bluuebunny/crossref_metadata_2025_split huggingface dataset:
Iron Overload Occurs Very Early In Newly-Diagnosed Patients With Congenital, Transfusion-Dependent Anemias
Authors: Kattamis Antonios , Delaporta Polyxeni , Papassotiriou Ioannis , Kyriakopoulou Dimitra , Tourkantoni Natalia , Kostaridou Stavroula 
Published: October 2019

Systematic transfusions are lifesaving for patients with severe congenital anemias, but they eventually lead to iron overload and the indispensable necessity of iron chelation therapy. Current official guidelines for the starting time of chelation therapy derives from data obtained with the use of desferrioxamine, which has been shown to have significant toxicity in very young patients, especially when used in low iron burden. No data exist on the use of the oral iron chelators in this setting. The purpose of this study was to evaluate the changes of iron parameters at the initial period of transfusion therapy in newly diagnosed patients with congenital anemias

Methods
Nine patients participated in this study. One patient was diagnosed with Diamond-Blackfan anemia, one patient with severe alpha-thalassemia, while 7 had beta-thalassemia. Three of the beta-thalassemia started transfusions at 1.5, 2 and 5 years, respectively. All others started transfusions between 2-4 months of age. Iron, transferrin saturation, ferritin levels. serum transferrin receptors (sTfR), were estimated by standard methods, while labile plasma iron (LPI) by the FeROS LPI kit (Aferrix, Ltd, Israel). The main results of the study show that: 1) transferrin saturation increases rapidly with transfusions (mean levels after 4 transfusions 49.2% (range: 23.8-90.5%), mean after 6 transfusions 69.1% (range: 39.5-112%)), though it has significant diversity in between patients, as indicated also by one patient that continued to have transferrin saturation at 65% even after 12 sessions. Transferrin saturation significantly correlates with ferritin levels (r=0.763, p<0.0001), with the number of previous transfusions (r=0.486, p=0.002) and with the levels of sTfR, which is also an index of the degree of erythropoiesis (r=0.550, p<0.001). The increase of ferritin correlates also with the sTfR levels (r=0.697, p<0.0001), while the rate of increasing transferrin saturation per transfusion correlates to sTfR levels (r=0.486, p=0.002). LPI levels appears early in the transfusion history and correlates with transfusion saturation.

Discussion
The results of the study indicate that iron overload starts early in the transfusion history of young patients with transfusion-dependent anemias. These findings dispute current guidelines suggesting starting chelation therapy, when the patients have already received 10 transfusions or when ferritin levels reach more than 1000ug/dl.

Disclosures:
No relevant conflicts of interest to declare.
Low Serum Vitamin B12 With Supplement In Pernicious Anemia
Authors: Jajeh Ahmad 
Published: October 2019

Pernicious anemia is commonly associated with autoimmune disorders. This abstract will describe three cases with low serum Vitamin B12 even with 2 weeks Vitamin B12 inrtamuscular injection of 1000 micrograms. First patient is thirty nine 39 years old white male with known history of pernicious anemia and Alopecia Totalis with prior history of Methotrexate and cyclosporin treatment. The patient had low serum iron and low iron saturation at initial presentation. He was given IV Iron supplement to saturate iron stores with good result. However, his serum vitamin B12 remain border line low normal below 300 pg/ml ( patient’s level is 210, normal range 180-941 pg/ml), even with every two weeks IM injection for more than six months. Patient was also given oral supplement with no increase in the serum vitamin B12 level. The second patient is sixty eight 68 years old white female with history of colon cancer that underwent resection and history of Hashimoto’s Thyroiditis who was on Thyroid hormonal supplement. Her serum Vitamin B12 level remain borderline low below 300. The third patient is forty 40 years old white female with history of Hypothyroidism and breast cancer that had received adjuvant chemotherapy post Lumpectoy and radiation therapy. This patient was treated with IV intravenous iron supplement for iron deficency with good result. All three patients had blocking antibodies to intrinsic factor and presented with various degree of iron deficency and treated with oral as well as IV iron supplement. Peripheral blood smear were reviewed on all the three patients. Hypersegmentation of neutrophils was seen with normocytic normochromic red cell morphology. One patient had low plateletes count. All patients had white blood cell counts below ten thousands. Two patients showed excess of apoptotic neutrophils. None of the patients had enlarged spleen or adenopathy or evidence of bone marrow hypofunction. All of the above patients improved clinically interm of sense of well being and increased level of energy with vitamin B12 supplement. None of the above patients had abnormal liver or kidney function. All patients had low serum vitamin B12 with one monthly dose IM injection plus oral supplement. All patients had normal LDH level and normal Folic acid level.

In conclusion
The low serum vitamin B12 levels with adequate supplement that should saturate the liver reserve open an interesting question about the possiblility of Transcobalamine receptor abnormality interm of abnormal function or deficency. Antibodies blocking the receptors or rapid neutrophils turn over is another possibility. Further study needed to solve this delema.

Disclosures:
No relevant conflicts of interest to declare.
Absolute Monocyte Count Trichotomizes Chronic Lymphocytic Leukemia Into High Risk Patients With Immune Dysregulation, Disease Progression and Poor Survival
Authors: Herishanu Yair , Kay Sigi , Deutsch Varda , Ben-Ezra Jonathan , Naparstek Elizabeth , Perry Chava , Katz Ben-Zion 
Published: October 2019

Peripheral blood absolute monocyte count (AMC) has been reported to correlate with clinical outcome in different types of cancers. This association may relate to alteration in circulating monocytic subpopulations and tumor infiltrating macrophages. In this study we evaluated the clinical significance of peripheral blood AMC in 80 treatment naive patients with CLL. The measurement of AMC was based on morphological enumeration using an automated microscope (CellaVision DM1200), due to our findings that automated complete blood count data may yield incorrect monocytes enumeration values in CLL. The median AMC in patients with CLL was not different from normal controls, however the AMC range exceeded the values of healthy individuals (median of 458/µL with a of range 0-4868/µL in CLL vs. median of 310/µL with a range of 105-1154 in healthy controls). The AMC divided the patients into 3 distinct sub-groups with different characteristics and outcomes. Patients with high AMC (>750/µL) were younger and also had higher absolute lymphocytes counts, while patients with low AMC (<250/µL) had prominent immune dysregulation (lower serum IgA levels, susceptibility to infections and a tendency for positive direct anti-globulin test). The low and high AMC patients had a shorter time to treatment compared to the intermediates AMC subgroup (250-750/µL), whereas low AMC was associated with increased mortality caused by infectious complications. In conclusion, AMC quantification during the disease course classifies CLL patients into subgroups with unique clinical features and outcomes.

Disclosures:
No relevant conflicts of interest to declare.
A Pilot Study To Examine The Effect Of Extracorporeal Membrane Oxygenation (ECMO) On Plasma Factor XIII Levels
Authors: Sanchez Dimarys , Stine Kimo , Crary Shelley E. , Fiser Richard , Schmitz Michael , Prodham Parthak , Nick Todd , Tang Xinyu 
Published: October 2019

Background
Children with acute, severe cardiopulmonary compromise may require support with ECMO. Adequate anticoagulation without inducing life-threatening hemorrhage plays a critical role in the management of these patients. Recent data from adult studies suggest that patients undergoing cardiac bypass for coronary artery bypass grafting (CABG) often have reduced Factor XIII levels (FXIII). This relative FXIII deficiency may be predictive of hemorrhage or severe blood loss. Such studies have never been conducted in the pediatric population. Our primary objective will be to determine if a relative deficiency in FXIII occurs in children undergoing ECMO and to determine any time dependency of these changes. Our secondary objective will be to determine if blood loss and/or transfusion requirements during ECMO correlates with FXIII levels.

Methods
Single center ongoing study utilizing a prospective design involving pediatric patients (ages 0-18) undergoing ECMO. Samples for FXIII, D-Dimers, Fibrinogen and Thrombin Time are being drawn at designated time points as follows: prior to or during ECMO cannulation, 2 hours, 24 hours, 3-5 days and 14-21 days after initiation of ECMO and 1-3 days after discontinuation of ECMO. Mixed effects analysis of covariance (ANCOVA) will be used for data analysis.

Results
To date, fifteen patients have been enrolled and analyses have been conducted for n=7 patients with a total of 36 time points of data. Figure 1a and 1b show the mean and standard deviation (SD) of FXIII and Fibrinogen, respectively. Figure 1c shows the mean ratio of FXIII to Fibrinogen. Error bars represent 1 SD around the mean (central point).

Conclusion and Significance
This is the first pediatric study evaluating FXIII activity in children undergoing ECMO. Firm conclusions cannot be drawn with the interim analyses conducted to date. If variations in FXIII are found, our results will provide important information towards determining if children undergoing ECMO could potentially benefit from FXIII replacement, in turn minimizing bleeding complications and/or transfusion requirements often encountered with this treatment modality.

Disclosures:
No relevant conflicts of interest to declare.
Plasma FXIII LEVEL Variations During Menstrual CYCLE
Authors: Halimeh Susan , Talat Sharief Lava A. , Lawrie Andrew S. , Kappert Guenther , Mackie Ian J. , Peyvandi Flora , Kadir Rezan A. 
Published: October 2019

Introduction
Factor XIII (FXIII) has an important role in the control of bleeding through fibrin cross-linking. While many physiological factors affect plasma FXIII level, the effect of the menstrual cycle is not fully understood.Aim: The study aimed to assess possible changes in plasma FXIII activity during the normal menstrual cycle and to assess any correlation between FXIII activity during the menstrual phase and the menstrual blood loss.

Methods
In this longitudinal study, a total of 32 women of reproductive age were recruited. Menstrual blood loss was measured using the pictorial blood-assessment chart (PBAC). A bleeding questionnaire and score were also completed. Blood samples were taken during menstrual phase (day 1-5), proliferative phase (day 6-11), periovulatory phase (day 12-17), secretory phase (days 18-23), and premenstrual phase (day 24-29) for assessment of FXIII level using quantitative ammonia release assay.

Results
Mean FXIII level was significantly lowest during menstrual and periovulatory phases of the cycle (114 IU/dL) compared to secretory (121 IU/dL) and premenstrual (122 IU/dL) phases (p=0.036). No significant correlation between FXIII activity during menstrual phase and women age (p= 0.53) or PBAC score (p=0.53). Among 14 women with PBAC score ≥ 100, the median FXIII activity during the menstrual phase of the cycle was 116 IU/dL, this was not statistically different from group with PBAC score <100 (113 IU/dL) (p = 0.72).

Conclusion
FXIII activity was lowest during the menstrual and periovulatory phases of the cycle. Understanding these changes in FXIII during menstrual cycle will help clinicians to perform blood tests during appropriate phase of the menstrual cycle and to capture the baseline level.

Disclosures:
Halimeh: Octapharma AG: Investigator Other, Research Funding.
The Pharmacokinetics Of Turoctocog Alfa Are Consistent Over Different Concentrations and Production Lots
Authors: Jiménez-Yuste Víctor , Lejniece Sandra , Klamroth Robert , Saugstrup Trine , Moss Judi 
Published: October 2019

Introduction
Turoctocog alfa is a B domain truncated human recombinant FVIII for treatment of patients with hemophilia A. The production yields a highly homogenous product with the same tyrosine sulphation as human FVIII. In order to confirm the consistency of turoctocog alfa pharmacokinetics (PK) over different production lots and vial strengths, a clinical trial was performed in 15 patients with severe hemophilia A.

Aim
To compare the PK of 3 lots of 2000 IU/vial and 1 lot of 3000 IU/vial of turoctocog alfa after i.v. administration of 50 IU/kg in patients with severe haemophilia A.

Methods
This was a multi-centre, open-label trial investigating the PK of 4 lots of turoctocog alfa (3 lots of 2000 IU/vial; Lots A, B and C, and 1 lot of 3000 IU/vial; Lot D) in patients with severe hemophilia A (FVIII<1%). The trial was performed as a two-period, incomplete block, cross-over trial, in which each patient was allocated at random to a predefined sequence of 2 different lots of turoctocog alfa.
The FVIII activity was assessed using both the one-stage clot and chromogenic assays. Both the primary endpoint, normalized AUC (AUC*(planned dose/actual dose)), and the secondary PK endpoints were analyzed by ANCOVA on the log transformed values, with lot, visit and patient as fixed effects. Each of the three 2000 IU/vial lots was compared and tested against the 2 other 2000 IU/vial lots. If not significantly different on a 5% level, the 3 lots were pooled together and tested against the 3000 IU/vial lot.

Results
Fifteen patients with a mean age of 38.6 years (ranging from 21 to 60 years) were included from 3 hemophilia centres in 3 different countries. Three adverse events (AEs) were reported in the trial by 2 separate patients; all AEs were judged to be unlikely related to the trial product. There was no development of inhibitors.
There was no pharmacokinetic difference observed between Lots A, B, C (2000 IU/vials) and there was no pharmacokinetic difference observed between the pooled data from lot A, B and C (2000 IU/vial) and lot D (3000 IU/vial) based on normalized AUC, half-life, incremental recovery and clearance. The estimated mean values (with 90% CI) for the PK parameters based on the chromogenic assay are presented in Table 1. The results were similar for the one-stage clot assay and the chromogenic assay.

Conclusions
No pharmacokinetic differences were observed between the three 2000 IU/vial lots (Lot A, Lot B and Lot C), nor were there pharmacokinetic differences between Lot D (3000 IU/vial) and pooled data from Lots A, B and C, based on normalized AUC, half-life, incremental recovery and clearance. There were no safety concerns and no inhibitor development in the trial.

Disclosures:
Jiménez-Yuste: Novo Nordisk: Consultancy, Research Funding, Speakers Bureau. Klamroth:Novo Nordisk, CSL Behring, Bayer, Baxter, Pfizer: Honoraria, Research Funding. Saugstrup:Novo Nordisk: Employment. Moss:Novo Nordisk: Employment.
Molecular Diagnosis Of One Chinese Patient With Hemophilia B
Authors: Zhou Rong-Fu , Gao Bo , Ou-yang Jian 
Published: October 2019

FTo investigate the molecular mutation leading to Hemophilia B in one patient.

Methods
FOne-stage method was used to detect APTT, PT, TT, Fibrinogen and FVIII:C, FIX:C. The genomic DNA was extracted from the peripheral blood of proband. All exons and their flanks of Factor IX gene were amplified by polymerase chain reaction (PCR). The PCR products were sequenced directly.

Results
FThe proband was a 20-month boy presenting with scalp hematoma after trauma. Regular coagulation tests showed that his APTT was 135.1s, PT 11.9s, TT 15.6s and Fibrinogen 2g/l. Normal mixed plasma could correct the prolonged APTT to 35s. His FIX:C was 6.4% and FVIII:C was normal. Direct sequencing of PCR products suggested that there was a 5085T>C mutation (NG_007994.1) in Exon1, and a 36060G>C mutation in Exon8 of F9 gene. The former mutation caused the substitution of Leu19 by Pro, which lies in -28th in signal peptide. The later mutation lead to the substituion of Gln370 by His.

Conclusion
FMutations of 5085T>C in Exon1 and 36060G>C in Exon8 might be the causes of coagulation factor IX defiency for the patient. These mutations are de novo ones according to the database presenting in http://www.factorix.org/.

Disclosures:
No relevant conflicts of interest to declare.
Evaluation Of Factor V Leiden, Prothrombin Mutations and The Homozygous mutation 677T In The MTHFR Gene In Patients With Venous Thrombosis
Authors: Pizzuti Michele , Santagostino Alberto , Rizzo Maria Antonietta , Dragonetti Daniela , Pietrafesa Maria Grazia , Attolico Immacolata , Amendola Angela , Filardi Nunzio , Cimminiello Michele , Matturro Angela , Vertone Domenico , Nuccorini Roberta , Pascale sara Pasquina , Coluzzi Sabrina 
Published: October 2019

Over the last few years there has been increased interest in laboratory tests for thrombophilia. Testing is predominantly performed to identify asymptomatic individuals at risk for a first thrombosis or patients (pts) at risk of relapse. The results are not always concordant, and the impact on clinical practice is not yet defined, especially for heterozygous forms.
We evaluated heterozygous and homozygous Factor V Leiden (FVL) and prothrombin (FII) mutations and the homozygous C677T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene in 98 pts with venous thrombosis distinguishing idiopathic forms from forms that are secondary to malignancy, surgery, forced immobilization or hormone treatments.
FII mutation was present in 17% of idiopathic and 5.8% of secondary forms. FVL mutation was present in respectively 17% and 15.8% and MTHFR homozygous state in 31.9% and 21.5%. At least one of FII or FVL mutations was present respectively in 31.9% and 19%, at least one of the three mutations examined was present in 57.4% and 36.2%.
In pts with limb venous thrombosis (n-64), the percentages for each mutation are respectively: FII-23.5% and 6.6%, FVL-20.5% and 6.6%, MTHFR 35.2% and 16.6% .At least one mutation between FII and FVL is present respectively in 42.1% and 13.3% (P = 0,028) while at least one of the three mutations is present in 61.7% and 30.5% (P = 0,022)
In our pts with pulmonary thromboembolism (n-36) FII mutation was absent while FVL mutation was present in 7.6% of idiopathic and 21.7% of the secondary thrombosis, MTHFR in 30.7% and in 30.4%. At least one of the three examined mutations was present in 38.4% and 47.8%.
The mutations we have studied are generally more frequent in idiopathic forms. The difference reaches statistical significance in limb venous thrombosis where they seem to have a significant relevance, although in a heterozygous state, and to promote thrombosis even in absence of other causes.
In pulmonary thromboembolism (PTE) pts FII mutation was absent, FVL mutation is less frequent in pts with idiopathic thrombosis and MTHFR homozygous state is equivalent between the two subgroups. Thus, they seem to not influence PTE pathogenesis that would be likely sought in different causes.

Disclosures:
No relevant conflicts of interest to declare.
Thrombin infusion in endotoxin-treated rabbits reduces the plasma levels of plasminogen activator inhibitor: evidence for a protein-C- mediated mechanism [see comments]
Authors: Colucci M , Triggiani R , Cavallo LG , Semeraro N 
Published: October 2019

Abstract
Plasminogen activator inhibitors (PAIs) play a pivotal role in the control of fibrinolysis. The mechanisms regulating the plasma levels of PAI(s) are still unknown. We report here that the infusion of bovine thrombin (1 U/kg/min, over 60 minutes) in rabbits treated with 0.5 microgram/kg endotoxin (to induce an increase in circulating fast- acting PAI) causes a marked reduction of PAI (50% of preinfusion value), as indicated by functional assay and reverse fibrin autography. Moreover, blood clots prepared from samples obtained after thrombin infusion lysed faster than preinfusion clots when exposed, in vitro, to tissue plasminogen activator. Donor-receiver transfusion experiments showed that the half-life of circulating PAI activity was shorter in thrombin-infused rabbits than in controls (4.1 minutes versus 7.4 minutes), suggesting an accelerated clearance. As expected, thrombin infusion resulted also in activation of protein C (PC). The following observations suggest a close relationship between PC activation and PAI reduction. (1) Infusion of thrombin in rabbits made deficient in vitamin K-dependent plasma proteins by warfarin treatment did not result in modification of PAI activity. (2) Treatment of the latter animals with a barium citrate eluate (PE) of rabbit plasma restored both the anticoagulant and profibrinolytic response to thrombin. (3) Short infusion of thrombin-activated PE (containing activated PC, PCa), but not of unactivated PE, induced both anticoagulation and reduction of PAI activity. In vitro, incubation of PAI-rich rabbit serum with thrombin-activated PE and phospholipids resulted in a progressive disappearance of PAI activity with a t1/2 of 30 minutes. However, this slow inactivation rate does not fully explain the results obtained in vivo. Our data suggest that thrombin infusion in rabbits causes a reduction of circulating PAI activity and that activation of PC is the intermediary mechanism involved in this phenomenon.
Hepatitis C infection in children with hemophilia A and B
Authors: Blanchette VS , Vorstman E , Shore A , Wang E , Petric M , Jett BW , Alter HJ 
Published: October 2019

Abstract
Antibodies to hepatitis C virus (anti-HCV) were quantitated in stored sera from selected groups of hemophilic children (less than or equal to 18 years of age). During the period 1987 to 1989, seropositivity rates were as follows: untransfused hemophiliacs 0% (0 of 11 cases), hemophiliacs treated exclusively with vapor-heated factor VIII or IX concentrates 0% (0 of 9 cases), hemophiliacs treated only with cryoprecipitate or single donor blood products 0% (0 of 9 cases), and hemophiliacs regularly treated with unheated or dry heat-treated factor VIII or IX concentrates 95% (21 of 22 cases). Corresponding alanine aminotransferase (ALT) results were similar: values were always below the upper limit of laboratory normal (40 U/L) in untransfused hemophiliacs, hemophiliacs treated with vapor-heated factor concentrates, or those who received only cryoprecipitate or single donor blood products. By contrast ALT values were greater than 40 U/L in 82% (18 of 22 cases) of hemophilic children regularly infused with unheated or dry heat-treated factor concentrates. Three conclusions are drawn from this data: (1) HCV is a major cause of chronic hepatitis in multitransfused hemophilic children, (2) unheated and dry heat-treated clotting factor concentrates carry a very high risk of transmitting HCV infection, and (3) clotting factor concentrates inactivated by vapor heating carry a very low and perhaps zero risk of transmitting HCV infection. These findings are of therapeutic significance for previously untransfused hemophiliacs susceptible to HCV infection.