bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutation Analysis and Clinical Sprectrum Of Patients With Glanzmann’s Thrombasthenia and Bernard Soulier Syndrome
Authors: Tokgoz Huseyin , Caliskan Umran , Nejat Akar , Ak Erdem 
Published: October 2019

Introduction and Aim
Glanzmann’s thrombasthenia (GT) is an inherited disorder of platelet aggregation, resulting from defective glycoprotein IIb/IIIa on platelet surface. Bernard Soulier Syndrome (BSS) is also an inherited disorder of platelet adhesion and associated with defective glycoprotein Ib-V-IX on platelet surface. Both of these disorders usually present with mucocutaneous bleedings. We aimed to evaluate the clinical and genetic characteristics of the patients diagnosed as BSS and GT in department of pediatric hematology of Meram Faculty of Medicine, retrospectively.

Method
Seven patients diagnosed with BSS and 20 patients diagnosed with GT were enrolled to the study. Medical records of patients were reviewed retrospectively. Glycoprotein IIb gen rearrangement was investigated in genetic department of Ankara University Medical School, Turkey. Mutational analysis for BSS was performed in Medicina Interna ed Oncologia Medica, Italy. The correlation between clinical outcome and genotyping was investigated.

Results
Of 20 patients of GT, 8 were male and 12 were female. Of 7 patients of BSS, all of them were female. Glycoprotein IIB gene rearrangement was detected in 7 patient of GT. 5 of 7 were newly described mutations in published literature. Mutations in GpIBB and GpIBA gene were detected in 7 patients with BSS. No correlation was observed among the clinical and genotype characteristics of patients both with GT and BSS. The most common patterns of bleeding were epistaxis and gum bleeding. Life threatening bleeding was seen in 5 of GT patients (4 gastrointestinal bleeding, 1 mediastinal hematoma) and 2 of BSS patients (1 splenic rupture and 1 gastrointestinal bleeding). No patients had died due to major bleedings. One patient with GT experienced spontaneous duodenal intramural bleeding resulting duodenal obstruction. One patient with BSS experienced spontaneous mediastinal hematoma. Although the BSS, it is interesting that the patient was able to control of mediastinal hematoma. Further investigations revealed the patient has prothrombotic mutation (heterozygous FV Leiden).

Conclusion
The most common bleeding pattern in patients with thrombocyte dysfunction is mucocutaneous bleeding. Some patients may suffer from life-threatening bleedings. Our study contributes to the literature because of five newly described mutations in GT patients. It may be hypothesed that the presence of prothrombotic mutation in patients with thrombocyte dysfunction may reduce the severity of bleedings.

Disclosures:
No relevant conflicts of interest to declare.
A Threshold Optical Density Value In Immunoassay Predicts Thrombosis In Patients with Heparin Induced Thrombocytopenia
Authors: Paul Asit K. , Fricke William , Kouides Peter A. 
Published: October 2019

Heparin-induced thrombocytopenia (HIT) is an IgG mediated adverse reaction of heparin use associated with increased thrombosis. Heparin-platelet factor 4 (HPF4) enzyme immunoassay (EIA) detects all classes of antibody against HPF4 resulting in potential over-diagnosis of HIT. The objective of the current study was to determine an optimal threshold for diagnosis of HIT by EIA that would improve the diagnostic specificity and predict thrombosis. We retrospectively analyzed data of 101 consecutive patients who were tested positive based on conventional cut-off value of optical density (OD) obtained from EIA. Study patients were grouped as low (n=22), intermediate (n=26) and high (n=53) clinical probability group of HIT based on the 4T clinical probability scoring. An OD ratio (ODR) by EIA was calculated for each patient by dividing patient’s OD by the cut-off OD. Using low and high clinical probability as negative and positive diagnosis of HIT, a receiver operating characteristic curve was generated for the range of ODRs. An ODR of >2.5 provided the best trade-off between sensitivity and specificity. When a combination of clinical probability and ODR>2.5 were used to diagnose HIT, 20/26 patients with intermediate probability were reclassified as not having HIT. This reduced the overall diagnosis of HIT by 42% compared to that by EIA alone. Using this diagnostic criterion, the rate (58% vs. 10%, P<0.001) and the risk (Odds ratio 7.6, 95% confidence interval, 3.4-17.2) of thrombosis were significantly greater in patients with HIT than in patients without HIT. Thus, when patient’s OD 2.5 times greater than cut-off OD in EIA was combined with clinical probability for the diagnosis of HIT, it improved the diagnostic specificity and predicted thrombosis. This data also suggest the use of a universal ODR rather than an assay-specific cut-off for the diagnosis of HIT by EIA.

Disclosures:
No relevant conflicts of interest to declare.
Comparison Of Distant Relapse Rates Of Immune Thromocytopenia In Patients Treated With Steroids Versus Anti-Rh(D) with/Without Steroids Versus Rituximab with/Without Steroids
Authors: Varma Mala , Grossbard Michael L. 
Published: October 2019

Background
Among therapies for immune thrombocytopenia (ITP) that achieve long unmaintained remissions, distant relapse rates have not been compared.

Specific Aims
To compare relapse rates following umaintained remissions exceeding 1 year in patients with ITP treated with steroids versus anti-Rh(D) with/without steroids versus rituximab with/without steroids.

Methods
Institutional Review Board approval was obtained. The charts of 52 consecutive patients with ITP followed in a hematology practice between 07/01/03 and 06/30/13 were reviewed. Remission was defined as a platelet count > 100,000/µL. Patients with the aforementioned treatment and remission characteristics were identified. Steroids were administered alone as dexamethasone 40 mg PO daily for 4 days. Anti-Rh(D) was administered as 75 mcg/kg IV with or without prednisone 60-85 mg PO daily tapered over 4 weeks or dexamethasone 40 mg PO daily for 4 days. Rituximab was administered as 375 mg/m2 IV weekly for 4 weeks or as a single dose with or without dexamethasone 40 mg PO daily for 4 days. Relapse was defined as a platelet count < 30,000/µL. Statistical calculations included ANOVA to compare demographics and chi-square contingency table analysis to compare distant relapse rates (http://www.physics.csbsju.edu/stats).

Results
There were 16 unmaintained remissions exceeding 1 year in 13 patients following treatment with steroids, anti-Rh(D) with/without steroids, or rituximab with/without steroids. Mean age on presentation, sex ratio, duration of ITP prior to therapy, and duration of follow-up after therapy were similar for the 3 groups (Table 1).
Distant relapse rates were 100%, 14.2%, and 66.7% for the steroid, anti-Rh(D) with/without steroid, and rituximab with/without steroid groups, respectively, P = 0.03 (Table 2).

Conclusion
Among patients who achieve long unmaintained remissions of ITP with steroids, anti-Rh(D) with/without steroids, or rituximab with/without steroids, those treated with anti-Rh(D)-based therapy are the most likely to have extended remission.

Disclosures:
Off Label Use: Rituximab therapy of ITP.
Surgeryand Invasive Procedure With Bypassing Agents In Hemophilic Patients With Inhibitors: A Single Center Experience
Authors: Park Young Shil , Ju Hee Young 
Published: October 2019

Inhibitory antibodies to factor VIII (FVIII) or factor IX (FIX) are one of the most important complications of managing patients with hemophilia A and B. For hemophiliacs with inhibitors, recent advances in the use of bypassing agents such as recombinant activated FVII (rFVIIa, NovoSeven®) and Factor VIII Inhibitor Bypassing Activity (FEIBA®) have enabled them to aggressively manage their diseases in emergency or elective surgery. This report shows an updated evaluation of the safety and effectiveness of bypassing agents in the treatment of peri-operative bleeding in this patient population.
We reviewed the cases of patients with hemophilia and inhibitors underwent surgery or other invasive procedures between May 2008 and July 2013 using bypassing agents or high dose FVIII concentrates at a single center. Thirty two procedures (23 orthopedic surgeries and 9 other surgeries and procedures) were conducted in 16 hemophilia patients with inhibitors. The median age of the patients was 30.5 years old (range, 7-52). Most patients (14/16, 87.5%) are hemophilia A and 2 patients (12.5%) were hemophilia B. The median titer of inhibitors at procedures was 15 BU (range, 0.7-1900). Patients with low responding inhibitors were 2 cases, and high dose factor VIII concentrates were used. Most patients had high responding inhibitors and one of two bypassing agents was used. Twenty one cases were covered using FEIBA®, nine with rFVIIa initially. The median duration of hospitalization was 14 days (range, 1-58). In most cases, bleeding stopped or controlled well. But, in 5 cases, patients’ bleeding was controlled by sequential bypassing therapy. 4 cases were performed at emergency conditions, and those are segmental resection of small bowel, craniectomy with intracerebral hematoma removal, exploratory thoracotomy, and angiography with embolization. Efficacy of bypassing agents at various surgeries and procedures, based on final patient outcome, was 93.8% (30/32). Two deaths occurred at emergency condition as a result of hypovolemic shock secondary to intracranial hemorrhage or retroperitoneal bleeding.
Good control of hemostasis can be achieved with bypassing agents in hemophilia patients with inhibitors undergoing invasive procedures. If surgery or procedure would perform at emergency condition, more active and aggressive management should be needed. The use of bypassing agents in peri-operative period can allow invasive procedure and surgery to be safe and successful in hemophilic patients with inhibitors.

Disclosures:
No relevant conflicts of interest to declare.
Naturally Occurring Anticoagulants and Their Association With Thromboembolism In Patients With β-Thalassemia Major
Authors: Sultan Sadia , Irfan Syed Mohammed , Zeeshan Rozina 
Published: October 2019

Introduction
Hypercoagulopathy and thromboembolic manifestations are being increasing acknowledged in transfusion dependent thalassemics; both intermedia and major. Studies in preceding decade have shown that hemostatic alterations including natural anticoagulant deficiency obligate thalassemic for thromboembolism. The aim of our study is to determine the status of natural anticoagulants and their association with thromboembolism during follow up.

Method
This is a prospective case-control study, during which 40 cases and 30 controls were registered between Jan 2009 to Dec 2009. Complete blood count, protein C, protein S, antithrombin, serum ferritin, liver function test; HbsAg and Anti HCV were determined. Patients were followed till 30th June 2012 for thromboembolic disease.
Data was entered and analyzed using SPSS version 17. The results were expressed as mean ± SD for quantitative variables and qualitative variables are presented as frequency & percentages. Student‘t’ test was applied for the comparison of means. We also computed spearman correlation at 5% level of significance to identify relationship between the deficiency of natural anticoagulants with maternal characteristics, hematological parameters and biochemical markers. Chi- square test was applied for correlation of prothrombotic markers with hepatitis B & C.

Results
The mean age of patients and control was 12.30±5.5 and 13.39±4.5 years respectively. There were 21 males and 19 females in patient group. The mean protein C, protein S and antithrombin in patients and control were 58.25±22.5 versus 110.67±22.60 (P<0.001), 67.90±19.58 versus 98.70±21.54 and 89.73±18.09 versus 104.0±10.98 (P<0.001) respectively. Protein C was exceedingly deficient in 65% followed by protein S & antithrombin in 35% and 20% respectively. Protein S deficiency revealed positive correlation with protein C deficiency and hemoglobin ≤ 8 gm% was correlated with antithrombin deficiency(P<0.05). No positive correlation of prothrombotic markers were established with others parameters evaluated. Till June 2012, 7 patients were lost to follow up and 2 died owing to cardiac failure. Of the 31 patients in regular follow up none has experienced thromboembolism both clinically and radiologically.

Conclusion
Decremented prothrombotic markers, primarily protein C, are implicated in elevated thrombotic risk in TM patients. However we did not encounter thromboembolism in our patients during follow up. We recommend prothrombotic screening and prophylactic anticoagulation in high risk group: bed bound splenectomized, cardiopulmonary complications and post operative.

Disclosures:
No relevant conflicts of interest to declare.
Thromboprophylaxis In Pregnancy: Are Current Guidelines Working?
Authors: Hodgins Mitchell , Hart Caroline , Brose Kelsey , Moodley Uthaman 
Published: October 2019

Thromboprophylaxis in pregnancy poses many challenges for physicians given the potential complications to both mother and fetus. Given the difficulty of enrolling this population in appropriately designed studies, current guidelines rely on results extrapolated from other populations and observational studies. The purpose of this quality assurance project is to examine thromboprophylaxis in pregnancy and ensure that, by following current practice-based guidelines, we are meeting treatment goals by providing therapy that is both safe and efficacious.
A retrospective chart review was completed on all patients between 2008 and 2013 who were treated with prophylactic doses of anticoagulation during their antepartum/postpartum period. Each pregnancy was followed throughout gestation and postpartum to assess for thrombotic events, major bleeding (as per the International Society for Thrombosis and Haemostasis (ISTH) definition), and outcomes.
A total of 44 patients were reviewed. Of these, 21 (48%) met criteria for recurrent miscarriage and 19 (43%) had documented thrombophilia. 19 (43%) had a previous history of VTE, and 18 of the 19 (95%) previous VTE were associated with increased hormonal states. There were no antepartum or postpartum thrombotic events. 4 (9%) patients underwent Doppler ultrasound for clinical suspicion of DVT, but all were negative studies. There were no major bleeding episodes. 15 (34%) patients reported some form of minor bleeding, which did not meet ISTH criteria for major bleeds. Of the 21 pregnancies that met criteria for previous recurrent miscarriage, 15 (71%) had successful term deliveries, 1 (5%) had fetal loss, and 5 (24%) unknown outcomes.
Given the absence of recurrent thrombosis and major bleeding events in the population examined, it would appear that following current practice guidelines is both a safe and efficacious practice.

Disclosures:
No relevant conflicts of interest to declare.
Intricacies Of Treating Heparin Induced Thrombocytopenia With Preexisting Antiphospholipid Syndrome and Renal Insufficiency
Authors: Gohari Pouyan , Rubin Philip 
Published: October 2019

Treatment of heparin induced thrombocytopenia (HIT) requires the use of alternatives anticoagulants, such as a direct thrombin inhibitor – argatroban. Use of argatroban relies on frequent laboratory monitoring of the activated partial thromboplastin time (aPTT) to maintain an adequate level of anticoagulation. This requirement poses a challenge in patients with prolonged baseline aPTT, such as in antiphospholipid syndrome. While other assays are being explored they require an extended turn around time because of their limited availability.
We present a case of a 63 year old male with a history of antiphospholipid syndrome, end stage renal disease on hemodialysis, hepatitis C, and on long term anticoagulation with warfarin for cerebral vein thrombosis. His hospital course required transition to unfractionated heparin and subsequently developed thrombocytopenia. A heparin-platelet factor 4 ELISA antibody assay was performed for an intermediate clinical likelihood of HIT and returned positive. Although not confirmed with the gold standard serotonin release assay (SRA), clinical suspicion for HIT obligated treatment with an alternative anticoagulant. Conventional dosing and administration of argatroban however could not be performed because of the patient’s prolonged baseline aPTT. Other agents such as fondaparinux were also not possible in the setting of renal insufficiency. Short of other treatment techniques accepted in this unique set of circumstances we practiced a fixed dose argatroban (0.5 mcg/kg/min for Child’s class B cirrhosis). The patient tolerated the empiric dosing well until discontinued because of a negative SRA. This case demonstrates the limitations of current treatment recommendations of HIT and need for further investigation in similar patients.

Disclosures:
No relevant conflicts of interest to declare.
Use Of Prothrombin Complex Concentrates In Warfarin Anticoagulation Reversal In The Emergency Department: A Quality Improvement Study Of Administration Delays
Authors: Bordeleau Simon , Marceau Daniele , Poitras Julien , Archambeault Patrick , Breton Carolle 
Published: October 2019

Introduction
In some bleeding situations, quick reversal of warfarin anticoagulation is important. In the event of a major life-threatening bleeding event, the anticoagulation reversal delay can have an impact on mortality. This study aimed to improve the administration delay when using Prothrombin Complex Concentrate (PCC) for the emergent reversal of warfarin anticoagulation in the emergency department.

Methods
An audit and feedback quality improvement project was conducted in three phases: a retrospective audit phase, an analysis and feedback phase and prospective evaluation phase. The charts of all eligible patients in a single Emergency Department (ED) in Québec, Canada, who received 4-factor PCC since the introduction of this product in 2009 until October 31, 2011 were retrospectively audited with pre-planned evaluation criteria. The administration delay of PCC was calculated from the time of prescription to the time of administration. After this retrospective chart audit, we determined where improvements could be attained, gave feedback to the ED and the blood bank, and we created an action plan to ensure the timely administration of PCC. The action plan was then implemented in practice to reduce the administration delay. Finally, a six-month prospective evaluation study was conducted to determine if our action plan was followed and improved the administration delays.

Results
Seventy-seven charts were reviewed in the retrospective chart audit. The mean administration delay was 73.6 minutes (STD [34.1]) with a median of 70.0 minutes (25-75% IQR [45.0-95.0]). We found that this delay was principally due to the following barriers that prevented timely administration of PCCs: communication problems between the ED and the blood bank and reconstitution and delivery inefficiencies. In order to address these barriers, we developed an action plan that involved the following elements: a flowchart to remind all clinicians how to order PCCs and a new delivery method from the blood bank to the ED. During the 6 months following the implementation of our action plan, 39 patients received PCCs and the mean administration time decreased to 33.2 minutes (STD [14.2]) (p<.0001) with a median of 30.0 minutes (25-75% IQR [24.3-38.8]).

Conclusion
This audit and feedback quality improvement project involving the development and the implementation of an action plan comprising of a flowchart and a new delivery process reduced the administration time of PCC by more than half. Future studies to measure the impact of implementing a similar audit and feedback process involving an action plan in other centers should be conducted before this type of improvement process is implemented on wider scale.

Disclosures:
No relevant conflicts of interest to declare.
Induction of protein kinase C mRNA in cultured lymphoblastoid T cells by iron-transferrin but not by soluble iron
Authors: Alcantara O , Javors M , Boldt DH 
Published: October 2019

Abstract
Iron-transferrin (FeTF) is an essential growth factor required for proliferation of lymphoid cells. FeTF activates protein kinase C (PKC) in the lymphoblastoid T-cell line, CCRF-CEM. We have treated CEM cells with human FeTF, then examined levels of PKC mRNA by hybridization analysis using cDNA probes specific for alpha-, beta-, and gamma-PKC subspecies. CEM cell mRNA hybridized with the beta-subspecies probe but not with probes for alpha- or gamma-subspecies. After exposure to FeTF an increase in PKC-beta mRNA was detectable at 10 minutes, peaked at 12 hours, and was sustained for 72 hours. Nuclear transcription assays demonstrated that rates of PKC-beta mRNA transcription were increased in FeTF-treated cells. By contrast, steady state levels of PKC-beta mRNA did not increase after treatment of cells with apotransferrin or gallium TF. Similarly, treatment with soluble iron as ferric ammonium citrate did not increase steady state levels of PKC-beta mRNA, despite producing a marked increase in cellular ferritin content. Ferritin increased from a baseline value of 63 ng/10(6) cells to 98 and 100 ng/10(6) cells in CEM cells treated for 1 hour with ferric ammonium citrate or FeTF, respectively. FeTF did not increase cytoplasmic-free calcium in CEM cells loaded with fura-2, indicating that binding of FeTF to transferrin receptors did not open membrane Ca2+ channels or release intracellular Ca2+. In addition, pretreatment of cells with desferrioxamine, but not ferrioxamine, blocked the FeTF-induced increase in PKC-beta transcripts. Therefore, iron as FeTF (not soluble iron or nonferric TF) stimulates transcription of the CEM cell PKC-beta gene. Transcriptional rate of the PKC-beta gene does not correlate with cellular iron content as judged by ferritin measurements. Furthermore, the requirement for FeTF does not appear to reflect activation of a classic agonist pathway as judged by stable cellular Ca2+. These data suggest that delivery of iron by FeTF to one or more specific cellular compartments may stimulate PKC-beta gene transcription in CEM cells.