ALBERT

Description: Fetal and neonatal immune thrombocytopenia (FNIT) is a life-threatening bleeding disorder, resulting from fetal platelet opsonization and destruction by maternal antibodies developed during pregnancy. The frequency of FNIT has been estimated at 0.5–1.5/1,000 liveborn neonates. However, the incidence of fetal mortality is currently unknown, as the rate of miscarriage in affected pregnant women has not been well studied. Integrin αIIbβ3 and Glycoprotein (GP) Ibα are major glycoproteins expressed on the platelet surface and are the two major antigens targeted by anti-platelet antibodies in autoimmune thrombocytopenia (ITP). However, it is unclear why the incidence of FNIT caused by anti-GPIbα antibodies is far lower than that of FNIT mediated by anti-β3 integrin antibodies. This difference cannot be well explained by the frequency of genetic polymorphisms of the two antigens. We hypothesized that: 1) GPIbα is less immunogenic, leading to less maternal antibody production during pregnancy, or 2) anti-GPIbα antibodies cause a less severe pathology, and thus have a lower chance of being reported, or 3) anti-GPIbα antibodies cause higher incidence of miscarriage, resulting in reduced reported cases. To test these hypotheses, the maternal immune response against fetal platelet GPIbα versus β3 integrin were compared in FNIT models, using syngeneic background BALB/c GPIbα−/− and β3−/− mice. The FNIT models were established by transfusing female GPIbβ −/− or α3−/− mice with 108 gel-filtered platelets from wild-type (WT) BALB/c mice weekly. After two platelet immunizations, flow cytometry assays were used to detect the titers of anti-GPIbα and anti-β3 antibodies, and the immunized females were bred with WT BALB/c male mice. We found that there was no significant difference in mean antibody titer between the two groups (P〉0.05). However, miscarriage occurred more frequently in anti-GPIbα-mediated FNIT (14/16 versus 8/16, P

Description: Background: Direct oral anticoagulants (DOACs) are slowly replacing warfarin for the prevention of stroke in atrial fibrillation and treatment and secondary prevention of venous thromboembolism. Patients with poor time in therapeutic range (TTR) are often switched to a DOAC. Poor TTR can be due to drug interactions but if the reason is poor compliance, outcomes could be worse using a DOAC without monitoring. Methods: To understand the compliance patterns we performed a retrospective chart review in patients from the anticoagulation clinic at Hamilton General Hospital that were switched from warfarin to a DOAC from April 2013 to April 2018. Patients who were taking warfarin for ≥ 2 months for any indication, except for mechanical valve prosthesis, and who were switched to a DOAC were included. We excluded patients who had a DOAC-to-DOAC switch, patients who had no reported TTR available, and those who were temporarily on warfarin after cardiac surgery. The documented reasons for a switch from warfarin to a DOAC were compared between patients with TTR ≤ 60% and 〉60%. Non-adherence to international normalized ratio (INR) monitoring was considered if 〉20% of tests were not done or delayed for more than 2 days. Results: A total of 643 eligible patients were initially screened and 288 patients were excluded: 179 had no available TTR, 93 were temporarily on warfarin after cardiac surgery, 11 were not actually switched from warfarin to a DOAC, and 5 had a DOAC-to-DOAC switch. The remaining 355 patients were included in the analysis: 223 had a TTR ≤ 60% and 132 patients had a TTR 〉60%. There were no differences in the median age or gender distribution. The most common indication for anticoagulation was atrial fibrillation in both groups. The median TTR was 43% in the TTR ≤ 60% group and 71% in the TTR 〉60% group. The median duration on anticoagulation with warfarin was significantly longer for the TTR 〉60% group compared with the TTR ≤ 60% group (42 months versus 19 months; P 60% were: switch by another physician for unknown reason (n=36), bleeding (n=30), and patient preference (n=20). The most common reasons for a switch in those with a TTR ≤ 60% were: unstable INR readings (n=42), drug interactions (n=33), and bleeding (n=30). There was no significant difference in the rate of non-adherence with the scheduled INR monitoring (42% in the group with a TTR 〉60% versus 49% in those with a TTR ≤ 60%). Conclusion: We found that about half of the patients on chronic anticoagulation with warfarin and switched to a DOAC were non-adherent with the scheduled INR monitoring. This, in combination with low TTR, should alert the physician of possible non-compliance with taking DOACs. Further prospective studies are needed to examine the DOAC adherence rate and clinical outcomes in this specific population. Disclosures Schulman: Boehringer-Ingelheim: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Sanofi: Honoraria; Bayer: Honoraria.

Description: Fetal and neonatal alloimmune thrombocytopenia (FNAIT) is a life-threatening disease in which intracranial hemorrhage (ICH) is the major risk. Although thrombocytopenia caused by maternal antibodies against β3 integrin and occasionally against other platelet antigens (e.g. GPIbα) has long been assumed to be the cause of bleeding, the mechanism of ICH has never been adequately explored. Utilizing murine models of FNAIT and a high frequency ultrasound imaging system, we found that ICH only occurred in fetuses and neonates with anti-β3 integrin- but not anti-GPIbα-mediated FNAIT, despite similar thrombocytopenia in both groups. Only anti-β3 integrin-mediated FNAIT reduced brain and retina vessel density, impaired angiogenic signalling, and increased endothelial cell apoptosis; which were abrogated by maternal administration of intravenous immunoglobulin (IVIG). ICH and impairment of retinal angiogenesis was further reproduced in neonates by injection of anti-β3 integrin- but not anti-GPIbα-antisera. Utilizing cultured human endothelial cells, we found that cell proliferation, network formation, and Akt phosphorylation were inhibited only by murine anti-β3 integrin-antisera and human anti-HPA-1a IgG purified from mothers with FNAIT children. Our data suggest fetal hemostasis is unique in that impairment of angiogenesis rather than thrombocytopenia is likely the cause of ICH; importantly maternal IVIG therapy can effectively prevent this devastating disorder. Disclosures No relevant conflicts of interest to declare.

Description: Abstract 361 Background: Patients with deep vein thrombus (DVT) can safely be treated as outpatients using subcutaneous low molecular weight heparin (LMWH). However the role of outpatient treatment in patients diagnosed with a pulmonary embolism (PE) is controversial. This practice is not accepted in many centers and majority of patients are still admitted to the hospital for observation. Clinicians are reluctant to discharge patients due to insufficient data supporting the safety of outpatient management of PE. Purpose: To determine the safety of outpatient treatment of acute symptomatic PE and the outcomes associated with outpatient management of PE including venous thromboembolism (VTE) recurrence, major bleeding, fatal PE, fatal intracranial hemorrhage (ICH), and overall mortality. Methods: A systematic literature search strategy was conducted using MEDLINE, EMBASE, the Cochrane Register of Controlled Trials and all EBM Reviews of published studies up to June 2012. We included randomized controlled trials (RCTs) and prospective cohort studies. We calculated the pooled proportions for the different outcomes at 3-months of follow-up. Ninety-five percent confidence intervals (95% CI) were calculated for each rate using the averaged, inverse variance-weighted estimates from each study. Results: Thirteen studies met all the inclusion criteria (3 RCTs and 10 prospective cohort studies). A total of 2458 patients were included in the systematic review. Different risk stratification methods were used to identify low risk patients with PE such as the pulmonary embolism severity index (PESI), the Geneva prognostic score, clinical gestalt and/or laboratory markers. The risk of recurrent VTE in patients with PE managed as outpatients was 1.64% (95% CI 0.69 – 3.0%; I2: 70.7%) during the 3 months follow-up period. The rate of fatal PE was 0.70% (95% CI 0.14 – 1. 7%; I2: 72.6%). The rates of major bleeding and ICH were 1.14% (95% CI 0.35 – 2.34%; I2: 72.8%) and 0.29% (95% CI 0.06– 0.68%; I2: 0%), respectively. The overall mortality rate was 2.3% (95% CI 0.41 – 5.7%; I-square: 92.8%). The I2 was moderate to high for most proportions, likely due to difference in the baseline characteristics (e.g. the inclusion of cancer patients in some studies). Conclusion: Independent of the risk stratification methods used, the rate of adverse events associated with outpatient PE treatment seems low. Based on our systematic review and pooled meta-analysis, numerous patients with acute PE can safely be treated as outpatients. Proportion meta-analysis showing the risk of recurrent VTE in patients with PE managed as outpatients for a 3 month follow up period. Disclosures: No relevant conflicts of interest to declare.

Description: Gaucher disease (GD) is a lysosomal storage disorder characterized by anemia and thrombocytopenia, hepatosplenomegaly, and skeletal involvement. The management of Gaucher disease was improved by the development of enzyme replacement therapy (ERT). However, the bone response to ERT is generally slower compared to other clinical manifestations. Some have recommended the early use of ERT to prevent the development of severe skeletal complications. Because we have access to over 30 untreated patients in Ontario, we questioned the extent to which the bony complications progress in severity over a long period of time. We examined retrospectively the natural history of GD and the extent of skeletal manifestations in 22 untreated type 1 GD adult patients (mean age 49 ± 3.3, range of 20–81 years). Ten patients were N370S homozygotes and twelve were compound heterozygotes. The patients were followed for a median of 9.5 years (range of 3 to 16 years). Assessments included complete blood counts (CBC); levels of angiotensin converting enzyme (ACE), ferritin, and chitotriosidase; liver and spleen volumes; and occurrences of bony complications. Dual Energy X-ray Absorptiometry (DEXA), Magnetic Resonance Imaging (MRI) of femurs, skeletal survey, and plain radiography were utilized to assess bony complications in 21 patients. Hemoglobin (Hb) concentration did not significantly change over time (mean baseline concentration of 12.8 ± 0.27 g/dL vs mean recent concentration of 12.6 ± 0.37 g/dL, p = 0.65). Mean platelet count also remained relatively stable over time (mean baseline count of 138 ± 13 × 109/L vs mean recent count of 138.5 ± 18 × 109/L, p = 0.98). Mean ferritin and ACE concentrations were elevated and were stable over time. Liver volumes decreased over time (mean baseline liver volume of 1.2 × normal (N) vs mean recent volume of 1.06 × N, p = 0.27) and 6/21 (29%) patients had moderate hepatomegaly (liver volume ≥ 1.25 × N). Spleen volumes remained stable over time (mean baseline spleen volume of 6.4 × N vs mean recent volume of 5.1 × N, p = 0.56). None of the changes was statistically significant. Three of 19 (15.8 %) patients had moderate splenomegaly (spleen volume ≥ 5 × N), 2/19 (10.5%) had severe splenomegaly (spleen volume ≥ 15 × N), and 2/22 (9%) had splenectomy. The most common skeletal manifestations were infiltration of the bone marrow in 15/21 (71%) patients followed by osteopenia in 14/21 patients (67%), and infarctions in 6/21 (29%) patients. Other bony complications included osteoporosis in 3/21 (14%), avascular necrosis (AVN) in the left knee and femur in 1/21 (5%), and osteolysis in 1/21 (5%) patients; there were no cases of fractures. Three of 21 (14%) patients developed new infarcts (2N370S homozygous patients) over time, 1/21 (5%) developed AVN, and 4/21 (19%) had an increase in the degree of osteopenia. There were no significant differences observed between the N370S homozygous and compound heterozygous patients. Although GD and its skeletal complications progress in severity in some patients, our results suggest that GD complications including bony disease may stabilize over time. Therefore, early use of ERT may not be necessary in all type 1 GD patients.

Description: Introduction: The true incidence of venous thromboembolism (VTE) in patients with acute spinal cord injury (SCI) is unclear. The management of thromboprophylaxis varies among clinicians and is challenging due to the balance against bleeding. There is limited data on the risk factors associated with VTE in patients with an acute SCI. Methods: We performed a retrospective chart review of consecutive adult patients with acute traumatic or non-traumatic SCI presenting within 1 week of injury from 2009 to 2015. We excluded patients who were already on therapeutic oral anticoagulation, those who had a short hospital admission (

Description: Gaucher disease (GD) is an inherited lysosomal storage disease, which is often managed by enzyme replacement therapy (ERT). While the response to ERT is gratifying in terms of hepatosplenomegaly, cytopenias, and general well-being, the response of bony disease is very slow, and in some cases non-existent. Skeletal manifestations are the most painful and debilitating components of GD type 1, and have a negative impact on the patient’s quality of life. Whether an increase in the dose of ERT has a beneficial effect, and whether substrate reduction therapy (SRT) stabilizes and/or ameliorates bony disease, is controversial. The aim of our study was to determine whether or not there is enough evidence to make a definitive statement about the effects of ERT and SRT on bony complications of Gaucher disease. We conducted a systematic review of all studies examining the effects of ERT and SRT on bony complications of Gaucher disease published before July 2008. The studies were identified by a computerized search using Medline, Embase, The Cochrane Database of Systematic Reviews, The Cochrane Central Register of Control Trials (CCTR), and bibliographies of papers subsequently retrieved from the search. Three hundred studies were grouped according to whether they deal with the natural history of GD or therapeutic issues and 17 studies were included in the review. Meta analyses were done using a random effects model and the studies compared baseline versus after-treatment values. Quantitative Chemical Shift Imaging (QCSI) of vertebral bone marrow (BM) fat fraction, Magnetic Resonance Imaging (MRI) T1-weighted signal, semi-quantitative MRI bone marrow burden (BMB) score, and bone mineral density (BMD) Z scores of spine and femur were used to assess the effects of ERT and SRT on bony complications. Of the 4 studies that measured BM fat fraction, 3 showed that fat fraction significantly increased after ERT (Weighted Mean Difference [WMD] of 0.17, 95 % CI of 0.13 to 0.2, n= 36, p 〈 0.00001) and one study showed a non-significant increase in fat fraction after SRT (n = 2, p = 1.23). MRI T1-weighted signal was measured in 6 studies (5 studies on ERT and one on SRT), and 44/78 (56%) of GD1 patients were responders to ERT versus 20/78 (25.6%) who did not respond to ERT. One study showed that BM infiltration generally decreased after SRT. Of the 3 studies that measured BMB score, 2 showed that BMB score significantly decreased after ERT (WMD of −4.98, 95 % CI of −8.38 to −1.57, n= 27, p = 0.004) and one study showed a stable BMB score after SRT (n = 6, p = 0.82).The 4 studies in which BMD Z score of lumbar spine (LS) was measured showed an increase in Z score after ERT (WMD of 0.37, 95 % CI of −0.05 to 0.79, n= 54, p = 0.09) and one study showed a significant increase in LS Z score after 6 months of SRT. Of the 3 studies that measured BMD Z score of femurs, 2 showed a non-significant increase in Z score after ERT (WMD of 0.16, 95 % CI of −0.29 to 0.61, n= 43, p = 0.48) and one study showed a significant increase in femur Z score after 6 months of SRT. These studies suggest that ERT may be more effective in ameliorating BM involvement than in increasing BMD Z scores. SRT may stabilize the BM involvement and generally increase the BMD Z scores. However, further investigations are needed on the effects of SRT on bony complications of GD.

Description: Background and hypothesis: Cyclosporine is administered to all patients undergoing allogeneic bone marrow transplantation in Hamilton. It is given intravenously at first then orally after engraftment. The manufacturer’s recommendation is to use a dose ratio of 1:3, IV to oral; the Hamilton unit uses a ratio of 1:2, yet has observed frequent rises of cyclosporine to toxic levels. We wished to confirm that the dose conversion ratio of 1:2 is associated with significantly high cyclosporine levels and nephrotoxicity. Methods and Results: Thirty-five consecutive patients undergoing allogeneic bone marrow transplantation at McMaster University Medical Centre were studied. We included patients who were diagnosed with a hematological cancer i.e. leukemia (76%), lymphoma (18%), or myelodysplastic syndrome (6%), and who underwent chemotherapy. The patients’ plasma cyclosporine levels were measured 4–5 days after its initiation and with every dose adjustment, and serum creatinine levels were measured daily. Forty four percent of the patients were males. In 53% of the patients 1:2 IV to oral conversion ratio caused elevation of plasma cyclosporine levels to the toxic range (p

Description: Background: Patients with acute spinal cord injury (SCI) have a high risk of venous thromboembolism despite thromboprophylaxis. Low molecular weight heparin (LMWH), the current standard of care, is inconvenient for long term thromboprophylaxis, costly, and partially effective. Direct oral anticoagulants (DOACs) have been shown to be at least as effective and as safe as LMWH in other thromboprophylaxis settings but there is no randomized evaluation of DOACs in this population. Aim: By conducting a feasibility randomized trial, we aimed to determine the likely recruitment rate of eligible patients into an RCT in which patients with acute SCI were randomized to a prophylactic dose of LMWH or apixaban. Methods: A pilot study was performed at Hamilton General Hospital (HGH). Adult patients with an acute traumatic SCI presenting to the hospital within 1 week of SCI and at least 36 h after the injury were included. Exclusion criteria were the need for therapeutic oral anticoagulation prior to enrolment; active bleeding, intracranial or peri-spinal hematoma, or a bleeding disorder; pregnancy or breastfeeding; severe renal failure (creatinine clearance ≤30 ml/min); severe cirrhosis (Child-Pugh class C); severe thrombocytopenia (platelets 1 week from SCI (n=2), indication for therapeutic anticoagulation (n=2), active bleeding (n=1), and minor injury with an expected short hospital admission (n=1). Four patients were randomized to each drug. Median age was 61 (range 51 to 70) and 7 (87.5%) were males. There were no symptomatic VTE or sudden deaths. One patient randomized to apixaban had major bleeding. There were no serious adverse events. Conclusions: Our pilot study is the first randomized trial to examine the role of a DOAC compared with LMWH for thromboprophylaxis in this high-risk group. The primary feasibility outcome was not met, and therefore a multicenter RCT is unlikely to be feasible. The efficacy and safety of DOACs on this indication should be evaluated in registry- or health care database studies. Disclosures Eikelboom: Heart and Stroke Foundation: Research Funding; Sanofi Aventis: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Glaxo Smith Kline: Honoraria, Research Funding; Eli Lilly: Honoraria, Research Funding; Daiichi Sankyo: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Boehringer Ingelheim: Honoraria, Research Funding; Bayer: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding.

Description: Anticoagulant therapy is often refrained from out of fear of hemorrhagic complications. The most frequent type of major bleeding is gastrointestinal, but intracranial hemorrhage has the worst prognosis. Management of these complications in patients on anticoagulants should follow the same routines as for nonanticoagulated patients, as described here with the previously mentioned bleeds as examples. In addition, for life-threatening or massive hemorrhages, reversal of the anticoagulant effect is also crucial. Adequate reversal requires information on which anticoagulant the patient has taken and when the last dose was ingested. Laboratory data can be of some help, but not for all anticoagulants in the emergency setting. This is reviewed here for the different types of anticoagulants: vitamin K antagonists, heparins, fondaparinux, thrombin inhibitors and factor Xa inhibitors. Specific antidotes for the latter are becoming available, but supportive care and nonspecific support for hemostasis with antifibrinolytic agents or prothrombin complex concentrates, which are widely available, should be kept in mind.