An Overvıew of Lower Gastroıntestınal Bleedıng ın Infants and Toddlers: A Revıew Artıcle

Lower gastrointestinal bleeding (LGIB) in infants and toddlers is commonly encountered in clinical practice. There are several factors producing LGIB in these children and are usually managed with regard to the underlying pathology that produces LGIB. Although majority of these bleeding episodes is self limited, certain infants and toddlers with LGIB may necessitate prompt management including urgent surgical intervention. In this review article it is aimed to review the etiology, epidemiology, clinical manifestations and principles of treatment of LGIB in infants and toddlers under the light of relevant literature.

Etıology and Management of Lower Gastroıntestınal Bleedıng ın Neonates: A Revıew Artıcle

Lower gastrointestinal bleeding (LGIB) in neonates is occasionally encountered in clinical practice. There are various causative factors prodicing LGIB in neonates and the babies are usually managed with regard to the underlying pathology that produces LGIB. Although majority of these bleeding episodes is self limited, certain neonates with LGIB may necessitate prompt management including urgent surgical intervention. In this review article it is aimed to review the etiology, epidemiology, clinical manifestations and principles of treatment of LGIB in neonates under the light of relevant literature.

Evaluation and Management of Mallory – Weiss Syndrome: A Review

Upper gastrointestinal bleeding is a symptom of Mallory-Weiss syndrome, which is caused by longitudinal mucosal lacerations (known as Mallory-Weiss tears) near the gastroesophageal junction or gastric cardia. Mallory-Weiss syndrome is rather prevalent, accounting for 3 to 10% of all upper gastrointestinal bleeding episodes. In mild circumstances, the disease may be asymptomatic. Hematemesis is the presenting symptom in 85 percent of patients. Blood is present in varying amounts, ranging from blood-streaked mucous to huge bright red haemorrhage. Other symptoms such as melena, dizziness, or syncope might occur as a result of heavy bleeding. The majority of the time, the bleeding is little and ends on its own. Endoscopy is frequently used to confirm the diagnosis of MWS. Although most patients may be treated with monitoring or conservative medicinal treatment, certain cases require endoscopic or surgical treatment. Despite the fact that MWS is a common cause of nonvariceal upper gastrointestinal bleeding (NVUGIB), little research has been done on it. This article discusses MWS Etiology, epidemiology, evaluation and management.

Surgery-Associated Bleeding Risk in Patients with Platelet Function Disorders - a Cross Sectional Study with the American Thrombosis and Hemostasis Network Dataset (ATHNdataset)

Introduction: Platelet function disorders (PFDs) are a group of heterogenous bleeding disorders with varying bleeding phenotype. Intraoperative and post-operative bleeding are serious complications among patients with PFDs undergoing surgery. There are very few studies in literature that have specifically investigated surgery associated bleeding complications in PFDs. The aim of this study was to utilize a large national dataset to describe surgeries performed in patients with PFD, characterize the bleeding associated with these surgical procedures and outline the therapeutic approaches adopted. Methods: In this retrospective study, the ATHNdataset was queried for demographic data, PFD diagnosis, surgeries among patients with PFD, intraoperative and post-operative bleeding episodes and treatment. Descriptive statistics were used. The ATHNdataset captures information from patients with bleeding and clotting disorders from over 140 federally funded hemophilia and thrombosis treatment centers (HTCs) in the US. Patients authorize inclusion of their demographic and clinical information in this de-identified Health Insurance Portability and Accountability Act (HIPAA)-compliant data set. Results: From January 2010 to March 2020, the ATHNdataset captured 2767 patients with PFDs, of which 1769 (63.93%) were female and 998 (36.1%) were male, with 1393 patients between 0-18 years (50%) and 1374 (50%) adults >18 years. PFDs identified include 32 patients with Bernard Soulier syndrome (1.16%), 131 patients with Glanzmann thrombasthenia (4.7%), 4 patients with Gray platelet syndrome (0.14%), 29 patients with Hermansky Pudlak syndrome (1%), 1548 patients with storage pool deficiency (55.9%), and 1023 patients diagnosed as PFD (36.9%). A total of 3252 procedures were reported between 2010 and 2020; 1271 patients (46%) patients with at least one documented procedure. Figure 1 shows common procedures among patients with PFDs. Surgery-associated bleeding episodes (includes intraoperative and post-operative bleeds) were reported with 69 procedures (2.1%), which included intraoperative bleeds reported for 18 procedures (0.5%) and post-operative bleeds reported for 51 procedures (1.6%). Of the 60 procedures in patients with Glanzmann thrombasthenia, surgery-associated bleeding episodes were reported after 9 dental procedures (41%), 1 circumcision (25%) and 11 other surgeries/procedures (18.3%). Of the 6 procedures in patients with Bernard Soulier syndrome, no intraoperative or post-operative bleeding episodes were reported. Of 1688 procedures in patients with storage pool deficiency, surgery-associated bleeding episodes were reported after 26 dental procedures (1.5%) and 62 other surgeries/procedures (3.67%). No intraoperative or post-operative mortality was reported among these patients. Of 1272 patients who underwent at least 1 procedure, 646 patients (50.7%) received some form of treatment before/during/after a procedure. Among these 646 patients, 2794 exposure days of hemostasis medications were used before/during/after procedures. Among these, 49% were prior to the procedure, 0.7 % during the procedure and 49.5% after the procedure. Treatments used are shown in figure 2. Conclusion: Our study shows that patients with PFDs have a substantial risk of bleeding associated with surgery. Identifying the risk of bleeding by type and providing appropriate pre-surgical prophylaxis can decrease rates of surgery-associated bleeding in PFDs. Figure 1 Figure 1. Disclosures Sidonio: Sanofi, Takeda, Octapharma, Bayer, Biomain, Grifols, Kedrion, Genentech. Catalyst, Guardian Therapeutics, Novo Nordisk, Hema Biologics, Uniqure.: Consultancy, Honoraria. Ahuja: Genentech: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: DSMB member ; XaTek, Inc: Patents & Royalties; Sanofi: Membership on an entity's Board of Directors or advisory committees.

A Real-World Study of Pre-Post Annualized Bleed Rates and All Cause Costs Among Non-Inhibitor Patients with Hemophilia a Switching from FVIII Prophylaxis to Emicizumab

Background Hemophilia A (HA) is a rare genetic disease characterized by a deficiency in clotting factor VIII (FVIII). Persons with HA suffer from spontaneous and traumatic bleeds which significantly impact short- and long-term quality of life. Prophylaxis treatment with FVIII replacement or non-factor replacement (e.g. emicizumab) intends to prevent bleeding episodes. To date, clinical comparisons between FVIII and emicizumab are limited to non-interventional studies and indirect comparisons. Comparisons of costs are limited to cost-effectiveness models or observational studies that include patients with and without inhibitors. An increase in availability of real-world data since emicizumab's approval in 2018 has created opportunity for comparative outcomes research in the non-inhibitor HA population. Objective To compare billed annualized bleed rates (ABR b) and all-cause costs (ACC) among non-inhibitor HA patients switching from prophylaxis with FVIII replacement to emicizumab. Methods This retrospective, observational, pre-post study used the IQVIA PharMetrics® Plus database (2015-2020)-a large longitudinal US commercial health plan database with over 190 million lives. International Classification of Diseases codes (ICD-10), National Drug Codes, and Healthcare Common Procedure Coding System were used to identify diagnoses, therapies, and procedures. Males with ≥1 claim for emicizumab who were on prophylaxis treatment with FVIII prior to initiating emicizumab were included in the analysis. Patients who received bypassing agents, immune tolerance induction, or rituximab were assumed to have inhibitors and were excluded. Patients with ≥2 occurrences of any of the following diagnoses were excluded: von Willebrand disease, hemophilia B, acquired HA, or other coagulation disorders. Annualized bleed rate was defined as billed ABR and represents bleeding episodes that required evaluation, treatment, or procedure resulting in an ICD-10 claim. Therefore, bleeds treated at home and untreated bleeds were not captured. A clinical review of ICD-10 codes resulted in a list of 535 codes used to identify HA-related bleeding episodes (e.g. hemarthrosis). The ACC were calculated as the mean cost per patient per year in 2020 US dollars actually paid by the insurer. Descriptive statistics were used to summarize, and Bayesian models were developed to compare, ABR b and ACC in the pre- and post-switch periods. Bayesian inferences estimated the population mean difference in ABR b and ACC after switching from FVIII prophylaxis to emicizumab. Inferences were conducted by computing posterior probabilities for hypotheses and summarized with 95% credible intervals (CrI). Results A total of 121 patients were included with mean age [range] of 25.9 [2-63] years. The majority of patients were over the age of 18 (60.3%), 33.1% were ≥7-18, and 6.6% were <7. The mean (SD) years on FVIII replacement (pre-switch) and emicizumab (post-switch) were 2.5 (1.5) and 1.1 (0.4), respectively (Table 1). Descriptive In the majority of patients, ABR b remained unchanged from pre-switch to post-switch (42%) while 38% had some magnitude of improvement, and 20% experienced a worsening of ABR b. The mean observed ABR b and ACC were 0.68 and $518,151, respectively, in the pre-switch period, and 0.55 and $652,679, respectively, in the post-switch period. Bayesian Model The Bayesian model demonstrated a mean change in ABR b of -0.128 [95% CrI: -0.441 to 0.184] after switch (Table 2). The mean change in ACC was +$159,680 [95% CrI: $74,842 to $247,841] after switch. The model determined there is a 21.0% probability ABR b will worsen after switch and a 99.9% probability ACC will increase after switch. Conclusions Prophylaxis with FVIII replacement and emicizumab result in similar prevention of billed bleeds in a real-world switch population. Although the population mean ABR b is more likely to fall after switching from FVIII replacement to emicizumab, there is only a 1.02% posterior probability the population mean ABR b will fall by ≥0.5 after switching to emicizumab and a 21.0% probability the ABR b will worsen after switch. Additionaly, ACC are almost certain to substantially increase after switching to emicizumab (99.9%). As additional real-world data becomes available in the non-inhibitor HA population, further research should help to strengthen clinical and economic outcomes for different prophylaxis treatment options. Figure 1 Figure 1. Disclosures Batt: Sanofi: Current equity holder in publicly-traded company; Bayer Therapeutics: Consultancy; Sprouts Consulting: Other: CEO, Principal Consultant; Merck: Current equity holder in publicly-traded company; Forma: Consultancy, Current equity holder in publicly-traded company; Precision Health: Consultancy; Takeda Pharmaceuticals U.S.A.: Consultancy. Schultz: Takeda Pharmaceuticals U.S.A., Inc.: Current Employment, Current holder of individual stocks in a privately-held company. Caicedo: Takeda Pharmaceuticals U.S.A., Inc.: Current Employment, Current holder of individual stocks in a privately-held company, Current holder of stock options in a privately-held company. Hollenbeak: Takeda Pharmaceuticals U.S.A., Inc.: Consultancy. Agrawal: Takeda Pharmaceuticals U.S.A., Inc.: Consultancy. Chatterjee: Takeda Pharmaceuticals U.S.A., Inc.: Consultancy. Dayma: Takeda Pharmaceuticals U.S.A., Inc.: Consultancy. Bullano: Takeda Pharmaceuticals U.S.A., Inc.: Current Employment, Current holder of individual stocks in a privately-held company.

A Multi-Institution Retrospective Study to Assess Bleeding Phenotype Among Patients with Platelet Function Disorders

Introduction: Platelet function disorders (PFD) clinically manifest with wide variability in mucocutaneous bleeding and significant hemorrhage post-surgery or trauma. The overall prevalence of PFD is not known, as there have not been large population-based studies. Treatment of these patients vary based on their bleeding phenotype. Additionally, the exact bleeding phenotype of many qualitative platelet defects are not well described in literature. This study aims to describe the bleeding phenotype among patients with different (PFD). Methods: This is a retrospective study among patients with PFD conducted at 3 Hemophilia Treatment centers - HOG Center for Bleeding and Clotting Disorders of CHOA, Children's Mercy hospital HTC and Rainbow babies & Children's hospital HTC. Institutional IRB approval was obtained at all 3 institutions. We collected data on demographics, bleeding symptoms at presentation, bleeding episodes, management of these bleeds over a 6-year time period (2015-2020). Results: We identified 131 patients with PFDs at 3 institutions. This included 67 males (51.2%) and 64 females (48.8%). Among 131 patients, 72 patients (55%) had a defect in platelet agonist interaction/receptor defect (ADP/Epinephrine/Collagen/TXA2/Arachidonic acid), 37 patients (28.2%) had delta storage pool defect, 8 patients (6.1%) had Glanzmann thrombasthenia, 7 patients (5.3%) had a platelet release defect, 3 patients (2.3%) with an alpha granule defect, 2 patients (1.5%) with Bernard Soulier syndrome and 1 patient (0.76%) with Wiskott Aldrich syndrome. The most common bleeding symptoms at presentation were epistaxis (40.4%), followed by easy bruising (31.3%), heavy menstrual bleeding (15.2%), gum bleeding (6.87%) and gastrointestinal bleeding (4.58%). From 2015-2020, a total of 162 bleeds were documented, and 68 patients (51.9%) with at least 1 documented episode of bleeding. 67.2% of these bleeds were spontaneous, 12.3% were secondary to trauma, 4.9% after a dental procedure, 2.5% after surgery and 0.6% after child birth. The most common type of bleeding episode in diagnosed patients included epistaxis (50%), heavy menstrual bleeding (17.9%), skin/soft tissue bleed (5.5%), gastrointestinal (5.5%) and dental/tooth related (4.9%). 93 bleeding episodes (57.4%) required some form of treatment in various settings - home (73%), clinic (15%), emergency room (7.5%), hospitalization (14%) and ICU stay (2%). Treatments included antifibrinolytics (68.8%), recombinant factor VIIa (11.8%), desmopressin (9.6%), hormonal therapy (9.6%) and platelet transfusions (5.3%). Conclusions: Our study helps characterize the bleeding phenotype and management in patients with various PFD. This data is crucial in understanding the burden of illness among different types of PFD, and to understand health care utilization to better serve the needs of these poorly characterized patients. Disclosures Sidonio: Sanofi, Takeda, Octapharma, Bayer, Biomain, Grifols, Kedrion, Genentech. Catalyst, Guardian Therapeutics, Novo Nordisk, Hema Biologics, Uniqure.: Consultancy, Honoraria. Silvey: Genentech: Speakers Bureau; Sanofi Genzyme: Membership on an entity's Board of Directors or advisory committees. Ahuja: XaTek, Inc: Patents & Royalties; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Other: DSMB member ; Genentech: Membership on an entity's Board of Directors or advisory committees.

A Cross-Sectional Study of the American Thrombosis and Hemostasis Network Dataset for Outcomes of Dental Extractions in People with Hemophilia

BACKGROUND: Dental extraction (DE) is one of the most common procedures in people with hemophilia A or hemophilia B (PWH-A, PWH-B), yet little is known about impact of the type of hemophilia, hemostatic therapies, and bleeding outcomes. To date, there is no standard protocol for how to treat PWH undergoing DE. Similar overall bleeding rates occur with pre- and postoperative factor replacement (FRP) therapy and single dose preoperative FRP (11.9% and 11.4%, respectively) (DE. Bajkin et al. Haemophilia 2020). METHODS: We analyzed the American Thrombosis and Hemostasis Network dataset (ATHNdataset) to assess trends in prophylactic factor use and its impact on bleeding outcomes following dental extraction in PWH-A and PWH-B ≥2 years of age. A DE bleeding episode was defined as any oral or mouth bleeding occurring during or within one week following a DE procedure. Treated bleeds were defined as any oral or mouth bleeds treated with hemostatic medications during or within one week post-DE. Hospitalization and emergency department (ED) visit events were defined as any that occurred during or one day after a DE. Data on sociodemographic, clinical characteristics, and outcomes were collected prospectively between 2013 and 2019 at annual clinical visits to 134 ATHN-affiliated sites. Categorical variables were summarized using frequency and percentage. Logistic regression was used to evaluate associations between DE and sociodemographic and clinical variables. Simple logistic regression models were applied to identify factors potentially associated with dental bleeding episodes among PWH. RESULTS: Sociodemographic and clinical characteristics revealed that of the 19,048 PWH in the ATHNdataset, 1,157 subjects underwent 1,301 episodes of DE; a majority (74.9%) were diagnosed hemophilia A and 94.4% were male. The odds of a DE were approximately 148% higher among male PWH compared to female PWH (OR: 2.48; 95%CI: 1.93-3.20). PWH with severe disease were less likely to undertake DE than those with mild hemophilia (OR: 0.83; 95%CI: 0.72-0.95). Compared to PWH-B, PWH-A tended to have DEs at a younger age (<30 years). The chance of a DE did not differ by race, hemophilia type, and currently having or having a history of inhibitor. No significant associations were found between dental extraction, education or employment among PWH ages >18 years. Dental extraction clinical outcomes and related treatments indicated approximately 34% of PWH used prophylaxis versus on-demand therapy (18%) 292for dental/mouth bleeding. Approximately 5% of PWH who underwent DE reported oral/mouth bleeds within one week of the procedure. Of those bleeding episodes, 28.0% of hemophilia A patients and 12.5% of hemophilia B patients reported two or more oral/mouth bleeds during, and one-week post-DE. Rates of hospitalizations and ED visits were 7.4% and 1.3% respectively for PWH-A and 8.8% and 0.9% respectively for PWH-B. Among oral/mouth bleeds related to dental extraction, 34.0% and 50.0% patients with hemophilia A and B respectively received hemostatic therapies such as DDAVP, factor concentrates, or antifibrinolytics. Factors associated with DE bleeding were as follows: Dental extractions performed with prophylactic regimen were found to experience insignificantly fewer dental bleeding episodes (P>0.05). Similarly, no statistically significant difference in bleeding rate after DE was found in those using extended half-life factor (EHL) compared to standard half-life products (SHL). Prophylaxis was more prevalent among PWH-A compared to PWH-B (37.3% vs. 25.2% respectively). SHL products were more commonly used than EHL products for on-demand therapy (8.3% vs. 0.5% respectively) as well as prophylaxis (19.8% vs. 8.1%). PWH who have ever developed an inhibitor significantly increased the odds of dental bleeding (OR:2.09, 95%CI: 1.21-3.63). However, no significant relationship was found between inhibitor and DE bleedings among PWH who have been exposed to emicizumab (P=0.168). DISCUSSION: This is the largest study of DE outcomes in PWH. DE tends to be performed more in those with mild hemophilia and at an earlier age. The use of hemostatic therapies and factor prophylaxis is associated with insignificantly less bleeding. The ATHNdataset allowed studies of outcomes in a large cohort of PWH. This project was part of the ATHN CARE Award. Disclosures He: ATHN: Ended employment in the past 24 months. Recht: Foundation for Women and Girls with Blood Disorders, Partners in Bleeding Disorders: Speakers Bureau; uniQure: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Pfizer: Consultancy; Octapharma: Consultancy; Novo Nordisk: Consultancy; Kedrion: Consultancy; Hema Biologics: Consultancy; Genentech: Consultancy; CSL Behring: Consultancy; Catalyst Biosciences: Consultancy; American Thrombosis and Hemostasis Network: Current Employment; Oregon Health & Science University: Current Employment. Kulkarni: Bayer: Consultancy, Research Funding; CSL Behring: Consultancy; Genentech/Roche: Consultancy, Research Funding; NovoNordisk: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Catalyst Bioscience: Research Funding; Foundation for Women and Girls with Blood Disorders: Membership on an entity's Board of Directors or advisory committees.

Prophylactic Treatment of Severe Haemophilia Á Patients with Inhibitors to FVIII with Peglip-FVIII

Background: FVIII replacement therapy is ineffective for severe haemophilia A (HA) patients who develop inhibitors to FVIII. Patients with intractable inhibitors currently require FVIII mimetics and/or bypassing agents to prevent bleeding. PEGylated liposomes (PEGLip) have been shown to protect FVIII from anti-FVIII antibodies in ex-vivo human studies and in combination with FVIII may present an option for the prophylactic treatment of inhibitor patients. Aims: To (a) demonstrate that PEGLip-FVIII administered intravenously (IV) to severe HA patients with history of inhibitors to FVIII enhances their clotting activity, (b) compare the number of bleeding episodes before and after PEG-Lip treatment, and (c) demonstrate that PEGLip-FVIII is well tolerated with no increase in inhibitor titres. Methods: Stage A: Four patients with a history of inhibitors were given single IV injections of PEGLip-FVIII (simoctocog alfa) at a dose of 22mg/kg PEGLip + 35 IU/kg FVIII and assessed for clotting activity at 0 hours (pre-injection) and at 20min, 1, 2, 4, 8, 24 hours, and daily thereafter up to 7 days using Rotational Thromboelastometry. Stage B: Patients received IV injections of PEGLip-FVIII for 6-weeks at a frequency determined by the investigator based on results obtained during Stage A. Inhibitor titres were monitored throughout. Results: Results are shown below. Treatment with PEGLip-FVIII was highly tolerated with no clinically significant changes in inhibitor titres. No Adverse Drug Reactions were reported. The mean frequency of administration of PEGLip-FVIII was every 5.7±1.4 days. The mean number of bleeding episodes reported during Stage B was 0.5±0.9 per month (due to 1 patient) compared with 0.9±0.4 per month recorded during the 24 weeks prior to enrollment. Conclusion: PEGLip-FVIII in inhibitor patients demonstrated efficacy in preventing spontaneous bleeds without increasing inhibitor titres, indicating a novel FVIII-based treatment for this cohort. Planned studies in a larger cohort may confirm our findings. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

A new insight into the treatment of factor V deficiency.

Inherited factor V deficiency is an extremely rare bleeding disorder with no proper treatment currently available and can result in fatal bleeding episodes for the most severe cases. It is characterized by mutations on the F5 gene and provokes reduced levels and activity of factor V (FV) , a critical protein involved in the coagulation process. One of the most promising biotechnologies in the medical field to tackle similar genetic disorders is the use of messenger RNA, being studied for the management of several conditions. Messenger RNA can be encapsulated into lipid nanoparticles, another promising non-viral delivery system. This present article will detail the possible therapeutic effects of a composition of FV mRNA encapsulated in LNPs, by hypothesizing its details, evaluating the possible treatment and suggesting a possible experimental study that may provide further data about this treatment.