bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Prospective Evaluation of Bleeding Tendency and Efficacy of Antihemorrhagic Treatments in Patients with Increased Von Willebrand Factor (VWF) Clearance (Von Willebrand Disease Vicenza AND C1130F Mutation).
Authors: Castaman Giancarlo , Tosetto Alberto , Federici Augusto B. , Rodeghiero Francesco 
Published: October 2019

Abstract
Background. von Willebrand disease Vicenza (VWD-VI) is characterized by severely reduced FVIII and VWF levels, the presence of ultra-large multimers in plasma, heightened response to desmopressin and increased clearance of VWF after desmopressin. Increased clearance of VWF has been identified in other VWF mutations, such as C1130F with similarly low FVIII/VWF levels as in VWD-VI. So far, the bleeding risk of these patients has not been formally established and it is unclear whether they need a different treatment approach.
Aims, Design of the study, Patients and Methods. We prospectively evaluated the clinical history of 60 patients (32 M, 28 F) with VWD Vicenza (carrying R1205H mutation) and 23 patients (9 M, 14 F) with C1130F mutation, both characterized by increased VWF clearance. All in-hospital visits for bleeding symptoms, treatments and prophylaxis prior to invasive procedures were recorded together with home-treatments. All the remaining patients were contacted yearly to update their bleeding symptoms, if any. The study lasted from January 2002 to December 2007.
Results. During follow-up, 21/60 (35 %) and 9/23 (39 %) of patients with VWD-VI or C1130F respectively did not require treatment for bleeding or prior to invasive procedures. Ten patients with VWD-VI and 5 with C1130F had 1 to 3 tooth extraction instances treated with a single desmopressin infusion plus oral tranexamic acid for 5 days, without mishap. A single patient carrying out dental extraction without any prophylaxis had bleeding promptly stopped by a single desmopressin infusion. Four women with VWD-VI and 6 with C1130F had 1 or 2 pregnancies during follow-up, and successfully completed delivery by using two or three desmopressin infusions over 24-48 hours after vaginal delivery. Epistaxis requiring consultation or treatment was almost limited to pediatric age and a single adult patient only required treatment for an isolated episode. A single post-traumatic joint bleeding required a successful treatment with desmopressin. Only 3/15 (20 %) women in fertile age with VWD-VI required treatment for menorrhagia (iron suppletion, combined oral estroprogestinic pill, tranexamic acid) compared to 8/9 (89 %) with C1130F mutation. Most minor surgical interventions were successfully covered with desmopressin while major surgery required FVIII/VWF concentrates since prolonged hemostasis was required.
Conclusions. Spontaneous bleeding in patients with VWD-VI and C1130F appeared to be mainly limited to epistaxis in pediatric age and menorrhagia in females. Most of clinical situations are successfully manageable with desmopressin, as usually occurs for other type 1 VWD patients, and despite the short FVIII and VWF half-life post-infusion.
Effects of Age on the Development of Arthropathy in Mice with Hemophilia.
Authors: Valentino Leonard A. , Hakobyan Narine , Sumner D. Rick , Enockson Candace 
Published: October 2019

Abstract
The National Hemophilia Foundation, World Federation for Hemophilia and the World Health Organization recommend that prophylaxis be continued indefinitely. Questions about stopping prophylaxis as boys become adolescents or adults have been raised. In particular, discontinuing prophylaxis after a boy reaches skeletal maturity has been suggested. The impact of joint bleeding on these mature joints is thought to be less deleterious than in those of younger patients. To test the hypothesis that older, skeletally mature joints are less susceptible to joint damage after hemarthrosis, mice deficient in factor 8 gene expression (n=42) were studied to determine the impact of age and skeletal maturity on the development of hemophilic arthropathy. Mice at different ages were subjected to needle puncture of the knee joint capsule to induce a single massive hemarthrosis and then sacrificed 30 days or one year after the joint bleed. The diameter of the right (R) and left (L) knee joints was measured and the greatest bone diameter recorded. The joints were then isolated and subjected to image analysis using micro-computed tomography (mCT). Images were reviewed by 6 examiners blinded to the experimental conditions. After 30 days, a single episode of hemarthrosis resulted in a significant increase (p=0.0152) in the size of the affected joints compared to the control contralateral joint (figure). Although all ages of mice demonstrated bone hypertrophy, this was most pronounced in older mice. mCT images showed that changes were present in bones of the affected knees both young and old mice compared to the contralateral control joints. A pitted appearance of the surface was prominent in young mice early after a joint bleed (day 30). By one year, this pitting was much less evident. Osteocyte formation was a prominent feature. The surface contour of older mice scarified on day 30 was rugose. By one year, osteocyte and new bone formation dominated the surface. Consistent with the observation in patients with hemophilia, the patella of older mice was laterally displaced. The knee joints of both young, skeletally immature and older skeletally mature mice demonstrate marked structural changes after a single hemarthrosis. These results indicate:
that bone hypertrophy is greater in older mice; the blood-induced joint damage is different depending on the age of the animal; that bleeding into the skeletally mature joint damages the bones resulting in new bone formation; bleeding into immature joints causes more pitting of the surface and bone changes.
Therefore, in conclusion, this data does not support the hypothesis that bleeding into the mature joint is less detrimental compared to hemarthrosis in the younger skeletally immature joint. This observation, if translatable to humans suggests that joint bleeding in adults is likely to result in bone damage and that prevention of joint bleeding should be a goal for patients of all ages.
Figure Figure
A Single Point Mutation Gln716His on the α2 Integrin: The New Platelet Alloantigen Casa.
Authors: Bertrand Gerald , Jallu Vincent , Kervran Dominique , Martageix Corinne , Kaplan-Gouet Cecile 
Published: October 2019

Abstract
We report here the identification and characterization of a new low-frequency platelet alloantigen Casa involved in a case of neonatal alloimmune thrombocytopenia (NAIT). A 29-year-old mother gave birth to a full-term male infant who exhibited petechiae at birth. Nine hours post-delivery the platelet counts revealed a severe thrombocytopenia (16.109platelets/L) leading to platelet transfusion therapy associated with IVIG. The outcome was uneventful. Blood samples from the parents and infant were referred to our laboratory for investigation because of suspected NAIT. Maternal serum showed a specific positive reaction with the antigen-capture assay (MAIPA) only when it was tested with the paternal platelets and the monoclonal antibodies Gi9 (Immunotech, Marseille, France), P16 (NIBSC, Bristol, UK), and AK7 (Abcys, Paris, France) directed against the GPIa-IIa (a2b1 integrin). Nucleotide sequence analysis of GPIa cDNA of the father and newborn showed a nucleotide substitution at position 2235 (2235G>T according to the International Nomenclature). This substitution induces a Q716H amino acid change in the GPIa mature protein, located outside the I domain involved in cell-adhesion for collagen. In vitro analysis of recombinant CHO cells expressing wild-type or mutant (Q716H) human GPIa allowed us to demonstrate that this single amino-acid substitution is responsible and sufficient for inducing Casa antigen expression. Adhesion of CHO cells to collagen coated on microtiter plates was not modified by the Cas polymorphism, nor by the maternal anti Casa alloantibodies, indicating that the mutation does not affect the function of the integrin a2b1. PCR-SSP was developed for Casa genotyping. In a Caucasian population study none of the 100 unrelated blood donors was found to be Casa carrier. In conclusion, the Casa antigen described here, implicated in a case of severe neonatal thrombocytopenia is a low-frequency platelet antigen in the Caucasian population. This study highlights the high polymorphism of the GPIa gene.
Profiles of Th1, Th2, Th17 and Treg Cells in Patients with Chronic Idiopathic Thrombocytopenic Purpura.
Authors: Zhou Rong-Fu , Ou-yang Jian , Chang Da-Yu , Xu Jing-Yan , Chen Bing , Yang Yong-Gong , Zhang Qi-Guo , Shao Xiao-Yan 
Published: October 2019

Abstract
Objective: To explore the profiles of Th1,Th2, Th17 and Treg cells in patients with chronic idiopathic thrombocytopenic purpura.
Methods: Samples of peripheral blood were collected from 30 chronic ITP patients ( 9 males and 21 females), aged 41, 21 being in active stage, and 9 in remission stage, and 9 healthy persons in control (3 males and 6 females), aged 36. Peripheral blood was cultured, and activated with PMA/ionomycin when Th1, Th2 and Th17 cells were detected. Flow cytometry was used to measure the intracellular cytokines interferon (IFN)-γ, interleukin (IL)-4 and interleukin (IL)-17 so as to identify the Th1 cells (CD3+ CD8− IFN-γ+ IL-4− cells), Th2 cells (CD3+ CD8− IFN-γ − IL-4+ cells) and IL-17 cells (CD3+ CD8− IL-17+ cells); Treg cells were identified to CD4+ CD25+ Foxp3+ cells and uncultured peripheral blood was used to measured the CD4+ CD25+ Foxp3+ cells by flow cytometry. The ratios of Th1/Th2 were calculated.
Results: The Th1/Th2 ratio for patients in active stage was 15.04±9.67, significantly higher than those for patients in remission stage (7.17±5.38, P <0.05) and in control (8.47±3.78, P <0.05); the percentage of Treg cells of the patients in active stage was 0.89±0.58%, significantly decreased than those of patients in remission stage (6.41±1.86%, P <0.001) and in control (6.06±0.85%, P <0.001); the percentage of Th17 cells was 1.94±0.77% for patients in active stage, 2.16±0.52% for patients in remission stage and 1.82±0.58% for patients in control, respectively, and there was no statistic significance between them.
Conclusion: Chronic ITP is a Th1 predominant disease; decreased number and function of Treg cells might be one of mechanisms that cause immune regulation dysfunction in chronic ITP; Th17 cells might not play a role in the development of chronic ITP.
Maternal Immune Response to Fetal Platelet GPIbα Causes More Frequent Miscarriage in An Animal Model: A Potential Explanation for Low Reported Incidence of Fetal and Neonatal Immune Thrombocytopenia Mediated by Anti-GPIbα Antibodies.
Authors: Li Conglei , Piran Siavash , Chen Pingguo , Lang Sean , Ware Jerry , Ruggeri Zaverio M. , Freedman John , Ni Heyu 
Published: October 2019

Abstract
Fetal and neonatal immune thrombocytopenia (FNIT) is a life-threatening bleeding disorder, resulting from fetal platelet opsonization and destruction by maternal antibodies developed during pregnancy. The frequency of FNIT has been estimated at 0.5–1.5/1,000 liveborn neonates. However, the incidence of fetal mortality is currently unknown, as the rate of miscarriage in affected pregnant women has not been well studied. Integrin αIIbβ3 and Glycoprotein (GP) Ibα are major glycoproteins expressed on the platelet surface and are the two major antigens targeted by anti-platelet antibodies in autoimmune thrombocytopenia (ITP). However, it is unclear why the incidence of FNIT caused by anti-GPIbα antibodies is far lower than that of FNIT mediated by anti-β3 integrin antibodies. This difference cannot be well explained by the frequency of genetic polymorphisms of the two antigens. We hypothesized that: 1) GPIbα is less immunogenic, leading to less maternal antibody production during pregnancy, or 2) anti-GPIbα antibodies cause a less severe pathology, and thus have a lower chance of being reported, or 3) anti-GPIbα antibodies cause higher incidence of miscarriage, resulting in reduced reported cases. To test these hypotheses, the maternal immune response against fetal platelet GPIbα versus β3 integrin were compared in FNIT models, using syngeneic background BALB/c GPIbα−/− and β3−/− mice. The FNIT models were established by transfusing female GPIbβ −/− or α3−/− mice with 108 gel-filtered platelets from wild-type (WT) BALB/c mice weekly. After two platelet immunizations, flow cytometry assays were used to detect the titers of anti-GPIbα and anti-β3 antibodies, and the immunized females were bred with WT BALB/c male mice. We found that there was no significant difference in mean antibody titer between the two groups (P>0.05). However, miscarriage occurred more frequently in anti-GPIbα-mediated FNIT (14/16 versus 8/16, P<0.05), particularly in pregnant mice with antibody titer less than 1:800 (11/13 versus 6/14, P<0.05). When antibody titers were higher than 1:800, miscarriage occurred in all mice and no difference was observed between the two groups (3/3 versus 2/2, P>0.05). Our data suggest that fewer reported FNIT cases mediated by anti-GPIbα antibodies cannot simply be explained by less immunogenicity of GPIbα, or less severe pathology caused by anti-GPIbα antibodies. Higher incidence of miscarriage caused by maternal immune response to fetal GPIbα likely masks the reported frequency and severity of this life-threatening disease. The mechanisms leading to miscarriage in FNIT, and the potential therapeutic effect of intravenous immunoglobulin (IVIG) in this disorder are currently being investigated. (Li C and Piran S contributed equally to this work).
A Predictive Cost-Effectiveness Analysis of the Treatment of Chronic, Refractory Immune Thrombocytopenic Purpura (ITP) with Novel Agents: An Economic Model Based on Long-Term Treatment Data with Rituximab Versus Romiplostim.
Authors: Oatis Wendy , Shankaran Veena , Saghir Faisal , Bennett Charles L. , Richey Elizabeth , Bussel James B 
Published: October 2019

Abstract
Introduction : Novel non-surgical options for treatment of chronic immune thrombocytopenic purpura (ITP) are emerging. These include rituximab, an anti-CD20 monoclonal antibody, and romiplostim, a soon to be approved thrombopoeitic receptor agonist. However, long-term clinical data with these agents have not been reported previously and the cost of romiplostim treatment has not been announced. Herein, we report a “break-even” cost-effectiveness analysis, based on 2.5 years clinical outcome data for both agents, which yields a suggested market cost for romiplostim that would result in equivalent cost-effectiveness profiles for the two agents when administered as treatment for chronic ITP.
Methods: Effectiveness data were based on 2.5-years results from studies of chronic ITP patients treated with rituximab or romiplostim. We calculated the total costs of treating a cohort of chronic ITP patients with ritiuxan with splenectomy salvage (estimated cost of $8,100) as the therapeutic choice for treatment failures. We subsequently calculated a break-even price for romiplostin with splenectomy salvage that would result in a total cost of treating an ITP cohort equivalent to the costs of treating the rituximab/splenectomy cohort.
Results: At 2.5 years follow-up, a cohort of 100 chronic ITP patients initially treated with rituximab is associated with 40 therapeutic failures going on to splenectomy annually. Total treatment costs for this cohort is estimated at $2.2 million. At 2.5 years follow-up, a cohort of 100 chronic ITP patients initially treated with romiplostim is associated with 10 splenectomy failures per year. Total 2.5 year treatment costs for this cohort is $1.9 million for splenectomy plus the costs of treating 70 ITP patients with romiplastim for 2.5 years, 20 ITP patients for two years, and 10 ITP patients for one year. Hence, annual break-even costs for romipslatim are estimated at $20,000. The higher annual cost with romiplostim versus rituximab is related to better 2.5 year outcome rates. Hence, these cost estimates are preliminary, pending reporting of additional long-term studies.
Conclusions: It will be of interest to compare this value with cost-effectiveness estimates that are based on actual pricing of romiplostim (when the drug receives FDA approval). Policy makers would be wise to develop break-even cost estimates for novel drugs prior to FDA approval. These analyses may help inform initial price setting efforts.
Effect of Reducing Intravascular Hemolysis on Ferritin Homeostasis in Eculizumab Treated Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients.
Authors: Roeth Alexander , Schubert Joerg , Hock Christina , Christoph Sandra , Duehrsen Ulrich 
Published: October 2019

Abstract
BACKGROUND: In paroxysmal nocturnal hemoglobinuria (PNH), the lack of the GPI-anchored terminal complement inhibitor CD59 on erythrocytes renders these cells susceptible to continuous complement mediated hemolysis. Hemolysis leads to anemia, fatigue, red blood cell transfusions, renal impairment and increases the risk of thromboembolic events. Urinary iron loss is also common in patients with PNH due to intravascular hemolysis. Eculizumab is a terminal complement inhibitor that has been evaluated in two phase III studies. In previous studies eculizumab significantly reduced intravascular hemolysis (characterized by significant reduction of LDH levels) and significantly reduced transfusion requirements as well as thromboembolic events. In this study we evaluated the change in hemolytic parameters and levels of ferritin parameters in PNH patients treated with eculizumab in two centers (Essen and Homburg/Saar).
METHODS: Nineteen PNH patients were treated with eculizumab as follows: 4 x 600mg IV every 7±2 days; 900 mg 7±2 days later; and then 900 mg every 14±2 days. The median therapy duration was 31 months (range 1–40 months). Hemolysis, transfusion requirements and serum iron parameters were analyzed over time of treatment.
RESULTS: Eculizumab effectively inhibited intravascular hemolysis in all PNH patients as evidenced by an 79% decrease in LDH levels (mean±SD: 2,110±802 to 349±182 U/l (normal range: 100–247); p=0.0001) and reduced transfusion requirements. Persistent elevation of reticulocytes as well as the reduction of haptoglobin and hemopexin were observed in most patients, which suggest continuing extravascular hemolysis. Interestingly, we observed an 709% increase in ferritin levels in patients treated with eculizumab (median from 73 to 965 μg/l (normal range: 20–290 μg/L); p=0.001). This was more pronounced in patients still requiring some transfusions. Three patients were started on oral iron depletion therapy. No thromboembolic or serious adverse events were observed in eculizumab-treated patients. Two PNH patients were diagnosed with PNH-associated hematological disease (MDS, myelofibrosis).
SUMMARY/CONCLUSIONS: Eculizumab is safe and well tolerated in the analyzed cohort of PNH patients. Iron parameters in PNH patients treated with eculizumab should be monitored to determine if iron supplementation should be altered or iron depletion therapy should be considered. While some extravascular hemolysis may persist, intravascular hemolysis is effectively controlled with eculizumab and is associated with a concomitant improvement in anemia and quality of life.
Critical and Opposing Effects of T Cell-Derived TNFα and Interferon-γ on IL-17 Induction Assessed in Vitro and in Vivo Following Allogeneic Bone Marrow Transplantation
Authors: Li Minghui , Sun Kai , Hubbard Mark , Redelman Doug , Panoskaltsis-Mortari Angela , Nedospasov Sergei , Taub Dennis , Blazar Bruce , Welniak Lisbeth A. , Murphy William J. 
Published: October 2019

Abstract
IL-17-producing CD4 T cells (Th17) are a recently identified T helper subset that plays a role in mediating host defense to extracellular bacteria infections and is involved in the pathogenesis of many autoimmune diseases. In vitro induction of IL-17 in murine CD4+ T cells has been shown to be dependent on the presence of the proinflammatory cytokines TGF-β and IL-6 whereas IFNγ can suppress the development of Th17 cells. In the current study, we examined the roles of TNFα and IFNγ on IL-17 production by purified T cells in vitro and in vivo after allogeneic bone marrow transplantation (BMT). We present findings that expression of TNFα by the T cell itself is necessary for optimal development of Th17 under in vitro polarizing conditions. A novel role for T cell-derived TNFα in Th17 induction was observed when in vitro polarization of Tnf−/−CD4+ T cells resulted in marked reductions in IL-17+CD4+ T cells compared to Tnf+/+CD4+ T cells. In marked contrast, T cell-derived IFNγ markedly inhibited Th17 development as more IL-17+CD4+ T cells were found in Ifnγ−/−CD4+ T cells than in Ifnγ+/+CD4+ T cells, and of particular interest was the dramatic increase in IL-17+CD8+ cells from Ifnγ−/− mice. To determine if T cell-derived TNFα or IFNγ can regulate Th17 development in vivo we examined the differentiation of alloreactive donor T cells following allogeneic BMT. We have found that donor-derived Th17 cells can be found in lymphoid tissues and GVHD-affected organs after allogeneic BMT. However, transfer of Tnf−/− CD4+ T cells after allogeneic BMT resulted in marked reductions in Th17 cells in the spleen (18×103 vs 7×103, P<0.05). In agreement with the in vitro data and in contrast to what was observed with transfer of Tnf−/− CD4+ T cells, transfer of donor Ifnγ−/− T cells resulted in marked increases in not only IL-17+CD4+ but also IL-17+CD8+ T cells infiltrating the liver (7×103 vs 14×103, P<0.05; 4×104 vs 12.5×104, P<0.05). These results suggest that the donor T cell-derived TNFα and IFNγ opposingly regulate IL-17 induction of both CD4+ and CD8+ T cells in vitro and after allogeneic BMT which correlates with GVHD pathology.