bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiplatelet Glycoprotein Antibodies Profile in Adult Patients with Primary Immune Thrombocytopenia and the Comparison with Regards to the Treatment Response to Corticosteroids
Authors: Atmakusuma Tubagus Djumhana , Sukrisman Lugyanti , Hardi Fransiska 
Published: October 2019

Abstract
Background: Platelet destruction in immune thrombocytopenia (ITP) is mediated by autoantibodies against platelet antigens. Anti-GPIIb/IIIa and anti-GPIb/IX antibodies are two major antibodies spesific for platelets and megakaryocytes. The diversity of clinical characteristics and therapeutic responses have been thought to be influenced by heterogeneity of spesific glycoprotein complexes. However, there has been no published data regarding either antiplatelet antibodies profile or response rates to corticosteroid, in adult patients with primary ITP.
Objectives: To determine antiplatelet glycoprotein antibodies profile in adult patients with primary ITP and to compare the response rate to corticosteroid referring to the profile.
Methods: This study is a cross sectional study in adult patients with primary ITP who visited Hematology Clinics in Dr Cipto Mangunkusumo Hospital, Jakarta, Indonesia, in a period of March to October 2013. The tests to determine the auto antibodies against the platelet GPIIb/IIIa and GPIb/IX surface antigens were performed by a direct MAIPA technique.
Results: A total of 40 patients who were diagnosed as primary ITP have been enrolled into the study. The subjects of the study were divided in two groups, 10 subjects with newly diagnosed ITP, and 30 subjects with persistent or chronic ITP. Most of the subjects were female (82.5 %) with the median age was 24,5 (17-55) years old.. Seventy (??) subjects had ITP Bleeding Score (IBLS) 2.. In a persistent/chronic ITP group (n= 30), the proportion of anti-GPIIb/IIIa was 20 / 30 (66,67 %) with the median optical density (OD) was 0,461 (0,093-2,116) and the proportion of anti-GPIb/IX was 25/30 (83.33%) with the median OD was 0,507 (0,190-1,924). Meanwhile, in a newly diagnosed ITP group (n=10) the proportion of anti-GPIIb/IIIa was 7/10 (70%) with the mean OD was 0,802 ± 0,71 and the proportion of anti-GPIb/IX was 8/10 (80%) with the mean OD 0,82 ± 0,57. The response rates to corticosteroid were as follows: 42.5 % of the subjects achieved complete response, 45 % achieved response, and 12.5 % achieved no response. Comparison between the subjects with and without anti-GPIIb/IIIa and anti-GPIb/IX antibodies showed similarity response rates to prednisone.
Conclusion: Sincemost of patients with primary ITP had anti GPIIb/IIIa and anti GPIb/IX antibodies, those antibodies may support a diagnosis of primary ITP. Since no differences in terms of the response rates to corticosteroid between subjects with and without anti-GPIIb/IIIa and anti-GPIb/IX antibodies, those antibodies can not be used as a predictor of the treatment

Disclosures
Sukrisman: Division of Hematology Medical Oncology: Other: Colleague.
Clinical Validation of a Radiolabeled PF-4 Staph-a Binding Assay for Confirming Heparin Induced Thrombocytopenia
Authors: Takala Hemasri , Davis John A. , Schwartz Kenneth A. 
Published: October 2019

Abstract
Introduction:Confirmatory laboratory assays for heparin induced thrombocytopenia (HIT) can broadly be classified as functional which have high specificity and rely on activation of platelets by the platelet factor 4 (PF4)-heparin-IgG immune complex or as immune based assays that are relatively more sensitive. At the time when the clinician is evaluating heparin as a cause of thrombocytopenia the 4 "T" criteria are helpful. However, an increase in the patient's platelet count after the heparin has been stopped is critical for confirmation of the diagnosis.
Methods: We developed a variation of a previously described technique (Newman Thromb Haemost 1998;80:292) and used clinical criteria as the standard for comparison to evaluate the assay. Radiolabeled 125-I-PF4 is incorporated into the immune complex of PF-4-heparin-immunoglobulin and the amount of radiolabeled immune complex is measured after binding to staphylococcal A protein sepharose (Staph-A). The hospitalized subjects medical record was reviewed to: measure a 4 "T" score, to determine if the patient's platelet count increased after heparin was stopped and to exclude other plausible causes of thrombocytopenia.
Aim: The assay relies on the binding of the heparin immune complexes to Staph A. Staph A preferentially binds to larger as compared to smaller immune complexes and the larger complexes produce a greater degree of F(c) mediated platelet activation when compared with the smaller complexes. This suggests the hypothesis that a Staph A based assay will have have better specificity and sensitivity than the currently used methodologies.
Results: 28 patient samples were evaluated. True positives were observed in 4 hospital patients and 4 known positives. 19 were true negatives and included 7 from hospital patients and 12 from thrombocytopenic patients who were not treated with heparin. 1 sample was negative in our assay, and was judged as false negative. Concordance between the radiolabeled PF-4 assay and the commercial PF-4 assay was observed in all the 28 patients.
Conclusions: To date when judged using clinical criteria, the radiolabeled PF-4 assay correctly distinguished true positives and true negatives in 27 of the 28 samples.

Disclosures
No relevant conflicts of interest to declare.
Effect of Carica Papaya leaf Extract on Platelet Count in Chronic Immune Thrombocytopenic Purpura: A Case Series
Authors: Hampilos Katherine E. , Corn Joshua , Hodsdon Wendy , Anderes Elise N. , Roop Ryan P. , Wagner Peter , Troy Lynn R. 
Published: October 2019

Abstract
Background:
The leaves of Carica papaya have been used to treat thrombocytopenia in the critical phase of Dengue fever in areas where the virus is endemic. This case series describes the use of C. papaya leaf liquid extract (CPLE) as an adjunctive therapy for four patients receiving standard-of-care treatment for chronic immune thrombocytopenic purpura (ITP).
Case 1:
A 67 yo M diagnosed with ITP in 1999 presented on 8/17/2013 with bruising and a platelet count of 5 x 103/ml. No response was seen to prednisone 125 mg QD. He subsequently received a course of IV Ig and IV methylprednisolone sodium succinate, but platelet count remained under 5 x 103/ml on 9/13/13. He was prescribed CPLE 3,000 mg QD on 9/30/13. Platelets increased to 148 x 103/ml by 10/8/13 and remained elevated above 250 x 103/ml for five months.
Case 2:
A 21 yo F diagnosed with ITP in 2011 underwent splenectomy on 11/7/13. Despite this intervention, platelet count decreased to 95 x 103/ml on 4/22/14. She was prescribed CPLE 3,000 mg QD as a monotherapy and by 5/8/14, platelet count increased to 156 x 103/ml. CPLE was discontinued and platelet count remained in normal range at 146 x 103/ml on 5/15/14.
Case 3:
A 56 yo M diagnosed with ITP in 2011 was referred for splenectomy on 9/19/12 after his platelet count dropped below 40 x 103/ml despite corticosteroid therapy. Prior to surgery, on 9/30/12, he initiated CPLE 3,000 mg QD in addition to prednisone 10 mg QD. On 11/7/12, pre-surgical labs revealed a platelet count of 115 x 103/ml and splenectomy was cancelled due to adequate platelet count. Platelets remained elevated over threshold for surgery for over four months.
Case 4:
A 60 yo F diagnosed with ITP in 1992 was referred for splenectomy and refused the procedure on 6/5/13. The patient's platelet count was 86 x 103/ml while on prednisone 10 mg QD and she was prescribed CPLE 3,000 mg QD. Her platelet count increased to 109 x 103/ml on 5/12/13 but subsequently dropped to 98 x 103/ml on 5/20/13. CPLE was discontinued at this time due to lack of beneficial action on platelet count.
Conclusion:
CPLE may prove beneficial in the management of refractory ITP for patients interested in alternative therapy before progressing to second-line treatments. Based on the association observed in these cases, a larger clinical trial is warranted to evaluate CPLE as an adjunctive therapy in chronic ITP.

Disclosures
No relevant conflicts of interest to declare.
Cyclic Thrombocytopenia: A Case Report
Authors: Fontenele Leila P. S. , Santucci Rodrigo , Centrone Renato , Aranha Milton A. F. , Bellesso Marcelo , Dias Daniela Ferreira 
Published: October 2019

Abstract
Cyclic thrombocytopenia (CTP) is a very rare disorder characterized by periodic fluctuations in platelet counts, typically resulting in episodes of thrombocytopenia alternating with normal platelet counts. Most cases are idiopathic while some are associated with a primary hematologic disease. Frequently CTP patients are misdiagnosed as idiopathic thrombocytopenic purpura (ITP), but usually they do not respond to standard ITP treatment.
A 49 year-old male presented a history of one year of symptomatic thrombocytopenia (<10x10(9)). He had been treated initially with corticosteroids without a consistent response. Later, he was subjected to splenectomy. After splenectomy platelet counts was checked weekly. On the first week the cont was 1.000x10(9)/L falling on the third week to 27x10(9)/L. As the patient had no bleeding we decided for no treatment, and platelet counts had been fluctuating from 800x10(9)/L to 20x10(9)/L about every four weeks, for three months of monitoring. No treatment was further required.
When evaluating patients with suspected ITP, CTP should always be included in the differential diagnosis, especially if they are not responding to standard ITP treatment.
Figure 1. Figure 1.

Disclosures
No relevant conflicts of interest to declare.
Identification of Novel Mutations with Molecular Modelling of Missense Mutations of Congenital Afibrinogenemia Patients in Pakistan
Authors: Khan Tehmina nafees sonia , Naz Arshi , Biswas Arjit , Goodeve Anne , Ahmed Nisar , Ahmed Shariq , Shamsi Tahir , Oldenburg Johannes 
Published: October 2019

Abstract
Background:
Congenital afibrinogenemia (OMIM #202400) is a rare coagulation disorder which was first described in 1920. It is transmitted as an autosomal recessive trait characterized by absent levels of fibrinogen (factor I) in plasma. Consanguinity in Pakistan and its neighboring countries has resulted in higher cases of congenital fibrinogen deficiency in their respective populations.
Aims: This study focuses on the detection of mutations in the fibrinogen genes by DNA sequencing and molecular modeling of missense mutations in all three genes (Fibrinogen gene alpha (FGA), beta (FGB) and gamma (FGG) in Pakistani patients.
Methods:
This descriptive and cross sectional study was conducted in Karachi and Lahore and fully complied with the Declaration of Helsinki. Patients with fibrinogen deficiency (tested by Fibrinogen functional assay from Laboratoire Stago, Asnieres, France) were screened for mutations in the Fibrinogen gene alpha (FGA), beta (FGB) and gamma (FGG) genes by direct sequencing. Molecular modeling was performed to predict the putative structure functional impact of the missense mutations identified in this study
Results:
Ten patients had FGA mutations, four have FGB mutations and one mutation was detected in FGG. Thirteen of these mutations were novel. The missense mutations are predicted to result in loss of stability since they (a) break ordered regions (b) cause clashes in the hydrophobic core of the protein.
Conclusion:
Congenital afibrinogenemia is a rapid growing problem in countries such as Pakistan where consanguinity is frequently practiced. This study illustrates the fact that mutations in FGA are relatively more common in our population than those in FGB where as FGG mutations appear rarer.

Disclosures
Oldenburg: SOBI: Consultancy.
Molecular Characterization of F8 Secreting Cell
Authors: El-Maarri Osman , Jamil Muhammad Ahmer , Pezeshkpoor Behnaz , Nüsgen Nicole , Hofmann Andrea , Hoffmann Per , Heilmann Stefanie , Nöthen Markus M , Frohlich Holger , Oldenburg Johannes 
Published: October 2019

Abstract
Different endothelial cells share common features but also acquire organ specificity: for example the liver sinusoidal endothelial cells (LSECs) are major site of F8 secretion as compared to other endothelial cells. To decipher this specificity in LSECs and to understand the molecular mechanism of F8 synthesis and secretion, we have compared genome wide expression and epigenetic data of fetal LSECs (N=3) and non-liver endothelial cells (HCMEC, HPAEC, HPMEC and HUVEC; N=3), hepatocytes (N=3) and adult total blood (N=3). At a false discovery rate of <5% we found 4134 differentially methylated CpG sites and 663 differentially expressed probes (corresponding to 623 genes/loci) between LSECs and other endothelial cells. The loci were found by ingenuity pathway analysis (IPA) to be enriched in EIF2, eIF4, p7056K and mTOR signaling pathways together with LXR/RXR activation pathway. On the other hand, only 21 different loci and 152 CpGs were found to be statistically different (at <5% FDR) between hepatocytes and LSECs. According to IPA these were found enriched in interferon signaling, activation of IRF by cytosolic pattern recognition receptors and role of pattern recognition receptor in recognition of bacteria and viruses. Additionally, gene ontology analysis showed enrichment in GO-terms such as regulation of cellular metabolic process for LSECs vs. endothelial cells and blood vessel development, cell adhesion and regulation of cell migration for LSECs vs. hepatocytes. Moreover, in each of the GO sub categories of general coagulation (GO:0007596) and transcription factors (GO:003700) a small number of loci successfully differentially identify the LSECs from other endothelial cells. The above described results show specific molecular signature that characterize the F8 secreting cells and highlight specific cellular pathways associated with this process.

Disclosures
Oldenburg: SOBI: Consultancy.
Factor VII Deficiency in the Negev - a 10 Years' Experience of One Tertiary Center
Authors: Fruchtman Yariv , Ben harosh Miri , Kapelushnik Joseph , Mazar Julia , Kenet Gili , Rosenberg Nurit 
Published: October 2019

Abstract
Inherited factor VII (FVII) deficiency is the most common among the autosomal recessive rare bleeding disorders, with an estimated prevalence of 1:300,000 in European countries. Affected individuals display a wide range of clinical phenotypes, ranging from mild non spontaneous bleeding to life threatening (i.e. central nervous system[CNS] bleeding, gastrointestinal [GI] bleeding or haemarthrosis), whereas up to one-third of individuals with a FVII deficiency are asymptomatic and are mainly diagnosed during family studies or after screening for surgery. Unfortunately, the residual activity of FVII does not predict the individual propensity to bleed, and even in individuals with the same mutation, differences in clotting phenotypes can be seen.
As our tertiary center serves a unique population in the Negev, we aimed at studying the prevalence and phenotype of FVII deficiency within the last decade.
Methods: We searched all electronic records for the last 10 years depicting rare bleeding disorders by ICD 9 code - 2863 and compared them to the hematologic record of factor VII deficiency depicted in our lab - 50% or less activity. Patients with any record of genetic diagnosis, were compared with clinical findings.
Results: The population in the Negev is estimated as 700000 people
Most of them are Jewish and 150000 of them are Arab-Bedouins. We found 800 records of rare bleeding disorders (ICD 9-2863), Including 200 with FVII deficiency - 100/200 had FVII levels below 50%.
Most (90%) of cases were of Jewish origin (mostly oriental Jews) and only 10% were Arab- Bedouins. Forty patients were asymptomatic with 50-30% FVII activity and 20 patients with 30-10% FVII activity were either asymptomatic or presented with mild bleeding diathesis. Out of 23 cases with lower than 10% FVII activity, 7 were symptomatic and suffered severe life threatening bleedings (2 infant died of perinatal ICH. Five families (3 Bedouin and 2 oriental Jews) were identified with severe FVII deficiencies. The 4 Bedouin patients were identified to be homozygous to unique mutation. Interestingly, most medical records depicted FVII deficiency were of women studies due to fertility problems.
Conclusions: The prevalence of FVII deficiency depicted in the Negev is much higher in comparison to literature reports (200/700000) Severe FVII deficiency was found in 23: 700000, consistent with 1: 30000 prevalence. As patients are highly variable, in order to "tailor" treatments according to disease severity, new directions should be pursued to identify those with the most severe phenotypes.

Disclosures
Kenet: Bayer, Novo Nordisk: Other: Advisory Boards, Speakers Bureau; Opko Biologics: Consultancy, Other: Advisory Boards; BPL; Baxelta: Research Funding; Pfizer: Honoraria.
Safety and Efficacy of New Moroctocog Alfa Drug (Octofactor) in Prophylactic Treatment in Adolescent Patients with Severe and Moderate Hemophilia a
Authors: Shiller Ekaterina , Vdovin Vladimir , Petrov Victor , Svirin Pavel , Andreeva Tatiana , Lavrichenko Inna , Bullikh Artem , Koltunov Igor , Davydkin Igor , Kurtov Igor , Shuster Alexandr , Kudlay Dmitry , Lukyanov Sergey , Borozinets Anton , Nikitin Eugene , Klykova Ekaterina 
Published: October 2019

Abstract
Efficacy and safety of a new domestically produced rFVIII-BDD (moroctocog alfa, Octofactor, CJSC "GENERIUM", Russia) was investigated in a controlled, open, prospective, multicenter clinical trial. After screening and a 4-days washout period 12 previously treated patients adolescents (age 12-18 years old) with severe hemophilia A (the activity of FVIII was less than 1%) were included in the clinical trial. The patients were given the moroctocog alfa as prophylactic treatment in a dose of 35±5 ME/kg 3 times per week during 21±1 weeks. Before participation in this clinical trial 2 pts had received treatment with another recombinant FVIII, 2 pts had therapy with pdFVIII and 8 pts had been treated with rFVIII and pdFVIII. The main criterion of drug efficacy was the incidence of spontaneous bleeding occurred within 48 hours after of the moroctocog alfa injection.
The additional criteria were:
· The severity of spontaneous bleeding occurred in 21 ± 1 week.
· Number of injections needed for the one episode of bleeding according of its severity.
· The total amount of drug administered over a period of prophylactic treatment and treatment "on demand".
· The number of patients with severe hemophilia A with a residual activity of FVIII ≥1% in 48 hours after the injection on prophylactic therapy.
During the follow up period (21±1 week) 17 bleeding episodes were registered, 2 of them (11,8%) were severe, 10 (58,8%) were moderate and 5 (29,4%) were mild (Tab.1). Number of bleeding episodes (spontaneous and traumatic) was 17 (1.55 in average). Number of spontaneous bleeding was 3 (17,6%), 1 of them was mild and 2 were moderate. The average number of injections that stop one bleeding episode was 1.7±0.8. The total amount of moroctocog alfa administered over a period was 1.502.000 ÌÅ for prophylactic treatment and 64.750 ÌÅ for "on demand" treatment. The number of patients with severe hemophilia A with a residual activity of FVIII ≥1% in 48 hours after injection on prophylactic therapy was 63,6% on visit 2, 90,09% on visit 3 and 81,1% on visit 4. The safety assessment was performed in 12 patients. There were 8 adverse events and 7 of them were not associated with drugs administration. There was one serious adverse effect, allergic reaction accompanied by arthralgia and cephalalgia. The patient was excluded from the trial without consequences for life and health. There were no infection transmissions and de novo inhibitor incident. The study showed that moroctocog alfa is effective and safe in prophylactic treatment and stopping of bleeding in adolescents with severe hemophilia A.
Table 1. Efficacy evaluation Table 1. Efficacy evaluation

Disclosures
No relevant conflicts of interest to declare.
Short and Long-Term Outcomes in Hemophilia Patients with Inhibitors Undergoing Orthopedic Prosthetic Surgery
Authors: Castaman Giancarlo , Linari Silvia , Carulli Christian , Innocenti Massimo 
Published: October 2019

Abstract
Introduction: Major orthopedic surgery is still a difficult challenge in hemophilic patients with high titer of inhibitor. In addition to possible peri-operative problems, the long-term outcomes are anecdotal.
Aim of the study: to evaluate the short and long term outcomes in prosthetic orthopedic procedures done in hemophilic patients with inhibitor from 1998 to 2014
Results: Sixteen knee replacements have been performed in 12 patients affected by hemophilia A with inhibitors. At the time of surgery 11 out of 12 patients had an inhibitor titer > 5UB (range 5 - 2,500). A preoperative pharmacokinetic with rFVIIa was made in 8 out of 12 patients, with the following mean values of clearance rate: 35 ml/h/kg and half-life: 2.85 hours. The average age was 46 years (range 29-55). All patients were treated with 2-3 doses of rFVIIa (90-120 mg/kg) every two hours during surgery up to suturing of the wound, followed by continuous infusion of rFVIIa at dose of 30-50 mg/kg/h on days 1-3 and 15 mg/kg/h on days 4-14. Plasma levels of FVII:C were maintained > 15U/mL. All but one patients were transfused with 2 units of red blood cells (RBC), according to standard procedure. Two peri-operative complications occurred: 1 pulmonary embolism and 1 major bleeding at the operated site, poorly responsive to rFVIIa and aPCC, treated with 6 units of RBC. Only two patients underwent to prosthesis revision for infection, while another due to rupture of the prosthesis metal cup. After surgery all patients showed a significant improvement in pain and a favorable functional recovery. After a median follow-up of 7 years (1-18 years), a good quality of life as to pain and function of the replaced knee were recorded.
Conclusions: The orthopedic prosthetic surgery in hemophilic patients with inhibitors can be done, with a good outcome. The continuous infusion of rFVIIa provides stable haemostatic coverage, saving on the rFVIIa total dose compared to the bolus standard dose. However, costs remain high and the possible risks of thromboembolic complications should not be overlooked

Disclosures
No relevant conflicts of interest to declare.