bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamics of Procalcitonin and Bacteremia In Adult Acute Myeloid Leukemia with Chemotherapy-Induced Neutropenia
Authors: Gac Anne-Claire , Parienti Jean-Jacques , Chantepie Sylvain , Leclercq Roland , Reman Oumedaly 
Published: October 2019

Abstract

Abstract 4378
Sensitive markers of infection are rare or of limited validity in neutropenic patients. Procalcitonin (PCT), a precursor protein of calcitonin, is a specific and sensitive marker of severe bacterial infections during short-term neutropenia. Because the value of PCT measurements among patients undergoing long periods of neutropenia remains uncertain and because several mechanisms, such as bacterial or fungal infections, reactions to drugs or blood products or tumor-associated events, can cause fever, we described the dynamics of PCT in 29 acute myeloid leukemia (AML) patients with 39 instances of chemotherapy-induced neutropenia. Plasma levels of PCT were determined prospectively by an immunoluminometric assay every four days starting at the onset of chemotherapy and continuing until the resolution of fever. We found that bacteremia did increase PCT levels above 0.5 ng/mL and these levels predicted bacteremia at day 15 of chemotherapy. This finding may be relevant in the decision to alter antibiotic regimens to decrease toxicity and cost when patients remain febrile at day 15.

Disclosures:
No relevant conflicts of interest to declare.
Fludarabine-Associated Acute Promyelocytic Leukemia
Authors: Hess Clayton B , Ehmann W. Christopher 
Published: October 2019

Abstract
Abstract 4383
Here we describe a case of acute promyelocytic leukemia (APL) (M3 leukemia) which developed in a patient treated with single-agent fludarabine for lymphoplasmacytic lymphoma (Waldenstrom's macroglobulinemia [WM]).
This 69-year-old male was diagnosed with WM in 2003. He received single-agent therapy with 4 cycles of fludarabine, after having an adverse reaction to his first and only dose of rituximab. Therapy was completed in 2007, with the patient in a complete remission. Two years later, he presented with leukocytosis and a consumptive coagulopathy. A bone marrow biopsy showed 90% abnormal promyelocytes with prominent Auer rods. PML/RARA fusion was positive by FISH. PCR was positive for t(15;17) (PML/RAR long (bcr1 and bcr2) and short (bcr3) form translocations. Cytogenetic studies showed abnormal 3q, monosomy 15 and 17, 2 unidentified marker chromosomes and a complex insertional translocation of chromosomes 15 and 17, with a PML/RARA fusion. The patient's APL was treated with ATRA and 7+ 3 chemotherapy because of a rising number of blasts in his peripheral blood. His subsequent clinical course was complicated by refractory atrial fibrillation, renal failure, a catheter-related upper-extremity deep venous thrombosis, and severe deconditioning. The patient died four months later from probable sepsis. A marrow performed two weeks prior to his death showed a complete hematologic remission, and no evidence of either Waldenstrom's or acute promyelocytic leukemia.
There are forty-eight cases published of hematologic malignancies which occurred after single-agent nucleoside-analog treatment: none were APL. Twenty-four of these cases consisted of a lymphoid transformation to a more aggressive histology and twenty-four cases described development of a myeloid leukemia or myelodysplastic syndrome. In these patients, a variety of chromosomal changes were demonstrated with abnormalities of chromosome 7 being the most frequently observed (exclusively in those with myeloid disorders). There were no cases of a t(15;17) reported. We then reviewed all documented cases of therapy-related APL. No cases implicating nucleoside analogs were found. Topoisomerase inhibitors were the most common agents implicated as were radiation, anthracyclines, and alkylating agents.
Because fludarabine was the only chemotherapy agent to which the patient was exposed, and the patient developed APL within the time frame expected for therapy-related leukemogenesis, we conclude that this is the first reported case of fludarabine-associated APL.

Disclosures:
No relevant conflicts of interest to declare.
Comparison of Branded Enoxaparin (Lovenox) and a Biosimilar Version of Enoxaparin (Fibrinox)
Authors: Jeske Walter , McGeehan Elizabeth , Iqbal Omer , Hoppensteadt Debra , Walenga Jeanine M. , Fareed Jawed 
Published: October 2019

Abstract
Abstract 4385
Several biosimilar versions of branded enoxaparin (Lovenox, Sanofi-Aventis, Paris, France) have recently become available throughout the world. These biosimilar enoxaparin preparations are distributed by multiple suppliers in Asia and in North and South America. Enoxaparin represents a complex mixture of oligosaccharides obtained by alkaline depolymerization of porcine mucosal heparin. It is the most widely used low molecular weight heparin which has been validated for clinical use in multiple indications. While the molecular profile and anti-Xa potencies of some of the biosimilar versions of enoxaparin are comparable, product based differences have been reported amongst some of the biosimilar versions of enoxaparin. The purpose of this study was to compare the biochemical and pharmacologic profile of one biosimilar version of enoxaparin, namely Fibrinox (Sandoz SA, Buenos Aires, Argentina) with the branded product Lovenox. The products were compared in equigravimetric amounts, assuming equivalent potency (100 AXa U/mg). Both products exhibited comparable molecular weight profiles in terms of average molecular weight and oligosachharide distribution. Analysis of the antithrombin binding hexasaccharide fractions of Fibrinox and Lovenox indicated the presence of eight distinct hexasaccharides. The relative proportions these hexasaccharides differed between Fibrinox and Lovenox. The anti-Xa and anti-IIa activities were comparable. In the whole blood clot-based assays such as TEG and ACT, both agents produced similar anticoagulant effects. In the plasma based assays such as the APTT, Heptest and thrombin time, both products showed comparable anticoagulant effects in the normal human pooled plasma samples. However, in plasma samples collected from patients with liver disease who were apparently anticoagulant free, the two products showed differences in their anticoagulant effects in the APTT assay (p<0.05). In the TF mediated thrombin generation assay, Fibrinox produced a stronger inhibition of thrombin generation compared to Lovenox (IC50; Fibrinox, 1.6 μ g/ml, Lovenox 2.2 μ g/ml). No differences were observed between the two products in the agonist induced platelet aggregation assays. However in the 14C serotonin release study, Fibrinox produced a stronger HIT serum mediated 14C release (p<0.05). Differences in the fibrinokinetic profile and the inhibition of thrombin activatable fibrinolytic inhibitor activation were observed with these LMWHs. These studies suggest while both the molecular profile and the pharmacopoeial potency of Fibrinox is similar to the branded product, these drugs can be differentiated in some of the other assays and should be evaluated in terms of additional pharmacologic mechanisims to demonstrate bioequivalence.

Disclosures:
No relevant conflicts of interest to declare.
Prevention of Deep Vein Thrombosis In Patients In the United States with Infectious Diseases
Authors: Amin Alpesh N , Lin Jay , Wiederkehr Daniel 
Published: October 2019

Abstract
Abstract 4389

Background:
Hospitalized patients with infectious diseases are at risk of venous thromboembolism (VTE), encompassing both deep-vein thrombosis (DVT) and pulmonary embolism (PE). Our analysis evaluated real-world thromboprophylaxis use and DVT/PE rates in patients with infectious diseases in hospital, and for 30 days post-discharge.

Methods:
Data were extracted from the US Premier Perspective(tm)-i3 Pharma Informatics linked database for patients with infectious disease (International Classification of Diseases Ninth Revision codes for infectious and parasitic diseases, skin infections, chronic infection, and postoperative infection) who had been admitted January 2005–November 2007. Included patients had at least 6 months’ continuous plan enrollment and were aged ≥ 18 years. Patients with a diagnosis of atrial fibrillation were excluded, as were patients with a hospital stay of 0 days or > 30 days.

Results:
Of the 5,488 at-risk patients analyzed, 31% received inpatient pharmacological or mechanical DVT prophylaxis, and 3.2% received outpatient pharmacological DVT prophylaxis. Mean ± standard deviation duration of prophylaxis was 1.1 ± 2.4 days for inpatients and 0.8 ± 4.6 days post-discharge, with a total duration of 1.9 ± 5.4 days. DVT/PE occurred in 3.61% of patients during hospitalization, and 0.98% of patients were rehospitalized or treated in the outpatient setting for DVT/PE.

Conclusions:
Our analysis highlights the considerable rate of DVT/PE and the underuse of DVT prophylaxis in hospitals. Furthermore, DVT/PE risk persisted post-discharge, yet few patients received outpatient prophylaxis. Improved prevention of DVT is required across the continuum of care to reduce preventable mortality and morbidity in patients with infectious diseases.

Acknowledgment:
this study was funded by sanofi-aventis U.S., Inc. The authors received editorial/writing support in the preparation of this abstract provided by Hester van Lier, PhD of Excerpta Medica, funded by sanofi-aventis U.S., Inc.

Disclosures:
Amin: sanofi-aventis US Inc.: Honoraria, Speakers Bureau. Lin:sanofi-aventis US Inc.: Employment, Research Funding. Wiederkehr:sanofi-aventis US Inc.: Research Funding.
Incidence and Outcome of Venous Thromboembolism In Terminally Ill Cancer Patients In Palliative Care unit
Authors: Lee Na-Ri , Yhim Ho-Young , Song Eun-Kee , Yim Chang-Yeol , Kwak Jae-Yong 
Published: October 2019

Abstract
Abstract 4390

Background:
The relation between venous thromboembolism (VTE) and cancer is well recognized, and risk of VTE increases with disease progression. However, the information available about VTE in terminally ill cancer patients in palliative care unit (PCU) is limited. We evaluated the incidence, risk factor and outcome of VTE in terminally ill cancer patients in PCU.

Methods:
The clinical records of Chonbuk National University Hospital were searched for all patients with acute, symptomatic deep-vein thrombosis (DVT) and pulmonary embolism (PE) in PCU from April 2008 through July 2010.

Results:
A total of 220 patients were included in the study and the median survival after palliative care was 16 days. Ten patients (4.5%) were newly diagnosed with VTE in PCU and nine patients (4%) had a history of VTE. All ten patients presented with DVT and the sites included lower extremities (eight) and upper extremities (two). All patients had more than one risk factor: immobilizations in 6 patients (54%), tumor compression in 3 patients (27%), and central venous catheter in 2 patients (18%). After diagnosis, 7 patients received treatment with low-molecular weight heparin (LMWH) and 4 of them switched to warfarin. The median duration of anticoagulation was 26 days. Major bleeding was noted 2 patients but VTE-related death did not occur. The median survival after diagnosis of VTE was 28 days.

Conclusion:
The incidence of VTE in PCU was relatively low. All patients had one or more risk factors and DVT of lower extremities was most frequent. Although anticoagulation was acceptable treatment except bleeding risk, the risks vs benefits need to be counterbalanced. Further large scale studies are needed to address many of these issues.

Disclosures:
No relevant conflicts of interest to declare.
Oral Anticoagulation In Patients with Atrial Fibrillation. Long-Term Follow-up
Authors: Colorio Cecilia Claudia , Puente Dolores Patricia , Rossi Andrea Silvia , Pombo Gonzalo , Guevara Eduardo , Martinuzzo Marta , Forastiero Ricardo 
Published: October 2019

Abstract
Abstract 4392
Atrial fibrillation (AF) is the most common cardiac rhythm disorder and an independent risk factor for stroke. It′s prevalence in AF pts without oral anticoagulation (OA) is 1 to 12%. OA is recommended in all valvular AF pts and in non valvular AF pts associated with other risk factors for stroke (CHADS2 score >1).

Objective:
to evaluate characteristics, evolution and incidence of thrombosis and bleeding in pts with AF under OA for at least 3 months.

Methods:
we retrospectively analyzed 850 pts between Jan 2003 and Jan 2010.

Results:
the mean follow-up was 25 months (range 3–169). The features of the entire group are listed in the table below:
Minor bleeding was observed in 32.7% of the entire group (278/850) and major bleeding in 2.7% (23/850). Most of the major bleedings occurred at the gastrointestinal tract, and 53% of those pts presented INR <2 (8/15). Fatal bleeding (located at CNS) developed in 0.2% (2/850). Ten pts developed thrombosis during the follow-up period (1.17%); 50% of them with INR < 2.

Conclusion:
45% of the pts were older than 74 years and most of them disclosed valvular AF. Minor bleeding was 15.4%/year, major bleeding: 1%/year, and thrombosis: 0.42%/year, according to the current literature.

Disclosures:
No relevant conflicts of interest to declare.
Thromboprophylaxis In Women with Recurrent Pregnancy Loss and Thrombophilia Undergoing Fertility Treatments: An Observational Study
Authors: Makarian Liana , Stein Daniel , Keltz Martin , Varma Mala 
Published: October 2019

Abstract
Abstract 4396
Thromboprophylaxis in women with recurrent pregnancy loss and thrombophilia undergoing fertility treatments: an observational study.

Background
Several phase II studies have suggested a benefit of thromboprophylaxis in pregnant women with histories of recurrent pregnancy loss (RPL) with and without thrombophilia. Two recent phase III studies (ALIFE, SPIN) showed no benefit of thromboprophylaxis in women with RPL, but they were not designed to study women with thrombophilia or with 3 or more miscarriages. In addition, plasminogen activator inhibitor-1 (PAI-1) has been linked to RPL, but there are limited data on the use of thromboprophylaxis in pregnant women with PAI-1 and RPL. A mechanism of unexplained RPL is thought to be placental thrombosis. The patients with thrombophilia who undergo assisted reproduction procedures might be at an increased risk of thrombosis due to multiple gestations, ovarian hyperstimulation and hyperestrogenemia. These could contribute to fetal loss via placental thrombosis. There are limited data on the outcome of pregnant women with histories of RPL treated with assisted reproduction and thromboprophylaxis.

Methods
We performed a retrospective review of 31 cases of women of age 20 to 42 that were referred to the Hematology Department at Roosevelt Hospital over the period of five years (between April 2005 and March 2010) for an evaluation prior to undergoing fertility treatment. Aspirin 81 mg daily prior to in vitro fertilization and enoxaparin 40 mg daily upon confirmation of pregnancy or following embryo transfer was recommended for the majority of patients. Aspirin and enoxaparin were recommended for 21 patients; aspirin alone for 5; enoxaparin alone for 4; and no therapy for 1.

Baseline Characteristics of the Patients

Results
Fifteen out of 31 patients took aspirin and enoxaparin; 9, aspirin alone; 4, enoxaparin alone; and 3, no treatment. Sixteen patients had assisted reproduction with in vitro fertilization or intrauterine insemination; 4 received ovulation induction medications; 7 had natural pregnancies; 2 patients had pregnancies by unknown means.
Twenty-five patients (81%) conceived; 13 (42%) had term deliveries; and 1(<1%) had a pre-term delivery at 31 weeks. Five patients (16%) were pregnant at last follow-up. Seven patients (22%) miscarried. Six patients (19%) did not conceive.

Conclusion
Thromboprophylaxis was associated with a high pregnancy rate and a high live birth rate in women with RPL, many with thrombophilia including PAI-1, presenting for fertility treatment.

Disclosures:
No relevant conflicts of interest to declare.
Characterizing the Effects of NN1731 and rFVIIa In Severe Hemophilia Patients with a Poor Laboratory Response to In Vivo Dosing of rFVIIa 90 μ g/Kg
Authors: Brophy Donald F , Martin Erika J , Barrett John Christian , Kuhn Jan G , Nolte Melinda , Hedner Ulla , Ezban Mirella 
Published: October 2019

Abstract
Abstract 4414

Introduction:
A rFVIIa analogue (NN1731) with increased prothrombinase activity on the activated platelet surface relative to rFVIIa has been shown to result in a more rapid and less variable response in spiking experiments with hemophilia whole blood samples. In a recent pharmacokinetic study of rFVIIa in 10 non-bleeding hemophilia A and B patients who received a dose of 90 mg/kg rFVIIa, we noted that there were two divergent groups based on their laboratory response to rFVIIa. Study participants who achieved clot formation time determined by Hemodyne (FOT) or Rotational Thromboelastography (CT) < 15 min were noted to have a “rapid laboratory response”; conversely, those with a FOT and CT value ≥ 15 min were noted to have a “delayed laboratory response”. In order to determine whether the participants with a delayed laboratory response to rFVIIa 90 μ g/kg would have an improved response to higher doses of rFVIIa and to NN1731, additional blood samples were collected and spiked ex vivo.

Patients and Methods:
Blood samples from ten severe FVIII or FIX deficient patients were spiked with 1.28, 2.56, 3.84 μ g/mL rFVIIa (corresponding to 90, 180 and 270.

Disclosures:
Hedner: Novo Nordisk A/S: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Speakers Bureau. Ezban:Novo Nordisk A/S: Employment, Membership on an entity's Board of Directors or advisory committees, Research Funding.
Procoagulant Activity of Sulfated Polysaccharides
Authors: Dockal Michael , Knappe Sabine , Panholzer Erwin , Palige Michael , Ehrlich Hartmut J. , Scheiflinger Friedrich 
Published: October 2019

Abstract
Abstract 4419
BAX513, a Laminaria japonica-derived fucoidan and other non-anticoagulant sulfated polysaccharides (NASPs) have been shown to improve clotting in FVIII- and FIX-deficient plasma (Liu et al. Thromb Haemost 2006; 95:68). In this study we assessed the procoagulant activities of fucoidans derived from a variety of brown sea algae species, and correlated the activity with molecular weight (MW) and degree of sulfation. Highly purified fucoidan preparations were studied in FVIII-inhibited whole blood by tissue factor-triggered thromboelastography (TEG). The procoagulant activity was characterized by calibrated automated thrombography (CAT) in FVIII- and FIX-deficient plasma and in combination with established hemophilia therapeutics. A dilute prothrombin time assay based on tissue factor pathway inhibitor supplementation (TFPI-dPT) was used to demonstrate the dose-dependent TFPI-inhibiting effect of BAX513 (EC50 = 0.18 ± 0.03 μ g/mL) in FVIII-deficient plasma. TEG in normal and FVIII-inhibited blood showed a dose-dependent procoagulant effect of most compounds where the optimal concentrations (1-100 nM) were dependent on the MW of the fucoidan. In FVIII-inhibited blood BAX513 at concentrations of ~10 nM (1.2 μ g/mL) completely normalized the TEG parameters. In contrast to sulfated fucoidans, undersulfated fucoidan hardly affected thrombin generation (TG). By CAT, the procoagulant window of NASPs in hemophilic plasma spanned more than two orders of magnitude with maximum effects being equivalent to (mU/mL) 730–940 FVIII, 32–80 FIX and 590–1230 FEIBA. NASPs combined with FVIII, FEIBA or FVIIa had an additive procoagulant effect. The optimal selection of molecular characteristics of NASPs will support the development of alternative hemophilia therapies.

Disclosures:
Dockal: Baxter Innovations GmbH: Employment. Knappe:Baxter Innovations GmbH: Employment. Panholzer:Baxter Innovations GmbH: Employment. Palige:Baxter Innovations GmbH: Employment. Ehrlich:Baxter Innovations GmbH: Employment. Scheiflinger:Baxter Innovations GmbH: Employment.
No Evidence of Cis-Acting SNPs In Immune Response Genes Previously Associated with Factor VIII Inhibitors: The San Antonio Family Heart Study
Authors: Howard Tom E. , Viel Kevin R. , Drigalenko Eugene , Cole Shelley , Epstein Melinda , Carless Melanie , Hughes Richard , Kim Benjamin , Dyer Tom , Pratt Kathleen P. , MacCluer Jean W. , Curran Joanne E. , Johnson Matthew P. , Moses Eric K. , Blangero John , Almasy Laura , Göring Harald 
Published: October 2019

Abstract
Abstract 4422

Background/Aims:
FVIII gene (F8) mutation type is a risk factor for FVIII inhibitors, which develop in ~20-30% of hemophilia A patients following FVIII replacement therapy. Studies have investigated immune response genes to determine why FVIII is immunogenic in some, but not all, patients with the same F8 abnormality. While some studies have found associations between inhibitor status and promoter polymorphisms in CTLA4, TNFA, and/or IL10, others have not. If these promoter polymorphisms influence inhibitor development, their alleles could modulate transcription initiation rates. The goal of this study was to investigate cis-acting genotype-specific differences in mean steady state mRNA levels.

Method:
We examined the relationship of lymphocyte CTLA4, TNFA, and IL10 mRNA levels with the genotypes of 49 SNPs located across their structural loci in 1189 Mexican American participants of the San Antonio Family Heart Study (SAFHS). Expression profiles were generated using Illumina's HWG-6 BeadChips and genotypes came from the Illumina Human HapMap 550 SNP panel. Measured genotype association analyses that accounted for non-independence of family members and employed an additive model were performed using the software package SOLAR.

Result:
Except for C(-13780)A, located upstream of CTLA4, which was modestly associated with CTLA4 mRNA levels (p<0.005), we observed no cis-acting regulatory variants associated with these genes’ transcription levels.

Conclusion:
We observed little evidence for cis-regulation of CTLA4, TNFA, and IL10 in Mexican Americans. It is possible that cis-acting functional variants are rare and not well-represented by the common GWAS SNPs used for these analyses. Because previously implicated polymorphisms were not included in this analysis and linkage disequilibrium patterns between markers are population-specific, we are currently genotyping these SNPs in the SAFHS.

Disclosures:
No relevant conflicts of interest to declare.