bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prevalence of Hepatitis C Infection and Virus Clearance in Patients with Hemophilia
Authors: Cisak Kamila Izabela , Pan Jianmin , Rai Shesh Nath , Ashby Patricia , Sharma Vivek R. 
Published: October 2019

Abstract
Introduction
Hemophilia A and B are hereditary genetic disorders caused by deficiency of clotting factor VIII and IX respectively. Infusions of clotting factors constitute the mainstay of treatment. Before availability of recombinant factor VIII and IX, patients with hemophilia received products derived from human plasma and were at risk of blood-borne infections exposure. Since then, ongoing advances have yielded not only safer recombinant clotting factors but also effective treatment of infections. Hepatitis C infection and its complications constitute a common cause of morbidity and mortality in older hemophilia patients. In the last few years, FDA approved various antiviral medications which allow achievement of sustained virologic response and even cure hepatitis C infection. Goal of our study is to show prevalence of hepatitis C infection and virus clearance at our hemophilia treatment center.
Methods
We performed retrospective chart review of patients followed at a single hemophilia treatment center in the United States. We included 59 patients with factor VIII or IX deficiency, age 30 and older, followed in clinic between 2005 and 2014. Patients with acquired hemophilia were excluded from study. Data was collected from physician notes and laboratory tests results which included hepatitis C antibodies and viral load.
Results
39 (66.1%) patients had history of hepatitis C infection. 21 (35.6%) patients had detectable hepatitis C viral load [95% CI 0.24-0.49] while 18 (30.5%) patients cleared the virus [95% CI 0.19-0.44].
Conclusions
Our study showed that 66.1% of hemophilia patients followed at our institution had current or past hepatitis C infection. More than half of them were virus carriers during their last viral load check. Many of them had refused interferon-based treatment due to the requirement of being on it for long duration and concerns about side effects. Others had received the treatment but failed it. This constituted as much as 35.6% of hemophilia patients at our hemophilia treatment center. Availability of the newer antiviral agents that are better tolerated and yield high cure rates provide an opportunity to further reduce the disease burden in these patients.

Disclosures
No relevant conflicts of interest to declare.
Types and Sub Types of Von Willebrand Disease Classified on the Basis of Multimer Analysis
Authors: Naz Arshi , Yadegari Hamideh , Driesen Julia , Oldenburg Johannes , Ahmed Shariq , Tariq Shahla , Amanat Samina Tufail , Razik fazal-E- , Ahmed Nisar , Nadeem Mohammad , Shamsi Tahir 
Published: October 2019

Abstract
Introduction: Von Willebrand disease is a common genetically inherited bleeding disorder. Types of VWD classified on the basis of coagulation factor assays but it cannot characterize further subtypes or verdict the quality and quantity of VWF. Multimer analysis facilitates the classification and prerequisite parameter to accurate diagnosis of VWD.
Objective: To characterize the type and subtypes of VWD type I and II on the basis of laboratory data and analysis of VWF multimer structure.
Setting: NIBD Karachi, University of Bonn Germany, Children Hospital & Chughtai Lab Lahore, PAEC Islamabad and HMC Peshawar.
Material And Method: VWF Ag, Ricof, FVIII, Glycoprotein Ib and multimer analysis of VWD plasma on 1.6% medium resolution SDS-agarose gel electrophoresis was carried out, and then VWF multimer were transferred on nitrocellulose membrane. Incubated nitrocellulose membrane with using polyclonal rabbit anti-human VWF antibody and Goat anti-rabbit IgG HRP conjugate then protein detected by immune reaction after evaluation of the membrane under luminescence.
Results: We studied 57 index patients, 2(3.5%) type I, 4(7.01%) type II, 3(5.26%) unclassified and 48(15.78%) were type III vWD. In type I,II, unclassified and III mean vWF Ag was 52.28, 35.15, 54.5 , 5.7 IU/dl, vWF RCo: 19.5, 18, 38.8, 7.22 IU/dl, vWF Ag/ RCof: 0.655, 0.393, 0.74, 0.55, FVIII 69, 25.7, 61.7, 7.22 IU/dl and GpIb: 27.25, 19.8, 39.8, 4.1. Significant loss of large multimers in type II while multimers were subtle in 2 cases, normal pattern in type I and entirely absence of multimers pattern in case of type III observed.
Conclusion: Types and subtypes of VWD classified on the basis of concentration and distribution of vWF multimer by functional and immunological assays but single test is not enough for appropriate diagnosis. We need molecular genetics for von Willebrand disease for further diagnosis.

Disclosures
Oldenburg: SOBI: Consultancy.
Prinzmetal Angina in Major Hemophilia a Patient: A Case Report
Authors: Massi Mahutondji Romaric , Houssou Bienvenu , Camara Marième , Nisserine Khoubila , Quessar Asmaa AQ , Oukkache Bouchra 
Published: October 2019

Abstract
Introduction: Prinzmetal anginais a special type ofacute coronary syndrome ST+ wich correspond to a transient occlusion of a coronary vessel secondary to spasm. This type of acute coronary syndrome is very rare and is characterized by the presence of signs of myocardial ischemia on electrocardiogram but coronary angiography and coroscaner are frequently normals. Its management in hemophilia patients is difficult because of the use of anticoagulant and antiplatelet drugs wich increase bleeding risk. We report the case of a major hemophilia A patient which presented Prinzmetal angina.
Observation: It is a 64 years old patient, hemophilia A major, chronic smoking (40 pack-year), not diabetic, not hypertensive, which had a retro sternal constrictive pain radiating to the shoulders. At admission he was consciousness. No breath in cardiac auscultation. The electrocardiography showed a heart rate at 61bpm, the axis of the heart was normal. ST-segment elevation was noticed in DIII and AVF: ischemia in the cardiac lower area. Echocardiography was normal. The coroscaner was normal. The troponin I level was at 0.03 µg/L (Normal: 0-0.1µg/L). This patient had a variant Prinzmetal angina. Treatement: Diltiazem Hydrochloride 60 mg 1 tablet / 8 hours. Acetylsalicylic acid 160 mg IV and Clopidogrel 300 mg IV the first day; relay with acetylsalicylic acid 100 mg and clopidogrel 75 mg per day. Transfusion of factor VIII at the dose of 40UI / Kg. Simvastatin 20 mg 1 tablet per day. Perindopril 5 mg 1 tablet the day. The evolution was favorable.
Discussion and conclusion: Coronary syndromes are not frequent in morocco hemophilia patients. Their management is complex and involves the presence of an hematologist.

Disclosures
No relevant conflicts of interest to declare.
Chronic IVC Occlusion Predisposing to Acute Lower Extremity DVT in Children
Authors: Tarango Cristina , Blackmore Anne , Palumbo Joseph S. 
Published: October 2019

Abstract
Congenital atresia of the inferior vena cava (IVC) is a known risk factor for spontaneous lower extremity thrombosis in adults. However, little is known about the incidence of IVC occlusion and its relationship to spontaneous lower extremity thrombosis in children. We reviewed the medical records of consecutive patients with IVC occlusion and lower extremity DVT who presented to our institution between 2008 and 2015. Data were reviewed for risk factors for thrombosis, treatment, and outcomes including recurrent thrombosis, bleeding complications, and post-thrombotic syndrome. This represents the largest reported analysis of previously healthy pediatric patients with occult chronic IVC occlusion presenting with unprovoked acute lower extremity thrombosis. Ten patients aged 13 to 18 years (median age 16.5yrs, 90% male) presenting with acute lower extremity thrombosis were found to have chronic occlusion of the IVC. One patient presented with pulmonary embolism. Seven patients underwent site-directed thrombolysis, and 3 patients received anticoagulation alone. All patients had persistent IVC occlusion regardless of treatment. Two patients had recurrent thrombosis while on anticoagulation. There were no provoking factors identified that preceded the presentation of acute lower extremity thrombosis, and none had predisposing risk factors that could explain the IVC occlusion. Four patients had a negative thrombophilia work up. Five had mild thrombotic risk factors such as heterozygosity for Factor V Leiden or elevated factor VIII levels. Only one patient had a significant thrombophilic risk factor, familial mild protein C deficiency. Five patients had post thrombotic syndrome based on standardized scoring tools. All patients remain on indefinite anticoagulation. This case series suggests that chronic IVC occlusion increases the risk of unprovoked lower extremity thrombosis and pulmonary embolism in healthy children with resultant long-term complications. It also highlights the importance of imaging the IVC in young patients with unprovoked or minimally provoked iliofemoral DVT. Indefinite anticoagulation in patients presenting with unprovoked thrombosis secondary to IVC occlusion should be considered.

Disclosures
No relevant conflicts of interest to declare.
Hyperviscosity Syndrome: A 30-Year Experience in a Tertiary Referral Center in Mexico City
Authors: Armillas-Canseco FM , Hernández-Mata CF , Gómez-Ruiz IA , Aguayo Alvaro , Martínez-Baños D 
Published: October 2019

Abstract
Background: The hyperviscosity syndrome (HVS) is a rare entity which refers to clinical consequences of the high blood viscosity due to abnormal increase in the cellular or acellular blood components. It frequently presents secondary to plasma cell dyscrasias but it also occurs in autoimmune diseases and chronic infections.
Methods: Retrospective and descriptive study. Clinical records of patients with HVS were analyzed between the period of January 1st 1984 and June 30th 2015. We reported etiology, clinical and biochemical features, treatment and outcome.
Results: During this period we evaluated 20 episodes of HVS in 14 patients (50% men). The mean age was 59 years. Ten patients (71%) debuted with HVS as the initial presentation of the underlying disease. Diseases associated to HVS were: five cases of multiple myeloma (MM) (35.7%), 4 Waldenström's macroglobulinemia (WM) (28.5%), 4 Sjögren's syndrome (SS) (28.5%) and 1 case with non-Hodgkin lymphoma (NHL). Seventy percent of the episodes were due plasma cells dyscrasias (IgM 55%, IgG 20%, IgA 10%). Neurological symptoms were present in 100% of the episodes, hemorrhagic manifestations in 70%, visual symptoms in 65% and cardiovascular in 30%. Visual symptoms were more frequent in SS in comparison with MM and WM (p=0.022, p=0.001, respectively). The mean of serum viscosity at diagnosis was 12.6±14.4 (higher in WM and SS, p=0.0216 and p=0.0285, respectively), and after treatment 3.7±2. The mean time elapsed between diagnosis and first session of plasmapheresis and diagnosis and specific treatment of the cause was 3.8±3.8 and 7.95±7.28 days, respectively. In all patients one plasma exchange for session was done and the median of sessions required was 2 (range 1-3). Twenty eight percent of the patients (4/14) had at least one relapse. Seven of the fourteen patients died during follow-up, none due to HVS. All deaths were secondary to infectious complications associated with underlying disease. The median of overall survival was 2071 days (CI95% .000-6201.386). Overall survival divided by diagnosis was different (p=0.002). One and 5 year overall survival were 84 and 58%, respectively. Progression-free survival was 485 days (CI95% .000-1975.58)
Conclusions: In 70% of cases the HVS was the initial presentation of the underlying disease. The main causes were multiple myeloma followed by Waldenström's macroglobulinemia and Sjögren's syndrome. The predominant clinical manifestations were neurological and hemorrhagic symptoms, however visuals symptoms predominated in SS. The highest serum viscosity mean was present in WM and SS. No patient died as a consequence of HVS.
This is the largest study of HVS in Latin America and one of the largest series of HVS worldwide.

Disclosures
No relevant conflicts of interest to declare.
Alteration of HSC Functions in Thalassemia
Authors: Aprile Annamaria , Lidonnici Maria Rosa , Gulino Alessandro , Tripodo Claudio , Mandelli Giacomo , Ferrari Giuliana 
Published: October 2019

Abstract
Beta-thalassemia represents one of the most globally widespread monogenic disorders and is characterized by significantly reduced or absent synthesis of hemoglobin beta-chains. In its severe form the insufficient production of adult hemoglobin results in altered erythropoiesis, hemolytic anemia, bone marrow (BM) hematopoietic hyperplasia and splenomegaly often associated with extramedullary hematopoiesis, requiring regular blood transfusions and iron chelation treatment. Over the last two decades many progresses were made in the field of allogeneic bone marrow (BM) transplantation to definitively cure beta-thalassemia. In parallel, experimental autologous transplantation protocols were developed to correct the disease by gene therapy also in patients lacking a compatible donor. Both in the allogeneic and autologous setting, thalassemic hematopoietic stem cells (HSCs) and the BM niche represent central elements.
Although many aspects of the pathophysiology of thalassemia have been extensively investigated, the HSC and its niche have never been explored. In thalassemia, the BM is a stressed environment, characterized by the compensatory expansion of erythroid progenitors secondary to ineffective erythropoiesis. Whether other hematopoietic subpopulations, such as primitive progenitors and/or HSCs, might be affected by such an altered hematopoietic microenvironment is unknown.
We investigated the frequency of hematopoietic progenitors in a murine model of severe beta-thalassemia intermedia. Immunophenotypic analyses revealed no differences in MEP, GMP, CMP, LMPP and MPP committed precursor subpopulations, whereas a significantly lower frequency of HSCs (Lin- Sca-1+ c-kit+ CD48- CD150+) was observed in thalassemic mice, as compared to age-matched wild-type controls. Competitive transplantation experiments revealed a disadvantage in the engraftment capacity of thalassemic HSCs, which was substantiated by the preliminary results from in vitro and in vivo cell cycle analyses suggesting an accelerated HSC exhaustion. Analyses of other cellular components, such as BM stroma and differentiated hematopoietic cells, revealed that additional elements are altered in the thalassemic BM microenvironment. The cellular and molecular bases of HSC-niche interaction in this pathological condition are under investigation.
Our results uncover a previously ignored defect of HSCs in beta-thalassemia. The investigation of cellular and molecular players that might affect in trans HSC functions in the complexity of this altered microenvironment is ongoing.

Disclosures
No relevant conflicts of interest to declare.
EC-18 (1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol) Exhibits the Immune Regulatory Role through HSC Differentiation of Bone Marrow Cells in Mice
Authors: Lee Ha-Reum , Shin Su-Hyun , Yoo Nina , Yoon Sun Young , Kim Myung-Hwan , Suh Cheolwon , Sohn Ki-Young , Kim Heung-Jae , Han Yong-Hae , Chong Saeho , Kim Jae Wha 
Published: October 2019

Abstract
EC-18 (1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol) was originally isolated as a component of an extract from deer antler is traditionally used as an oriental medicine for hematopoiesis. A trace of MADG (monoacetyldiacylglyceride) could be detected in the deer antler, animal tissue, seed oils and bovine udder, which is identical to its natural source of MADG was chemically synthesized with glycerol, palmitic acid and linoleic acid. Previous study described that EC-18 has effect on the proliferation of hematopoietic stem cells (HSCs) (Biol. Pharm. Bull. 2004, 27(7): 1121-1125). Successively, we investigated the biological role of EC-18 in the differentiation of bone marrow cells into progenitor cell population in mice. EC-18 was administered daily for 1, 5 and 15 days to 6 week-aged C57BL/6 mice. Bone marrow cells of EC-18 administrated mice were collected from femurs and tibiae. Cell population was analyzed by FACs. As results, the total number of bone marrow cells was increased in EC-18 administered mice. To identify hematopoietic lineage cell population, we used lineage cocktail antibody kit including anti-mouse CD3, CD11b, CD45R, Gr-1 and TER-119. The lineages negative population contains HSCs which can self-renew and generate into all lineages of the hematopoietic system. The lineage negative cells significantly increased in time dependent manner in the EC-18-daily administrated mice. Cell population between myeloid progenitor (Lin- Sca1- Kit+) and common lymphoid progenitors (Lin- Sca1+ Kit+ IL-7R-α+) were analyzed using the antibody for Sca-1, c-Kit, IL-7R-α. The data showed that the population of myeloid progenitor cells was markedly increased rather than common lymphoid progenitor cells. In myeloid progenitor cell population, the cell population of megakaryocyte/erythrocyte progenitors (MEP) and granulocyte-monocyte progenitors (GMP) also elevated significantly. Taken together, EC-18 may have a potential role in the HSC differentiation and could be used as a therapeutic agent for anemia and neutropenia.

Disclosures
No relevant conflicts of interest to declare.
Late Clonal Disorders in Patients with Aplastic Anemia
Authors: Kokhno Alina , Mikhaylova Elena A , Fidarova Zalina T. , Ustinova Elena , Troitskaya Vera V. , Sokolov Andrey N. , Mendeleeva Larisa P. , Kuzmina Larisa A. , Tsvetaeva Nina V. , Dvirnyk Valentina N. , Obukhova Tatiana N. , Kovrigina Alla M. , Parovichnikova Elena N. , Savchenko Valeri 
Published: October 2019

Abstract

Long-term survival of AA patients as a result of effective immunosuppressive therapy (IST) is accompanied by an increased risk of MDS / AML development. Clonal evolution of AA in MDS / AML is detected in 2,3-10,6% of cases ( M.G.Afable et al, Hematology ASH Educ Program., 2011; p.90-95).
From 1996 till 2015 385 pts were treated in National Research Center of Hematology, Moscow, Russia. Seventeen (4,4%) pts ( 8 men and 9 women; median age 23 years) with AA (6 severe and 11 moderate AA) were diagnosed with clonal evolution to MDS, AML and CMML.
At the moment of AA diagnostics all those 17 pts had normal cytogenetics and were treated by: ATG+CsA+/-splenectomy (n=8); CsA+/-splenectomy (n=9). G-CSF was not administered in any case. Primary response (hematological response) was registered in all 17 pts with the further development of CR in 13 pts; median response duration till the clonal evolution was 78 (10-360) months. Three pts at the time of progression are conducted IST (CsA).
Clonal disorders developed at a median of 80 (47-408) months from the time of AA diagnosis. The median age at the moment of clonal evolution was 34 (27-60) years. Abnormalities of chromosome 7 were found in 8 pts (44%). In pts with monosomy 7 the median time response duration till the clonal evolution was twice less than in pts with another abnormalities of karyotype (70 (47-209) months vs 145 (70-408) months).
At the moment the clonal expansion was detected all the 17 pts had morphological characteristics of dismyelopoesis, however, bone marrow was hypercellular in 7 cases, hypocellular - in 4; mixed (hyper- or hypoplasia) - in 4 cases. Fibrosis was found in 2 pts, it was difficult to detect karyotype in these cases (not mitosis).
The therapy was conducted in accordance to the type of disease and bone marrow cellularity (IST, hypomethylating agents, chemotherapy). Five pts were transplanted from allogeneic donors. The median life duration since clonal evolution was 22 (2-203) months. Five of the 17 pts are alive ( the median - 64(5 -203) months): after allo- HSST (n=3); IST (n=1); "watch and wait" strategy (n=1).
Conclusion: Our 20 years study of a big cohort of AA pts has demonstrated low frequence of clonal evolution to myeloid disorders - 4,4%. We suggest that the absence of G-CSF in our IST programs may contribute to this fact. Almost half of AL/MDS cases harboured monosomy 7 and the median time to clonal evolution was twice less to this pts (70 vs 145 months). The only curative approach in case of clonal evolution to AL/MDS in pts with AA is allo-HSST.

Disclosures
No relevant conflicts of interest to declare.
No Observation of Chromosomal Instability after Transplantation of RPS14- and TP53-Modified Human HSCs in NSG/NSGS Mice
Authors: Thomay Kathrin , Salari Azam , Vajen Beate , Schienke Andrea , Hagedorn Maike , Ebersold Juliane , Kreipe Hans Heinrich , Krueger Andreas , Schambach Axel , Schlegelberger Brigitte , Göhring Gudrun 
Published: October 2019

Abstract
Chromosomal instability (CIN) is one of the characteristics of myelodysplastic syndromes (MDS) and plays an important role in diagnosis and prognosis as well as in disease progression. Candidate genes are known, but their role in induction of CIN has never been shown due to difficulties in culturing MDS cells long-term, showing the urgent need to have a model to study the fate of cells with typical MDS abnormalities with regard to CIN. The aim of our approach was to establish a xenograft transplantation model, transplanting human hematopoietic stem cells (HSC) with different independent lentivirally-mediated MDS-related modifications into immunodeficient mice. The establishment of appropriate xenograft mouse models is increasing worldwide. Thus, experiences should be shared to contribute towards minimizing loss of mice in this process.
HSCs were intrafemorally transplanted into immunodeficient NSG and/or NSGS mice. Here, we chose 3 different modifications that, in part, were to be combined in later experiments. 1) RPS14-haploinsufficient HSCs via shRNA knockdown, 2) TP53-deficient HSCs via shRNA knockdown and 3) HSCs, with different lentivirally introduced TP53 hotspot mutations (R248W, R175H, R273H, R249S).
We achieved engraftment with HSC in these mice (Figure 1). Cytogenetic analyses of the bone marrow showed human cells with normal karyotypes. However, we were not able to induce chromosomal instability into the cells. NSGS mice transplanted with HSCs carrying a TP53 mutation developed anemia but no histopathological signs of myelodysplasia. In all experiments with NSG mice, mainly control cells as well as the untransduced GFP-negative (GFP-) cells engrafted, not allowing observation of the modified HSCs over a long period. In NSGS mice, the engraftment rate was higher, but mice developed graft-versus-host disease (GVHD).
In summary, engraftment of HSC cells in NSG and NSGS is very promising and could be used to analyze the induction of chromosomal instability. However, the analysis of transduced HSCs with different vectors is limited as yet and further transplantations with the co-transplantation of mesenchymal stroma cells and the inhibition of GVHD are required to improve this model.
Selected examples from the different transplantation experiments representing engraftment success to some extent. Depicted is the median percentage of CD45+ cells equaling engraftment of human cells in target vector- and control vector-transduced cells as well as untransduced mock cells.
Figure 1. Figure 1.

Disclosures
No relevant conflicts of interest to declare.