BACKGROUND: Adults who require long-term anticoagulation with low-molecular-weight heparin (LMWH) such as cancer patients or the elderly may be at increased risk of fractures. OBJECTIVE: To determine the effects of LMWH therapy of at least 3 months' duration on fractures and bone mineral density (BMD) in non-pregnant adult populations. METHODS: We systematically reviewed electronic databases (e.g., MEDLINE, EMBASE), conferences and bibliographies until June 2015 and included comparative studies in non-pregnant adult populations that examined the effects of LMWH (≥3 months) on fractures and BMD. We synthesized evidence qualitatively and used random-effects meta-analysis to quantify the effect of LMWH on fractures. RESULTS: Sixteen articles reporting 14 studies were included: 10 clinical trials (n = 4865 participants) and four observational cohort studies (3 prospective, n = 221; 1 retrospective, n = 30). BMD and fractures were secondary outcomes in the majority of trials, while they were primary outcomes in the majority of observational studies. In participants with venous thromboembolism and underlying cardiovascular disease or cancer (5 RCTs, n = 2280), LMWH for 3-6 months did not increase the relative risk of all fractures at 6-12 months compared to unfractionated heparin, oral vitamin K antagonists or placebo [pooled risk ratio (RR) = 0.58, 95 % CI: 0.23-1.43; I 2 = 12.5 %]. No statistically significant increase in the risk of fractures at 6-12 months was found for cancer patients (RR = 1.08, 95 % CI: 0.31-3.75; I 2 = 4.4 %). Based on the data from two prospective cohort studies (n = 166), LMWH for 3-24 months decreased mean BMD by 2.8-4.8 % (depending on the BMD site) compared to mean BMD decreases of 1.2-2.5 % with oral vitamin K antagonists. CONCLUSIONS: LMWH for 3-6 months may not increase the risk of fractures, but longer exposure for up to 24 months may adversely affect BMD. Clinicians should consider monitoring BMD in adults on long-term LMWH who are at increased risk of bone loss or fracture.

INTRODUCTION: Hereditary hemochromatosis is an autosomal recessive disorder of iron absorption, leading to organ dysfunction. C282Y gene homozygosity is implicated in 80%–95% of cases of hereditary hemochromatosis. The clinical penetrance of this genotype remains unclear. The purpose of the study was to better describe the clinical penetrance and disease progression of C282Y homozygotes. METHODS: This is a retrospective study of all individuals in Newfoundland and Labrador, Canada, homozygous for the C282Y mutation from 1999 to 2009. Using electronic health records, laboratory values, phlebotomy status, radiologic reports, and clinic records were recorded up to November 2017. Iron overload status was classified via the HealthIron study. SPSS Version 19.0 (IBM Corporation) was used for descriptive statistics. Predictors of disease penetrance were assessed with logistic regression; a Student t test was used for continuous variables, and χ 2 tests were used for categorical variables. RESULTS: Between 1999 and 2009, 360 individuals tested positive for C282Y/C282Y. The mean age of diagnosis was 49.1 years. Three hundred six individuals had adequate follow-up for analysis (mean 11.6 years). End-organ damage was observed in 18.3%, with 5.8% developing liver disease. End-organ damage was more frequently observed in men 24.3% vs 10.5% ( P < 0.05). Clinical penetrance in postmenopausal women approached that of men 18.3%. DISCUSSION: This is the largest reported cohort of C282Y homozygotes, followed for an extended duration of time in North America. The findings reflect outcomes in routine clinical practice and suggest that C282Y homozygosity uncommonly causes end-organ damage and liver disease.

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Introduction:The association between thrombosis (TE) and cancer has been well established. The risk for thrombosis in Multiple Myeloma (MM) is further compounded by therapy-related factors, which increase the risk for both arterial and venous TE. Lenalidomide + dexamethasone (Ld) is the most widely used backbone therapy for MM and may increase the risk of TE. The current standard TE prophylaxis for patients on Ld is low dose aspirin (ASA) for low risk patients or low molecular weight heparin for high risk patients. Direct oral anticoagulants have been used empirically and have been evaluated in small prospective cohort studies with promising results. Methods: RithMM is an ongoing open label Canadian multicenter pilot feasibility RCT to assess the efficacy and safety of daily oral rivaroxaban 10 mg (Riva) versus ASA 81 mg in patients with MM on Ld-based therapy. Our primary objective is to assess the feasibility of accrual of patients with MM starting on Ld-based therapy. Patients not on therapeutic anticoagulation or antiplatelet agents for another indication (e.g. atrial fibrillation) are eligible for RithMM. Primary clinical endpoints are major cardiovascular (CV) events or major bleeding as per the ISTH criteria. The study will be considered feasible if 86 patients in 4 Canadian sites (London, Ottawa, Halifax, Niagara) can be enrolled in 12 months after each site activation. Sites are expected to accrue an average of 1.8 patients per month. Patients are randomly assigned to receive ASA (control) or Riva (intervention) using a simple randomization sequence run by the Redcap system, utilizing an automated assignment procedure. Patients enter the study at the time of anticoagulant initiation and are followed for 6 months, or until they withdraw from the study; die or develop a primary clinical outcome; whichever comes first. Herein we present the interim analysis of RithMM after study completion in 2 of 4 sites. Feasibility assessment: 17 patients were randomized to ASA and 17 to Riva (1 patient did not take the study drug). Feasibility assessment was severely impacted by the temporary but prolonged research activity closures secondary to the COVID-19 pandemic that limited direct patient accrual and led to significant delays in REB approval of the participating sites. The first patient was enrolled in January 2019 in London. Ottawa opened in October 2019, Halifax in December 2020 and Niagara in May 2021. A total of 34 patients have been enrolled: 22 London, 11 Ottawa and 2 Halifax. London was the only site actively accruing for 12 consecutive months. Ottawa opened for 3 months, held accrual for 9 months, then reopened for 7 months. Halifax was open for only 1 month. Niagara opened in May 2021, the time of study data lock for this abstract. In addition, 7 potentially eligible patients were not screened given that they were enrolled in a MM treatment trial that did not permit enrolment in another trial. The accrual rate was excellent for London (105%) and Ottawa (52% in 10 months). The drop-out rate was 6% (2 patients) and drug compliance 100%. Clinical Outcomes: Baseline characteristics are depicted in the table. One patient in the ASA arm developed a proximal deep vein thrombosis 2 months after starting treatment, and another developed a clinically relevant nonmajor bleeding 6 weeks after starting ASA. Discussion: This is the interim analysis of the RithMM pilot trial that aims to evaluate the feasibility of accrual of MM patients on Ld -base therapy to assess the efficacy and safety of Riva versus ASA in preventing TE complications. The study was initiated during the COVID-19 pandemic turmoil, which severely impacted in the proper activation of 3 of the 4 participating sites. Despite this significant limitation, 2 sites were able to maintain the accrual of patients. Only 1 site remained opened according to the pre-specified consecutive 12- month study period. Despite this barrier, we could still attain an excellent accrual rate of 39.5% in 2 sites (London and Ottawa). The incidence of TE or bleeding was low, with no difference between ASA and Riva. However, the study was not powered to assess these outcomes. Lastly, Ld is the most widely used backbone therapy in MM, both in upfront and relapsed settings. Our group does not anticipate any barriers to achieving successful completion of accrual provided the hospital's activities remain safe and research activities open. Figure 1 Figure 1. Disclosures Louzada: Celgene: Honoraria; Janssen: Honoraria; Pfizer: Honoraria; Amgen: Honoraria. McCurdy: Sanofi: Honoraria; GSK: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Phua: Pfizer: Honoraria; Amgen: Honoraria; AstraZeneca: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Le Gal: Aspen: Honoraria; Bayer: Honoraria; Pfizer: Honoraria; LEO Pharma: Honoraria; BMS: Honoraria; Sanofi: Honoraria. Lam: Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; SeaGen: Honoraria, Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Rivaroxaban 10 mg oral daily for thrombosis prophylaxis in myeloma patients on lenalidomide-based therapy. Health Canada approved the off label use for study purposes

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.

This study demonstrated high patient satisfaction and acceptability of a short-stay model for treatment of uncomplicated VOC in adult SCD patients in Toronto, the first of its kind in Canada.

The management of a patient with hemophilia undergoing cardiovascular surgery relies on accurate coagulation test results. Both unfractionated heparin (UFH) and protamine sulfate used during cardiac surgery can interfere with factor and inhibitor assays. Here we describe the effects of UFH and protamine sulfate on routine coagulation, factor activity, and inhibitor assays. Pooled normal plasma (PNP) with UFH, PNP with protamine sulfate, PNP with both protamine sulfate and UFH were tested for the activated partial thromboplastin time (aPTT), prothrombin time (PT), thrombin time (TT), UFH anti-Xa, one-stage factor VIII (FVIII) activity, one-stage factor IX (FIX) activity, and Bethesda inhibitor assays for FVIII and FIX. UFH had a dose-dependent effect with TT, aPTT, and PT. On Bethesda inhibitor testing, FIX inhibition was detected at 1 U/ml UFH and 3 U/ml UFH for FVIII. Increasing protamine sulfate concentration in PNP prolonged the PT and aPTT in a dose-dependent manner, decreased FVIII and FIX activity and did not affect TT or UFH anti-Xa. At protamine sulfate doses of at least 200 μg/ml there was weak FVIII and FIX inhibition detected. At lower ratios of protamine sulfate to UFH (0.6 : 1–0.8 : 1), the aPTT decreased, suggesting reversal of UFH. However, at protamine sulfate to UFH ratios of 1.0 : 1 and higher, aPTT prolongation was observed. Inhibition of FVIII and FIX was detected at low ratios of protamine sulfate to UFH (below 0.4 : 1) and disappeared at higher ratios. UFH and protamine sulfate, alone or in combination, impact factor activity and inhibitor testing for both FVIII and FIX. Hence, factor activity and inhibitor assay results should be interpreted with caution when UFH or protamine sulfate are present.

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