bluuebunny/crossref_metadata_2025 huggingface dataset:
Clinical Features and Morbidities of Hb H Disease in Taiwan
Authors: Lu Meng Yao , Kuo Ming Chung , Wang Shih Chung , Chen Shih Hsiang , Ko Bor Sheng , Chang Cheng-Shyong , Tang Jih-Luh
Published: October 2019

Introduction Patients with non-transfusion-dependent thalassemia experience a wide array of clinical complications despite their independence from frequent, regular red blood cell transfusions. They have the higher incidence of osteoporosis, extramedullary hematopoeisis (EMH), hypogonadism, cholelithiasis, thromboembolic disease, pulmonary hypertension, silent cerebral ischemia, and leg ulcers. Thalassemia is highly prevalent in Taiwan and Hb H disease is predominant. But limited data are available about clinical features and morbidities. Here, we studied clinical features and morbidities in Taiwanese patients with Hb H disease.

Methods & Results We collected 90 patients with Hb H disease in three hospitals since 2014 Nov till 2016 July. Male to female were 43/59. The mean age was 33.1 years ( from 0.5 to 92.3 years). Two cases died of pulmonary hypertension and old age at 31 years old and 87 years old. Alfa-globin gene genotype studies were done in 44 cases. The (- -(SEA)) type of α(0)-thalassemia mutation was detected in all patients. Twenty- four (57.1%) cases were deletional (α(3.7)/ α(4.2)/unknown 19/4/1) and 20 (42.9%) were nondeletional (CS/RS 18/2) type. The mean of Hemoglobin (Hb) and serum ferritin level were 8.7 g/dL and 730 ng/mL. We also revealed the positive correlation between age and serum ferritin level. The liver iron concentration (LIC) were 6.694 mg Fe/g dw (n=35). The Hb, ferritin and LIC level were not different between deletional and non- deletional groups. They received the transfusion management : 1 with regular transfusion ≦ 6 weeks interval, 5 with irregular transfusion ≧ 6 weeks interval, 27 with occasional transfusion and 57 without transfusion. Fifteen cases received splenectomy. There were significantly higher prevalence for transfusion frequency and splenectomy in non-deletional group. The prevalence of morbidities were 16/79 for cholelithiasis, 12/90 for thromboembolic event, 4/90 for heart failure symptoms ( 2 for pulmonary hypertension), 5/90 for arrhythmia, 3/90 for bone fracture, 5/20 for osteoporosis and 0 for renal stone. There were non-significantly higher prevalence for morbidities in non-deletional group.

Discussion & Conclusion The study provides the clinical features and the prevalence of morbidities in Hb H disease in Taiwan. Surprisingly, the prevalence of thromboembolic event and pulmonary hypertension are overlooked in our routine Hb H disease care. We need to schedule close and careful clinical follow up of Hb H patients as they get older, they get some morbidities or they are non-deletional genotype.

Disclosures

No relevant conflicts of interest to declare.
Use of the Platelet Indices for Differential Diagnosis of Pediatric Immune Thrombocytopenic Purpura ( ITP )
Authors: Nakadate Hisaya , Ishiguro Akira , Matsumoto Kimikazu
Published: October 2019

Introduction

The prognosis of pediatric immune thrombocytopenic purpura (ITP) has a favorable prognosis, but it is difficult to predict the course of this disease at the time of diagnosis. Recent advances of automated blood cell analyzer enable to measure platelet indices such as mean platelet volume (MPV), platelet size deviation width (PDW) and platelet-large cell ratio (P-LCR). These have brought about some information for thrombocytopenia. We studied the significance of such platelet indices in the differential diagnosis of immune thrombocytopenic purpura (ITP) and their ability to discriminate the clinical courses of ITP.

Methods

Ninety-three patients were enrolled this study at our institution from 2004 to 2006. Their ages ranged from 1 to 17 years (media 4.3 years). Of 93, patients were divided into two goups for analysis, according to the diagnosis of ITP. 34 were diagnosed as ITP and 59 were diagnosed various blood diseases other than ITP. In these 59 non-ITP patients, five were with thrombocytopenia (platelet count < 100.0 x 109/L), the other without thrombocytopenia. Of 34 ITP patients, 29 were acute subtype and 5 were chronic. The Sysmex-XE2100 automated blood cell analyzer (Sysmex, Kobe, Japan) was used to measure the blood parameters, including the platelet indices.

Results

According to MPV, PDW and P-LCR, there were no significant differences between ITP patients and non-ITP. In children with ITP, there were significant inverse correlations between the platelet count and evaluated parameters, MPV (R2=0.376), PDW (R2=0.26) and P-LCR(R2=0.338). But no significant correlations were found between the platelet count and these evaluated platelet indices in non-ITP. Also, we have found all platelet indices were significantly higher in chronic ITP than in acute ITP. In particular, PDW (9.910 vs 13.080) and P-LCR (21.071 vs 33.220) showed marked differences between the two groups.

Conclusions

ITP is considered as a result of hyper-destruction of platelets. Increase of platelet count is regarded as decrease of destruction of platelets. Our data suggested that platelet indices, MPV, PDW and P-LCR showed the useful information for the degree of platelet destruction and the ability to predict the clinical courses of ITP.

Disclosures

No relevant conflicts of interest to declare.
Primary Thrombophilia in Mexico XII: Miscarriages Are More Frequent in Persons with the Sticky Platelet Syndrome (SPS)
Authors: Ruiz-Delgado Guillermo J , Cantero-Fortiz Yahveth , Méndez-Huerta Mariana , León-González Mónica , León-Peña Andrés A. , Nuñez-Cortés Ana Karen , Ruiz-Arguelles Guillermo J.
Published: October 2019

Background: The sticky platelet syndrome (SPS) is an inherited condition which leads into arterial and venous thrombosis. There is scant information about the association between the SPS and obstetric complications.

Objective: To assess the relationship of the SPS and fetal loss in a single institution.

Material and methods: The obstetric history of all the consecutive female patients prospectively studied along a 324 month period, in a single institution with a history of thrombosis and a clinical marker of primary thrombophilia was reviewed.

Results: Between 1989 and 2016, 268 consecutive patients with a clinical marker of primary thrombophilia and a history of arterial or venous thrombosis were studied; of these, 108 were female patients. Within this subset, 77 (71%) had been pregnant at some moment. Twenty eight of these 77 patients (37%) had had an abortion and 24 out of these (86%) were found to have the SPS. On the other hand, in a subset of 73 female patients with the SPS who had been pregnant, 32% had miscarriages (14 had one abortion, 5 two abortions and 4 three or more abortions). These figures are significantly higher than the prevalence of abortions in the Mexican general population of pregnant women, which is 12-13% (chi square = 7.47; p = 0.0063). Accordingly, the relative risk of having a miscarriage is 2.66 times higher in female patients with the SPS than in the general population (p = 0.0014 ).

Conclusion: In México, female patients with the SPS experience significantly more miscarriages than the general population. Since the treatment of the SPS is simple and effective and could in turn prevent adverse obstetric outcomes, its investigation in women studied because obstetric complications may be useful and deserves further research.

Disclosures

No relevant conflicts of interest to declare.
Therapeutic Plasma Exchange for Thrombotic Microangiopathy
Authors: Ilhan Osman , Atilla Erden , Ataca Atilla Pinar , Civriz Bozdag Sinem , Kurt Yuksel Meltem , Toprak Selami Kocak , Topcuoglu Pervin , Akan Hamdi , Demirer Taner , Beksac Meral , Arslan Onder , Ozcan Muhit , Gurman Gunhan
Published: October 2019

Background: Thrombotic microangiopathy (TMA) is a syndrome characterized by thrombocytopenia, microangiopathic hemolytic anemia, neurologic abnormalities, fever and renal dysfunction. Therapeutic Plasma Exchange (TPE) is a standart treatment approach for the patients. Our aim is to determine the clinical characteristics and outcome of patients with TMA treated with TPE in our center.

Patients and Methods: We retrospectively evaluated 46 patients who have been diagnosed as TMA at Ankara University Department of Hematology between 2007 and 2015. Patients were treated with TPE (Frensenius Kabi AG, Homburg, Germany) until the normalization of laboratory parameters. The plasma exchanged was 1.5 times the predicted plasma volume with fresh frozen plasma for the first procedure, and usually 1.0 time the predicted volume thereafter until remission.

Results: 22M/24F was included in the study with a median age of 55 (range, 18-8310 of 46 patients (22%) were consultated from intensive care units, 7/46 (15%) from emergency unit and 6/46 (13%) from nephrology unit. The most common presenting symptom was purpura in 52%, followed by neurological disturbance 48%, renal function abnormality in 43% and fever in 28% of patients. At diagnosis the median hemoglobin (g/dl), leucocyte count (10^9/L) and thrombocyte count (10^9/L) were as follows: 9.4, 11.4 and 58.6. Median time period of procedure was 99 minutes (range, 64-313). 5/46 (11%) patients had femoral catheters and central venous catheters were the access for the rest of patients. None of the patients had severe adverse events during procedures. 21 patients achieved complete response (46%) after 2-40 sessions and 2 of them were died during follow-up. Responders were diagnosed mostly with infectious related TMA. 21 patients (46%) who had progressive disease died within 30 days after diagnosis. 2 non-responder patients had diagnosis of TTP and treated with succesfully with Rituximab (Table 1).

Conclusions: TPE is safe treatement modality in patients with TMA however there is still high mortality rate.

Disclosures

No relevant conflicts of interest to declare.
Treatment with Plasma Exchange Followed By Plasma Infusion for Thrombotic Thrombocytopenic Purpura Associated with SjöGren's Syndrome
Authors: Sun Xingfu , Lu Hua
Published: October 2019

Abstract: Thrombotic thrombocytopenic purpura (TTP) is rarely associated with Sjögren's syndrome (SS) with only 12 previously reported cases in the literature. All of them were women. A case of a previously healthy 64-year-old Chinese male presenting with microangiopathic hemolytic anemia, otherwise unexplained thrombocytopenia, and central nervous system involvement is reported. At the beginning the patient's family refused plasma exchange (PE) therapy due to cost consideration, later plasma infusion (PI) was initiated along with methylprednisolone pulse therapy. Significant clinical and laboratory response was achieved. However, recurrence happened after discontinuing the treatment for only three weeks without consulting his doctor. Then the patient received another two cycles of therapy of PE with again an excellent clinical and laboratory response. The patient was discharged in a state of remission on methylprednisolone and thymopolypeptides. In order to prevent further complications, prophylactic infusions of plasma was performed per month. The patient remained asymptomatic thereafter. Autoimmune workup revealed positive antinuclear antibodies and Anti-SSA. Lip biopsy revealed findings consistent with SS. TTP with SS tends to be recurrence. PE along with immunosuppressive therapy followed by prophylactic PI can prevent long-term organ complications in these cases.

Disclosures

No relevant conflicts of interest to declare.
Highly Procoagulant Extracellular Vesicles in Amniotic Fluid
Authors: Thaler Johannes , Hell Lena , Wisgrill Lukas , Spittler Andreas , Schwameis Michael , Jilma Bernd , Altevogt Peter , Ay Cihan , Pabinger Ingrid
Published: October 2019

Background: The pathomechanisms underlying disseminated intravascular coagulation (DIC) following amniotic fluid (AF) embolism remain to be fully elucidated. Highly procoagulant phosphatidylserine (PS)- and tissue factor (TF) expressing extracellular vesicles (EVs) might play a central role.

Objective: To perform extensive analyses of the procoagulant properties of AF with a panel of functional coagulation assays and flow cytometry to investigate the pathogenesis of AF induced DIC.

Methods: A prothrombinase assay, an EV-TF dependent factor Xa (FXa) generation assay, a modified thrombin- and fibrin-generation assay, a whole blood clotting model and flow cytometry were applied in AF- and control plasma.

Results: Phosphatidylserine expression was 21-fold increased in AF compared to plasma. Factor Xa generation was extremely high when TF-expressing EVs from AF were co-incubated with recombinant FVIIa. In the thrombin- and fibrin generation assay AF-derived EVs strongly activated the blood coagulation cascade via PS and TF. In a whole blood clotting model AF-derived TF-expressing EVs significantly shortened the clotting time from 734 ± 139 seconds in the presence- to 232 ± 139 seconds in the absence of an anti-TF antibody. The contact activation pathway via factor FXII was not affected. Applying flow cytometry, a sub-population of PS- and TF co-expressing EVs was clearly identified in AF.

Conclusions: We thoroughly investigated the effect of AF on blood coagulation and found that PS+ and TF+ EVs determine its procoagulant potential. Taken together our data further delineate the pathomechanisms underlying AF-induced coagulopathy, which could improve diagnostic- and treatment modalities.

Disclosures

No relevant conflicts of interest to declare.
Real World Data Analysis of Coagulation Factor IX Costs in Specific Patients with Hemophilia B Switching from Standard Half-Life to Extended Half-Life Products
Authors: Tortella Bartholomew J. , Fogarty Patrick F. , Alvir José , McDonald Margaret , Spurden Dean , Pleil Andreas M.
Published: October 2019

Introduction: Hemophilia B, an X-linked genetic disease characterized by low clotting factor IX (FIX) levels, leads to spontaneous and traumatic bleeding in affected individuals. Intravenous FIX replenishment is administered to maintain adequate levels. The recent introduction of an extended half-life (EHL) FIX replacement product provided the opportunity to compare costs of care associated with treatment with an EHL product versus a standard half-life (SHL) product.

Methods: The Truven Marketscan US claims database (Oct 2010 - Apr 2016) was used to identify factor concentrate charges for patients who had claims data for at least 3 months prior to and after switching from SHL to EHL products. Additionally, available data for up to 12 months pre- and post-switch on these identified patients were analyzed.

Results: Thirteen patients, ranging from 3-64 years of age (median 18) were included in the analyses. Factor concentrate costs were higher after switch from SHL to EHL in each of the time periods examined (Table). Median costs were used since they were less influenced by isolated outliers and were similar to means in most cases. The median costs were 238% higher in the 3 months just after switching to the EHL product compared to the 3 months just prior to switching from the SHL product. Median costs were $51,881, $79,654, $75,695 and $61,515 in the 12-10, 9-7, 6-4 and 3-1 months prior to switch respectively compared to $173,515, $147,061, $149,971 and $207,973 in the corresponding quarterly month intervals post switch.

Conclusion: This analysis of real world administrative data following individual patients through the switch from SHL to EHL products continuum suggests that switching from an SHL to an EHL product is associated with increased median factor costs throughout the 12 months following the switch, and that further analysis with larger numbers of patients should be explored.

Disclosures

Tortella: Pfizer Inc: Employment. Fogarty:Pfizer Inc: Employment. Alvir:Pfizer Inc: Employment. McDonald:Pfizer Inc: Employment. Spurden:Pfizer Inc: Employment. Pleil:Pfizer Inc: Employment.
Defining Haemostatic Safety Zones for the Practice of Sport in Patients with Severe Haemophilia By Thromboelastography
Authors: Fernandez-Bello Ihosvany , Alvarez-Román MT , de la Corte-Rodríguez H , Butta N , Hernández-Moreno AL , Rivas Muñoz S , Martín-Salces M , Rodriguez-Merchan EC , Canales Albendea Miguel , Jiménez-Yuste V
Published: October 2019

Introduction: Sport may comprise variable physical activity associated bleeding risk(BRisk) in haemophilia. We aimed to determine value of global thromboelastography (TEG) profile for tailoring prophylaxis in patients younger than 18 years old (YO) with severe haemophilia A (SHA) subjected to activities with different BRisk.

Methods: Patients with SHA, younger than 18 YO and on prophylaxis at least 12 months before inclusion were invited to participate. Patients signed informed consent before inclusion. Samples before prophylactic dosing were collected. Factor VIII (FVIII) and kaolin-activated TEG profile were determined. Physical activity (PhA) and annual joint bleeding rate (AJBR) were recorded retrospectively. BRisk was categorized following the US-National Haemophilia Foundation guidelines (1= safe; 1.5= safe-moderate risk; 2= moderate risk; 2.5= moderate-dangerous risk; 3= dangerous risk of bleeding).

Results: 26 patients, median age (min-max) 10.3 (6.8-14.3) YO were included. Sixty one percent of patients had BRisk= 1.0; 7.7% had BRisk= 2.0 and 2.5; 23,1% had BRisk= 3. In the last 12 months, haemarthrosis were presented in 33% of patients with BRisk=3.0 and 13% in those with BRisk= 1.0. Interesting, patients with BRisk= 2.0 or 2.5 did not present any joint bleeding in the previous year. Median levels of FVIII was 0.5 (0.0-1.9) IU/dl. There were no differences on trough FVIII levels between patients with or without joint bleeds (FVIII= 0.3 [0.0-1.9] and 1.1[0.2-4.4] IU/dl respectively, p=0.515) in the year before. There was no correlation between FVIII trough plasma levels and the AJBR (p=0.416). TEG trough profiles were similar in patients with and without haemarthrosis. However, patients with AJBR=0 presented a clear correlation between trough TEG parameters and BRisk (BRisk vs. k: r=-0,439; p= 0.047 and BRisk vs. alpha angle: r= 0.478; p= 0.025) so that, the higher the exercise-associated BRisk the higher procoagulant state needed to keep a joint-bleeding-free state. This correlation was not found for FVIII.

Conclusions: Kaolin-activated TEG assay may help to define safety zones to minimize bleedings in response to PhA in patients < 18 YO with SHA and may guide prophylaxis tailoring depending on BRisk of PhA.

Disclosures

No relevant conflicts of interest to declare.
Patern of Acquired Hemophilia in Saudi Arabia
Authors: Al-Momen Abdul Kareem M , Owaidah Tarek M , Sayed Zaidi Z , Ahmed Mady F , Amr Hanbali , Saud Balelah , Shahid Iqbal , Imran Tailor , Rehman Zaidi
Published: October 2019

Background: Acquired Hemophilia (AH) is a rare bleeding disorder that develops secondary to an autoantibody against Factor VIII in persons who are not known to have any previous bleeding disorder. Aim: The aimof this retrospective case review is to explore the pattern of confirmed cases of AH that were managed in Saudi Arabia over a 5 years' period.

Patients and Methods: We reviewed the charts of documented cases of AH that were managed in 5 Tertiary Hospitals (4 in Riyadh and 1 in Al Madinah Al Monawarah) from 2010 to 2014. All cases underwent medical history, physical examination, laboratory tests including complete blood count, activated partial thromboplastin time (PTT), mixing studies, factor VIII level, and Factor VIII Inhibitor titer. All patients received standard treatment.

Results: We found 19 cases, but we could obtain data only for 13 cases, 4 males and 9 females, median age was 30 years (range 20-85). Risk factors were pregnancy in 5, Autoimmune disease in 2, Cancer in 1, Clopedogril in 1 and 4 were idiopathic. All cases presented with various degrees of bruises. in addition, 4 cases presented with menorrhagia, 4 cases with soft tissue hematomas, and 2 cases with gross hematuria. All cases had prolonged aPTT, which was only partially corrected with mixing studies, very low factor VIII level (median 1, range <1-12.5%), and high factor VIII inhibitor titer (median 22.4 BU, range 3.5-1932). Treatment included steroids, cyclophosphamide, immunoglobulins and Rituximab. There were 9 remissions (with 2 relapses, which responded to treatment), 2 partial responses, and 2 deaths due to massive blood loss (Hematuria).

Discussion: Our case series indicates only severe AH, because many milder cases are underdiagnosed or misdiagnosed. Although the number of our cases are small, they indicate a different pattern from the published studies, because of younger age group and female predominance.

Conclusion: Our case series indicates that most of our cases are young adults, with female predominance. A comprehensive review of cases from other hospitals is underway

Disclosures

No relevant conflicts of interest to declare.
Characterization of Two Cases of Congenital Thrombotic Thrombocytopenic Purpura (TTP)
Authors: Bai Xia , Su JIan , Cao Lijuan , Ruan Changgeng
Published: October 2019

Introduction: Congenital thrombotic thrombocytopenic purpura (TTP) is characterized by disseminated thrombus due to the mutations of ADAMTS13, which cleaves its substrate von Willebrand factor(VWF) in shear-induced unfolding condition. Most of the congenital TTP we found is woman with pregnancy. Here, we characterize two children suspected with congenital TTP.

Methods:ADAMTS13 activities were analyzed by residual collagen binding assay (R-CBA) plus FRET-VWF substrate. And the inhibitors of ADAMTS13 were analyzed by 9:1 mixture of patient and pooled normal plasma followed by R-CBA. The secretion of recombinant ADAMTS13 mutants was studied.

Results: Two children, one aged four months and the other aged three years old, were diagnosed with congenital TTP because their ADAMTS13 activities were less than 5% (both FRET-VWF and R-CBA), and there are short of ADAMTS13 inhibitors. The following mutations were found: Q1385P, Y177C, C522R. In addition to the previously reported mutation of Y177C, the two novel mutations (Q1385P and C522R) failed to secrete from the HEK293 cells.

Conclusion: Two children with congenital TTP were determined thanks to screening of ADAMTS13 activity and its corresponding inhibitor assays, and it seems that congenital TTP could occur in different ages although most of congenital TTP we found were women with pregnancy.

Disclosures

No relevant conflicts of interest to declare.
Safety and Feasibility of Treatment with Rivaroxaban in Children for Non-Routine Indications: A Case Series Analysis
Authors: Dickerson Kathryn E. , Sarode Ravi , Zia Ayesha
Published: October 2019

Background. Anticoagulation therapy is the cornerstone of acute treatment of venous thromboembolism (VTE) and for prevention of recurrent VTE. The need for anticoagulation is increasing in children, largely in part due to increasing VTE rates. Conventional anticoagulants, including heparin, low-molecular weight heparins (LMWH), Fondaparinux, and vitamin K antagonists (VKA) are widely used in children but have limitations. Standard of care management with these agents is plagued with the trade-off between daily or twice daily injections or frequent monitoring of therapeutic effect. The advent of direct oral anticoagulants (DOACs) have catalyzed significant changes in the therapeutic landscape of VTE management. DOACs have been evaluated for safety and efficacy in large, randomized controlled trials in the treatment and prevention of VTE in adults, with results that are comparable to conventional therapy. None of the current DOACs have FDA-approved indications and dosing in children yet. Off-label use of these agents is largely based on adult data and doses, and is increasing at many Children's Hospitals across US. Rivaroxaban, a DOAC, is a factor Xa inhibitor with predictable pharmacokinetic and pharmacodynamics properties.

Methods. We describe a case series of 8 unique pediatric cases, treated with Rivaroxaban, for a variety of non-routine indications, due either to adverse effects, intolerability of LMWH or VKA or the need for ongoing, long term anticoagulation. Rivaroxaban was started after informed consent and assent from parents or patients respectively, and was initiated at a fixed dose but titrated to a final dose after monitoring of trough and peak Rivaroxaban levels (Aniara, West Chester,OH, USA).

Results. The mean age of patients in this case series is 14 years (median: 16, range 3-17) (see Table). The most common indication to use Rivaroxaban was the need for long term anticoagulation after having completed therapeutic anticoagulation, except in two patients, one of whom developed warfarin skin necrosis due to protein C deficiency and another with heparin induced thrombocytopenia. Only two patients needed dose adjustments to achieve target trough and peak drug levels. The mean duration of follow-up is 9 months (median= 5.5; range 3-24) (see Table) at this time. None of the patients developed recurrent VTE while on Rivaroxaban. A soft tissue traumatic bleed occurred in one patient which was treated with holding off the drug for 48 hours. No other bleeding complications were observed.

Conclusions. Clinical application of DOACs in a real world clinical setting, including strong thrombophilia and malignancy, results in treatment profile of high efficacy and safety in children; however, larger studies are needed to validate these findings.

Disclosures

Sarode: CSL Behring: Consultancy, Honoraria.
A Spin-Off in Non Valvular Atrial Fibrilation (NVAF) and Cancer : Doacs As a Safe and Effective Alternative to the Convencional Avks
Authors: Johansson Erik , Olivera Pável , Canals Tania , Bosch Francesc , Pons Verónica , Santamaría Amparo , Cortina Vicente
Published: October 2019

Introduction:

The anticoagulation is common in patients with cancer such as treatment or prevention of venous thromboembolic events (VTE) or atrial fibrillation (AF). The evidence for the effectiveness and safety of the direct oral anticoagulants (DOACs) in those clinical setting are sparse, even more in AF patients.

Aim: to analyze the effectiveness and safety of the DOACs, and other clinical aspects of patients with active cancer in the treatment of atrial fibrillation in daily clinical practice.

Methods:

Between Nov 2011 and May 2016 we had included consecutively adult patients with AF who initiated DOACs treatment. We selected patients with active cancer. Follow-up (FU) was an outpatient visits each 3 months and thereafter effectiveness, safety and other related to treatment data were collected. All bleeds were classified using the ISTH criteria.

Results:

900 patients were included in our register where 6.1% (n=55) had an active cancer. Median age was 78 years (range 57-91) and 45.5% were women and 55.5% men. The median of creatinina clearance 59 ml/min (range 30-101). The distribution for treatment groups was: dabigatran 16.4% (n=9) with 24 months or days FU, rivaroxaban 50% (n=28) with 8 months and apixaban 32.7%(n=18) with 4 months. Ischemic strokes occurred in 16.4% of the patients with cancer (n=9).During FU, 10 patients presented bleeding complications (7.3 % minor,7.3% non-major clinically relevant and 3.6 % major bleeding according to ISTH definition).The mucocutaneous bleeding was the most common site of bleeding (30% of total bleeding) in the 5.5% drugs. In the clinical FU we observed 2 deaths, related to progression of the underlying disease. The DOACs discontinuation occurred in 16.4% (n=9) due to presence of bleeding events, hematological toxicity in chemotherapy; and worsening functio renal. The DOAC treatment was maintained concomitant with antineoplastic therapy in 83.6% (n=46) without associated complications.

Conclusion:

DOACs in active cancer-patients patients showed a good effectiveness and safety and they can be a great option in the treatment of NVAF, especially in those cases with unestable INR ranges.. There is an urgent need for more clinical studies in cancer patients treated with DOACs that can be candidates to these, in terms to offer them a better therapeutic options.

Disclosures

Bosch: Roche: Consultancy, Honoraria, Research Funding; Gilead Sciences: Membership on an entity's Board of Directors or advisory committees.
Decrease of Aggregation By Platelet Impedance Aggregometry ( MULTIPLATE ) in Patients Treated with Dabigatran
Authors: Cabañas Valentin , Cerezo-Manchado Juan Jose , Garcia-Candel Faustino , Salido Eduardo , Lopez-Perez Raul , Garcia-Hernandez Ana , Berenguer Merecedes , Labbadia Francesca , Blanquer Blanquer Miguel , Moraleda Jose Maria
Published: October 2019

Introduction: Dabigatran is a direct oral anticoagulant (DOAC) that has been proved effective and safe in preventing thromboembolic events experienced by patients with non-valvular atrial fibrillation (AF). This drug acts directly inhibiting thrombin and particularly affects the intrinsic and the final coagulation pathways. Thrombin is a platelet agonist therefore dabigatran could be involved in altering the aggregation. However, it is not well known whether they modify the platelet function. We conducted an initial study in our hospital to assess platelet aggregation in patients treated with dabigatran.

Methods: An observational study was conducted in 17 randomly selected patients who had started dabigatran in the last year in our center. The results were compared with 8 healthy platelet donors randomly selected from our database. Platelet aggregation was quantified in patients and controls using MEA (Multiplate, Roche Diagnostics, Switzerland). The indication and dosing of dabigatran was performed as clinically indicated. The main variables investigated were: aggregation time with four agonists: thrombin, ADP, collagen, ristocetin, APTT, INR addition, D Dimer, kidney and liver function and the usual demographic parameters. Statistical analysis were performed using SPSS 21.0 (SPSS Inc., Chicago, IL).

Results: All patients had AF as an indication for treatment with dabigatran. Dabigatran doses were 110 mg in 7 patients (41%) and 150 mg in 10 patients (58%). No patient was on any antiplatelet agent. Platelet aggregation induced by TRAP measured by MEA was not significantly different in patients compared to controls: 121 RI (94-127) vs. RI 122 (108-137) units (p = 0.711). Aggregation using collagen and ristocetin as agonists was significantly decreased compared to that of controls: RI 48 (32-63) vs. 83 RI (69-110) (p = 0.05) and 76 RI (71-32) vs. 120 RI (97-142) units (p <0.01). There were no differences in the aggregation depending on the dose of dabigatran. Conclusion: Despite the limitations of the study we observed a change in the aggregation of patients treated with dabigatran measured by MEA, compared with healthy controls. Contrary to what one might expect, it was not dependent on the thrombin pathway unless the ristocetin and collagen agonists. These findings must be confirmed in more powerful studies designed for this purpose because others studies, with the same characteristics than our work, have shown TRAP-induced platelet aggregation enhance in patients treated with dabigatran.1

1 TRAP-induced platelet aggregation is enhanced in cardiovascular patients receiving dabigatran. Christoph B. Olivier et al. Thrombosis Research Thromb Res. 2016 Feb;138:63-8

Disclosures

Blanquer Blanquer: Pfizer: Research Funding.
Blood Donation May Not Reduce Risk of Testosterone-Induced Polycythemia
Authors: Chin-Yee Benjamin Hull , Lazo-Langner Alejandro , Foster Terrie , Hsia Cyrus C. , Chin-Yee Ian
Published: October 2019

Background:Polycythemia is the most common adverse effect of testosterone replacement therapy (TRT) and may predispose patients to adverse vascular events. Current Canadian guidelines recommend regular laboratory monitoring and discontinuing TRT or reducing the dose if the hematocrit exceeds 54% (hemoglobin ≥180 g/L). This threshold has been interpreted by some physicians and patients to indicate the need for phlebotomy or blood donation while on TRT.

Study Design and Methods: We reviewed all male blood donors in Southwestern Ontario at Canadian Blood Services from December 2013 to March 2016 who self-identified or were found on donor screening to be using TRT in any form. Hemoglobin concentration was measured at the time of donation or clinic visit and with each subsequent appointment in repeat donors.

Results:We report a case series of 39 patients on TRT who presented for blood donation over a two-year period. The mean hemoglobin at all donor clinic visits was 173 g/L (range 134-205 g/L, n = 108). Hemoglobin concentrations of ≥180 g/L (calculated hematocrit ≥54%) were measured at 25% of appointments. Of the 27 repeat donors, 12 (44%) had persistently elevated hemoglobin levels (≥180 g/L) at subsequent donations.

Conclusions: Hemoglobin concentrations were elevated in blood donors on TRT, with a significant number above levels recommended by current guidelines. These data also suggest that repeat blood donation was insufficient to maintain hematocrit below 54%. Our findings raise concerns about persistent risk of vascular events in these donors, particularly when coupled with the misperception by patients and health care providers that donation has abrogated the risks of TRT-induced polycythemia.

Disclosures

No relevant conflicts of interest to declare.
Audit of Red Cell Transfusions in the Neonatal Intensive Care Unit, Rotunda Hospital 2011-2015
Authors: Enright Siobhan , Ní Áinle Fionnuala , Foran Adrienne
Published: October 2019

Introduction/Background

Neonates are an intensively transfused group of vulnerable patients. Neonatal transfusion practice and general care has evolved over recent years, including the introduction of pedi-packs to limit donor exposure, and it remains important to audit practice. Inappropriate transfusions expose babies to potential adverse effects of transfusion. A national audit performed in the UK in 2010 concluded that there is a lack of evidence to back many of the existing recommendations for neonatal transfusion.

We undertook a prospective audit in order to review 5 years of transfusion practice in a tertiary NICU. Our current neonatal transfusion guidelines are based upon internationally published guidelines.

Aims & Objectives:

To determine the number of babies transfused, whether transfusions were adherent to local guidelines, to identify areas requiring improvement and to determine whether continuous auditing and feedback to clinicians improves practice

Methodology/Interventions This was a prospective audit conducted over a 5 year period. Data were prospectively and retrospectively retrieved from patient charts and electronic databases. Data were stored in a password-protected excel spreadsheet created on a secure hospital network.

Results and Discussion A total of 557 babies were transfused with red cells during the period 2011 -2015, representing 7-12% of babies admitted to NICU. The median number of transfusions decreased in babies of all birth weight categories between 2011-2015. The biggest change was in babies <750g, where median donor exposure was reduced from 2 to 1 during this time. The overall percentage of babies admitted to NICU requiring a blood transfusion reduced from 12% to 7%. The most significant reduction was seen in babies ≥1500g with a reduction from 4% in 2011 to 2% in 2015.

Conclusions Auditing of neonatal transfusion especially in the area of pedi-pack top up transfusions highlighted specific areas where improvements could be made. This includes adherence to guidelines, consultant-led decision to transfuse (when time permits), and on-going audit and feedback to clinicians. These measures along with a multi-disciplinary approach to blood management have seen an overall reduction in percentage of babies being transfused without compromising the well-being of the baby. This has led to a reduction of donor exposure to the baby and a reduction in the cost and workload across all disciplines of staff associated with blood transfusion leading to an overall improvement to patient safety and quality of care. Despite this, the transfusion rate in babies of < 1000g remains the highest however this would be expected given the overall clinical needs of babies in this birth weight category.

Figure 1 Figure 1. Figure 2 Figure 2.

Disclosures

Ní Áinle: Actelion UK: Research Funding.
Suppression of Mir-708 Promotes DKK3 to Inhibit Wnt/β-Catenin Signaling Pathway in Adult B-ALL
Authors: Zhang Yingjie , Li Huibo , Cao Rongyi , Sun Lili , Wang Yan , Fan Shengjin , Zhao Yanqiu , Kong Desheng , Cui Lin , Lin Leilei , Wang Ke , Wang Chen , Li Yinghua , Zhou Jin
Published: October 2019

Dickkopf-3 (DKK-3) is a Wnt signaling antagonist, and DKK3 inactivation is associated with poor prognosis in various solid tumors and hematologic malignancies. Epigenetic hypermethylation has been implicated in downregulation of DKK3, but other regulatory mechanisms remain to be investigated. In this study, we examined DKK3 expression and the role of microRNA in the regulation of DKK3 in adult B-ALL. Our results showed low levels of DKK3 expression in Nalm-6 and BALL-1 cell lines, and leukemia cells from adult B-ALL patients. DKK3 expression was remarkably lower in the initial diagnosis and relapse samples than in the matched samples during remission. In addition to hypermethylation, low levels of DKK3 were associated with high expression of miR-708. This finding was similar to that in childhood ALL. The miR-708 was predicted to bind to the 3'-UTR of DKK3. By using miR-708 mimics, we found that miR-708 targets DKK3 to promote B-ALL cell proliferation through cell cycle promotion and apoptosis inhibition. The treatment with 5-aza-2'-deoxycytidine significantly increased DKK3 and decreased p-GSK3β, cyclin D1 and nuclear and cytoplasmic β-catenin protein expression. A synergistic effect was seen when the miR-708 inhibitor and 5-aza were used simultaneously. Although miR-708 was reported to either promote or suppress tumorigenecity in some solid tumors, our findings indicate that suppression of miR-708 increases DKK3 expression to inhibit the Wnt/β- catenin signaling pathway in B-ALL.

Disclosures

No relevant conflicts of interest to declare.
The Level of Histone Deacetylase 7 in Pediatric ALL and Its Effect on Survival
Authors: Hou Bei , Zheng Huyong
Published: October 2019

Background

Leukemia is the most common pediatric malignancy and a major cause of mortality and morbidity in children. Nearly 15,000 children are newly diagnosed with leukemia in China each year and among them, acute lymphoblastic leukemia (ALL) accounts for more than 75%. Altered expression of histone deacetylases (HDACs) is a common feature in several human malignancies and may represent an interesting target for cancer treatment . With increasing focus on precision medicine, HDACs have emerged as promising therapeutic target in pediatric ALL.

Methods

We detect the histone deacetylase 7(HDAC7) expression in the bone marrow samples of 254 children with newly diagnosed acute lymphoblastic leukemia (ALL) at Hematology Oncology Center of Beijing Children`s Hospital from January 2010 to the end of 2012 via qRT-PCR using the TaqMan gene expression probes. 3 patients that have been completely remission for 3 years are used as normal control. We find out that the expression levels of HDAC7 are associated with the unfavorable events (such as induction failure, relapse and/or death due to any cause ) occurence rates and 5-EFS.

Results

Here we find that the HDAC7 expression levels are associated with the unfavorable events occurence rates and 5-EFS. We find that in the intermediate risk group of 157 patients, the patients who have lower level of HDAC7 expression have higher unfavorable event occurence rates than the higher expression of HDAC7 group (p=0.001). The group of higher HDAC7 expression have higher 5-EFS than the lower group in both the intermediate risk group(p=0.001) and the T-ALL group(n=18).

Conclusion

We conclude that HDAC7 has a potent anti-oncogenic effect on specific pediatric B-cell leukemia, indicating that its deregulation may contribute to the pathogenesis of the disease.

Disclosures

No relevant conflicts of interest to declare.
Potent Anti-Leukemic Effects of Small Molecule ONC212, a Member of the Imipridone Class of Anti-Cancer Compounds
Authors: Prabhu Varun V , Tarapore Rohinton S , Garnett Mathew J , McDermott Ultan , Benes Cyril H , Wagner Jessica M , El-Deiry Wafik S. , Stogniew Martin , Oster Wolfgang , Allen Joshua E
Published: October 2019

ONC201, the founding member of the imipridone class of anti-cancer compounds, is a highly selective small molecule GPCR antagonist that is in Phase I/II advanced cancer clinical trials. In this study, we evaluated the anti-cancer effects of ONC212, an ONC201 analogue that possess the same unique core chemical structure shared by imipridones.

The in vitro efficacy of ONC212 was assessed in the Genomics of Drug Sensitivity in Cancer collection of cell lines (>1,000 cell lines). Cell viability assays were performed to generate dose responses curves at concentrations from 78nM upto 20uM and at 72 hours post-treatment. ONC212 was broadly efficacious across most solid tumors and hematological malignancies in the low nanomolar range. Ranking the ONC212 sensitivity dataset revealed that leukemia is the most responsive tumor type based on completeness of response (area under the dose-response curve, AUC).

ONC212 was tested in 65 leukemia cell lines in this study that is comprised of acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML) and hairy cell leukemia. ONC212 demonstrated broad spectrum anti-leukemic activity and was equally efficacious across all leukemia subtypes tested, in terms of AUC. Most cell lines (63/65) were responsive to ONC212 with GI50 ranging from <78nM to 312nM. Within ALL, both B-cell and T-cell ALL were highly sensitive to ONC212. ONC212 reduced cell viability in AML independent of complex karyotypes that are associated with poor clinical prognoses.

Thus, ONC212 possesses robust anti-leukemic activity irrespective of subtype and provides further validation of the anti-cancer efficacy of the novel imipridone class of small molecules.

Disclosures

Prabhu: Oncoceutics: Employment. Tarapore:Oncoceutics: Employment, Equity Ownership. El-Deiry:Oncoceutics: Equity Ownership. Stogniew:Oncoceutics Inc.: Employment, Equity Ownership. Oster:Oncoceutics: Employment, Equity Ownership. Allen:Oncoceutics: Employment, Equity Ownership.
The Role and Mechanism Study of Lncrnas Involved in Glucocorticoid Resistance in Paediatric Acute Lymphoblastic Leukemia
Authors: Xiaowen Zhai , Fan Cuiqing , Wang Hongsheng
Published: October 2019

Objective: Glucocorticoids (GCs) are key components in the treatment of childhood acute lymphoblastic leukemia (ALL) and most ALL therapeutic failures can be explained by cellular resistance to GCs. However, the mechanisms of GC resistance are poorly understood. LncRNAs are involved in normal hematopoiesis and leukemia development, whereas the roles of lncRNAs in GC resistance are still unknown. Our goal was to investigate the role of lncRNAs involved in glucocorticoid resistance in paediatric acute lymphoblastic leukemia, and also elucidate the mechanism preliminarily.

Methods: In this study, lncRNA microarray was performed on GC-resistant cell line CEM-C1 and GC-sensitive cell line CEM-C7 to screen the differential expression of lncRNAs. Five up-regulated and five down-regulated lncRNAs were randomly chosen for validation by Real-time PCR. GO-Pathway analysis was done to investigate potential signaling pathways regulated by the lncRNAs.

Results: The microarray revealed that 4286 lncRNAs differed (p<0.05 and fold change>2.0) in GC-sensitive cell from those in GC-resistant cell. 826 lncRNAs changed more than 5-fold, while 356 lncRNAs changed more than 10-fold. Among them, 203 lncRNAs were up-regulated and 153 lncRNAs were down-regulated. Expression of ten selected lncRNAs was validated by Real-time PCR. GO analysis indicated that differentially expressed lncRNAs were involved in apoptotic process related GO terms. Pathway analysis revealed that these lncRNAs were involved in apoptosis, cell cycle, mTOR and some other signaling pathways.

Conclusions: Our study showed that lncRNA expression profile was altered in GC-sensitive and GC-resistant cells, indicating that differentially expressed lncRNAs may play important functional roles in GC resistance of ALL. And these lncRNAs may be involved in GC resistance by regulating signaling pathways associated with cell proliferation, differentiation and apoptosis. Our study provides new biological foundations for further mechanism study in GC resistance and also provides a new strategy for therapeutic development of ALL.

Disclosures

No relevant conflicts of interest to declare.
Phase I Study of Combination Chemotherapy Plus Ixazomib in Adults with Relapsed or Refractory Acute Lymphoblastic Leukemia/Lymphoma (ALL)
Authors: Atallah Ehab , Michaelis Laura C , Carlson Karen B. , D'Souza Anita , Fenske Timothy S. , Pasquini Marcelo C. , Hamadani Mehdi , Baim Arielle , Guhl Jessica , Parameswaran Hari
Published: October 2019

Introduction: The outcome of adult patients with relapsed/refractory ALL remains dismal. In pediatric patients with relapsed/refractory ALL, the combination of vincristine, doxorubicin, pegaspargase, dexamethasone (VXLD) and bortezomib yielded significant response rates. Based on those results, this study was designed to test the safety of VXLD combined with the oral proteosome inhibitor Ixazomib in adult patients with relapsed/refractory ALL.

Study design: This was a phase I study combining vincristine 1.3 mg/m2 (maximum dose 2 mg) D1, 8, 15, and 22, doxorubicin 60 mg/m2 D1, PEGaspargase 2500 units/m2 (capped at 3750 mg) D2, D15, dexamethasone 10 mg/m2 D1-14, with escalating doses of ixazomib. Ixazomib dose was started at 2.3 mg D1, 8, and 15 aiming to increase the dose to 4 mg.

Results: Five patients were enrolled on the study between 10/1/13 and 2/26/16, prior to study termination. The median age was 49 years and 3 were female. Median number of prior regimens was 2 (range 2-3). At dose level one, 3 patients were enrolled. Of those patients, one developed grade 5 liver toxicity. That patient achieved complete remission, but died secondary to hyperbilirubinemia and liver failure. One patient developed grade 4 hyperbilirubinemia, did not respond to therapy and died from disease progression. The third patient developed transient grade 3 hyperbilirubinemia, had no response to treatment and went on to receive other therapies. Hepatic toxicities were attributed to pegaspargase. Based on that, the protocol was amended to remove pegaspargase (VXD + Ixazomib). Two patients were enrolled on dose level one (2.3 mg). One patient developed grade 5 infection. Due to increased toxicity in this population, the study was terminated.

Conclusion: In our experience, VXLD and VXD were poorly tolerated in adult patients with relapsed/refractory ALL. Ixazomib should be studied with other chemotherapy combinations in adults with relapsed/refractory ALL.

Table Table.

Disclosures

Atallah: Incyte: Consultancy; CTI biopharma: Consultancy; Novartis: Consultancy; BMS: Consultancy; Pfizer: Other: Grant review; Takeda: Research Funding; Ariad: Honoraria. Michaelis:Pfizer: Equity Ownership; Cellgene Corporation: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte Corporation: Consultancy, Honoraria. Hamadani:Takeda: Research Funding. Parameswaran:Takeda: Consultancy.