Higher Bleeding Rates Research Articles

Overview of cerebral cavernous malformations: comparison of treatment approaches

ObjectivesThe comparison of treatment efficacy for cerebral cavernous malformations (CCMs) has not yet been well researched.DesignPubMed, Cochrane Library, Science Direct, ISI Web of Science, Embase and additional sources were searched...

Incidence of bleeding and thromboembolism and impact on overall survival in adult patients with hemophagocytic lymphohistiocytosis: A 20‐year provincial retrospective cohort study

BackgroundHemophagocytic lymphohistiocytosis (HLH) is a rare syndrome characterized by uncontrolled immune activation and high risk of death. There is scarce data on the incidence of bleeding and thromboembolism in HLH. ObjectivesTo determine the cumulative incidence of bleeding and thromboembolism and impact on survival in adults with HLH. Patients/MethodsWe conducted a multicenter retrospective cohort study of adults with HLH in Alberta, Canada (1999–2019). The cumulative incidence of bleeding and thromboembolism were calculated, accounting for competing risks. Cox proportional hazards models were used to assess the impact of bleeding and thromboembolism on overall survival (OS). ResultsWe identified 97 adults with HLH (median age 46 years). Venous thromboembolism (VTE) occurred in 11 (11%) patients at a median of 9 days from admission. ISTH major bleeding and clinically relevant non‐major bleeding occurred in 39 (40%) patients, at a median of 16 days after admission. Nadir platelet count (adjusted odds ratio [aOR] 1.8 per log decrease, 95% confidence interval [CI] 1.2–2.8) and mechanical ventilation (aOR 4.9, 95% CI 1.8–14.8) were independent predictors of bleeding on multivariable analysis. Adjusting for competing risks, the 90‐day cumulative incidences of bleeding and thromboembolism were 39% and 13%, respectively. The median OS was 18.8 months. VTE, but not bleeding, was significantly associated with adverse OS (adjusted hazard ratio 2.5, 95% CI 1.1–5.7). ConclusionsIn adults with HLH, VTE appears more common than previously described and is a predictor of mortality, although this may be due to unadjusted confounding. VTE prevention and treatment are challenging due to high bleeding rates.

The most common disease-causing mutation of factor XIII deficiency is corrected by CRISPR/CAS9 gene editing system.

Factor XIII (FXIII) deficiency is one of the most severe congenital bleeding disorders, with an estimated incidence of one person per one million. Patients with severe FXIII deficiency present a wide range of clinical manifestations, including umbilical cord bleeding, intracranial haemorrhage and recurrent miscarriages. Due to the high rate of life-threatening bleeding, primary prophylaxis is mandatory from the time of diagnosis. Although replacement therapy is the most common therapeutic choice, gene therapy remains the only curative option. In the present study, we assessed the efficacy of the clustered regularly interspaced short palindromic repeats - CRISPR-associated protein 9 (CRISPR/Cas9) system in the correction of the most common FXIII disease-causing mutation (c.562 T > C). A dermal fibroblast was harvested from the human skin biopsy of a young patient with FXIII deficiency. Sanger sequencing was used to confirm the presence of c.562 T>C mutation in the patient and in the harvested fibroblasts. PX459 vector was digested with BbsI restriction enzyme, and after annealing and ligation of two 20-bp guide-RNAs (g-RNAs) close to the PAM (NGG) sequence, the constructed vectors were amplified in Escherichia coli Top 10. Transfection was performed by a nucleofector device, and DNA extraction was performed after puromycin selection and serial dilution from potentially transfected colonies. A 50-bp template oligonucleotide was used to aid homologous repair for correction of the underlying mutation and synonymous mutation as an internal control. The synonymous mutation (AAT to ACT) near the mutation site was used as internal control. Sanger sequencing was done in order to check the gene correction. The c.562 T > C mutation was detected in homozygote state in the primary fibroblasts of the patient and wild-type alleles were confirmed in the normal individual. Colony PCR and sequencing revealed successful cloning of the designed gRNAs. The detected mutation was corrected from a homozygote mutant state (c.562 T > C) to a homozygote wild type in transfected dermal fibroblasts of the patient. The control mutation, as an internal control, was also corrected in the same fibroblasts in the heterozygote manner. The result of the study shows that the CRISPR/CAS9 gene editing system is an effective tool for correction of point mutations in transfected fibroblasts of patients with congenital FXIII deficiency and represents a new, potentially curative, option.

Bleeding Complications Associated With Intrauterine Contraception in Women Receiving Anticoagulation Therapy

ObjectiveTo determine whether anticoagulation therapy is associated with an increased risk of complications after initiation of intrauterine contraception (IUC). Patients and MethodsWe retrospectively reviewed records of women receiving anticoagulation therapy at the time of IUC placement from 2000 to 2017 and records of controls (no anticoagulation), matched by race, age, and body mass index. The primary outcome was the cumulative incidence of bleeding (more than spotting [World Health Organization bleeding grades 2 to 4]), IUC expulsion, and IUC removal. Secondary outcomes included treatment for bleeding and bleeding patterns stratified by medication and IUC type. Outcomes were assessed at 24 hours, 30 days, and 6 months after IUC placement. ResultsWe matched 208 women taking anticoagulants with 421 controls. The most common anti-coagulant agents were aspirin (60.1%) and warfarin (36.1%). Most women received the levonorgestrel IUC. No complications occurred within 24 hours. Patients receiving anticoagulants had higher rates of the primary composite outcome at 30 days (odds ratio, 1.77 [95% CI, 1.04 to 3.04]; P=.04) and at 6 months (odds ratio, 2.05 [95% CI, 1.29 to 3.26]; P=.002). Primary complications did not differ by IUC type among control patients, but among women receiving anticoagulants, nonhormonal IUC was associated with an increased rate of complications (P=.04). ConclusionAnticoagulation therapy was associated with higher rates of bleeding at 30 days and 6 months, and nonhormonal IUC plus anticoagulation therapy was associated with higher rates of primary complications. Our findings support current periprocedural anticoagulation guidelines, which state that anticoagulation and antiplatelet therapy can be continued at the time of IUC insertion.

Antiplatelet Use in Ischemic Stroke.

Objective:A literature review of antiplatelet agents for primary and secondary stroke prevention, including mechanism of action, cost, and reasons for lack of benefit.Data sources:Articles were gathered from MEDLINE, Cochrane Reviews, and PubMed databases (1980-2021). s from scientific meetings were considered. Search terms included ischemic stroke, aspirin, clopidogrel, dipyridamole, ticagrelor, cilostazol, prasugrel, glycoprotein IIb/IIIa inhibitors.Study selection and data extraction:English-language original and review articles were evaluated. Guidelines from multiple countries were reviewed. Articles were evaluated independently by 2 authors.Data synthesis:An abundance of evidence supports aspirin and clopidogrel use for secondary stroke prevention. In the acute phase (first 21 days postinitial stroke), these medications have higher efficacy for preventing further stroke when combined, but long-term combination therapy is associated with higher hemorrhage rates. Antiplatelet treatment failure is influenced by poor adherence and genetic polymorphisms. Antiplatelet agents such as cilostazol may provide extra benefit over clopidogrel and aspirin, in certain racial groups, but further research in more diverse ethnic populations is needed.Relevance to patient care and clinical practice:This review presents the data available on the use of different antiplatelet agents poststroke. Dual therapy, recurrence after initiation of secondary preventative therapy, and areas for future research are discussed.Conclusions:Although good evidence exists for the use of certain antiplatelet agents postischemic stroke, there are considerable opportunities for future research to investigate personalized therapies. These include screening patients for platelet polymorphisms that confer antiplatelet resistance and for randomized trials including more racially diverse populations.

Development and validation of a coding framework to identify severe acute toxicity from systemic anti-cancer therapy using hospital administrative data

BackgroundThe capture of toxicities from systemic anti-cancer therapy (SACT) in real-world data will complement results from clinical trials. The aim of this study was to develop and validate a comprehensive coding framework to identify severe acute toxicity in hospital administrative data. MethodsA coding framework was developed to identify diagnostic codes representing severe acute toxicity in hospital administrative data. The coding framework was validated on a sample of 23,265 colon cancer patients treated in the English National Health Service between 1 June 2014 and 31 December 2017. This involved comparing individual toxicities according to the receipt of SACT and according to different SACT regimens, as well as assessing the associations of predictive factors and outcomes with toxicity. ResultsThe severe acute toxicities captured by the developed coding framework were shown to vary across clinical groups with an overall rate of 26.4% in the adjuvant cohort, 53.4% in the metastatic cohort, and 12.5% in the comparison group receiving no chemotherapy. Results were in line with regimen-specific findings from clinical trials. For example, patients receiving additional bevacizumab had higher rates of bleeding (12.5% vs. 2.7%), gastrointestinal perforation (5.6% vs. 2.9%) and fistulation (1.4% vs. 0.5%), and allergic drug reactions (1.4% vs. 0.5%). Severe acute toxicity was associated with pre-existing renal (p = 0.001) and cardiac disease (p = 0.038), and urgency of surgery (p = 0.004). Severe toxicity also predicted lower rates of completion of chemotherapy (p = <0.001) and an increased likelihood of altered administration route (p = <0.001). ConclusionThese results demonstrate that the developed coding framework captures severe acute toxicities from hospital administrative data of colon cancer patients. A similar approach can be used for patients with other cancer types, receiving different regimens. Toxicity captured in administrative data can be used to compare treatment outcomes, inform clinical decision making, and provide opportunities for benchmarking and provider performance monitoring.

Rivaroxaban and apixaban in patients with atrial fibrillation; a real-world data.

This study aims to analyze the real-life data of patients who were prescribed rivaroxaban and apixaban and to emphasize the points that we think will make a difference compared to randomized controlled studies. The patients who accepted to participate in the study in whom rivaroxaban (15-20 mg) and apixaban (2.5-5 mg) were started with the diagnosis of atrial fibrillation between 01 January 2018 and 31 December 2019 and whose records were fully accessed through the hospital automation system were included in the study. One hundred and ninety-four (48.5%) of a total of 400 patients using rivaroxaban and apixaban were women. The mean age was 73.34 ± 10.45 years, and the age range was 41-98. There was no significant difference in terms of demographic characteristics, background information of the patients, and the medications. Drug-induced complications and mortality rates were also similar. The GFR change rates of the patients in both groups were similar even though the initial GFRs were significantly higher in rivaroxaban group. The mean age and ejection fractions of the patients using rivaroxaban 15 mg were found to be lower than those of patients using rivaroxaban 20 mg whereas the mean systolic blood pressure and HAS-BLED score were found to be higher. Ischemic stroke and mortality rates were higher in patients using 15 mg rivaroxaban than patients using 20 mg rivaroxaban. The rates of nonmajor bleeding in patients using rivaroxaban 15 mg were lower compared to those using 20 mg, and this difference was statistically significant. Stroke rates were found to be higher and to have similar bleeding rates compared to major clinical studies in our real-life analysis. However, high ischemic cerebrovascular event and low nonmajor bleeding rates are remarkable in low dose use of rivaroxaban. It is clear that there is a need to consider existing dose reduction criteria in terms of correct prescribing.

Incidence of venous thromboembolism in advanced lung cancer and efficacy and safety of direct oral anticoagulants: a multicenter, prospective, observational study (Rising-VTE/NEJ037 study).

Background:Venous thromboembolism (VTE) is a well-known type of cancer-associated thrombosis and a common complication of malignancy. However, the incidence of VTE associated with lung cancer and the effectiveness of direct oral anticoagulants remain unclear. This study aimed to identify the incidence of VTE associated with lung cancer at the time of diagnosis or during treatment, the efficacy and safety of edoxaban, and associated risk factors.Methods:The Rising-VTE/NEJ037 study was a multicenter prospective observational study. Altogether, 1021 patients with lung cancer who were unsuitable for radical resection or radiation were enrolled and followed up for 2 years. Patients with VTE at the time of lung cancer diagnosis started treatment with edoxaban. The primary endpoint of this trial was the rate of newly diagnosed VTE after enrollment or recurrence rate 6 months after treatment initiation.Results:Data were available for 1008 patients. The median age was 70 years (range: 30–94 years), and 70.8% were men. Sixty-two patients had VTE at the time of lung cancer diagnosis, and 38 (9.9%) developed VTE at follow-up. No cases of VTE recurrence were recorded 6 months after treatment initiation with edoxaban. Major and clinically relevant non-major bleeding events occurred in 4.9% of patients and increased to 22.7% in the edoxaban treatment group.Conclusions:VTE occurrence should be monitored during lung cancer treatment. Although treatment with edoxaban was highly effective in preventing VTE recurrence, its administration should be cautiously considered because of the high bleeding rate.Trial registration:jRCTs061180025.

ASSESSMENT OF ORAL HEALTH CONDITION IN CHILDREN WITH DIFFERENT SOCIAL STATUS IN GEORGIA

Task: Oral diseases are prevalent worldwide. Children from the families with low economic capacity are particularly vulnerable to this group of diseases. Planning dental care is impossible without studying the intensity and prevalence of dental diseases. The aim of the research is to study the oral health condition in a contingent of children with different social status in Georgia. Methods: During the study was selected a prospectus, cross-sectional study through the direct consultation. Children and adolescents deprived of care included within the leaving prevention and deinstitutionalization process are the subjects of study. Target population was studied in 10 facilities located in Tbilisi, Rustavi, Kutaisi, Batumi, Martkopi, Norio (276 beneciaries). And control population was studied in secondary education institutions of Tbilisi, Rustavi, Chiatura, Kutaisi and Poti (276 students). The contingent studied was divided into two age groups - the study and control group: children and adolescents aged 6-13 and 13-18. Age and gender distribution were similar to the group of target children. The results obtained were recorded in the medical and dental cards, where information on the following variables was lled: name of the institution; social status of the object; age; sex; oral hygiene index; caries intensity (DMFT index); prevalence of caries; BoP index; determination of the teeth with extraction indication; prematurely extracted teeth. The standard software was used for the statistical analysis (SPSS 24). Results: The prevalence rate of caries among the children and adolescents of the target group is 98.9% and in the control group the same rate is 64.8%. The prevalence rate of caries among the female individuals of the target group is 93.4%, and in the female population of the control group is 56.8%. The prevalence rate of caries in the male population of the target group is 97.8%, and in male individuals of the control group it is 69.5%. The prevalence rate of caries among the children of the target group aged 6-13 is 94.2%, and among the children of the control group is 64.6%. The prevalence rate of caries among the adolescents of the target group aged 13-18 is 97.1%, and among the adolescents of the control group is 61.9%. Statistical analysis showed that the DMFT index is signicantly higher by age, gender and region among the children and adolescents of the target group (p&lt;0.001). 40.6% of the study group has very high levels of caries intensity and 13% the has higher level. A different data is among the children and adults of the control group, only 4% has very high level of caries intensity and 2.9% has a high level. Comparing the sex, age and region of the control and target groups showed that the difference between these two groups is statistically signicant, the individuals of the target group have a higher caries intensity than those of the control group (P&lt;0.001). The hygiene index rate of a third of the beneciaries studied is very poor (31.2%), and if poor in 15.2%. Only a fth (19.2%) had a good condition. Comparison of the sex, age and region of the control and target groups showed that the difference between these two groups is statistically signicant, and the individuals from the target group had a poorer oral hygiene index rates than those of the control group (P&lt;0.001). 62% of the target group had no signs of bleeding (0 %), 11.6% in total had a high bleeding rate (25-75% and 75-100%). 96.7% of the control group had no signs of bleeding.15.1% of the study population had a prematurely extradited permanent dentitions and 2% of the control group. 15.7% of the control population had a caries complication of the permanent dentitions and 38.1% of the study population.

Abstract 12512: Antithrombotic Strategies According to Age in Patients With Atrial Fibrillation and a Recent Acute Coronary Syndrome or Percutaneous Coronary Intervention: Insights From the Augustus Trial

Background: In AUGUSTUS, apixaban led to lower rates of bleeding and hospitalization than VKA, and aspirin caused more bleeding than placebo, in patients with AF and ACS and/or PCI treated with a P2Y12 inhibitor. We evaluated the safety and efficacy of different antithrombotic strategies by age in this population. Methods: Patients were stratified into 3 age groups: &lt;65, 65-74, and ≥75 years. Outcomes of interest were adjudicated ISTH major or clinically relevant nonmajor (CRNM) bleeding, ISTH major bleeding, death or rehospitalization, and death or ischemic events. The treatment effects of apixaban vs. VKA and aspirin vs. placebo were assessed across age categories using Cox models. Results: Of 4614 patients, 1267 (27.5%) were &lt;65, 1802 (39.0%) were 65-74, and 1545 (33.5%) were ≥75 years. All events, including bleeding, rehospitalization, and ischemic events, were more common with older age. Compared with VKA, apixaban was associated with lower rates of ISTH major or CRNM bleeding, ISTH major bleeding, and death or hospitalization, regardless of age (Fig). Apixaban was associated with greater absolute reduction in ISTH major bleeding than VKA in the older age groups, reflecting the higher bleeding risk in these groups. No differences were observed in rates of death or ischemic events between apixaban and VKA according to age. Patients who received aspirin had higher rates of bleeding than those receiving placebo in all age groups. Rates of death or rehospitalization and death or ischemic events were similar among patients receiving aspirin or placebo in different age categories. Conclusions: The safety and efficacy of apixaban compared with VKA was consistent with the overall trial findings, irrespective of age. Aspirin compared with placebo increased ISTH major or CRNM bleeding in all age groups. Our findings support the use of apixaban plus a P2Y12 inhibitor without aspirin as the standard therapy for this patient population, regardless of age. Figure: Outcomes by Age

Anticoagulation Use and Outcomes Among Patients with Atrial Fibrillation and Von Willebrand Disease

Intro: Von Willebrand disease (VWD) is a coagulopathy caused by deficiency or dysfunction of von Willebrand factor (VWF), resulting in prolonged and excessive bleeding. Patients are advised to avoid aspirin (ASA), P2Y12 inhibitors, or anticoagulation (AC) so as not to exacerbate this condition. However, typical treatment for atrial fibrillation (AF) includes anticoagulation, particularly if the risk of stroke by CHA 2DS 2-VASC score is 2+. Current recommendations suggest giving necessary antiplatelet (AP) or AC therapy over no treatment with assessment of bleeding risk throughout the course. However, this is a conditional recommendation based on low certainty in evidence, and there are no specific guidelines on treating AF in patients with VWD. This study aims to assess anticoagulation use, bleeding risk, and stroke risk in patients with VWF and AF.Methods: We conducted an IRB-approved analysis of coded data from institutional electronic medical records to select patients with diagnosis of VWD, low ristocetin cofactor level, or any abnormal VWF panel as well as patients with diagnosis of AF or atrial flutter. Three hundred and forty patients met criteria. Patients were manually screened for inclusion criteria and excluded for inaccurate diagnosis or insufficient data. Eighty-nine patients were included in the analysis. Primary endpoint was rate of major bleeding defined by ISTH criteria while on AC or AP. Categorical data were tested using the Fisher exact test at the nominal 0.05 two-sided significance level, and all person-time comparisons are made against the rate of bleeding on AC alone.Results: Most patients were female (64.0%; 57/89), and 28.1% (25/89) were deceased at the time of data collection. Date of diagnosis of AF ranged from 1980-2020. 42.7% (38/89) of patients were ever prescribed ASA, 43.8% (39/89) a P2Y12 inhibitor, 56.2% (50/89) AC, and 23.6% (21/89) had never been prescribed AP or AC. Of patients with a CHA 2DS 2-VASC of 2+, 57.5% (46/80) were ever prescribed AC. 32.0% (16/50) of patients ever prescribed AC and 25.6% (10/39) patients never prescribed AC had at least one major bleeding event (p=0.428). The rate of major bleeding on AC alone was 8.9 events per 100 person-years (32 events/359.2 years), 10.2 events per 100 person-years on AP alone (41 events/402.3 years) (p=0.572), and 1.06 events per 100 person-years (8 events/757.47 years) in patients never prescribed AC or AP (p=<0.0001). Notably, the rate of major bleeding on AC and AP together was 28.07 events per 100 person-years (23 events/81.94 years) (p=<0.0001) occurring in 7 patients, 6 of whom also had a diagnosis of acute coronary syndrome (ACS). Length of time to first major bleed is shown in Figure 1. 16.9% (15/89) of patients had thromboembolic strokes after diagnosis of AF, and 53.3% (8/15) of those strokes occurred when patients were not prescribed AC.Discussion: This retrospective observational study over 40 years characterizes AC and AP use in patients with VWD and AF. Only 57.5% of patients with CHA 2DS 2-VASC of 2+ received standard of care AC despite conditional recommendations to give necessary anticoagulation to patients with VWD. In parallel with the general population, AC use significantly increases the rate of major bleeding in patients with VWD, but there was no difference in bleeding rate between standard AC and AP monotherapy. However, major bleeding rates were notably elevated in patients prescribed concomitant AC and AP which most commonly occurred in the setting of ACS. This analysis is limited by its retrospective nature, the lack of granular details in the coded database, and incomplete data in older charts. Overall, these data do not support the use of AP monotherapy over standard AC to reduce bleeding rates for patients with VWD and AF. Additionally, AC and AP co-administration should be avoided due to high rates of major bleeding, but more studies are required to understand AP and AC strategies in patients with VWD, AF, and ACS. Although the rate of major bleeding is elevated with AC use in patients with VWD, there is no difference in lifetime prevalence of major bleeding events by AC vs no AC use. Finally, over half of thromboembolic strokes occurred when not prescribed AC. Shared decision-making around stroke and bleeding risk is advised in considering AC use for AF in patients with VWD. Prospective studies should further evaluate the risk of major bleeding and stroke in patients with VWD and AF on standard AC vs no AC. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Ex Vivo T-Cell Receptor αβ +/CD19 +depletion of Peripheral Stem Cell Grafts for Pediatric Patients with Bone Marrow Failure (BMF) Undergoing Unrelated Donor Transplantation

Background: Success of alternative donor stem cell transplantation (SCT) for acquired and inherited bone marrow failure (BMF) syndromes has previously been limited by significant risks of severe graft versus host disease (GvHD) and graft failure, particularly for patients who lack fully HLA-matched donors. The development of post-transplant cyclophosphamide (ptCy)-based haploidentical donor SCT has mitigated but not eliminated these risks, and the relatively slow engraftment seen with ptCy bone marrow grafts may not be ideal given high rates of infectious disease and bleeding concerns in patients with BMF. Partial T cell depletion of mobilized peripheral stem cell (PSC) grafts can greatly reduce risks of graft versus host disease while facilitating rapid and robust engraftment by providing a high stem cell dose. We previously reported excellent outcomes with minimal GVHD and no graft rejection using peripheral stem cell transplant (PSCT) combined with ex vivo CD3 +/CD19 +depletion and low dose CD3+ T cell addback from matched unrelated donors (MUD) and mismatched unrelated donors (MMUD) in pediatric patients with BMF. Here, we describe the use of selective ex vivoT cell receptor (TCR)αβ +/CD19 +depletion of mobilized PSC from MUD and MMUD for pediatric patients with BMF, which has the advantage of retaining TCRgd +T cells which may help facilitate engraftment and decrease infections.Methods: We report the outcomes of 26 pediatric patients with BMF (excluding MDS-defining clonal evolution) who underwent MUD/MMUD PSCT with TCRαβ +T cell/CD19 +depletion using CliniMACS at The Children's Hospital of Philadelphia from 2017 to 2021. Patients were enrolled on a prospective clinical trial for patients with BMF (NCT03047746, n=21)or on an expanded access study (NCT03145545, n=5). Conditioning regimens consisted of thymoglobulin (9mg/kg), cyclophosphamide (100mg/kg), fludarabine (150mg/m 2), and low dose TBI (200-300 cGy) for patients with acquired BMF disorders, thymoglobulin (9mg/kg), busulfan (PK-adjusted), fludarabine (150mg/m 2), and thiotepa (10mg/kg) for patients with single lineage BMF or thymoglobulin. One patient with Fanconi Anemia received thymoglobulin and fludarabine, with reduced dosing of busulfan and cyclophosphamide. Patients undergoing MSD-BMT for BMF over a similar time period served as a comparison group for engraftment kinetics, rates of GVHD, donor chimerism, immune reconstitution, and overall survival.Results: Subjects included 18 with severe acquired aplastic anemia (SAAA), 4 with SAAA and concurrent paroxysmal nocturnal hemoglobinuria (PNH), 2 patients with acquired BMF not otherwise specified, 1 patient with DBA, and 1 patient with Fanconi Anemia. 11 patients with SAAA underwent SCT as initial therapy while 11 patients had SCT after failing previous medical therapies. Median age at diagnosis was 10.3 years (0.1-20.6) and at transplant 11.1 years (0.9-21). HLA match of unrelated donors was either 10/10 (n=15), or 9/10 (n=11). Median CD34 +and TCR αβ +T cell dose was 12.0x10 6cells/kg (3-22.6) and 0.1x10 5cells/kg (0.0-4.2). Median times to neutrophil and platelet engraftment per CIBMTR criteria were 15 days (10-22) and 15 days (13-19), respectively, both significantly earlier than engraftment following MSD-BMT (Fig 1a). At a median follow-up of 727 days (39-1498), 25 of 26 patients are alive with resolved hematologic disease (Fig 1b). One patient with SAAA+PNH who failed prior IST achieved trilinear engraftment without GVHD, but died on Day+95 due to acute disseminated toxoplasmosis. No patients exhibited immunologic graft rejection. 2/26 patients had grade II acute GVHD that responded to steroids and none developed Grade III-IV acute or chronic extensive GVHD (Fig 1c) CMV viremia/reactivation occurred in 5 subjects, all responding to antiviral pharmacotherapy, and none developed end-organ CMV disease (Fig 1d). One patient developed recipient-derived EBV post-transplant lymphoproliferative disorder requiring multimodal treatment. Only one patient developed BK cystitis. Total peripheral chimerism exceeded 90% in all patients. Immune reconstitution kinetics were similar to that seen in MSD-BMT.Conclusion: MUD/MMUD PSCT with TCRαβ +T cell/CD19 +depletion in patients with BMF enables rapid, durable engraftment with minimal risk of GVHD and immunologic graft rejection. [Display omitted] DisclosuresMonos: Omixon: Consultancy, Patents & Royalties. Grupp: Jazz Pharmaceuticals: Consultancy, Other: Steering committee, Research Funding; Novartis, Adaptimmune, TCR2, Cellectis, Juno, Vertex, Allogene and Cabaletta: Other: Study steering committees or scientific advisory boards; Novartis, Kite, Vertex, and Servier: Research Funding; Novartis, Roche, GSK, Humanigen, CBMG, Eureka, and Janssen/JnJ: Consultancy.

Clinical and Non-Clinical Determinants of the Effect of Mechanical Thrombectomy and Post-Stroke Functional Status of Patients in Short and Long-Term Follow-Up.

To date, inconsistent results evaluating the effect of parameters on mechanical thrombectomy (MT) outcomes in stroke-patients have been published. This study aimed to identify the key parameters for functional status after MT in stroke-patients in short and long-term follow-up. Method: The study analysis focused on the relevance of selected clinical and non-clinical parameters to the functional status of the patients after MT. Results: 417 stroke-patients (mean age 67.8 ± 13.2 years) were qualified. Atrial fibrillation, and leukocytosis were significant for the neurological status on the first day of stroke (p = 0.036, and p = 0.0004, respectively). The parameters with the strongest effect on the functional status on day 10 were: age (p = 0.009), NIHSS (p = 0.002), hyperglycemia (p = 0.009), the result in TICI (p = 0.046), and first pass effect (p = 0.043). The parameters with the strongest effect on the functional status on day 365 were: age and NIHSS on the first day of stroke (p = 0.0002 and 0.002, respectively). Leukocytosis and the neurological status at baseline were key parameters associated with ICB after MT (p = 0.007 and p = 0.003, respectively). Conclusions: Age and neurological status in the ultra-acute phase of stroke are crucial for the functional status in short and long-term observations of patients treated with mechanical thrombectomy. Atrial fibrillation, hyperglycemia, and inflammatory state are relevant to the short-term post-stroke functional status. First pass effect and the degree of post-interventional reperfusion are important technical parameters to the short-term functional status. Neurological status and white blood count during the acute phase are associated with a high rate of post-procedural intracranial bleeding.

Management and outcomes of patients with left atrial appendage thrombus prior to percutaneous closure

ObjectiveLeft atrial appendage (LAA) thrombus has heretofore been considered a contraindication to percutaneous LAA closure (LAAC). Data regarding its management are very limited. The aim of this study was to...

Blood Loss and Transfusion in a Pediatric Scoliosis Surgery Cohort in the Antifibrinolytic Era.

Children and adolescents undergoing posterior spinal fusion for scoliosis experience high rates of bleeding and blood product transfusion. Antifibrinolytic therapy is one key strategy to decrease blood loss and transfusion in pediatric scoliosis surgery. Here we review 172 pediatric scoliosis patients (birth to 21 y) who underwent posterior spinal fusion at our institution from 2017 to 2018. We reported rates of blood loss and transfusion, compared patients receiving tranexamic acid to a ε-aminocaproic acid, and evaluated antifibrinolytic agent and laboratory parameters as predictors of blood loss and transfusion. Intraoperatively, 62% received tranexamic acid and 38% received ε-aminocaproic acid. Overall, blood loss (mean intraoperative estimated blood loss=14.9±9.7 mL/kg, 22% with clinically significant blood loss [>20 mL/kg], and mean calculated hemoglobin mass loss=175.9±70.1 g) and transfusion rates (15% with intraoperative allogeneic red blood cell transfusion and mean intraoperative allogeneic red blood cell transfusion volume=12.5±7.1 mL/kg) were similar to previous cohorts studying intraoperative antifibrinolytics. There was no difference in intraoperative estimated blood loss, clinically significant blood loss, calculated hemoglobin mass loss, or transfusion rates between the antifibrinolytic groups. Antifibrinolytic choice was not predictive of blood loss or transfusion. Routine hematologic laboratory parameters and antifibrinolytic choice were insufficient to predict blood loss or other outcomes. Future prospective laboratory-based studies may provide a more comprehensive model of surgical-induced coagulopathy in scoliosis surgery and provide a better tool for predicting blood loss and improving outcomes.

Antithrombotic therapy and bleeding complications in patients with atrial fibrillation and active cancer

Abstract Background Little is known about the extent to which an active cancer diagnosis increases bleeding and thromboembolic risks in atrial fibrillation (AF) patients. Data on major bleeding rates per antithrombotic management strategy are lacking in AF patients with active cancer. Purpose To examine the incidence rates of major bleeding per antithrombotic treatment in AF patients with active cancer and to examine whether cancer type impacts major bleeding and thromboembolic risks. Methods We used Danish population-based health care databases to conduct this cohort study. We included all incident AF (including atrial flutter) patients aged ≥50 years between January 1st 1995 and December 31st 2016, out of whom we identified AF patients who subsequently developed cancer. We used International Classification of Diseases 10th Revision codes to identify data on cancer type and outcomes (i.e. major bleeding, arterial and venous thromboembolism). We used Anatomical Therapeutic Chemical codes to provide information on antithrombotic treatment (e.g. no anticoagulant treatment, platelet inhibitors, vitamin K antagonists, direct oral anticoagulants, or a combination of antithrombotic drugs) which was evaluated as a time-dependent variable. The follow-up started from the incident cancer diagnosis until the occurrence of an outcome, death or the end of the two year follow-up. Incidence rates per 100 patient-years and adjusted hazard ratios were computed. Results 22,996 AF patients with a subsequent incident cancer diagnosis were included in the study. These patients had higher major bleeding and thromboembolic risk compared to those without cancer, with adjusted HRs of 2.11 (1.99–2.23) and 1.36 (1.27–1.44), respectively (Figure 1). Highest bleeding risk was observed for intracranial and respiratory cancer, while haematological and respiratory cancer were associated with highest thromboembolic risk. Bleeding risk increased with increasing number of antithrombotic drugs and was higher in AF patients with active cancer compared to those without, across all exposure categories (Figure 2). Conclusions Patients with AF and active cancer are at increased risk of major bleeding and thromboembolisms than those without cancer. Treatment with dual or triple antithrombotic therapy in AF patients with active cancer showed very high bleeding rates. Funding Acknowledgement Type of funding sources: None.

Utility and safety of the MANTA device for access site closure after removal of the mechanical hemodynamic support device Impella on the intensive care unit

Abstract Background The percutaneously implanted hemodynamic mechanical support devices Impella are commonly used in patients at risk for or with cardiogenic shock (CS). Impella removal after hemodynamic stabilization on the intensive care unit (ICU) remains a major challenge and is prone to high rates of bleeding and vascular complications. Purpose It is unknown if the use of the novel large-bore access closure device MANTA® is safe and facilitates access management compared to manual compression. Methods Between January 2017 and December 2020, 172 CS patients were treated with an Impella® device at our centre. Of those, in 89 patients the Impella® was removed on the ICU and access site management occurred with either MANTA® device or manual compression. The criteria for MANTA® 14 french device deployment included: (i) femoral artery Diameter &amp;gt;6mm and (ii) absence of significant peripheral arterial disease (PAD). Bleeding and vascular access site complications were assessed and adjudicated according to the Valve Academic Research Consortium-2 (VARC-2) criteria. Results Among the 89 included patients, Impella® removal was performed using the MANTA® device in 31 cases and manual compression in 58 cases. Mean age was 66±11 years, and 50 (56.2%) patients had a CS classified as Society for Cardiovascular Angiography and Interventions (SCAI) D or higher due to myocardial infarction. Median support time was 40 (IQR 24; 69) hours. Baseline characteristics are displayed in Table 1. Immediate haemostasis was more frequently achieved by MANTA® device compared to manual compression (p=0.034). Moreover, we observed significantly less overall (2 (6.5%) vs. 22 (37.9%), p=0.001) and minor bleedings (1 (3.2%) vs. 15 (25.9%), p=0.006) with the MANTA® device when compared to manual compression. Of note, there were no significant differences in vascular complications between the two groups (Table 2). Conclusions In patients requiring Impella® support and residing on ICU, the MANTA® device, compared to standard of care manual compression, seems to be a safe and effective option for access site management, especially with regards to the reduction of bleeding events. However, physicians should carefully assess the vascular anatomy and degree of calcification prior to deployment of the MANTA® device. Nevertheless, more prospective data is necessary for evaluating the optimal access closure among CS patients treated with a percutaneously implanted Impella® device. Funding Acknowledgement Type of funding sources: None. Table 1. Baseline demographicsTable 2. Outcomes

Atrial fibrillation in patients with a history of cancer and risk of bleeding complications associated with antithrombotic therapy

Abstract Background Up to one in four patients with atrial fibrillation (AF) has a cancer diagnosis. It is largely unknown to which extent a prior cancer diagnosis affects major bleeding and thromboembolic risk in AF patients. Moreover, data on major bleeding rates per antithrombotic treatment type are lacking in these patients. Purpose To examine the incidence rates of major bleeding per antithrombotic treatment in AF patients with prior cancer and to examine whether cancer type and the time-interval between AF and cancer influence major bleeding and thromboembolic risks. Methods This nationwide population-based cohort study included incident Danish AF patients aged ≥50 years between 01–01–1995 and 31–12–2016. Data on prior cancer, major bleeding and thromboembolisms (i.e. arterial and venous) were obtained from Danish health registries via International Classification of Diseases 10th Revision codes. We stratified according to prior cancer and by time between the AF and cancer diagnosis (i.e. &amp;lt;1 year, 1–3 years, &amp;gt;3 years), and cancer type. Data on antithrombotic exposure (e.g. no anticoagulant treatment, platelet inhibitors, vitamin K antagonists, direct oral anticoagulants, or combination of antithrombotic drugs) were evaluated as a time-dependent variable. We computed incidence rates per 100 patient-years and adjusted hazard ratios in a Cox regression model. Results We identified 39,178 AF patients with a prior cancer diagnosis. Bleeding risk increased with increasing number of antithrombotic drugs and was higher in AF patients with a history of cancer compared to those without, across all exposure categories (Figure 1). The increased bleeding risk was similar across different time intervals between cancer and AF diagnosis. The increased thromboembolic risk steeply declined with increasing time intervals between AF and cancer diagnosis (Figure 2). Prior gastrointestinal, intracranial, haematological, respiratory and urogenital cancers were associated with an increased bleeding risk. The two latter cancer types were also associated with increased thromboembolic risks. Conclusion We showed that patients with atrial fibrillation and a prior history of cancer experience higher rates of bleeding than those without cancer. Both respiratory and urogenital cancers had the highest rates of bleeding and thromboembolisms. Funding Acknowledgement Type of funding sources: None.

386 Prevalence of Abnormal Uterine Bleeding in a Multicenter Implementation Study Using Apixaban and Rivaroxaban to Treat Venous Thromboembolism

Direct oral anticoagulants (DOACs), such as apixaban and rivaroxaban have been endorsed by clinical practice guidelines for the outpatient treatment of venous thromboembolism (VTE). Concerns have been raised from registries about a high rate of abnormal uterine bleeding (AUB) associated with DOACs. To further explore the hypothesis that the frequency of AUB is different between women with venous thromboembolism treated with rivaroxaban versus apixaban, we conducted a secondary analysis of a multicenter implementation trial of patients discharged from the emergency department (ED) on VTE monotherapy that employed both of these anticoagulants.

Philadelphia-Negative Myeloproliferative Neoplasms Around the COVID-19 Pandemic.

Purpose of ReviewCoronavirus disease 2019 (COVID-19) is associated with a high rate of respiratory failure, thromboembolism, bleeding, and death. Patients with myeloproliferative neoplasms (MPNs) are prone to both thrombosis and bleeding, calling for special care during COVID-19. We reviewed the clinical features of MPN patients with COVID-19, suggesting guidance for treatment.Recent FindingsOne study by the European LeukemiaNet collected 175 MPN patients with COVID-19 during the first wave of the pandemic, from February to May 2020. Patients with primary myelofibrosis (PMF) were at higher risk of mortality (48%) in comparison with essential thrombocythemia (ET) (25%) and polycythemia vera (19%); the risk of death was higher in those patients who abruptly discontinued ruxolitinib. In patients followed at home, in regular wards, or in ICU, the thrombosis rate was 1.0%, 2.8%, and 18.4%, respectively. Independent risk factors for thrombosis were ET phenotype, transfer to ICU, and neutrophil/lymphocyte ratio; major bleeding occurred in 4.3% of patients, particularly those with PMF.SummaryMPN patients with non-severe COVID-19 treated at home should continue their primary or secondary antithrombotic prophylaxis with aspirin or oral anticoagulants. In the case of hospitalization, patients assuming aspirin should add low molecular weight heparin (LMWH) at standard doses. In contrast, LMWH at intermediate/therapeutic doses should replace oral anticoagulants prescribed for atrial fibrillation or previous venous thromboembolism. Intermediate/high doses of LMWH can also be considered in ICU patients with ET, particularly in the case of a rapid decline in the number of platelets and progressive respiratory failure.