bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety of Recombinant Human Factor IX, Nonacog Alfa, for Usual Use In Pediatric Patients: Results From a Prospective Registry of European Hemophilia B Patients.
Authors: Rendo Pablo , Berntorp Erik , Keeling David M. , Makris Michael , Hermans Cedric R. , Mauser-Bunschosten Ereline Pauline , Musso Roberto , Tagliaferri Annarita , Kollmer Carl , Baumann James , Charnigo Robert 
Published: October 2019

Abstract
Abstract 3664

Objective:
To evaluate the long-term safety of nonacog alfa in pediatric hemophilia B patients during usual use.

Design/Methods:
An open-label, multicenter, prospective registry was conducted in 9 European countries to evaluate the safety of nonacog alfa in patients with hemophilia B in a usual-use setting. The registry was initiated in March 2002, with a period of enrollment of 7 years. Patients had received at least 1 dose of the original formulation of BeneFIX or a newer, reformulated version of the product. Of 218 patients enrolled in the registry, 66 (30.3%) were pediatric patients <18 years of age.

Results:
A total of 41 (62.1%) of the pediatric patients completed the registry per protocol. Seven events of special interest (ESIs) occurred in 6 (9%) patients. Allergic reaction was the sole ESI in 2 patients, lack of drug effect/low FIX recovery occurred in 3 patients, and 1 patient had an allergic reaction and developed a factor IX inhibitor. Two (3.0%) patients withdrew from the registry due to an ESI and/or a serious adverse event. Both were patients who developed an allergic reaction and one was the patient who also developed an inhibitor.

Conclusion:
The events reported for pediatric patients participating in this long-term prospective study demonstrated an acceptable safety profile for nonacog alfa in the pediatric population. The events did not differ in type, frequency, or severity from those previously observed in pediatric hemophilia B patients treated with nonacog alfa.

Disclosures:
Rendo: Pfizer: Employment. Keeling:Boehringer-Ingelheim:; Bayer: Membership on an entity's Board of Directors or advisory committees, lecture fee. Kollmer:Pfizer: Employment. Baumann:Pfizer: contract. Charnigo:Pfizer: Employment.
Bleeding and Thrombosis In 90 Iranian Patients with Inherited Afibrinogenemia.
Authors: Lak Manijeh , Toogheh Gholamreza , Keyhani Manoutchehr 
Published: October 2019

Abstract
Abstract 3667

Background:
Afibrinogenemia is a rare coagulation disorder transmitted as an autosomal recessive trait. In Iran, where consanguineous marriages are common coagulation disorders occur approximately ten times more frequently than in western countries. Afibrinogenemia is characterized by abnormal thrombin time, prothrombin time, activated partial thromboplastin time and absent plasma fibrinogen levels. We investigated the clinical manifestations of bleeding and thrombosis in a series of patients with Afibrinogenemia in Iran. To our knowledge this is the largest series ever reported.

Patients & Methods:
All patients in our cohort were diagnosed and registered in the Iranian National Registry of Inherited Bleeding Disorders. Every patient with an inherited blood disorder is reported to this registry because it is the only source of free treatment for bleeding disorders in the country. Afibrinogenemia has been tracked in Iran since 1965. Diagnoses in all patients was confirmed when plasma fibrinogen levels were absent both as functional activity (the Clauss method) and using the antigen level (electroimmunoassay). We retrospectively evaluated data from all 90 Afibrinogenemia patients available in the registry.

Results:
There were 46 males and 44 females in our cohort. Ages ranged from 1 to 71 years. 82% of patients were born from consanguineous marriages with asymptomatic parents. The most frequent symptoms in our patients were umbilical cord bleeding (87%), hematomas (74%) epistaxis (70%) and hemarthrosis (52%). Central nervous system bleeding was relatively rare (2.2%). In women of reproductive age, menorrhagia occurred in 75% of cases. Recurrent spontaneous abortions (more than 2) were seen in 28% of women (range 2 to 6). With prophylactic treatment (cryoprecipitate and limited fibrinogen) two (16.6%) of our patients with recurrent spontaneous abortion out of the 12 treated were able to carry pregnancies to term. A total of 7 patients in our population developed arterial or venous thromboses (3 males and 4 females). Four cases of the thromboses observed occurred after infusion of fibrinogen concentrate. Three episodes of spontaneous thrombosis were observed including a case of mesenteric thrombosis.

Discussion:
Afibrinogenemia is associated with severe and life threatening bleeding symptoms. Treatment can help women afflicted with this disease carry pregnancies to term. As reported elsewhere, thrombotic complications both spontaneous and acquired from treatment were also seen in our population.

Disclosures:
No relevant conflicts of interest to declare.
Evaluation of Clotting Factor Concentrates for Treatment of Thrombotic Thrombocytopenic Purpura.
Authors: Falter Tanja , Qorraj Mirjeta , Steinemann Sarah , Vigh Thomas , Scharrer Inge 
Published: October 2019

Abstract
Abstract 3678

Introduction:
Thrombotic thrombocytopenic purpura (TTP) is characterized by microthrombi, hemolytic anemia as well as thrombocytopenia. These symptoms are caused by a decreased activity of the protease ADAMTS13 which cleaves the von Willebrand Factor (VWF), due to mutation of the ADAMTS13-gene or autoantibodies. At the moment, the only available immediate therapy is plasmapheresis with Fresh Frozen Plasma (FFP) which may induce side effects. Therefore an alternative therapy might be the treatment with clotting factor concentrates.

Methods:
40 plasma samples were tested, consisting of FFP and solvent/detergent treated plasma, four batches of each blood group; VWF/VIII concentrates (Wilate®; Wilfactin®; Haemate®P; Immunate®; Kogenate®, Beriate®). In all samples ADAMTS13 activity, antigen and autoantibodies against ADAMTS13 were investigated. Additionally, the samples were tested for the presence of ultralarge VWF multimers. The BCS method according to Böhm, two ELISAs (Technozym®ADAMTS13 and Actifluor™ADAMTS13) and the electrophoresis on a SDS gel were used.

Results:
ADAMTS13 activity was found in all VWF)VIII concentrates, which are produced from human plasma, but only with a very low activity (Wilate® 5.6%; Wilfactin® 2.8%; Haemate®P 13%; Immunate® 3.7%). ADAMTS13 activity was not detectable in the factor VIII concentrates (Kogenate® <2%; Beriate® <2%). Usual FFP and solvent/detergent treated plasma samples, contained much higher ADAMTS13 activity and antigen values than concentrates (FFP 78.6%, solvent/detergent treated plasma 77.6%). However a difference of activity between individual blood groups was evident in FFP samples (blood group A 69.4%; B 64.9%; AB 98.1%; 0 82.0%). Ultralarge VWF multimers could be demonstrated in VWF containing concentrates, less in VIII concentrate from human plasma and not in FFP and solvent/detergent treated plasma samples. As expected recombinant-produced VIII concentrate contained no traces of ultralarge VWF. In all analyzed samples antibodies were negative.

Conclusion:
For therapy of TTP clotting factor concentrates cannot be used as an alternative to the usual FFP and solvent/detergent treated plasma, because their ADAMTS13 activity values are too low.
In addition, the VWF/VIII concentrates contain higher quantities of ultralarge VWF multimers, which are contraindicated for TTP patients. The differences of ADAMTS13 activity in FFP samples varies between the individual blood groups and batches. Solvent/detergent treated plasma shows less variation in ADAMTS13 activity due to the manufacturing process involving plasma pooling.

Disclosures:
No relevant conflicts of interest to declare.
Potential Identification of High Risk Populations for Acute Hemolytic Reactions Following Rh0 (D) Immune Globulin.
Authors: Ramachandran Paraneedharan , Li Daniel , Muller Carmen , Little Gregg , Sinclair Chris , Genereux Maurice 
Published: October 2019

Abstract
Abstract 3685
Acute Hemolytic Reactions (AHR) post Rh(D) Immune Globulin (Rh IgIV; WinRho® SDF, Cangene Corporation, Winnipeg, MB, Canada) have been reported since its approval for ITP in 1995. Cangene evaluated all post-marketing safety reports to ascertain whether certain populations may be at risk of AHR occurrence. AHR's were defined as one or more of the following: hemoglobin decrease, haptoglobin decrease or elevation of bilirubin occurring within days of Rh IgIV administration. Cases of Intravascular Hemolysis (IVH) were defined as AHR reports with demonstrated plasma hemoglobinemia and/or hemoglobinuria.

Purpose:
Identify populations that may be at higher risk of developing Acute Hemolysis when treated with Rh IgIV for ITP.

Methods:
Adverse Events (AE) were categorized as Acute Hemolytic Reactions (AHR) and Non Hemolytic Reactions (NHR) cases and both were evaluated retrospectively to identify if co-morbid conditions or other risk factors were implicated. Analyses were performed looking at: gender, age group, Rh IgIV dose, co-morbidities grouped by system organ class.

Results:
Between 1995 and March 2010 there were 684 AE reported, AHR were 312/684 (46%) and NHR were 372/684 (54%). Of the 312 AHR reports, IVH was identified in 70 (22%) of cases.

Conclusion:
91% of fatal outcome after AHR were found in patients with significant co-morbid conditions that contributed to death. Elderly patients (above 65 yrs) with following co morbid conditions appear to be more susceptible to AHR including definitive IVH and its complications. The following factors have been reported in the majority of Acute Haemolytic Reactions (AHR):
This review implies that choosing the right patient, the right dose and close monitoring of higher risk patients will improve the safety outcomes among ITP patients treated with Rh IgIV.

Disclosures:
Ramachandran: Cangene Corporation: Employment. Li:Cangene Corporation: Employment. Muller:Cangene Corporation: Employment. Little:Cangene Corporation: Employment. Sinclair:Cangene Corporation: Employment. Genereux:Cangene Corporation: Employment.
Pre-Stem Cell Transplant Induction Therapy Does Not Affect Post-Transplant Survival In Light Chain (AL) Amyloidosis
Authors: Madan Sumit , Kumar Shaji , Lacy Martha , Dispenzieri Angela , Buadi Francis , Hayman Suzanne R. , Dingli David , Rajkumar S. Vincent , Gertz Morie 
Published: October 2019

Abstract
Abstract 370

Background:
Light chain (AL) amyloidosis is characterized by the deposition of amyloid derived from immunoglobulin light chains in various organs. Autologous peripheral blood stem cell transplantation (SCT) is a commonly used and effective treatment for AL. For patients (pts) undergoing this procedure, a proportion of pts receive treatment similar to induction therapy employed in pts with myeloma undergoing SCT. However, the significance of induction therapy and its impact on the overall survival (OS) in AL is unknown. We conducted this study to ascertain the role of pre-SCT therapy on the post-transplant outcomes in AL.
Patients and methods: 435 pts with AL who underwent SCT at our institution between March 1996 and May 2010 form the study group. Groups were compared using Fisher's exact test or t-test, and survival was calculated using Kaplan Meier method. Survival curves were compared using log rank test.

Result:
The median (range) age of pts at the time of SCT was 57.4 years (26-75); 260 (60%) were males. The median (range) duration from AL diagnosis to SCT was 4 mos (1-87), and 284 (65%) pts were alive at the time of analysis. Melphalan 200/m2 (271 pts) or Mel/TBI (17 pts) was used for conditioning in 66% pts, whereas the remaining one-third had reduced doses of melphalan (100-160 mg/m2). The median OS for pts that received pre-SCT therapy (N=286) compared with those who did not (N=149) was 94.7 and 96.5 months, respectively (P=0.6) (Fig 1). Among the group of pts who underwent pre-SCT therapy and were evaluable for response, the median OS for those with a hematologic response (N=42) and no hematologic response (N=42) was 82.1 and 51 months (P=0.2), respectively (Fig 2).

Conclusion:
Our study demonstrates no difference in the OS of AL patients who received a pre-SCT therapy compared with those who received a SCT after their diagnosis of AL. In patients receiving pre-SCT therapy, there was a trend towards reduced OS among those with no hematologic response to pre-transplant therapy, but this difference was not significant.

Disclosure:
Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria.
Efficient and Selective Prevention of Graft-Versus-Host Disease by Ag-Specific Induced Regulatory T Cells In Mice.
Authors: Semple Kenrick , Yu Yu , Wang Dapeng , Anasetti Claudio , Yu Xue-Zhong 
Published: October 2019

Abstract
Abstract 3745
Naturally occurring regulatory T cells (nTregs) suppress the development of graft-versus-host disease (GVHD). The non-selective suppression against tumor associated antigens in some models severely dampened our enthusiasm for the application of nTregs in the control of GVHD after allogeneic hematopoietic cell transplantation (HCT). In this study, we used an alternative strategy to generate antigen-specific, induced Tregs (iTregs), and tested their potential in the prevention of GVHD in murine model of myeloablative BMT. CD4+CD25+Foxp3+ iTregs generated from OT-II TCR transgenic mice specific for OVA target antigen efficiently prevented GVHD induced by polyclonal T effector cells (Teffs) in allogeneic recipients that express OVA protein but not in those that do not express OVA. The efficacy of these antigen-specific iTregs was significantly higher than polyclonal iTregs in preventing GVHD. As controls, OT-II CD4+Foxp3− cells had no effect on GVHD development in OVA− recipients and exacerbated GVHD in OVA+ recipients when transplanted together with polyclonal Teffs. Mechanistically, OT-II iTregs expanded extensively, and significantly suppressed expansion and infiltration of Teffs in OVA+ recipients. In sharp contrast, OT-II iTregs failed to expand and had no effect on Teffs in OVA− recipients. These results reveal the therapeutic potential of TGFβ-induced, antigen-specific iTregs to prevent GVHD efficiently and selectively.

Disclosures:
No relevant conflicts of interest to declare.
Potentially Fatal Neutropenia Associated with the Use of Cocaine Adulterated with Levamisole.
Authors: Shah Surbi , Goswami Umesh , Rachel Koreth , Williams David N , Mathew Josy 
Published: October 2019

Abstract
Abstract 3790

Background:
Cases of neutropenia associated with the use of cocaine adulterated with levamisole are being increasingly reported and have become a serious public health hazard. As reported by the US Drug Enforcement Administration (DEA) up to 69% of total cocaine seized in the US is adulterated with this veterinary antihelminthic known to cause agranulocytosis in certain susceptible populations. The rationale for selecting levamisole as an adulterant is unclear, but is likely related to the fact that it shares some physico-chemical properties with cocaine and potentiates the activity of dopaminergic (D2) and NMDA receptors in brain thus enhancing its effects.

Methods:
A case review was performed of adult patients who presented with neutropenia after the use of levamisole adulterated cocaine. Their laboratory results and treatment outcomes were studied to establish an expected course of the illness.

Results:
Over a one year period, 5 patients (4 female, 1 male) with age range of 45–60 years, presented with neutropenia in the setting of cocaine use. 4 were positive for levimasole in urine (detected by the use of gas chromatography/mass spectrometry analysis within 4–6 hours of presentation). Bone marrow biopsies were performed in 4 cases showed granulocytic hypoplasia with myeloid maturation arrest, lymphocytic hyperplasia and polytypic plasma cells. Antigranulocyte antibodies (AGA) were positive in 3 of the 4 patients tested. One each had positive serology for serum fluorescent antinuclear antibody (FANA), rheumatoid factor (RF) and antineutrophil cytoplasmic antibody (ANCA). Four of the five patients had hepatitis C infection. One patient had marginal zone B cell lymphoma and another was diagnosed with HIV at her first presentation. The median duration of neutropenia was 5–7 days. 2 patients died as a result of their various co-morbidities. Discussion: Use of cocaine adulterated with levamisole can result in profound neutropenia which could be fatal despite aggressive medical therapy. In patients presenting with neutropenia and a history of substance abuse, a high index of suspicion for cocaine adulterated with levamisole is needed and can be confirmed with rapid testing for both substances in patients' urine. Further diagnostic studies including a bone marrow biopsy with characteristic findings as described above and serologic testing for AGA can aid in confirming the diagnosis and ruling out other common causes of neutropenia. The treatment is usually supportive and based on the Infectious Diseases Society of America (IDSA) guidelines for managing neutropenic patients. The role of public health advisories in providing awareness among patients and care givers cannot be overstated, which can lead to early detection and reduced mortality.

Disclosures:
No relevant conflicts of interest to declare.
Safety of Outpatient Treatment In Acute Pulmonary Embolism.
Authors: Erkens Petra MG , Gandara Esteban , Wells Phil , Shen Alex Yi-Hao , Bose Gauruv , Gal Gregoire Le , Rodger Marc A. , Prins Martin H , Carrier Marc 
Published: October 2019

Abstract
Abstract 3796

Introduction:
Systematic reviews have shown that subcutaneous low molecular weight heparins (LMWH) are at least as safe and effective in the treatment of venous thromboembolism (VTE) as intravenous unfractionated heparin (UFH). LMWH allows patients with VTE to be treated as outpatients. However, patients with pulmonary embolism (PE) are still systematically admitted to the hospital for a few days to avoid potential complications. Physicians are reluctant to discharge patients due to insufficient data supporting the safety of outpatient management of PE. This study evaluates the safety of outpatient treatment of acute PE at the Ottawa Hospital.

Methods:
This is a retrospective cohort study of consecutive patients presenting at the Ottawa Hospital with acute PE diagnosed between January 1, 2007 and December 31, 2008. PE was defined as an arterial filling defect on CTPA or a high probability V/Q scan. Patients diagnosed with PE during hospitalization, patients with chronic PE and patients in whom anticoagulation treatment was not initiated (e.g. palliative care patients, small clinical non-significant PE) were excluded from the analyses. Patients were managed as outpatients if they were hemodynamically stable, did not require supplemental oxygenation and did not have contraindications to low molecular weight heparin therapy.

Results:
In this cohort of 473 patients with acute PE, 260 (55.0%) were treated as outpatients and 213 (45.0%) were admitted to the hospital. The majority of the patients were admitted because of severe comorbidities (45.5%) or hypoxia (22.1%).No outpatient died of fatal PE during the 3 month follow-up period. At the end of follow-up, the overall mortality was 5.0% (95% CI: 2.7 to 8.4%). The rates of recurrent venous thromboembolism (VTE) in the outpatient group were 0.4% (95% CI: 0.0 to 2.1%) and 3.8% (95% CI: 1.9 to 7.0%) within 14 days and 3 months, respectively. The rates of major bleeding episodes were 0% (95% CI: 0 to 1.4%) and 1.5% (95% CI: 0.4 to 3.9%) within 14 days and 3 months, respectively. Four (1.5%) outpatients were admitted to hospital within the first 14 days because of progressive shortness of breath and pain, a pre-syncopal episode or heparin induced thrombocytopenia.

Conclusion:
A majority of patients with acute PE can be managed as outpatients with a low risk of mortality, recurrent VTE and major bleeding episodes. Outpatient treatment in PE is feasible and safe in uncomplicated patients.

Disclosures:
Rodger: Pfizer: Research Funding; Leo Pharma: Research Funding; Sanofi Aventis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Canadian Institutes of Health Research: Research Funding; Heart and Stroke Foundation: Research Funding.
ESAS (Edmonton Symptom Assessment System) as An Effective Outpatient Serial-Longitudinal Symptom Assessment Tool In Patients with Sickle Cell Disease.
Authors: Lopez Gabriel , Liles Darla K , Knupp Charles L 
Published: October 2019

Abstract
Abstract 3798

Purpose:
Our goal is to implement an ongoing symptom assessment strategy using a validated palliative care tool in the outpatient management of adult patients with sickle cell disease at a comprehensive sickle cell center.

Methods:
Sickle cell disease is a chronic lifetime illness with intermittent acute exacerbations to daily symptoms. The extension of palliative care symptom management strategies to patients with sickle cell disease has been proposed. Symptom assessment tools such as the ESAS (Edmonton Symptom Assessment System), validated in the palliative care population, may have a role in sickle cell disease management. Ten symptoms are assessed, with the average 24 hour symptom score reported on a 0 to 10 numerical scale, 10 being the worst possible. In our study, 75 adult patients with sickle cell disease presenting for their outpatient visit at a comprehensive sickle cell center were enrolled; they were asked to complete the ESAS and a survey regarding their opinion of the ESAS at each clinic visit.

Results:
Study patients were 100% African American, 56% (42/75) female, ages 19–67, with disease types 71% (53/75) HgbSS, 19% (14/75) HgbSC, and 11% (8/75) HgbS/beta thal. At least 49% (37/75) of patients had one follow up visit after enrollment, for a total of 112 clinic visits. On the initial visit, 92% (65/71) agreed or strongly agreed with the statement “the ESAS is easy to complete”; 97% (71/73) reported instructions as clear; 96% (72/75) reported no words were difficult to understand; 83% (59/71) were satisfied or very satisfied with the ESAS as a way to report symptoms; 93% (68/73) would recommend the ESAS to other patients. 62% (45/73) of patients reported the ESAS helped them remember symptoms they were experiencing; 34% (25/73) were encouraged to discuss medical issues more openly with their health care provider. In a comparison of visit 1 (V1) and 2 (V2) in the 37 patient subset with a single follow up visit, 94% (33/35) on V1 and 94% (33/35) on V2 recommended the ESAS to other patients; 78% (28/36) on V1 and 86% (31/36) on V2 were satisfied or very satisfied with the ESAS. Including all 75 patients on their initial visit, the most intense symptoms (≥ 4 on ESAS scale) recorded were pain 4.6 (± 3.1) and sleep 4.1 (±3). In the 37 patient subset with follow up, V1 pain 4.7 (± 2.7) and V1 sleep 3.5 (± 2.5); V2 pain 4.4 (± 3.2) and V2 sleep 4.3 (± 2.6).

Conclusion:
The ESAS is an acceptable, brief, easy to understand symptom assessment tool which can be integrated into an outpatient sickle cell clinic as part of a serial-longitudinal symptom management strategy. Future studies should include measuring the impact of symptom-directed interventions on self-reported symptoms.

Disclosures:
No relevant conflicts of interest to declare.