Search

Background: Women with von Willebrand disease (VWD) often face diagnostic delays, leading to increased bleeds, stress, and healthcare use. The factors influencing these delays and their effects on gynecologic outcomes are not well understood., Objectives: This study aimed to 1) identify the prevalence and predictors of diagnostic delays and loss to follow-up in women with VWD and 2) determine how these delays affect severe gynecologic bleeding, emergency visits, transfusions, and hysterectomies., Methods: We conducted a single-center retrospective cohort study and included women aged ≥18 years diagnosed with VWD. Delayed diagnosis was defined as ≥3 bleeding events prior to VWD diagnosis, excluding easy bruising due to its subjectivity. Loss to follow-up was defined as ≥5 years since the last hematology visit. We used logistic regression for analysis., Results: Among 178 diagnosed women (median age, 27 years), 71 (40%) experienced ≥3 bleeding events before diagnosis. The median time from the first bleeding event to VWD diagnosis was 14.2 years. Severe bleeding events significantly predicted diagnostic delays (adjusted odds ratio, 3.1; 95% CI, 1.5-6.2). Fifty-four (30%) women were lost to follow-up, with remote era of initial bleed and VWD type identified as significant predictors. Delays were associated with increased risks of hysterectomies (odds ratio, 2.7; 95% CI, 1.2-6.3) and other gynecologic procedures., Conclusion: Delayed diagnosis and loss to follow-up in VWD are common even in a specialized Hemophilia Treatment Centre. Such delays lead to more severe bleeding and increased gynecologic interventions. Prompt diagnosis is paramount for better patient outcomes and reduced healthcare utilization., (© 2024 The Authors.)

Introduction: Treatment selection in haemophilia is increasingly challenging given evolving therapeutic options and the need for individualization. Shared decision-making (SDM) approaches have recently gained interest, though a synthesis of available studies is lacking., Aim: A scoping review was conducted to summarize literature reporting on factors impacting treatment SDM in haemophilia and tools or models available to support such decisions., Methods: PubMed, Embase, the Cochrane Library, Web of Science and grey literature were searched for studies published through August 2023. Original studies reporting on facilitators and barriers to haemophilia SDM and SDM tools were included and analyzed for themes, characteristics and gaps., Results: A total of 625 records were identified and 14 unique studies were selected (factors influencing treatment SDM, n = 7; SDM tools, n = 7). The studies typically included input from persons with haemophilia, caregivers and healthcare practitioners (HCPs). Thematic organization of factors influencing SDM revealed three main categories: knowledge, patient characteristics and HCP-patient interactions. Availability of information was a commonly reported facilitator of SDM, while poor HCP-patient engagement was a commonly reported barrier. Tools varied in focus, with some facilitating general treatment SDM while others supported selection of certain therapy types. The studies underscored additional factors critical for SDM, such as alignment of HCP-patient perceptions, shared language and tailoring of tools to specific subpopulations., Conclusion: Few studies report on treatment SDM factors and tools in haemophilia; available tools vary considerably. It remains unclear whether published tools have been successfully implemented into clinical practice. Additional research is warranted., (© 2024 The Authors. Haemophilia published by John Wiley & Sons Ltd.)

Introduction: Increasing rate of postpartum haemorrhage (PPH) has been observed between 2003 and 2010 in Canada. Inherited bleeding disorders contribute to the risk of PPH., Aim: To identify the trend in PPH in the last decade, assess the impact of bleeding disorders on pregnancy outcomes and evaluate their coagulation workup during pregnancy., Methods: We conducted a population-based retrospective cohort study using the Alberta Pregnancy Birth Cohort from 2010 to 2018. We included women with von Willebrand disease (VWD) and haemophilia, identified by previously validated algorithm and matched with controls. Logistic regression was used to compute odds of PPH and other pregnancy outcomes., Results: We identified 311,330 women with a total of 454,400 pregnancies with live births. The rate of PPH did not change significantly from 10.13 per 100 deliveries (95% CI 10.10-10.16) in 2010-10.72 (95% CI 10.69-10.75) in 2018 (p for trend = .35). Women with bleeding disorders were significantly more likely to experience PPH (odds ratio [OR] 2.3; 95% CI 1.5-3.6), antepartum haemorrhage (OR 2.9; 95% CI 1.5-5.9) and red cell transfusion (OR 2.8; 95% CI 1.1-7.0). We observed a nonsignificant rise in the rate of PPH in women with VWD and haemophilia. Only 49.5% pregnancies with bleeding disorders had third trimester coagulation factor levels checked. Higher odds of PPH and antepartum haemorrhage were observed even with factor levels ≥0.50 IU/mL in third trimester., Conclusion: Despite comprehensive care in women with bleeding disorders, they are still at higher risk of adverse pregnancy outcomes compared to population controls., (© 2024 John Wiley & Sons Ltd.)

Introduction: Individuals with sickle cell disease (SCD) and central venous catheters (CVC) are at high risk for venous thromboembolism (VTE). Minimal data exist regarding the use of anticoagulation as thromboprophylaxis of VTE in this demographic, and as a result, clinical equipoise exists. Prophylactic dose rivaroxaban, a direct oral anticoagulant, is efficacious and safe as thromboprophylaxis in other demographics, and may be an optimal agent in SCD with CVC. Prior to conducting a full clinical trial to assess rivaroxaban as thromboprophylaxis in SCD with CVC, a pilot study is needed to gauge its feasibility., Methods and Analysis: THromboprophylaxis In Sickle Cell Disease pilot trial is an investigator-initiated, multicentre, double-blinded, randomised controlled trial (RCT) assessing if it is feasible and safe to conduct an adequately powered RCT comparing rivaroxaban to matching placebo as thromboprophylaxis in those with SCD and CVC. Fifty adult patients with SCD and CVC will be randomised to receive either rivaroxaban 10 mg daily or matching placebo for the duration of the CVC in situ for up to 1 year. After randomisation, follow-up visits will occur every 3 months. The primary outcomes pertain to the feasibility of a full trial and include numbers of eligible and recruited participants. Exploratory outcomes include overall incidence of VTE and bleeding complications, as well as quality of life. If the full trial is feasible, blinding will be maintained and patients in the pilot study will be included in the full trial., Ethics and Dissemination: The trial was initially approved by the University Health Network Research Ethics Board (REB) in Toronto, Canada. All sites will obtain approval from their respective REB prior to commencement of study activities. Study results will be disseminated through presentations at medical conferences and peer-reviewed publications., Trial Registration Number: NCT05033314., Competing Interests: Competing interests: SF has received research funding from the Canadian Hematology Society, and PFIZER; Honoraria from Novartis; and Consultancy fees from Novo Nordisk and Vertex. PB has received research funding from Bluebird, NOVARTIS, ROCHE Fabre Foundation and ADDMEDICA; Consultancy fees from AGIOS, EMMAUS, GBT, ROCHE, HEMANEXT, Bluebird, NOVARTIS, and ADDMEDICA; lecture fees from Jazz Pharma, NOVARTIS, and ADDMEDICA; is the cofounder of INNOVHEM, is on steering committees for NOVARTIS, ROCHE, ADDMEDICA, and PFIZER. KHMK has received research funding from AGIOS and PFIZER; Consulting fees from Alexion Pharmaceuticals, AGIOS, Bristol Myers Squibb, Forma Therapeutics, Pfizer, Novo Nordisk, and Vertex; Honoraria for speaking from AGIOS, and Bristol Myers Squibb; and is a member of a Data Safety Monitoring Board or Advisory Board for Bioverativ/Sanofi/Sangamo. The other authors have no competing interests to declare., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Introduction: Improvements in treatment strategies have led to increased life expectancy of persons with haemophilia (PWH). Consequently, age-related comorbidities become increasingly relevant., Aim: To evaluate the prevalence of age-related comorbidities, mortality, health service utilisation and predictors of hospitalisation in PWH compared to the general population., Methods: We conducted a population-based retrospective cohort study using linked administrative data. Men with haemophilia were identified in Alberta, Canada (2012-2019) with a validated case definition and were age-matched with male population controls. We calculated the prevalence of major comorbidities, all-cause mortality, and examined health service utilisation including Emergency Department visits and hospitalisations. Logistic regression was applied to identify predictors of hospitalisation., Results: We identified 198 and 329 persons with moderately severe haemophilia and mild/moderate, respectively. Moderately severe haemophilia had a higher risk of death (standardised mortality ratio 3.2, 95% confidence interval [CI] 1.4-6.3) compared to the general population. PWH had a significantly higher prevalence of hypertension, liver diseases and malignancies than controls. Moderately severe haemophilia was associated with significantly higher rates of hospitalisations (52.5% vs. 14.5%), Emergency Department visits (89.1% vs. 62.7%) and intensive care admissions (8.9% vs. 2.3%). Age > 65 years (adjusted odds ratio [aOR] 6.8) and presence of multiple comorbidities (aOR 3.9) were significant predictors of hospitalisations among PWH., Conclusion: Despite advanced care, haemophilia is associated with higher acute care utilisation than the general population, highlighting the substantial burden of illness on patients and the health care system., (© 2022 John Wiley & Sons Ltd.)

Background: Immune thrombocytopenia (ITP) is a diagnosis of exclusion that can resemble other thrombocytopenic disorders., Objectives: To develop a clinical prediction model (CPM) for the diagnosis of ITP to aid hematogists in investigating patients presenting with undifferentiated thrombocytopenia., Methods: We designed a CPM for ITP diagnosis at the time of the initial hematology consultation using penalized logistic regression based on data from patients with thrombocytopenia enrolled in the McMaster ITP registry (n = 523) called the Predict-ITP Tool. The case definition for ITP was a platelet count less than 100 × 10 9 /L and a platelet count response after high-dose corticosteroids or intravenous immune globulin, defined as the achievement of a platelet count above 50 × 10 9 /L and at least a doubling of baseline. Internal validation was done using bootstrap resampling. Model discrimination was assessed by the c-statistic, and calibration was assessed by the calibration slope, calibration-in-the-large, and calibration plot., Results: The final model included the following variables: (1) platelet count variability (based on three or more platelet count values), (2) lowest platelet count value, (3) maximum mean platelet volume, and (4) history of major bleeding (defined by the ITP bleeding scale). The optimism-corrected c-statistic was 0.83, the calibration slope was 0.88, and calibration-in-the-large for all performance measures was <0.001 with standard error <0.001, indicating good discrimination and excellent calibration., Conclusions: The Predict-ITP Tool can estimate the likelihood of ITP for a given patient with thrombocytopenia at the time of the initial hematology consultation. The tool had high predictive accuracy for the diagnosis of ITP., (© 2022 International Society on Thrombosis and Haemostasis.)

Introduction: The reasons for the high prevalence of hypertension in persons with haemophilia (PWH) are poorly understood., Aim: To examine the roles of diabetes, Hepatitis C Virus (HCV) and Human Immunodeficiency Virus (HIV) in the etiology of hypertension for PWH., Methods: Retrospective cross-sectional design. Adult PWH (n = 691) were divided into two groups: (A) free of diabetes, HCV and HIV; (B) with diabetes and/or HCV positivity and/or HIV positivity. Each group was matched by race and age with random samples from the general population of the US (National Health and Nutrition Examination Surveys, NHANES) and outpatients at the Veterans Affairs Medical Center (VAMC) in San Diego. Generalized additive models (GAMs) were fitted for graphical analysis of hypertension risk over the lifespan., Results: In Group A, PWH had the highest prevalence of hypertension compared to NHANES and VAMC, especially in young adults. In Group B, diabetes increased the risk of hypertension for all three cohorts (PWH, NHANES and VAMC), especially for PWH. In PWH, hypertension risk was also increased by HIV, in NHANES by HCV, and in VAMC by HCV and HIV., Conclusion: Diabetes conferred the greatest risk of hypertension for all three cohorts. However, curves of hypertension in relation to age revealed that diabetes, HCV and HIV modulated hypertension risk differently in PWH. PWH experienced a disproportionally high risk increase with diabetes. Therefore, haemophilia care should include screening for hypertension and diabetes at a young age., (© 2022 John Wiley & Sons Ltd.)

Introduction: Persons with haemophilia (PWH) have a higher prevalence of hypertension compared to the general population, which cannot be explained entirely by the usual cardiovascular risk factors. Neutralizing antibodies (inhibitors) against clotting factors might have some relation to cardiovascular disease in PWH. However, whether inhibitors facilitate hypertension is unknown., Aim: We investigated the relationship between hypertension/blood pressure and inhibitors in PWH. Additional goals were to determine the relationships with haemophilia type, race, and viral status., Methods: Records were extracted retrospectively for PWH (age ≥18 years) between 2003 and 2014 from four Hemophilia Treatment Centers in North America and included demographics, weight, height, haemophilia type/severity, HCV and HIV infection status, hypertension, use of anti-hypertensive medications, and inhibitor status. We fitted semiparametric generalized additive models (GAMs) to describe adjusted curves of blood pressure (BP) against age., Results: Among 691 PWH, 534 had haemophilia A and 157 had haemophilia B, with a median age of 39 years (range 18 to 79). Forty-four PWH (6.5%) had a history of inhibitors, without evidence for a higher prevalence of hypertension or higher BP. A higher prevalence of hypertension and higher BP were noted for haemophilia A (vs. haemophilia B), coinfection with HCV/HIV (vs. uninfected), or moderate haemophilia (vs. severe haemophilia)., Conclusion: While there was no signal to suggest that a history of inhibitors is associated with hypertension, differences based on haemophilia type, severity, and viral infection status were identified, encouraging prospective investigations to better delineate haemophilia-specific risk factors for hypertension., (© 2022 John Wiley & Sons Ltd.)

The "therapeutic relationship" in physiotherapy refers to the beneficial or healing relationship between the patient and physiotherapist. Interest in researching therapeutic relationships in physiotherapy is growing and there is a need for a measure of therapeutic relationship with a strong conceptual foundation.  Body of paper: We begin with a general discussion of the state of therapeutic relationship measurement in physiotherapy research - notably, how current research is based on measures borrowed and adapted from psychotherapy. Then, we introduce Miciak's physiotherapy therapeutic relationship framework, discuss why it offers a solid foundation for measurement development, and describe the key concepts in the framework. We then discuss various approaches to measuring therapeutic relationship, illustrating how Miciak's framework could be used to inform their development. We end by discussing current challenges in measuring therapeutic relationship and how these could be addressed.

Hemophagocytic lymphohistiocytosis (HLH) is a heterogeneous, life-threatening clinical syndrome. There are scarce data on the quality of care in HLH or data comparing treatment patterns and outcomes between different triggers. We aimed to examine quality-of-care indicators and outcomes in adults with various HLH triggers. In this multi-centre retrospective cohort study of adult HLH in the province of Alberta, Canada (1999-2019), we examined quality indicators including diagnostic testing, time to diagnosis and treatment and trigger identification. We also compared treatment regimens and outcomes across HLH triggers. Logistic regression was used to identify predictors of etoposide use. Overall survival (OS) was estimated using the Kaplan-Meier method. We identified 97 patients; 66 (68%) were male. Triggers included malignancy (36%), infection (35%), autoimmune disease (21%) and idiopathic/others (8%). Specialized tests such as sCD25 (53%) and natural killer degranulation assay (19%) were under-performed, as were testing for infectious triggers. Etoposide was administered in only 33 (34%). Neutropenia, hyperbilirubinemia and hyperferritinemia, but not age, sex and comorbidities, were significant predictors of etoposide use. At median follow-up of 32 months, median OS was 18.8 months. Worse OS was seen in malignancy-associated and idiopathic HLH (log-rank P < 0.001). Our study showed low rates of specialized testing such as sCD25 and a low rate of etoposide use. Development of a standardized provincial protocol has the potential to improve quality of care in adult HLH., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: The diagnosis of immune thrombocytopenia (ITP) is one of exclusion. Although guidelines recommend against routine bone marrow examination (BME) at time of ITP diagnosis, the role of BME in relapsed/refractory ITP is unclear., Objectives: To examine the frequency and predictors of BME in relapsed/refractory ITP., Patients/methods: This multicenter retrospective cohort study included adults with ITP who received second-line therapy in Alberta, Canada from 2012 to 2019. We calculated the frequency of BME and rate of abnormal marrow findings. Logistic regression was performed to assess predictors of BME and predictors of bone marrow pathology., Results: Of 324 patients with presumed ITP, 181 (56%) underwent BME. We observed a marked decline in the rates of BME among patients >60 years over the past decade, but not in patients younger than age 60 years. On multivariable logistic regression, older age (adjusted OR [aOR] 1.03, p = .0001), anemia (aOR 2.5, p = .01), splenomegaly (aOR 3.2, p = .01), splenectomy (aOR 2.4, p = .02), and lack of splenectomy response (aOR 3.4, p = .04) were significant predictors of BME. Abnormal marrow findings were found in eight (2% of overall cohort; 4% of BME): four myelodysplastic syndrome, one aplastic anemia, one chronic lymphocytic leukemia, one metastatic cancer, and one megaloblastic anemia. Seven (88%) underwent BME for bicytopenias/pancytopenias. Macrocytosis (aOR 9.6, p = .03) and rural residence (aOR 6.7, p = .02) were independent predictors of abnormal bone marrow findings., Conclusions: Although routine BME is frequently performed in relapsed/refractory ITP, abnormal findings are rare. Future prospective studies are needed to help identify a subgroup of relapsed/refractory ITP who may benefit from BME., (© 2022 International Society on Thrombosis and Haemostasis.)

Timely diagnosis of hemophagocytic lymphohistiocytosis (HLH) is critical and relies on clinical judgment. The HLH-2004 criteria are commonly used diagnostic criteria, whereas HScore was recently developed for reactive HLH., Objective: In this external validation study, we sought to compare the diagnostic accuracy of the HLH-2004 criteria and HScore and identify optimal cutoffs stratified by underlying etiology., Methods: In this retrospective cohort of all hospitalized adults in Alberta, Canada, (1999-2019) who had ferritin >500 ng/ml and underwent either biopsies or soluble CD25 testing, we calculated the diagnostic accuracy of HLH-2004 and HScore for the overall population and different etiologies., Results: Of 916 patients, 98 (11%) had HLH. HLH-2004 criteria ≥5 predicted HLH with a sensitivity of 91%, specificity of 93%, positive predictive value of 90%, and negative predictive value of 94% (c-statistic 92%). HScore ≥169 predicted HLH with better sensitivity (96%) but reduced specificity (71%), whereas the optimal cutoff ≥200 performed comparably to HLH-2004. HLH-2004 criteria outperformed HScore in most etiologies, whereas HScore improved sensitivity in inflammatory/autoimmune-HLH. The optimal cutoff of HScore was higher in hematopoietic cell transplant due to higher prevalence of fevers and cytopenias., Conclusion: HLH-2004 criteria and HScore demonstrated excellent discriminatory power in identifying HLH. HScore may improve diagnostic accuracy in autoimmune-HLH., (© 2022 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Introduction: Ageing patients with haemophilia (PWH) develop cardiovascular risk factors impacting care. Little is known about the prevalence of diabetes in PWH and its relation to other comorbidities., Aim: To examine the risk of diabetes for adult PWH compared to men from the general United States population (National Health and Nutrition Examination Surveys [NHANES]) and outpatients attending a Veterans Affairs Medical Center (VAMC) clinic., Methods: Retrospective cross-sectional design. PWH from four haemophilia centres (n = 690) were matched with random samples from NHANES and VAMC. Diabetes (yes/no) was the outcome, while age, body mass index (BMI), race and Hepatitis C (HCV; by serology) and human immunodeficiency virus (HIV) positivity were covariates. We fitted semiparametric generalized additive models (GAMs) in order to compare diabetes risk between cohorts., Results: Younger PWH were at lower risk of diabetes than NHANES or VAMC subjects irrespective of BMI. However, the risk of diabetes rose in older PWH and was closely associated with HCV. For HCV-negative subjects, the risk of diabetes was considerably lower for PWH than NHANES and VAMC subjects. The difference persisted after controlling for BMI and age, indicating that the low risk of diabetes in PWH cannot be explained by lean body mass alone., Conclusion: Since many ageing PWH are HCV positive and therefore at heightened risk for diabetes, it is important to incorporate diabetes screening into care algorithms in Haemophilia Treatment Centers, especially since PWH are not always followed in primary care clinics., (© 2022 John Wiley & Sons Ltd.)

Background: The Canadian Bleeding Disorders Registry (CBDR) captures data from 24 hemophilia treatment centers and patients directly. Nonacog beta pegol (N9-GP) was approved in Canada in 2018., Objectives: To assess treatment outcomes following switching to N9-GP in a real-world setting., Methods: CBDR data for Canadian male patients (aged 7-72 years) with hemophilia B receiving prophylactic N9-GP for ≥6 months as of March 31, 2021, were included. To allow comparison with the previously used products, only patients for whom data were available in the CBDR for at least 6 months before the switch to N9-GP were included in this retrospective analysis., Results: Forty-two patients were included in the analysis (total observation period: 148.0 patient-years). The distribution of disease severity was 62% severe, 36% moderate, 2% mild, with 62% of patients previously receiving recombinant factor IX-Fc-fusion protein (rFIXFc) and 38% previously receiving standard half-life (SHL) recombinant factor IX (rFIX). During a median follow-up period of 2.3 years on N9-GP prophylaxis, 232 bleeds were reported in 30 patients, 29% of patients reported zero bleeds. The median overall annualized bleeding rate on N9-GP was 0.73 for patients switching from rFIXFc (previously 1.44) and 2.10 for patients switching from SHL rFIX (previously 6.06). Median total annualized factor consumption (IU/kg) was lower with N9-GP than with previous SHL rFIX (2152 vs 3018) and previous rFIXFc (1766 vs 2278)., Conclusions: Results from this first real-world study of N9-GP in patients with hemophilia B suggest optimal bleeding control with low factor consumption after switching to N9-GP, irrespective of the previous product., (© 2022 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Background: Hemophagocytic lymphohistiocytosis (HLH) is a rare syndrome characterized by uncontrolled immune activation and high risk of death. There is scarce data on the incidence of bleeding and thromboembolism in HLH., Objectives: To determine the cumulative incidence of bleeding and thromboembolism and impact on survival in adults with HLH., Patients/methods: We conducted a multicenter retrospective cohort study of adults with HLH in Alberta, Canada (1999-2019). The cumulative incidence of bleeding and thromboembolism were calculated, accounting for competing risks. Cox proportional hazards models were used to assess the impact of bleeding and thromboembolism on overall survival (OS)., Results: We identified 97 adults with HLH (median age 46 years). Venous thromboembolism (VTE) occurred in 11 (11%) patients at a median of 9 days from admission. ISTH major bleeding and clinically relevant non-major bleeding occurred in 39 (40%) patients, at a median of 16 days after admission. Nadir platelet count (adjusted odds ratio [aOR] 1.8 per log decrease, 95% confidence interval [CI] 1.2-2.8) and mechanical ventilation (aOR 4.9, 95% CI 1.8-14.8) were independent predictors of bleeding on multivariable analysis. Adjusting for competing risks, the 90-day cumulative incidences of bleeding and thromboembolism were 39% and 13%, respectively. The median OS was 18.8 months. VTE, but not bleeding, was significantly associated with adverse OS (adjusted hazard ratio 2.5, 95% CI 1.1-5.7)., Conclusions: In adults with HLH, VTE appears more common than previously described and is a predictor of mortality, although this may be due to unadjusted confounding. VTE prevention and treatment are challenging due to high bleeding rates., (© 2021 International Society on Thrombosis and Haemostasis.)

Introduction: Haemophilic arthropathy is a serious complication of haemophilia often requiring surgical intervention. It is unclear whether advances in comprehensive care are associated with a reduction in orthopaedic interventions and peri-procedural resource utilization., Aim: To determine temporal patterns of orthopaedic interventions in persons with haemophilia (PWH), and evaluate changes in healthcare utilization and outcomes., Methods: In this Canadian multicentre retrospective cohort study, adult PWH from Northern Alberta and British Columbia who underwent orthopaedic procedures (1990-2018) were included. Temporal changes in the type of procedures, length of stay (LOS), factor utilization and outcomes were examined., Results: Sixty-five patients (78% haemophilia A) underwent 102 surgeries at a median age of 46.3. Of the 46 severe PWH, 28 (61%) were on prophylaxis at time of surgery. The proportion of total knee arthroplasties (TKA) declined over time (56% 1990-1999, 51% 2000-2009, 27% 2010-2018), with a concomitant rise in ankle arthrodesis (0% 1990-1999, 18% 2000-2009, 27% 2010-2018). Over time, PWH underwent orthopaedic procedures at an older age (P = .02). There was a significant reduction in perioperative factor VIII utilization (P = .003) and median LOS (P < .0001). Major bleeds, prosthetic joint infections and thrombosis were not observed in the last decade., Conclusion: In the last three decades, there was a decline in the proportion of TKA, likely reflecting the impact of widespread use of tertiary prophylaxis. However, ankle arthrodesis rates increased, suggesting that higher trough levels may be required to prevent ankle arthropathy. We observed a significant reduction in LOS and factor utilization, reflecting improvements in perioperative management., (© 2021 John Wiley & Sons Ltd.)

Introduction: Improvements in haemophilia treatment over the last decades resulted in increased life expectancy in persons with haemophilia (PWH)., Aim: We conducted a systematic review and meta-analysis to examine all-cause mortality and causes of death among PWH., Methods: We systematically searched EMBASE, MEDLINE, Web of Science, CINAHL and Cochrane central register of controlled trials from inception through March 15, 2021. Studies that reported a mortality estimate of PWH compared with the general population and/or reported causes of death were included. Random-effects meta-analysis with inverse variance method was used to obtain pooled estimates. We stratified the analysis by the year of cohort entry (before 2000 vs after 2000)., Result: Of the 4769 studies identified, 52 met the eligibility criteria. The pooled all-cause standardized mortality ratio (SMR) from 9 studies in PWH was 1.93 (95% CI 1.38-2.70; I 2 = 97%). The pooled SMRs before and after the year 2000 were 2.40 (95% CI 1.92-3.00; I 2 = 87%) and 1.20 (95% CI 1.03-1.40; I 2 = 62%), respectively. Before the year 2000, 31.2% deaths occurred due to HIV followed by haemorrhage (26.0%), cardiovascular disease (18.2%), liver disease (9.0%), and cancer (8.9%). Fewer (13.9%) deaths were attributable to HIV after the year 2000 with the proportion of deaths due to haemorrhage remaining unchanged., Conclusion: With treatment advances, mortality in PWH has declined over the last few decades approaching that of the general population. However, haemorrhage remains a leading cause of death requiring further attention., (© 2021 John Wiley & Sons Ltd.)

Background: Recombinant factors VIII and IX Fc (rFVIIIFc/rFIXFc) were the only available extended half-life (EHL) products in Canada during 2016 to 2018., Objectives: To evaluate if patient-reported outcome measures (PROMs) improved in Canadian persons with hemophilia who switched from standard half-life (SHL) to EHL products (rFVIIIFc/rFIXFc)., Patients/methods: This prospective cohort study enrolled persons with moderate or severe hemophilia aged ≥6 years who switched to rFVIIIFc/rFIXFc (2016-2018) and those who remained on SHL. Health-related quality of life (HRQoL) was assessed using the Haemophilia-specific Quality of Life (Haem-A-QoL) and 36-item Short-Form Survey (SF-36) at baseline, 3-months, 12 months, and 24 months. Other PROMs included the Work Productivity and Impairment Questionnaire, chronic pain scale, partner/parent ratings of mood, International Physical Activity Questionnaire, and Treatment Satisfaction Questionnaire for Medication. We identified meaningful changes using minimally important difference for SF-36 and responder definition for Haem-A-QoL., Results: We enrolled 25 switchers (16 rFVIIIFc, 9 rFIXFc) and 33 nonswitchers. Those switched to rFVIIIFc/rFIXFc had improved overall HRQoL, and improved subscale physical activity, mental health, and social functioning at 3 months. The rFIXFc switchers had improved chronic pain and ability to engage in normal activities while the rFVIIIFc switchers had improved treatment satisfaction. There was no change in work impairment after the switch. Observed improvement disappeared by 24 months in most domains., Conclusion: Switching from SHL to rFVIIIFc/rFIXFc resulted in short-term meaningful improvement in overall HRQoL and other PROMs in a small proportion. Longitudinal changes on PROMs are affected by ceiling effects and response shift, warranting further studies in instrument optimization in the era of EHL and nonfactor products., (© 2021 The Authors. Research and Practice in Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis (ISTH).)

Introduction: Recombinant factors VIII and IX Fc (rFVIIIFc/rFIXFc) became available in Canada in 2016 and were the only extended half-life (EHL) factor concentrates available in Canada until 2018., Objectives: We aim to describe the change in product utilization in Canadians who switched to rFVIIIFc/rFIXFc., Methods: This prospective and retrospective cohort study enrolled males aged ≥6 years with moderate or severe haemophilia who switched to rFVIIIFc/rFIXFc and those who remained on standard half-life (SHL) between 2016 and 2018. Factor utilization and annualized bleeding rates (ABR) were collected at baseline, 1-year and 2-years. Due to low prospective enrolment (n = 25 switchers), prospective and retrospective data were pooled., Results: 125 switchers (93 rFVIIIFc, 32 rFIXFc) and 33 non-switchers were included. The median age was 17 (rFVIIIFc) and 38 years (rFIXFc). Prior to switch, over 80% were on prophylaxis. There was a statistically significant reduction in the prescribed weekly prophylactic dose after the switch to rFVIIIFc/rFIXFc for all age groups, with a corresponding reduction (15-16%) in actual annualized FIX utilization in switchers (combined adults and children) to rFIXFc, and a smaller non-significant reduction in actual annualized FVIIII utilization (7%) in children who switched to rFVIIIFc. A significant reduction in the median ABR was only observed in children who switched to rFVIIIFc, but not in adults who switched to rFVIIIFc or rFIXFc., Conclusion: Switching from SHL to EHL products led to a small reduction in factor utilization, while preserving a low ABR in children and adults with haemophilia. Further patient-reported outcomes data will further elucidate the role of EHL in the haemophilia landscape., (© 2021 John Wiley & Sons Ltd.)

Introduction: Administrative data is useful in population-based studies in hemophilia, but few studies validated the coding accuracy., Aim: We validated the accuracy of a case definition using a combination of International Classification of Diseases diagnostic codes and coagulation factor level for identifying hemophilia in administrative data., Methods: This is a retrospective population-based study of all residents of Alberta, Canada, who underwent testing for coagulation factor VIII (FVIII) or factor IX (FIX) activity between 2009 and 2017 using linked administrative data. Our predefined algorithm was a combination of the relevant ICD codes and FVIII/FIX activity <0.4 IU/ml. Medical charts of 2114 randomly selected patients tested for FVIII and 528 patients tested for FIX were reviewed to identify physician diagnoses of hemophilia. Sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) were calculated., Results: With our algorithm, 72 (3.4%) patients tested for FVIII and 21 (4.0%) tested for FIX met the combined ICD code and laboratory criteria for hemophilia A and hemophilia B, respectively, whereas 63 (3.0%) and 22 (4.2%) had confirmed hemophilia A and hemophilia B upon chart review. Our algorithm had a sensitivity of 93.7% and specificity of 99.4% for identifying hemophilia A, and a sensitivity of 90.9% and specificity of 99.8% for identifying hemophilia B., Conclusion: This study showed that using a case definition of ICD codes and coagulation factor activities can identify hemophilia in administrative data with very high accuracy and can be used for future research., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background: Hematologic malignancies are at increased risk of developing venous thromboembolism (VTE)., Objectives: We aimed to identify the prevalence of hematologic malignancy in VTE patients and compare the survival with or without VTE., Methods: Using linked administrative data and a validated algorithm we identified VTE cases in Alberta, Canada from 2003 to 2015. Subjects having International Classification of Diseases code for hematologic malignancies, solid tumors and both cancers within 1 year before and after the VTE index event were defined as cancer associated VTE cases. We also identified patients with no VTE. Cox proportional hazards model was applied to estimate the hazard ratio (HR) of death. Kaplan Meier analysis was performed to compare survival rate between different groups., Results: We identified 5157 cancer associated VTE patients and 24,932 cancer patients with no VTE. Among the cancer associated VTE patients 697 (13.5%), 4376 (84.9%) and 84 (1.6%) had hematologic malignancies, solid tumors and both cancers, respectively. The median survival (in months) was significantly shorter in myelodysplastic syndrome (MDS), myeloproliferative neoplasm (MPN) and plasma cell dyscrasia patients with VTE than those without (16.6 vs 27.1, p = 0.004; 70.6 vs 99.2, p = 0.023 and 32.9 vs 55.5, p = 0.007 respectively). Occurrence of pulmonary embolism in MDS and MPN patients and deep vein thrombosis in plasma cell dyscrasia patients were significantly associated with increased risk of death (adjusted HR: 3.0, 95% CI: 1. 46-6.16; adjusted HR 1.60, 95% CI:1.01-2.51 and adjusted HR: 1.40, 95% CI: 1.03-1.89 respectively)., Conclusions: VTE adversely affects the survival among patients with hematologic malignancies., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Guidelines are lacking for management of acute ischemic stroke and stroke prevention in patients with immune thrombocytopenia (ITP). Our aim is to highlight the dilemma inherent in managing patients with both significant bleeding and thrombotic risk factors. In this review, we present two patients with history of ITP who presented with acute ischemic stroke and received tissue plasminogen activator (tPA) and endovascular thrombectomy (EVT), a rare management strategy in this patient population. In addition, we identified 27 case reports of ischemic stroke in patients with ITP; none of them received tPA or EVT. Furthermore, there are 92 patients with significant thrombocytopenia with no available data regarding the cause of thrombocytopenia, who were acutely treated with tPA or EVT. Conclusive evidence cannot be determined based on these limited number of cases. Future multicenter prospective cohort studies in patients with ITP are needed to provide better evidence-based treatment plans. At present, treatment of acute ischemic stroke in patients with ITP requires close collaboration between hematology and vascular neurology experts to find a balance between the benefit and risk of hemorrhagic complications.

Background: Thrombotic thrombocytopenic purpura (TTP) is a life-threatening thrombotic microangiopathy (TMA) that requires prompt plasma exchange. Clinical prediction tools may facilitate decision-making in institutions with delayed turnaround time or limited access to ADAMTS13 assays. The PLASMIC score and Bentley score have been shown to predict severe ADAMTS13 deficiency with excellent sensitivity and specificity., Objectives: To validate the PLASMIC score using a population of suspected TTP, and evaluate its discriminatory power in predicting severe ADAMTS13 deficiency in comparison with Bentley score and clinical gestalt., Methods: Adults presenting with suspected TTP in Alberta, Canada between 2008 and 2018 with available ADAMTS13 results were included. The sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) were calculated for PLASMIC score, Bentley score and clinical gestalt. Receiver operator characteristics analysis assessed the performance of the scoring systems., Results: Among 163 individuals with suspected TTP, ADAMTS13 activity was available in 117 (72%). Severe ADAMTS13 deficiency <10% was present in 62 (53%). High-risk PLASMIC score (≥6) predicted severe ADAMTS13 deficiency with a sensitivity of 81.7%, specificity 71.4%, PPV 75.4% and NPV 78.4% (c-statistic 0.80). Intermediate-high risk Bentley score (≥20) had a lower sensitivity (59.5%) and higher specificity (93.9%) with similar c-statistic (0.77). Clinical gestalt had similar sensitivity as PLASMIC score but very low specificity (16.1%)., Conclusions: Both PLASMIC and Bentley scores had good discriminatory power in identifying severe ADAMTS13 deficiency in a Canadian TMA population compared to clinical gestalt. Integration into institutional clinical pathways may help supplement clinical judgment and reduce costs., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Introduction: It is unclear which outcome indicators should be used to measure the success of haemophilia transition programs, and what are key elements of a haemophilia transition program to ensure success., Aim: To establish by expert consensus a list of important and feasible outcome indicators of successful haemophilia transition, and a list of key elements of transition planning., Methods: A modified two-stage Delphi survey was developed and disseminated among a panel of Canadian interdisciplinary haemophilia care providers. Participants were asked to rate the importance and feasibility of outcome indicators of effective haemophilia transition and elements of haemophilia transition program. In the second round, participants were asked to choose the top five outcomes suitable for inclusion in a core outcome set of transition effectiveness, and the top five elements that are important and feasible for implementation within the next 5 years., Results: In total, 34/73 (47%) of participants completed the first round and 33 completed the second round, representing a variety of disciplines. Top outcome indicators recommended for a core outcome set include measurement of adherence, change in bleeding rate, self-efficacy skills, haemophilia knowledge, patient and caregiver satisfaction, time gap between last paediatric and first adult clinic, and number of emergency room or hospital admissions. Fourteen elements of transition achieved consensus in importance ratings, while eight were felt to be feasible for implementation within next 5 years., Conclusions: Results will contribute towards the development of a haemophilia transition outcome instrument and provide guidance for future studies of the effectiveness of transition programs., (© 2019 John Wiley & Sons Ltd.)

Introduction: Patients with haemophilia (PWH) are experiencing a nearly normal life span with safe factor replacement therapy and effective antiviral treatments for co-infections. As a result, many ageing-related health issues are starting to emerge. One rarely discussed health issue is erectile dysfunction (ED). ED can affect overall well-being and predict future cardiac events, but is not well studied in PWH., Aim: This prospective study aims to examine the prevalence and risk factors for ED in PWH using the validated International Index of Erectile Function (IIEF) questionnaire., Methods: Patients with haemophilia A and B at all severities were invited to participate in IIEF questionnaire at the provincial Hemophilia Treatment Centre. Risk factors for ED including cardiovascular risk factors, prior surgeries, viral infections, medications and haemophilia-specific factors were obtained. Fasting laboratory tests including but not limited to renal function, haemoglobin, lipid profile, glucose and CRP were performed the same day. Blood pressure and anthropomorphic indices were measured. Endothelial function was assessed by brachial artery flow-mediated dilation (FMD and hyperaemic velocity time integral [VTI])., Results: Out of the 56 subjects approached, 44 completed the IIEF. Median age was 49 years. About 38.6% of the cohort reported ED symptoms. There was no significant difference in endothelial function measured by FMD and VTI between patient with ED and without. IIEF score correlated with age in multivariable analysis., Conclusion: Erectile dysfunction symptoms appear prevalent in PWH, particularly in the older group. This disorder along with the underlying causes needs to be explored further in future larger observational study., (© 2019 John Wiley & Sons Ltd.)

Inhibitor risk in nonsevere hemophilia A increases with cumulative factor VIII (FVIII) exposure days and high-risk mutations. A standardized approach to minimize inhibitor risk is warranted. Following establishment of a systematic approach to reduce inhibitor risk in nonsevere hemophilia, we evaluated the uptake of these strategies into clinical practice. All adult males with nonsevere hemophilia A followed by British Columbia Adult Hemophilia Program from 2004 to 2016 were included in this retrospective audit. Quality-of-care indicators on inhibitor prevention were examined. Of 108 patients, 18 patients had high-risk FVIII mutations for inhibitor development. Rates of FVIII genotyping and 1-deamino-8-d-arginine-vasopressin (DDAVP) testing in mild patients without contraindications were both over 90%, although DDAVP was used for surgical prophylaxis in only 70% of procedures. Inhibitor testing and clinic visits occurred at a median interval of 22 months. Over 80% of patients with high-risk mutations had documentation and education on their inhibitor risk. Our practice audit demonstrated a high level of recognition and patient education of individual inhibitor risk. Impact of our standardized approach on the incidence of inhibitor development is yet to be determined.

Bleomycin pulmonary toxicity (BPT) is a well-described complication of bleomycin-containing regimens. Previous data on risk factors and the impact of BPT on survival in Hodgkin lymphoma (HL) were conflicting. We reviewed 253 HL patients treated with adriamycin, bleomycin, vinblastine, dacarbazine (ABVD) at the Princess Margaret Hospital from 1999 to 2009 to examine the incidence and risk factors for BPT, and the effect of BPT on survival. BPT was defined by pulmonary symptoms, bilateral interstitial infiltrates on computed tomography, and the absence of infection. Kaplan-Meier estimates were used to compare overall survival (OS) and progression-free survival (PFS) between groups. The incidence of BPT was low (11%). Age ≥45 (OR = 2.5) and granulocyte colony-stimulating factor use (OR = 3.6) were identified as predictors of BPT on multivariable logistic models. At a follow-up of 5 years, OS and PFS were 88% and 82%, respectively. Neither BPT nor bleomycin discontinuation had significant impact on survival outcomes.

Introduction: Adults with severe haemophilia A (SHA) may experience breakthrough bleeds despite standard weight-based FVIII prophylaxis three times weekly. Individualized prophylaxis has evolved to optimize patient outcomes., Aims: This study aimed to evaluate the impact of a standardized approach to individualized prophylaxis on annualized bleeding rates (ABR), factor utilization, physical activity and quality of life in adults with SHA., Methods: In this prospective cohort study, patients with baseline FVIII:C <2% and ABR >3 on weight-based prophylaxis received a standardized approach to individualized prophylaxis. Changes in ABR, annualized FVIII consumption and adherence from the 12-month prestudy and 12-month intervention period were compared. Changes in Haemo-QoL-A total score, Physical Functioning (PF) subscale and physical activity level measured by accelerometry were also examined., Results: Eighteen patients participated (median age 26 years). Individualized prophylaxis decreased total bleeds in the population by 69% and traumatic bleeds by 73%. The median ABR decreased from 7.5 to 2 (P<.001). Annualized factor consumption increased by 7.3%, as a result of 66% reduction in factor utilization for treatment of bleeds and 25% increase in factor utilization for prophylaxis. Adherence scores for frequency and dosing did not change. There was a significant increase in the Haemo-QoL-A total score (P=.02) and PF score (P=.01) from baseline to 4 months but no change in physical activity., Conclusion: Patients with SHA who switched from standard to individualized prophylaxis show reduced ABR and increased FVIII consumption, and also improved their health-related quality of life. The mechanism is independent of adherence to prescribed prophylactic regimen., (© 2017 John Wiley & Sons Ltd.)

Neutropenia is a major dose-limiting toxicity associated with lenalidomide in relapsed/refractory multiple myeloma (MM). The optimal dosing schedule of granulocyte colony-stimulating factor (G-CSF) is unclear. We developed an intermittent G-CSF schedule (4-6 doses per cycle) initiated upon onset of grade 3-4 neutropenia. Of 216 patients with relapsed/refractory MM treated at our center with lenalidomide/dexamethasone on an Expanded Access Program, there was a high incidence of grade 3-4 neutropenia (61%) and grade 3-4 infections (37%). Despite intermittent G-CSF use in 117 patients, recurrent grade 3-4 neutropenia was common (59%), and dose reductions were required in 40% of G-CSF recipients, most due to thrombocytopenia. G-CSF recipients had a longer duration on therapy and achieved a higher rate and depth of response. Intermittent G-CSF may be an effective approach for lenalidomide dose-preservation, which may lead to improved outcomes, although it does not prevent infections or thrombocytopenia-related dose limitations.

Patients with double-hit lymphoma (DHL), which is characterized by rearrangements of MYC and either BCL2 or BCL6, face poor prognoses. We conducted a retrospective multicenter study of the impact of baseline clinical factors, induction therapy, and stem cell transplant (SCT) on the outcomes of 311 patients with previously untreated DHL. At median follow-up of 23 months, the median progression-free survival (PFS) and overall survival (OS) rates among all patients were 10.9 and 21.9 months, respectively. Forty percent of patients remain disease-free and 49% remain alive at 2 years. Intensive induction was associated with improved PFS, but not OS, and SCT was not associated with improved OS among patients achieving first complete remission (P = .14). By multivariate analysis, advanced stage, central nervous system involvement, leukocytosis, and LDH >3 times the upper limit of normal were associated with higher risk of death. Correcting for these, intensive induction was associated with improved OS. We developed a novel risk score for DHL, which divides patients into high-, intermediate-, and low-risk groups. In conclusion, a subset of DHL patients may be cured, and some patients may benefit from intensive induction. Further investigations into the roles of SCT and novel agents are needed., (© 2014 by The American Society of Hematology.)