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Background The efficacy and safety of wilate (human von Willebrand factor/coagulation factor VIII) in patients with von Willebrand disease (VWD) has been demonstrated in clinical trials. Here, we present real-world data on the use of wilate for the routine care of patients with VWD. Objectives The objectives of this observational, prospective, phase 4 study were to evaluate the safety, tolerability, and effectiveness of wilate in on-demand treatment of bleeding episodes (BEs), long-term prophylaxis, and surgical prophylaxis among patients with any type of VWD. Methods Patients were enrolled at 31 study centers in 11 countries and followed for up to 2 years. Safety endpoints included adverse drug reactions (ADRs) and drug tolerability. Effectiveness was assessed using annualized bleeding rates (ABRs) during prophylaxis and predefined criteria for the treatment of BEs and surgical prophylaxis. Results A total of 111 patients (76 [68%] female) including 41 (37%) children were treated with wilate. Twenty-five patients received prophylaxis, 29 on-demand treatment, and 62 surgical prophylaxis. Tolerability was rated by patients as “excellent” for 96.2% of 6,497 infusions. No unexpected ADRs or thrombotic events were reported. Median ABR during prophylaxis was 1.9. Effectiveness was assessed as “excellent” or “good” by patients and investigators for 100% of BEs treated on-demand, 98% (patient rating) and 99% (investigator rating) of breakthrough BEs, and 99% of surgical procedures (investigator rating). Conclusion wilate was safe, well tolerated, and effective for the prevention and treatment of bleeding in pediatric and adult VWD patients in a real-world setting.

Endothelial injury and microvascular/macrovascular thrombosis are common pathophysiological features of coronavirus disease-2019 (COVID-19). However, the optimal thromboprophylactic regimens remain unknown across the spectrum of illness severity of COVID-19. A variety of antithrombotic agents, doses, and durations of therapy are being assessed in ongoing randomized controlled trials (RCTs) that focus on outpatients, hospitalized patients in medical wards, and patients critically ill with COVID-19. This paper provides a perspective of the ongoing or completed RCTs related to antithrombotic strategies used in COVID-19, the opportunities and challenges for the clinical trial enterprise, and areas of existing knowledge, as well as data gaps that may motivate the design of future RCTs.

Ferritin is a key diagnostic marker of iron deficiency (ID), but the interpretative guidance provided to physicians varies significantly. Clear discrepancies exist between clinical guidelines that recommend evidence-based ferritin cutoffs and clinical laboratories that report highly variable ferritin reference intervals (RIs) derived from apparently healthy populations. In this study, clinical laboratories across North America were surveyed to assess the RIs provided with ferritin results. Although clinical guidelines often recommend ferritin cutoffs of 15 or 30 µg/L to identify uncomplicated ID, the survey showed that 18 of 23 responding laboratories reported female RI lower limits well below 15 µg/L. To understand the clinical impact, we analyzed 52 027 unique patient ferritin values over a 5-year period (2013–2017) from a tertiary care hospital. In this population, the 90th percentile ferritin cutoff to identify ID anemia in adults was 24 µg/L in female patients and 25 µg/L in male patients. Distribution of ferritin results in female patients showed that menopausal status had a significant effect on median values, which increased 2- to 3-fold in the postmenopausal state. Furthermore, sorting the data for female patients by physician specialty showed the highest prevalence of low ferritin values in patients seen in obstetrics and gynecology. This study highlights the discrepancy between clinical guidelines and clinical laboratory practice for ferritin reporting and indicates that ferritin RIs, particularly for female patients, are set to an inappropriately low threshold in most clinical laboratories in North America; this level provides good specificity but poor sensitivity when screening for ID.

Background: Patients with immune thrombocytopenia are at risk of bleeding during surgery, and intravenous immunoglobulin is commonly used to increase the platelet count. We aimed to establish whether perioperative eltrombopag was non-inferior to intravenous immunoglobulin. Methods: We did a randomised, open-label trial in eight academic hospitals in Canada. Patients were aged at least 18 years, with primary or secondary immune thrombocytopenia and platelet counts less than 100 × 109 cells per L before major surgery or less than 50 × 109 cells per L before minor surgery. Previous intravenous immunoglobulin within 2 weeks or thrombopoietin receptor agonists within 4 weeks before randomisation were not permitted. Patients were randomly assigned to receive oral daily eltrombopag 50 mg from 21 days preoperatively to postoperative day 7 or intravenous immunoglobulin 1 g/kg or 2 g/kg 7 days before surgery. Eltrombopag dose adjustments were allowed weekly based on platelet counts. The randomisation sequence was generated by a computerised random number generator, concealed and stratified by centre and surgery type (major or minor). The central study statistician was masked to treatment allocation. The primary outcome was achievement of perioperative platelet count targets (90 × 109 cells per L before major surgery or 45 × 109 cells per L before minor surgery) without rescue treatment. We did intention-to-treat and per-protocol analyses using an absolute non-inferiority margin of –10%. This trial is registered with ClinicalTrials.gov, NCT01621204. Findings: Between June 5, 2013, and March 7, 2019, 92 patients with immune thrombocytopenia were screened, of whom 74 (80%) were randomly assigned: 38 to eltrombopag and 36 to intravenous immunoglobulin. Median follow-up was 50 days (IQR 49–55). By intention-to-treat analysis, perioperative platelet targets were achieved for 30 (79%) of 38 patients assigned to eltrombopag and 22 (61%) of 36 patients assigned to intravenous immunoglobulin (absolute risk difference 17·8%, one-sided lower limit of the 95% CI 0·4%; pnon-inferiority=0·005). In the per-protocol analysis, perioperative platelet targets were achieved for 29 (78%) of 37 patients in the eltrombopag group and 20 (63%) of 32 in the intravenous immunoglobulin group (absolute risk difference 15·9%, one-sided lower limit of the 95% CI –2·1%; pnon-inferiority=0·009). Two serious adverse events occurred in the eltrombopag group: one treatment-related pulmonary embolism and one vertigo. Five serious adverse events occurred in the intravenous immunoglobulin group (atrial fibrillation, pancreatitis, vulvar pain, chest tube malfunction and conversion to open splenectomy); all were related to complications of surgery. No treatment-related deaths occurred. Interpretation: Eltrombopag is an effective alternative to intravenous immunoglobulin for perioperative treatment of immune thrombocytopenia. However, treatment with eltrombopag might increase risk of thrombosis. The decision to choose one treatment over the other will depend on patient preference, resource limitations, cost, and individual risk profiles. Funding: GlaxoSmithKline and Novartis.

Hemophilia A (HA) and B (HB) are X-linked bleeding disorders caused by mutations in the F8 or F9 gene that result in the absence, or reduced activity, of the corresponding clotting factor. The severity of bleeding and related complications is proportional to the amount of residual circulating functional factor. The development of a safe and effective hemophilia treatment lasted several decades and has been mainly based on clotting factor replacement. Advances in the engineering and manufacturing of clotting concentrates have led to the widespread availability of extended half-life products that reduced the number of intravenous infusions needed to achieve adequate trough levels. The recent development of new nonfactor replacement treatments and biotechnology techniques has offered therapeutic alternatives for hemophilia patients with and without inhibitors. These are characterized by an easier route of administration, low immunogenicity, and, regarding gene therapy and cell-based treatments, potential long-term protection from bleeding after a single treatment course. In this review, we analyze recent progresses in the management of hemophilia and discuss opportunities and challenges.

Fostamatinib demonstrated efficacy in phase 3 trials of adults with immune thrombocytopenia (ITP). Post hoc analysis compared patients who received fostamatinib as second‐line therapy (after steroids ± immunoglobulins) versus third‐or‐later‐line therapy (after ≥2 prior lines of therapy including a second‐line agent). Platelet responses ≥50 000/µl were observed in 25/32 (78%) second‐line and 54/113 (48%) third‐or‐later‐line patients. Bleeding events were less frequent in second‐line (28%) versus third‐or‐later‐line (45%) patients. Responses once achieved tended to be durable in both groups. The safety profile was similar in both groups. In this post hoc analysis, fostamatinib was more effective as second‐line than third‐or‐later‐line therapy for ITP.

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.

Objectives To determine the effect of therapeutic anticoagulation, with low molecular weight heparin (LMWH) or unfractionated heparin (UFH, high dose nomogram), compared to standard care in hospitalized patients admitted for COVID-19 with an elevated D-dimer on the composite outcome of intensive care unit (ICU) admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death up to 28 days. Trial design Open-label, parallel, 1:1, phase 3, 2-arm randomized controlled trial Participants The study population includes hospitalized adults admitted for COVID-19 prior to the development of critical illness. Excluded individuals are those where the bleeding risk or risk of transfusion would generally be considered unacceptable, those already therapeutically anticoagulated and those who have already have any component of the primary composite outcome. Participants are recruited from hospital sites in Brazil, Canada, Ireland, Saudi Arabia, United Arab Emirates, and the United States of America. The inclusion criteria are: Laboratory confirmed COVID-19 (diagnosis of SARS-CoV-2 via reverse transcriptase polymerase chain reaction as per the World Health Organization protocol or by nucleic acid based isothermal amplification) prior to hospital admission OR within first 5 days (i.e. 120 hours) after hospital admission; Admitted to hospital for COVID-19; One D-dimer value above the upper limit of normal (ULN) (within 5 days (i.e. 120 hours) of hospital admission) AND EITHER: D-Dimer ≥2 times ULN OR D-Dimer above ULN and Oxygen saturation ≤ 93% on room air; > 18 years of age; Informed consent from the patient (or legally authorized substitute decision maker). The exclusion criteria are: pregnancy; hemoglobin platelet count 9/L in the last 72 hours; known fibrinogen known INR >1.8 (if testing deemed clinically indicated by the treating physician prior to the initiation of anticoagulation); patient already prescribed intermediate dosing of LMWH that cannot be changed (determination of what constitutes an intermediate dose is to be at the discretion of the treating clinician taking the local institutional thromboprophylaxis protocol for high risk patients into consideration); patient already prescribed therapeutic anticoagulation at the time of screening [low or high dose nomogram UFH, LMWH, warfarin, direct oral anticoagulant (any dose of dabigatran, apixaban, rivaroxaban, edoxaban)]; patient prescribed dual antiplatelet therapy, when one of the agents cannot be stopped safely; known bleeding within the last 30 days requiring emergency room presentation or hospitalization; known history of a bleeding disorder of an inherited or active acquired bleeding disorder; known history of heparin-induced thrombocytopenia; known allergy to UFH or LMWH; admitted to the intensive care unit at the time of screening; treated with non-invasive positive pressure ventilation or invasive mechanical ventilation at the time of screening; Imminent death according to the judgement of the most responsible physician; enrollment in another clinical trial of antithrombotic therapy involving hospitalized patients. Intervention and comparator Intervention: Therapeutic dose of LMWH (dalteparin, enoxaparin, tinzaparin) or high dose nomogram of UFH. The choice of LMWH versus UFH will be at the clinician’s discretion and dependent on local institutional supply. Comparator: Standard care [thromboprophylactic doses of LMWH (dalteparin, enoxaparin, tinzaparin, fondaparinux)] or UFH. Administration of LMWH, UFH or fondaparinux at thromboprophylactic doses for acutely ill hospitalized medical patients, in the absence of contraindication, is generally considered standard care. Main outcomes The primary composite outcome of ICU admission, non-invasive positive pressure ventilation, invasive mechanical ventilation or death at 28 days. Secondary outcomes include (evaluated up to day 28): All-cause death Composite of ICU admission or all-cause death Composite of mechanical ventilation or all-cause death Major bleeding as defined by the ISTH Scientific and Standardization Committee (ISTH-SSC) recommendation; Red blood cell transfusion (>1 unit); Transfusion of platelets, frozen plasma, prothrombin complex concentrate, cryoprecipitate and/or fibrinogen concentrate; Renal replacement therapy; Hospital-free days alive; ICU-free days alive; Ventilator-free days alive; Organ support-free days alive; Venous thromboembolism (defined as symptomatic or incidental, suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); Arterial thromboembolism (defined as suspected or confirmed via diagnostic imaging and/or electrocardiogram where appropriate); Heparin induced thrombocytopenia; Trajectories of COVID-19 disease-related coagulation and inflammatory biomarkers. Randomisation Randomisation will be stratified by site and age (>65 versus ≤65 years) using a 1:1 computer-generated random allocation sequence with variable block sizes. Randomization will occur within the first 5 days (i.e. 120 hours) of participant hospital admission. However, it is recommended that randomization occurs as early as possible after hospital admission. Central randomization using an interactive web response system will ensure allocation concealment. Blinding (masking) No blinding involved. This is an open-label trial. Numbers to be randomised (sample size) 462 patients (231 per group) are needed to detect a 15% risk difference, from 50% in the control group to 35% in the experimental group, with power of 90% at a two-sided alpha of 0.05. Trial Status Protocol Version Number 1.4. Recruitment began on May 11th, 2020. Recruitment is expected to be completed March 2022. Recruitment is ongoing. Trial registration ClinicalTrials.gov Identifier: NCT04362085 Date of Trial Registration: April 24, 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest of expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

[See related article at [www.cmaj.ca/lookup/doi/10.1503/cmaj.210795][2]][2] KEY POINTS In a related case report, Jones and colleagues describe a 63-year-old man who developed thromboses in his popliteal and pulmonary arteries.[1][2] The patient’s thromboses were likely caused by vaccine-induced

We present a case of hereditary thrombotic thrombocytopenic purpura (hTTP) caused by a previously undescribed mutation in a 36-year-old woman who presented with seizures in the context of a possible infection. Her hematologic manifestations were mild, despite undetectable ADAMTS13 (A Distintegrin and Metalloproteinase with Thrombospondin Motifs 13) activity. Genetic analysis showed a homozygous variant in ADAMTS13 gene which was not previously reported but predicted to be associated with disease. She responded to plasma therapy. Her diagnosis subsequently led to the diagnosis of hTTP in her younger sibling who presented with unexplained strokes a few years earlier.

Introduction Ferumoxytol is an intravenous (IV) iron formulation for treatment of iron deficiency (ID) that faced post-marketing reports of serious adverse events (SAEs). Objectives To determine the safety and efficacy of ferumoxytol compared to other iron formulations and placebo. Methods We searched the Cochrane Library, Medline, and EMBASE from inception until February 2018 as well as trial registries and reference lists of relevant articles for randomized or quasi-randomized controlled trials. Results The review included nine studies with 5691 participants. Studies were at low risk of bias. When comparing ferumoxytol to other IV iron formulations, there is moderate quality evidence (QE) of little to no difference in treatment emergent adverse events (TEAEs) (risk ratio [RR] 0.88, 95% confidence interval [CI] 0.80-0.97), treatment related adverse events (TRAEs) (RR 0.73, 95% CI 0.61-0.88), SAEs (RR 1.13, 95% CI 0.77-1.67), hypotension or hypersensitivity reactions (RR 0.58, 95% CI 0.31-1.09), or composite cardiovascular outcomes (RR 0.56, 95% CI 0.24-1.29), low QE of little to no difference in related SAEs (RR 0.55, 95% CI 0.05-6.16), and high QE of little to no difference in the number of patients with an increase in hemoglobin by at least 1 g/dL (RR 1.04, 95% CI 0.96-1.12). Ferumoxytol had less TEAEs compared to oral iron (RR 0.78, 95% CI 0.61-0.98), but more compared to placebo (RR 1.62, 95% CI 1.01-2.61). Discussion Ferumoxytol is as efficacious and safe as alternative IV iron formulations with no clear safety concerns.

Objectives Assess the appropriateness of the use of intravenous immunoglobulin (IVIG) for immune thrombocytopenia (ITP). Background IVIG is suggested for ITP when a rapid increase in platelet count is desired or as first line therapy if corticosteroids are contraindicated. A recent Canadian audit of IVIG requests found a lack of compliance with provincial requirements and inadequate documentation of efficacy which led the authors to conclude that the use of IVIG was broadly inappropriate for all treated diseases. Methods Retrospective review of patients with ITP who received IVIG at our institution over a one-year period. Results 40 patients received IVIG for ITP over the study period for a total of 76 infusions. The most common indications for IVIG within currently accepted guidelines were: active bleeding (13, 17%), pre-operative or antepartum care (22, 29%), contraindication to corticosteroids (8, 11%), and requirement for antithrombotic or myelosuppressive therapy (5, 7%). Indications that fell outside of guidelines included use of IVIG as a diagnostic challenge where the etiology of thrombocytopenia was unclear. IVIG was generally well tolerated. Conclusion At our institution, use of IVIG for ITP was generally appropriate and carefully considered. Detailed utilization/knowledge data inquiries are required to develop tools and policies to enhance appropriate IVIG use in multiple settings.

Gastric cancer is highly prevalent amongst men and women. Previous studies have described the high prevalence of iron deficiency anemia (IDA) in gastrointestinal cancer patients, but few have focused on the gastric cancer population. We aimed to determine the point prevalence of patients with gastric cancer who developed IDA and chemotherapy-induced anemia, and to identify types and frequencies of IDA therapies.A retrospective review was carried out for 126 gastric cancer patients from 2006 to 2016 at St Michael's Hospital, Toronto, Canada. Patient demographics, laboratory (ferritin, iron parameters) and clinical data regarding IDA were reviewed. IDA was defined as transferrin saturation less than 20%, ferritin less than 100 μg/l, and hemoglobin less than 130 g/l in men and less than 120 g/l in women.Of the 126 patients with gastric cancer identified (median age 70, interquartile range: 59-77), 64.3% were men. Only 18.3% of patients had a self-reported history of IDA, 40% had IDA at the time of gastric cancer diagnosis, and 58.7% were anemic. A total of 77 patients received chemotherapy, and of these, 54.2% developed chemotherapy-induced anemia. At the final follow-up, 21.4% of patients were diagnosed with IDA along their treatment course, and 79.4% were anemic. Red blood cell transfusions were most frequently prescribed (48.4%; median: 4 U; interquartile range: 2-6), compared with oral (31.8%) or intravenous iron (16.7%) therapy.The point prevalence of IDA was high in our gastric cancer patients despite inconsistent screening for IDA. Our findings indicate the need for a consistent diagnostic and therapeutic approach to IDA in this vulnerable patient population.

Acquired factor XIII (FXIII) deficiency is a rare bleeding disorder that can manifest with spontaneous or delayed life-threatening hemorrhage. Causes of acquired deficiency include immune-mediated inhibition, as well as non-immune FXIII hyperconsumption or hyposynthesis. The occurrence of acquired FXIII deficiency can be idiopathic or may be associated with comorbidities, such as malignancies or autoimmune disorders. Recognition of acquired FXIII deficiency and its underlying cause is imperative, as treatment options vary depending on the etiology. Diagnosis requires quantitative FXIII testing in addition to supplemental inhibitor studies if the clinical situation suggests an immune-mediated pathophysiology. Treatment may involve FXIII replacement, antifibrinolytic administration, and/or inhibitor eradication. However, treatment targets and thresholds are undefined in acquired FXIII deficiency. This review will focus on the clinical characteristics, diagnostic issues and therapeutic options for both immune and non-immune acquired FXIII deficiency. Cases are described to illustrate the clinical features of acquired FXIII deficiency.

Background: Major bleeding is the most serious complication of oral anticoagulation. Consensus criteria to define major bleeding have been established by the International Society for Thrombosis and Haemostasis (ISTH), Bleeding Academic Research Consortium (BARC) and Thrombolysis in Myocardial Infarction (TIMI). Significant variability exists across these definitions, and their agreement for identifying oral anticoagulant (OAC) related major bleeding is unknown. Furthermore, the association between each definition and mortality in cases of OAC bleeding has not been evaluated. We therefore, sought to evaluate the agreement of cases identified as major bleeding by the ISTH, BARC and TIMI definitions, and to assess associated in-hospital (emergency department or inpatient) and 30-day mortality of cases identified by these criteria. Methods: We used an existing dataset of individuals ≥66 years in Ontario, Canada, who presented to one of five tertiary care institutions with OAC related bleeding across three cities from 2010-2015. Detailed clinical data on consecutive episodes of OAC-associated bleeding were linked to population-based databases held at the Institute for Clinical Evaluative Sciences. We calculated Cohen's κ for agreement between the three major bleeding definitions, and used Pearson's χ2 to determine any differences in in-hospital and 30-day mortality for cases defined as major bleeding by ISTH, BARC and TIMI criteria. Results: We included 2,002 cases of OAC related bleeding in the analysis (460 on direct oral anticoagulants, 1,542 on warfarin). ISTH, BARC and TIMI major bleeding definitions were met in 75%, 77% and 29% of cases, respectively. 18% of cases did not meet criteria for major bleeding by any definition. Age, sex, CHA2DS2-VASc and HAS-BLED score, as well as proportion of chronic kidney disease were similar across ISTH-, BARC- and TIMI-defined cases. Over 9 in 10 cases of TIMI-defined major bleeding events involved an intracranial hemorrhage (94.4%), compared to 37% and 36% of cases identified by ISTH or BARC definitions respectively (p Conclusions: Among patients with OAC-associated bleeding, major bleeding events identified by ISTH and BARC criteria showed good agreement and similar prognostic utility. Meanwhile, TIMI criteria identified patients with higher clinical risk and subsequent mortality. Patients presenting with OAC-associated bleeding who did not fulfill ISTH or BARC major bleeding criteria had considerable risk of 30-day mortality and was even higher among those not meeting the TIMI criteria. Our findings suggest the need to refine current major bleeding definitions to identify additional patients at risk of death. Disclosures Wells: Bayer: Honoraria; BMS: Honoraria, Research Funding; Sanofi: Honoraria; Janssen: Honoraria. Sholzberg:Amgen: Research Funding; CSL Behring: Research Funding; Octapharma: Research Funding; Shire: Research Funding.

Introduction Women with inherited bleeding disorders experience excessive bleeding that may impair their quality of life, making early diagnosis and treatment critical. However, the experiences of these women regarding access to care has been minimally described. The primary objective of this study was to evaluate and describe barriers to care for women with bleeding disorders. This study was a continuation of our previous work describing the lived experiences of these women. Methods We undertook a qualitative descriptive study. Inclusion criteria for study enrollment were the following: age ≥ 18 years, English-speaking, and confirmed diagnosis of an inherited bleeding disorder. Women were recruited across Canada by treating healthcare providers and members of the Canadian Hemophilia Society. Telephone interviews were conducted using a semi-structured interview style, transcribed verbatim, and analyzed using descriptive thematic analysis. Results A total of 15 participants were interviewed. Median age was 31 years (range 24-70 years). Four primary themes surrounding barriers to care emerged: 1. Lack of healthcare provider awareness of bleeding disorders, 2. Healthcare provider dismissal of symptoms, 3. Limited access to specialized care and treatment plans, and 4. Need for self-education and advocacy. Discussion We found that women with inherited bleeding disorders experience tension with the healthcare system, feeling unheard and poorly understood. Based on our findings, we identified key knowledge and care gaps that could be addressed with awareness and educational initiatives: patient education on vaginal blood loss, updated medical curricula, clear referral guidelines, and tele-health initiatives for patients residing far from hemophilia treatment centres.

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

Coagulopathy correlates with severity of COVID-19 and may include increased d-dimer concentrations (≥ 2 times above normal range), mildly prolonged prothrombin time (~ 1–3 s prolongation above normal range), mild thrombocytopenia (platelet count > 100 ×109/L) and, in late disease, decreased

Background Iron deficiency in pregnancy is associated with inferior maternal and fetal outcomes. Postpartum depression, prematurity, intrauterine growth restriction, impaired childhood cognition and transfusion are all sequelae of maternal iron deficiency anemia. Transfusion to women of childbearing age has important consequences including increasing the risk of hemolytic disease of the fetus and newborn with future pregnancies. The relative contribution of iron deficiency to transfusion rates in the peripartum period is unknown. This study aimed to identify the prevalence of iron deficiency and anemia in pregnant women that received peripartum transfusions relative to age-matched non-transfused controls. Methods We performed a retrospective case-control study of all women that were transfused in the peripartum period from January, 2014 to July, 2018. Cases were compared to the next age matched control to deliver at our institution. The primary objective was to determine the proportion of patients with iron deficiency in pregnancy or anemia in pregnancy in cases and controls. Charts were reviewed for predisposing risk factors for iron deficiency, laboratory measures of iron deficiency and anemia, iron supplementation history and maternal and fetal outcomes. Factors associated with peripartum transfusion were analyzed using a multivariate logistic regression. Results 169 of 18, 294 (0.9%) women were transfused in the peripartum period and 64 (44%) of those transfused received 1 unit. Iron deficiency or anemia were present in 103 (71%) transfused women and 74 (51%) control women in pregnancy (OR 2.34, 95% CI: 3.7–18.0). Multivariate analysis identified social work involvement (adjusted OR 4.1, 95% CI: 1.8–10.1), intravenous iron supplementation in pregnancy (adjusted OR 3.8, 95% CI: 1.2–17.4) and delivery by unscheduled cesarean section (adjusted OR 2.8, 95% CI: 1.3–6.2) as significant predictors of peripartum transfusion. Conclusions Pregnant women being followed by a social worker, receiving intravenous iron supplementation in pregnancy or who deliver by unscheduled cesarean section are more likely to receive a red blood cell transfusion. Women with iron deficiency or anemia in pregnancy are at increased risk of peripartum blood transfusions and warrant early and rigorous iron supplementation.

Iron deficiency in pregnancy is associated with inferior maternal and fetal outcomes. Postpartum depression, prematurity, intrauterine growth restriction, impaired childhood cognition and transfusion are all sequelae of maternal iron deficiency anemia. Transfusion to women of childbearing age has important consequences including increasing the risk of hemolytic disease of the fetus and newborn with future pregnancies. The relative contribution of iron deficiency to transfusion rates in the peripartum period is unknown. This study aimed to identify the prevalence of iron deficiency and anemia in pregnant women that received peripartum transfusions relative to age-matched non-transfused controls.We performed a retrospective case-control study of all women that were transfused in the peripartum period from January, 2014 to July, 2018. Cases were compared to the next age matched control to deliver at our institution. The primary objective was to determine the proportion of patients with iron deficiency in pregnancy or anemia in pregnancy in cases and controls. Charts were reviewed for predisposing risk factors for iron deficiency, laboratory measures of iron deficiency and anemia, iron supplementation history and maternal and fetal outcomes. Factors associated with peripartum transfusion were analyzed using a multivariate logistic regression.169 of 18, 294 (0.9%) women were transfused in the peripartum period and 64 (44%) of those transfused received 1 unit. Iron deficiency or anemia were present in 103 (71%) transfused women and 74 (51%) control women in pregnancy (OR 2.34, 95% CI: 3.7-18.0). Multivariate analysis identified social work involvement (adjusted OR 4.1, 95% CI: 1.8-10.1), intravenous iron supplementation in pregnancy (adjusted OR 3.8, 95% CI: 1.2-17.4) and delivery by unscheduled cesarean section (adjusted OR 2.8, 95% CI: 1.3-6.2) as significant predictors of peripartum transfusion.Pregnant women being followed by a social worker, receiving intravenous iron supplementation in pregnancy or who deliver by unscheduled cesarean section are more likely to receive a red blood cell transfusion. Women with iron deficiency or anemia in pregnancy are at increased risk of peripartum blood transfusions and warrant early and rigorous iron supplementation.

Background: Thrombotic thrombocytopenic purpura (TTP) presents with microangiopathic hemolytic anemia, thrombocytopenia and microvascular thrombosis. Arterial thromboembolic events are relatively common and well-described in these patients. However, the literature describing venous thromboembolism (VTE) in this patient population is scarce and outdated. We hypothesize that patients with TTP are at greater risk for VTE due to the use of central venous catheters and use of solvent-detergent plasma (SDP) for plasma exchange (PLEX). Methods: Eligible patients from a single tertiary care centre were identified through apheresis records, and a retrospective chart review was conducted. The criteria for TTP diagnosis included the presence of accepted clinical/laboratory criteria and ADAMTS13 activity Results: We identified 77 consecutive patients with 123 episodes of TTP between January 1, 2008 and December 31, 2018. 51 patients (66%) were female, and 74 (96%) had immune TTP. Standard of care was daily PLEX and high-dose steroids, while rituximab was used for relapsed/refractory disease. In addition, 6 patients received caplacizumab. 13 of the 77 patients (17%) experienced a VTE (14 events: 6 PE, 5 DVT, 3 SVT), all of which were acute and associated with admission for either first presentation or relapse of TTP. None of the VTEs were catheter related. 8/13 patients were female, and all had immune TTP. Median age at diagnosis of VTE was 45 years (IQR: 36.0-56.5 years). 10/14 events were symptomatic; diagnosis was confirmed a median of 1.5 days after VTE symptom onset (IQR: 1-3 days). All patients were treated with PLEX, receiving a median of 17 exchanges (IQR: 10-23 exchanges). In addition, 13/14 TTP episodes were treated with corticosteroids, 9 with rituximab, and no patients received caplacizumab. 8 patients experienced a VTE while receiving daily PLEX; the majority (6/8) were being exchanged with SDP. VTE was diagnosed a median of 13.5 days after initiation of PLEX (IQR: 9.2-23.5 days). At TTP presentation, median platelet count was 11 x 109/L (IQR: 7-16 x 109/L), and median LDH was 894 U/L (IQR: 508-1272 U/L). At VTE diagnosis, the median platelet and LDH levels were 170 x 109/L (IQR: 126-248 x 109/L), and 232 U/L (IQR: 176-254 U/L) respectively. No patients had D-dimer testing at VTE symptom onset or diagnosis. Of the 6 patients with PE, 3 had elevated troponin levels (>0.040 ug/L) at VTE diagnosis. In terms of VTE risk factors, median BMI was 30.0 (IQR: 28.7-32.1); the majority of patients (7/13) were obese (BMI>30). 4/13 patients were active cigarette smokers. No patients had a history of lupus or antiphospholipid antibody syndrome. 2 patients had a past history of VTE, one was associated with a prior TTP episode. Most VTEs (8/14) occurred while patients were not on any pharmacologic thromboprophylaxis. For the remaining patients, dalteparin (3), ASA (2) and rivaroxaban (1) were used. VTE events were treated with direct oral anticoagulants (DOACs) including rivaroxaban and apixaban, in 10 cases. 7 of these patients were started on a DOAC after a brief initial period of low molecular weight or unfractionated heparin, 3 patients were given DOAC as upfront therapy. 4 cases were treated with warfarin (3 bridged with heparin and 1 following rivaroxaban). One distal DVT was not treated. None of the VTEs were fatal. Discussion: The point prevalence of VTE was 17% over one decade amongst patients with TTP; this is higher than previously reported in the literature. Our data also suggests that TTP patients may be at greater risk for VTE compared to general hospitalized medical patients. The majority of affected patients on PLEX were receiving SDP at VTE diagnosis. SDP contains reduced levels of proteins C and S and may have a pro-thrombotic effect. Almost all VTEs occurred after platelet recovery and normalization of hemolytic markers, suggesting a different pathophysiology than arterial thrombosis in this setting. VTE thromboprophylaxis was uncommon since it was often held due to thrombocytopenia and not resumed upon platelet recovery. Our findings suggest the need to implement VTE thromboprophylaxis earlier in patients admitted with TTP. Disclosures Sholzberg: Novartis: Honoraria; Amgen: Honoraria, Research Funding. Pavenski:Ablynx: Honoraria, Research Funding; Alexion: Honoraria, Research Funding; Shire: Honoraria; Octapharma: Research Funding; Bioverativ: Research Funding.

The primary objective was to introduce an intraoperative blood conservation bundle (BCB) checklist into clinical practice and assess its impact on perioperative blood transfusion rates during myomectomy.Prospective cohort study with retrospective control group.A Canadian tertiary-care teaching hospital.One hundred and eighty-six women who underwent myomectomy.The BCB is a physical checklist attached to the patient chart and consists of evidence-based medical and surgical interventions to reduce intraoperative blood loss. It was introduced in October 2018, and data were collected prospectively during a 12-month period for all open, robotic, and laparoscopic myomectomies at our institution. The primary outcome was the perioperative transfusion rate, and the secondary outcomes included estimated intraoperative blood loss, perioperative complications, readmissions, and BCB usage rates. Data were compared with those of a historic control group for a 24-month period before the BCB introduction.In the pre-BCB period, 134 myomectomies (90 open, 31 robotic, and 13 laparoscopic) were performed, and during our study period, 52 myomectomies (33 open, 10 robotic, and 9 laparoscopic) were performed. There was a decrease in transfusion rate from 15.7% (21/134) to 7.7% (4/52) after introduction of the BCB; however, this was not significant (p = .152). The mean estimated blood loss was lower postintervention (491 mL ± 440 mL vs 350 mL ± 255 mL; p.05) as was the mean delta hemoglobin (-28 g/L ± 13.0 g/L vs -23 g/L ± 11.4g/L; p.05]. The checklist was used in 92.3% of cases (48/52). There were no differences in intraoperative or postoperative complications or readmission rates.Best practice care bundles can improve knowledge translation of guidelines into care delivery. The introduction of the BCB was successful in reducing intraoperative blood loss during myomectomy at our institution. The BCB is a simple, effective tool that can be easily adopted by gynecologic surgeons to guide intraoperative decision-making during myomectomy.

Introduction The ways in which social determinants of health affect patients with inherited bleeding disorders remains unclear. The objective of this study was to understand healthcare provider perspectives regarding access to care and diagnostic delay amongst this patient population. Methods A healthcare provider survey comprising 24 questions was developed, tested, and subsequently disseminated online with recruitment to all members of The Association of Hemophilia Clinic Directors of Canada (N = 73), members of the Canadian Association of Nurses in Hemophilia Care (N = 40) and members of the Canadian Physiotherapists in Hemophilia Care (N = 44). Results There were 70 respondents in total, for a total response rate of 45%. HCPs felt that there were diagnostic delays for patients with mild symptomatology (71%, N = 50), women presenting with abnormal uterine bleeding as their only or primary symptom (59%, N = 41), and patients living in rural Canada (50%, N = 35). Fewer respondents felt that factors such as socioeconomic status (46%, N = 32) or race (21%, N = 15) influenced access to care, particularly as compared to the influence of rural location (77%, N = 54). Discussion We found that healthcare providers identified patients with mild symptomatology, isolated abnormal uterine bleeding, and residence in rural locations as populations at risk for inequitable access to care. These factors warrant further study, and will be investigated further by our group using our nation-wide patient survey and ongoing in-depth qualitative patient interviews.

The ability to monitor Factor VIII (FVIII) and Factor IX (FIX) levels is integral to the clinical management of hemophilia A and B patients, respectively. Factor activity levels are checked during regular follow-up, post-infusion of factor concentrates, during pre- and post-operative assessments, and when the presence of an inhibitor is suspected. However, the ability to accurately and reproducibly measure factor activity levels with standard coagulation assays has been challenging due to the emergence of recombinant factor concentrates with extended half-lives. Similarly, special considerations must be given to the type of inhibitor assay used in patients with acquired hemophilia receiving recombinant porcine FVIII replacement. Alternative approaches to achieve hemostasis with clotting factor mimetics and interference of endogenous anticoagulants lack standardized assays for monitoring hemostatic efficacy. Laboratory assays measuring dynamic clotting parameters such as thrombin generation or whole blood viscoelasticity may provide a way forward, but have yet to enter routine clinical use. This review highlights the role of specialized coagulation assays in an era where multiple new hemostatic therapeutics for hemophilia are available, and underscores the need for clear communication between bedside and laboratory clinicians.

Asplenia and hyposplenia (a/hyposplenia) are associated with increased morbidity and mortality from complications including infection. The recommended measures to reduce the risks associated with infection include patient education, vaccination and early initiation of antibiotic therapy for fever. Despite these recommendations, there is poor adherence to best practice management of patients with asplenia or hyposplenia (PWA/H). We present the development methodology and pilot data of a quality improvement project that explored whether a programme involving a novel medical alert card together with a patient and healthcare provider educational booklet increased vaccination rates and improved awareness and understanding of the infectious implications of a/hyposplenia. Our aim was to increase the proportion of those appropriately vaccinated and the proportion of patients with proper understanding of fever management by twofold in 18 months. Questionnaires were used locally as a root-cause-analysis to confirm the need for education and evaluate the effectiveness of the programme, as well as patient satisfaction. An interdisciplinary team developed a toolkit composed of a medical alert card and booklet. The toolkit was distributed to PWA/H who presented for a haematology clinic visit at a tertiary care centre. A separate set of questionnaires was then used to evaluate satisfaction and obtain feedback from patients and practitioners receiving the toolkit for the first time. Changes suggested by patients and practitioners with unanimous agreement among study investigators were made to the toolkit. The pilot study showed an increase in vaccination rates and awareness of vaccination status and appropriate fever management. The majority of the patients and practitioners found the information provided by the toolkit helpful. Given these promising single-centre findings, the intervention is being extended to another tertiary care centre with a large red blood cell disorders programme to evaluate its generalisability. The next step will be to expand the scope to paediatric PWA/H.

Background Anemia is a common condition in patients with gastrointestinal cancer. Current evidence for the use of intravenous compared with oral iron in this clinical setting is inconclusive. A systematic review was performed to assess evidence on the efficacy of intravenous iron versus oral/observation in gastrointestinal cancer patients in the preoperative and postoperative setting. Materials and methods We searched Medline and Embase from inception until December 2017 with no language restrictions. Outcomes included hemoglobin response, red blood cell transfusion, and adverse events. Screening, data abstraction, and risk of bias appraisal were performed by two independent reviewers. The risk of bias was assessed using the Cochrane tools for randomized and nonrandomized studies. Results A total of 10 studies (three randomized-controlled trials and seven nonrandomized studies) were included. Of the six preoperative studies, five reported that hemoglobin was significantly higher in the intravenous group compared with oral iron/observation. Among the four postoperative studies, three studies suggested that hemoglobin was significantly higher in the intravenous group compared with oral iron/observation. The overall risk of bias for all randomized-controlled trials was low. Quality assessments for nonrandomized studies found the risk of bias to be moderate for four studies and critical for three studies. Conclusion Despite the limitations of the current body of evidence, there is a likely benefit to the use of intravenous iron in this patient population. Further confirmatory research is needed to draw empirical conclusions.

Objective Myomectomy is offered for treatment of symptomatic uterine fibroids in women who desire to maintain fertility. An open approach, sometimes necessitated by the size or number of fibroids, is associated with a high rate of perioperative blood transfusion. Our goal was to obtain expert consensus on interventions aimed at reducing blood loss and subsequent transfusion in open myomectomy for inclusion in an intraoperative care pathway. Methods A two-round modified Delphi approach was used to generate consensus on a pathway of interventions to reduce blood loss in open myomectomy. A multidisciplinary expert panel consisting of anaesthesiologists, hematologists, and gynaecologic surgeons rated interventions for inclusion in or exclusion from the pathway (Canadian Task Force Classification III). Results Twenty-three expert panel members participated in the Delphi. Consensus was achieved in both the Delphi's first (Cronbach α = 0.92) and second (Cronbach α = 0.94) rounds. Of 11 proposed interventions, five (dilute vasopressin, tranexamic acid, pericervical tourniquet, cell saver, and restrictive transfusion practice) reached consensus for inclusion in the pathway. Conclusion A modified Delphi consensus approach was used to inform the development of an intraoperative pathway to reduce blood loss and subsequent transfusion in women undergoing open myomectomy. Future studies will investigate the effect of this intraoperative blood conservation pathway on reducing intraoperative blood loss and blood transfusion rates among women undergoing open myomectomy.

Background The Bridging ITP Trial is an open-label randomized trial designed to compare the oral thrombopoietin receptor agonist eltrombopag and intravenous immune globulin (IVIG) for patients with immune thrombocytopaenia (ITP) who require an increase in platelet count before elective surgery. Here, we report the study methods and rationale. Methods We designed a multi-centre, non-inferiority randomized trial comparing daily oral eltrombopag starting 3 weeks pre-operatively, and IVIG administered 1 week pre-operatively for patients with ITP requiring a platelet count increase prior to surgery. Starting dose of eltrombopag is 50 mg daily with a weekly pre-operative dose titration schedule, and treatment is continued for 1 week after surgical haemostasis is achieved. IVIG is administered at a dose of 1 to 2 g/kg 1 week pre-operatively with the allowance for a second dose within 1 week after surgical haemostasis. The objective of the study is to demonstrate non-inferiority of eltrombopag for the primary endpoint of achieving the pre-operative platelet count threshold (50 × 109/L for minor surgery; or 100 × 109/L for major surgery) and sustaining platelet count levels above the threshold for 1 week after surgical haemostasis is achieved, without the use of rescue treatment. Secondary endpoints include thrombosis, bleeding and patient satisfaction. Conclusion The Bridging ITP Trial will evaluate the efficacy and safety of eltrombopag as an alternative to IVIG in the peri-operative setting for patients with ITP. The protocol was designed to provide a management strategy that can be applied in clinical practice. ClinicalTrials.gov Identifier NCT01621204.

Direct oral anticoagulants (DOACs) have become the standard for thromboembolic risk management. In cases of major bleeding, trauma, or urgent surgery, accurate monitoring of DOAC activity is desirable; however, there is often no rapid, readily available test. We therefore explored the degree to which DOAC activity correlated with two coagulation assays: rotational thromboelastometry (ROTEM) and a standard coagulation assay in bleeding patients. We conducted a retrospective review of patients who experienced bleeding while on DOAC therapy from 2015 to 2017 at a Level 1 trauma center. ROTEM (EXTEM-clotting time {CT} in seconds), activated partial thromboplastin time (aPTT) (in seconds), prothrombin time (PT) (in seconds), DOAC specific drug test (anti-Xa and Hemoclot in ng/mL), and relevant clinical parameters were recorded. Descriptive statistics (median, range) and Spearman correlation coefficients were estimated. Differences between correlations were tested using Williams’ t test. Twelve cases were reviewed (13 separate bleeding episodes). Sixteen measurements of DOAC activity, EXTEM-CT, and PT were obtained. The correlations with rivaroxaban activity were 0.96 and 0.86 (p = 0.2062) for PT and EXTEM-CT, respectively. The correlations with apixaban activity were 0.63 and 0.56 (p = 0.7175) for PT and EXTEM-CT, respectively. Analyses were not conducted for dabigatran due to limited data. Although not statistically significant, PT appears to have a higher correlation with direct Xa inhibitor activity than EXTEM-CT. Further research with larger samples is necessary to clarify the differences between ROTEM and standard assays in detecting DOAC activity.

Introduction A recombinant porcine factor VIII B-domain-deleted product (rpFVIII; OBIZUR, Baxalta Incorporated, Deerfield, IL 60015, USA) was recently approved for treatment of bleeding episodes in adults with acquired haemophilia A (AHA) in the United States. To date, no clinical experience outside the registration study has been reported. Aim To describe early clinical experience using rpFVIII for AHA. Methods A retrospective chart review of seven patients with AHA treated with rpFVIII at four institutions from November 2014 to October 2015. Results The time to diagnosis of AHA ranged from 5 days to 6 weeks. Six major and one other bleed were treated with rpFVIII following unsatisfactory bypassing agent (BPA) therapy. Good haemostatic efficacy was seen in five of seven cases. rpFVIII loading doses of 100 (n = 6) or 200 U kg−1 (n = 1) increased FVIII activity from

La coagulopathie est en correlation avec la gravite de la COVID-19 et pourrait inclure des concentrations elevees de d-dimeres (≥ 2 fois la limite superieure de la normale), un temps de prothrombine legerement prolonge (~ 1–3 s par rapport a la normale), une legere thrombocytopenie

Recent data suggest unnecessary medical testing and treatment is relatively common in Canada. A number of harms to patients can arise as a result of unnecessary tests and treatments. In addition to patient harm, unnecessary tests and treatments add to the cost of medical care. Inspired by the Choosing Wisely campaign, St. Michael’s Hospital in Toronto, Ontario, developed a hospital-wide program to address many different forms of overutilization at our hospital. The program prioritizes harm reduction over cost-containment and aims to create sustainable change through grassroots clinician engagement. This article will review important lessons learned from the St. Michael’s experience.

More recent immune thrombocytopenia (ITP) treatment strategies enhance platelet production with the use of thrombopoietin receptor agonists (TPO-RA) such as eltrombopag. Patients receiving TPO-RA agents may be at an increased risk of thromboembolism, however the pathophysiology and common underlying risk factors are not well understood. We present the case of a young asplenic woman on eltrombopag for chronic ITP with acute myocardial infarction involving the right coronary artery. Past medical history was significant for remote mediastinal radiation for lymphoma and splenectomy for ITP. She had no other risk factors for coronary artery disease. She underwent coronary catheterization and balloon angioplasty to the culprit lesion, although stenting was deferred due to concerns with dual antiplatelet therapy. She was discharged from hospital on single antiplatelet therapy with acetylsalicylic acid. We believe that the patient’s ITP, recent eltrombopag use, surgical asplenia and history of mediastinal radiation synergistically contributed to her myocardial infarction. The risks of bleeding and thromboembolism must be carefully weighed in patients receiving TPO-RA therapy.

Background The anticoagulated trauma patient presents a particular challenge to the critical care physician. Our understanding of these patients is defined and extrapolated by experience with patients on warfarin pre-injury. Today, many patients who would have been on warfarin are now prescribed the Direct Oral Anticoagulants (DOACs) a class of anticoagulants with entirely different mechanisms of action, effects on routine coagulation assays and approach to reversal. Methods Trauma registry data from Toronto’s (Ontario, Canada) two Level 1 trauma centres were used to identify patients on oral anticoagulation pre-injury from June 1, 2014 to June 1, 2015. The trauma registry and medical records were reviewed and used to extract demographic and clinical data. Results We found 81 patients were on oral anticoagulants pre-injury representing 3.2% of the total trauma population and 33% of the orally anticoagulated patients were prescribed a DOAC prior to presentation. Comparison between the DOAC and warfarin groups showed similar age, mechanisms of injury, indications for anticoagulation, injury severity score and rate of intracranial hemorrhage. Patients on DOACs had higher initial mean hemoglobin vs warfarin (131 vs 120) and lower serum creatinine (94.8 vs 129.5). The percentage of patients receiving a blood transfusion in the trauma bay and total in-hospital transfusion was similar between the two groups however patients on DOACs were more likely to receive tranexamic acid vs patients on warfarin (32.1% vs 9.1%) and less likely to receive prothrombin concentrates (18.5% vs 60%). Patients on DOACs were found to have higher survival to discharge (92%) vs patients on warfarin (72%). Conclusion Patients on DOACs pre-injury now represent a significant proportion of the anticoagulated trauma population. Although they share demographic and clinical similarities with patients on warfarin, patients on DOACs may have improved outcomes despite lack of established drug reversal protocols and challenging interpretation of coagulation assays. Level of Evidence: III; Study Type: Retrospective Review.

Introduction: Despite the manifold symptoms that women with inherited bleeding disorders may experience, no study has specifically sought to understand the lived experiences of these women, nor the barriers to care that they may face. Indeed, the literature on this topic remains sparse. A MEDLINE search assessing literature on access to care for women with inherited bleeding disorders yielded 526 abstracts; of these, only a small subset (N=12) focused on women's health, and less (N=2) made any note of potential barriers to care. Given the lack of data on this subject to date, the objective of this qualitative descriptive study was to understand women's lived experiences with inherited bleeding disorders, and their perceptions around access to care. Methods: A semi-structured qualitative interview guide was developed in conjunction with experienced hematologists (MS and RW), patient advocates from the Canadian Hemophilia Society (CHS; PW and DP), and a qualitative research expert (KD). Inclusion criteria for study enrollment included age ≥ 18 years old, English-speaking, and confirmed diagnosis of an inherited bleeding disorder. Women were recruited across Canada through identification by treating healthcare providers and study members of the CHS. They were then consented for telephone interview by SA. Interviews were transcribed verbatim, and analyzed using descriptive thematic analysis on NVIVO software. A random selection of interviews was coded by 2 team members (SA, KD) to ensure similar data interpretation. Results: Ten interviews with women with bleeding disorders were completed. Ages ranged from 24-70, and diagnoses included hemophilia B carriership (N=2), hemophilia A carriership (N=2), von Willebrand disease (N=2), disorders of platelet function (N=3) and dysfibrinogenemia (N=1). Common themes in the data included diagnostic uncertainty, affected family members, bleeding disorders' effect on life, the importance of treatment plans, experienced barriers, and access to care factors (Table 1). The most common barriers to care noted were healthcare provider dismissal of bleeding symptoms, lack of healthcare provider awareness, geographical barriers, and perceived barriers specific to women. Patients noted the importance of as-needed treatment, treatment for abnormal uterine bleeding, iron supplementation, and the need for family planning. They also highlighted the importance of access to clinic and treatment, and the need for self-advocacy. Discussion: To our knowledge, this is the first study to assess lived experiences and barriers to care for women with inherited bleeding disorders. Our data indicates that women often feel dismissed by healthcare providers, and feel disempowered by not feeling understood or heard. These results may have implications for the ways in which healthcare providers communicate with their patients, particularly in the face of diagnostic uncertainty or predominantly gynecologic-related bleeding symptoms. By better understanding patients' lived experiences, providers may be able to provide more comprehensive, person-centered care. Disclosures Teitel: Novo Nordisk: Consultancy; Octapharma: Consultancy; CSL Behring: Consultancy; Pfizer: Consultancy, Research Funding; Bayer: Consultancy, Research Funding; Shire: Consultancy; BioMarin: Consultancy. Sholzberg:Novartis: Honoraria; Amgen: Honoraria, Research Funding.

Background Iron deficiency (ID) in pregnancy is a common problem that can compromise both maternal and fetal health. Although daily iron supplementation is a simple and effective means of treating ID in pregnancy, ID and ID anemia (IDA) often go unrecognized and untreated due to lack of knowledge of their implications and competing clinical priorities. Methods and findings In order to enhance screening and management of ID and IDA in pregnancy, we developed a novel quality-improvement toolkit: ID in pregnancy with maternal iron optimization (IRON MOM), implemented at St. Michael’s Hospital in Toronto, Canada. It included clinical pathways for diagnosis and management, educational resources for clinicians and patients, templated laboratory requisitions, and standardized oral iron prescriptions. To assess the impact of IRON MOM, we retrospectively extracted laboratory data of all women seen in both the obstetrics clinic and the inpatient delivery ward settings from the electronic patient record (EPR) to compare measures pre- and post-implementation of the toolkit: a process measure of the rates of ferritin testing, and outcome measures of the proportion of women with an antenatal (predelivery) hemoglobin value below 100 g/L (anemia), the proportion of women who received a red blood cell (RBC) transfusion during pregnancy, and the proportion of women who received an RBC transfusion immediately following delivery or in the 8-week postpartum period. The pre-intervention period was from January 2012 to December 2016, and the post-intervention period was from January 2017 to December 2017. From the EPR, 1,292 and 2,400 ferritin tests and 16,603 and 3,282 antenatal hemoglobin results were extracted pre- and post-intervention, respectively. One year after implementation of IRON MOM, we found a 10-fold increase in the rate of ferritin testing in the obstetric clinics at our hospital and a lower risk of antenatal hemoglobin values below 100 g/L (pre-intervention 13.5% [95% confidence interval (CI) 13.0%–14.11%]; post-intervention 10.6% [95% CI 9.6%–11.7%], p < 0.0001). In addition, a significantly lower proportion of women received an RBC transfusion during their pregnancy (1.2% pre-intervention versus 0.8% post-intervention, p = 0.0499) or immediately following delivery and in the 8 weeks following (2.3% pre-intervention versus 1.6% post-intervention, p = 0.0214). Limitations of this study include the use of aggregate data extracted from the EPR, and lack of a control group. Conclusions The introduction of a standardized toolkit including diagnostic and management pathways as well as other aids increased ferritin testing and decreased the incidence of anemia among women presenting for delivery at our site. This strategy also resulted in reduced proportions of women receiving RBC transfusion during pregnancy and in the first 8 weeks postpartum. The IRON MOM toolkit is a low-tech strategy that could be easily scaled to other settings., Michelle Sholzberg and colleagues report on the implementation of a toolkit aimed at improving management of anemia in pregnancy., Author summary Why was this study done? Iron deficiency is a common problem in pregnancy, with serious health consequences including maternal anemia requiring blood transfusions, early labor, low birth weight, and long-term developmental issues in the child. If detected early, iron deficiency in pregnancy can be treated with convenient and inexpensive daily oral iron pills. Unfortunately, due to low awareness and other competing medical issues during pregnancy, iron deficiency often goes undiagnosed and untreated. What did the researchers do and find? We created a toolkit including treatment algorithms, educational information for doctors and patients, modified blood work requisitions, and standardized iron prescriptions in order to help obstetricians detect and treat iron deficiency. We found that after implementation of the toolkit, there was an increase in testing for iron deficiency, a decrease in maternal anemia, and a decrease in maternal blood transfusions during and after pregnancy. What do these finding mean? The implementation of the toolkit successfully helped obstetricians detect and treat iron deficiency in pregnancy. The toolkit is a low-tech strategy that could be adapted to be used in other patient groups with iron deficiency.

Introduction Care for persons with haemophilia (PWH) is most commonly delivered through the integrated care model used by Hemophilia Treatment Centers (HTCs). Although this model is widely accepted as the gold standard for the management of haemophilia; there is little evidence comparing different care models. Aim We performed a qualitative study to gain insight into issues related to outcomes, acceptability, equity and feasibility of different care models operating in the US. Methods We used a qualitative descriptive approach with semi-structured interviews. Purposive sampling was used to recruit individuals with experience providing or receiving care for haemophilia in the US through either an integrated care centre, a specialty pharmacy or homecare company, or by a specialist in a non-specialized centre. Persons with haemophilia, parents of PWH aged ≤18, healthcare providers, insurance company representatives and policy developers were invited to participate. Results and Conclusions Twenty-nine interviews were conducted with participants representing 18 US states. Participants in the study sample had experience receiving or providing care predominantly within an HTC setting. Integrated care at HTCs was highly acceptable to participants, who appreciated the value of specialized, expert care in a multidisciplinary team setting. Equity and feasibility issues were primarily related to health insurance and funding limitations. Additional research is required to document the impact of care on health and psychosocial outcomes and identify effective ways to facilitate equitable access to haemophilia treatment and care.

Background Integrated care models have been adopted for individuals with chronic conditions and for persons with rare diseases, such as haemophilia. Objective To summarize the evidence from reviews for the effects of integrated multidisciplinary care for chronic conditions in adults and to provide an example of using this evidence to make recommendations for haemophilia care. Search methods We searched MEDLINE, EMBASE, CINAHL and Cochrane Database of Systematic Reviews up to January 2016, and reviewed reference lists of retrieved papers. Selection criteria Systematic reviews of at least one randomized study, on adults with non-communicable chronic conditions. Data collection and analysis Two investigators independently assessed eligibility and extracted data. Quality of reviews was assessed using ROBIS, and the evidence assessed using GRADE. Results We included seven reviews reporting on three chronic conditions. We found low to high quality evidence. Integrated care results in a reduction in mortality; likely a reduction in emergency visits and an improvement in function; little to no difference in quality of life, but shorter hospital stays; and may result in little to no difference in missed days of school or work. No studies reported educational attainment, or patient adherence and knowledge. When used for haemophilia, judgment about the indirectness of the evidence was driven by disease, intervention or outcome characteristics. Conclusion This overview provides the most up to date evidence on integrated multidisciplinary care for chronic conditions in adults, and an example of how it can be used for guidelines in rare diseases.

Introduction. The phase 3 randomized, placebo-controlled trials of the SYK inhibitor fostamatinib in adult patients with ITP were followed by an open-label extension (OLE) study to examine durability of response to fostamatinib and to allow patients in the placebo group in the phase 3 trials to crossover to fostamatinib. This abstract provides an additional year of data from the OLE study in patients with up to 3 years of fostamatinib treatment. Methods. Patients were adults with persistent or chronic ITP who had failed ≥1 prior therapy and had ≥3 platelet counts below 30,000/μL at screening. Patients initiated fostamatinib treatment at 100mg BID PO and increased to 150 mg BID based on tolerability and if platelets were Results. In the OLE study, 123 patients received fostamatinib, including 44 who had received placebo in the phase 3 studies. At baseline, the median age was 52 years (range 20-88), and 7% had persistent ITP ( The median duration of fostamatinib exposure was 8.9 months (range 1.5-41.3). The median treatment compliance was 98%. At the time of analysis, 42 of 123 subjects (34%) continued fostamatinib treatment. Main reasons for discontinuation included lack of a platelet response after Week 12 (36%), study-specific adverse event (AE) (7%), and other AEs (7%). Of 27 patients with a stable response, 21 (78%) have maintained the response at Month 12 of fostamatinib treatment, and 15 (56%) at Month 24. At Month 12, median platelet count for the 49 subjects with data at that time point was 72,000/µL (range: 9000-333,000 µL). For the 32 subjects with data at Month 24, median platelet count was 80,500/µL (range: 7000-315,000/µL). See figure. An overall platelet response was achieved by 57/123 (46%) patients. AEs were reported by 95 (77%) patients and were mild/moderate in 92 (75%). See table. The most common AEs were diarrhea and hypertension, which were manageable with targeted treatment, fostamatinib dose modifications, or treatment withdrawal (5 patients withdrew due to diarrhea and none due to hypertension). Serious adverse events (SAE) were reported in 28 patients (23%), were considered unrelated to fostamatinib in 23 patients (19%) and included bleeding-related SAEs in 11 subjects (9%), thrombocytopenia in 6 subjects (5%), epistaxis in 3 (2%), sepsis in 2 (2%) and transaminases increased in 2 (2%). Adverse events were consistent with those reported during the placebo-controlled trials. Conclusion. In this open-label extension study of the two phase 3, placebo-controlled trials, 56% of subjects with a stable response maintained the response for ≥24 months. No new safety signals have been detected during long-term treatment of ITP with fostamatinib. Figure. Figure. Disclosures Duliege: Rigel: Employment, Equity Ownership. Arnold:UCB: Consultancy; Amgen: Consultancy, Research Funding; UCB: Consultancy; Amgen: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding; Bristol Myers Squibb: Research Funding. Boccia:Amgen: Research Funding, Speakers Bureau; Pfizer: Consultancy; Abbvie: Speakers Bureau; AstraZeneca: Research Funding, Speakers Bureau; Celgene: Speakers Bureau; Sandoz: Consultancy; Genentech: Research Funding, Speakers Bureau; BMS: Research Funding. Boxer:Rigel: Speakers Bureau; Incyte: Speakers Bureau; AbbVie: Speakers Bureau. Cooper:Amgen, Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Hill:Novartis: Honoraria; Novartis: Honoraria. Zayed:Rigel: Employment, Equity Ownership. Tong:Rigel: Employment, Equity Ownership. Bussel:Uptodate: Honoraria; Protalex: Consultancy; Novartis: Consultancy, Research Funding; Prophylix: Consultancy, Research Funding; Momenta: Consultancy; Amgen Inc.: Consultancy, Research Funding; Rigel: Consultancy, Research Funding.

We thank Dr. Giles[1][1] for her interest and commentary on our article.[2][2] For clarification, Drs. Sholzberg, Teitel and Hicks are hematologists, and Dr. Sholzberg is the medical director of the coagulation laboratory at St. Michael’s Hospital. In addition, Drs. Sholzberg and Teitel co-direct

The PT/INR (prothrombin time/international normalized ratio) and aPTT (activated partial thromboplastin time) were tests developed in the early 20th century for specific and unique indications. Despite this, they are often ordered together routinely. The objective of this study was to determine if a multimodal intervention could reduce PT/INR and aPTT testing in the emergency department (ED). This was a prospective multi-pronged quality improvement study at St. Michael's Hospital. The initiative involved stakeholder engagement, uncoupling of PT/INR and aPTT testing, teaching, and most importantly a revision to the ED order panels. After changes to order panels, weekly rates of PT/INR and aPTT testing per 100 ED patients decreased (17.2 vs 38.4, rate ratio=0.45 (95% CI 0.43-0.47), p

Rivaroxaban, apixaban and dabigatran are now commonly used as alternatives to vitamin K antagonist therapy (e.g., warfarin) for patients with atrial fibrillation, and for the treatment and prevention of venous thromboembolism. Dabigatran is a direct thrombin inhibitor, whereas apixaban and