disease burden and among high-quality studies. No unfavorable effects were observed. CONCLUSIONS: The use of patient-centered digital health records in nonhospitalized individuals with chronic health conditions is potentially associated with considerable beneficial effects on health care utilization, treatment adherence, and self-management or self-efficacy. However, for firm conclusions, more studies of high methodological quality are required. TRIAL REGISTRATION: PROSPERO (International Prospective Register of Systematic Reviews) CRD42020213285; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=213285.

Treatment-related risk factors for inhibitor development in non-severe hemophilia A after 50 cumulative exposure days: A case-control study.

BACKGROUND: Non-severe hemophilia A patients have a life-long inhibitor risk. Yet, no studies have analyzed risk factors for inhibitor development after 50 factor VIII (FVIII) exposure days (EDs). OBJECTIVES: This case-control study investigated treatment-related risk factors for inhibitor development in non-severe hemophilia A and assessed whether these risk factors were different for early versus late inhibitor development. PATIENTS/METHODS: Non-severe hemophilia A patients (FVIII:C 2%-40%) were selected from the INSIGHT study. Inhibitor-positive patients were defined as early (<50 EDs) or late (>50EDs) cases and matched to 1-4 inhibitor-negative controls by year of birth, cumulative number of EDs, and center/country. We investigated treatment intensity during the last 10 EDs prior to inhibitor development. Intensive treatment was defined as: surgery, peak treatment (10 consecutive EDs), and high mean FVIII dose (>45 IU/kg/ED). Odds ratios (OR) were calculated by logistic regression. RESULTS: Of 2709 patients, we analyzed 63 early and 26 late cases and 195 and 71 respectively matched controls. Peak treatment was associated with early and late inhibitor risk (crude OR 1.8, 95% confidence interval [CI] 1.0-3.4; 4.0, 95%CI 1.1-14.3). This association was slightly less pronounced after adjustment for mean FVIII dose. High mean FVIII dose was also associated with early and late inhibitor risk (crude OR 2.8, 95%CI 1.5-5.1; 4.5, 95%CI 1.2-16.6). Surgery increased inhibitor risk for early cases. This was less pronounced for late cases. CONCLUSIONS: Our findings suggest that intensive FVIII treatment remains a risk factor for inhibitor development in non-severe hemophilia A after more than 50 EDs. Therefore, persistent caution is required throughout the life-time treatment course.

Mortality, life expectancy, and causes of death of persons with hemophilia in the Netherlands 2001-2018.

BACKGROUND: Treatment of patients with hemophilia has advanced over the past decades, but it is unknown whether this has resulted in a normal life expectancy in the Netherlands. OBJECTIVE: This observational cohort study aimed to assess all-cause and cause-specific mortality in patients with hemophilia in the Netherlands between 2001 and 2018 and to compare mortality and life expectancy with previous survival assessments from 1973 onward. PATIENTS/METHODS: All 1066 patients with hemophilia who participated in a nationwide survey in 2001 were followed until July 2018. RESULTS: Information on 1031 individuals (97%) was available, of whom 142 (14%) deceased during follow-up. Compared with the general Dutch male population, mortality of patients with hemophilia was still increased (standardized mortality ratio: 1.4, 95% confidence interval: 1.2-1.7). Intracranial bleeding and malignancies were the most common causes of death. Estimated median life expectancy of patients with hemophilia was 77 years, 6 years lower than the median life expectancy of the general Dutch male population (83 years). Over the past 45 years, death rates of patients with hemophilia have consistently decreased, approaching the survival experience of the general population. Over the past decades, mortality due to human immunodeficiency virus and hepatitis C virus infections has decreased, death due to intracranial hemorrhages has increased, and death due to ischemic heart disease has remained consistently low over time. CONCLUSIONS: Survival in patients with hemophilia in the Netherlands has improved over time but is still lower than that of the general population.

Antibody therapies for lymphoma in children.

BACKGROUND: Lymphomas are the third most common malignancy in childhood. Cure rates are high but have reached a plateau. Therefore new treatment modalities should be developed. Antibody therapy is a successful new treatment option in adult lymphoma. However, none of the therapeutic antibodies available for adults with cancer have been approved for treatment of paediatric lymphoma. OBJECTIVES: To assess the efficacy of antibody therapy for childhood lymphoma in terms of survival, response and relapse rates, compared with therapy not including antibody treatment. To assess quality of life and the occurrence of adverse effects caused by antibody therapy treatment in children compared with therapy not including antibody treatment. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL, 2014, Issue 10), MEDLINE in PubMed (from 1945 to October 2014), EMBASE in EMBASE.com (from 1980 to October 2014) and reference lists of relevant articles. Furthermore, we searched conference proceedings abstracts of SIOP, ASCO and ASH for studies from 2009 to 2013), and the World Health Organization (WHO) ICTRP portal and ClinicalTrials.gov for ongoing trials. SELECTION CRITERIA: Randomised controlled trials and controlled clinical trials comparing conventional therapy with antibody therapy in children with lymphoma. DATA COLLECTION AND ANALYSIS: Two authors independently performed the study selection. MAIN RESULTS: We found no studies meeting the inclusion criteria of the review. AUTHORS' CONCLUSIONS: At this moment, it is not possible to draw evidence-based conclusions regarding clinical practice. Phase I and II studies show a positive effect of using antibody therapy in childhood lymphoma. Further research is needed to evaluate and implement antibody therapy for paediatric lymphoma.

Intensity of factor VIII treatment and inhibitor development in children with severe hemophilia A: the RODIN study.

The objective of this study was to examine the association of the intensity of treatment, ranging from high-dose intensive factor VIII (FVIII) treatment to prophylactic treatment, with the inhibitor incidence among previously untreated patients with severe hemophilia A. This cohort study aimed to include consecutive patients with a FVIII activity < 0.01 IU/mL, born between 2000 and 2010, and observed during their first 75 FVIII exposure days. Intensive FVIII treatment of hemorrhages or surgery at the start of treatment was associated with an increased inhibitor risk (adjusted hazard ratio [aHR], 2.0; 95% confidence interval [CI], 1.3-3.0). High-dose FVIII treatment was associated with a higher inhibitor risk than low-dose FVIII treatment (aHR, 2.3; 95% CI, 1.0-4.8). Prophylaxis was only associated with a decreased overall inhibitor incidence after 20 exposure days of FVIII. The association with prophylaxis was more pronounced in patients with low-risk F8 genotypes than in patients with high-risk F8 genotypes (aHR, 0.61, 95% CI, 0.19-2.0 and aHR, 0.85, 95% CI, 0.51-1.4, respectively). In conclusion, our findings suggest that in previously untreated patients with severe hemophilia A, high-dosed intensive FVIII treatment increases inhibitor risk and prophylactic FVIII treatment decreases inhibitor risk, especially in patients with low-risk F8 mutations.

The multifactorial etiology of inhibitor development in hemophilia: genetics and environment.

The most important complication in the treatment of hemophilia A patients today is the development of inhibitory antibodies against infused factor VIII (FVIII). Inhibitor development is caused by a complex interplay between both genetic and environmental factors. The risk of developing inhibitors is greatest in previously untreated patients with severe hemophilia A. Several genetic factors, such as a positive family history of inhibitors, ethnicity, FVIII genotype, and certain polymorphisms in immune modulatory genes, are associated with the risk of inhibitor development. Treatment-related factors, such as intensive treatment with FVIII for bleeds or surgery, are associated with a higher inhibitor risk. However, regular prophylaxis seems to have a protective effect on inhibitor development. Knowledge about the risk factors of inhibitor development is a condition for predicting and in the future possibly even preventing the development of inhibitors in patients with severe hemophilia A. This review summarizes the current knowledge on the potential risk factors of inhibitor development. At present, many uncertainties still remain that will require collaborative investigation.