DeLoughery, Emma P.

Background: Identifying individual and systemic risk factors are key to reducing cancer incidence and improving mortality. Unfortunately for hematologic malignancies, few clear-cut common cause-and-effect relationships exist. Multiple myeloma has been associated with Black race and obesity, and the lymphomas and leukemias differ in incidence with age. In order to identify potential risk factors, in this study we compared incidence and mortality rates among U.S. states for myeloma, all leukemias and lymphomas, and correlated these rates with the prevalence of several lifestyle and demographic characteristics. Methods: Data came from the following sources: cancer incidence and mortality data from 1999-2015 came from the CDC WONDER database; race and poverty prevalence from the 2015 American Community Survey; gross domestic product (GDP) data from the Bureau of Economic Analysis; median household income from the Census Bureau; and weight and physical activity data from the Behavioral Risk Factor Surveillance System survey. Spearman's rank correlation coefficient was used to compare cancer incidence/mortality and potential risk factors. Results: Myeloma incidence and mortality were more common in obese individuals (incidence, rho = 0.27, P = 0.05; mortality, 0.38, P = 0.006) and individuals identifying as Black (0.65, P < 0.001; 0.42, P = 0.002). Incidence was lower in physically active individuals. (-0.51, P < 0.001). Leukemia incidence and mortality were more common in individuals identifying as white (0.45, P = 0.001; 0.36, P = 0.009). Mortality was positively associated with obesity (0.39, P = 0.005), and negatively associated with physical activity (-0.36, P = 0.009) and median household income (-0.39, P = 0.004). Lymphoma incidence and mortality were more common in white individuals (0.38, P = 0.006; 0.40, P = 0.004). Incidence was negatively associated with state poverty percentage (-0.40, P = 0.003). Mortality was positively associated with obesity (0.35, P = 0.01), and negatively associated with a healthy weight (-0.35, P = 0.01). Discussion: This data suggests that weight and activity are modifiable risk factors for a variety of hematologic cancers, while race may be a non-modifiable risk factor. Individual and state wealth do not appear to play a large role in incidence or mortality. Although further study is needed, these results underscore the importance of maintaining a healthy weight and regular physical activity in cancer prevention. This data also confirms the higher incidence of myeloma in Black individuals and suggests lymphoma and leukemias may be more common among those identifying as white. Disclosures Shatzel: Aronora, Inc.: Consultancy.

Abstract Introduction: Myeloproliferative neoplasms (MPN) are associated with an increased risk of venous (VTE) and arterial (ATE) thromboembolic events (TE). Anticoagulation needs to be balanced between the risk of incident and recurrent TE and risk of hemorrhage. While data on outcomes of anticoagulation with warfarin in patients with MPN are available, data on safety and efficacy of direct oral anticoagulants (DOACs) in this subgroup are not. Herein, we present outcomes of use of DOACs in patients with MPN at our institution. Methods: In this retrospective cohort study, we searched the Mayo Clinic clinical databases for patients meeting the WHO criteria for MPN who had been prescribed a DOAC between 2011 and 2017. The MPN diagnosis had to have predated the DOAC prescription. Medical records of consenting patients meeting study criteria were reviewed and data on demographics, diagnosis of MPN, indication for DOAC prescription, and their efficacy (incident or recurrent TE) and safety (hemorrhagic events) were abstracted. Results: Over the study period, 19 patients (female = 10) met inclusion criteria. The median age of patients at MPN diagnosis was 67 years (35-83), and 73 years (53-86) at initiation of DOAC. Prescribed DOACs included rivaroxaban (n=12), apixaban (n=6), and dabigatran (n=2) (one patient received rivaroxaban and was switched to apixaban). MPN diagnoses included polycythemia vera (PV) (n=9), essential thrombocythemia and chronic myeloproliferative neoplasm NOS (3 each), chronic myeloid leukemia and myelofibrosis (2 each). Indications for DOAC included thromboembolism (n=13; 68%) (arterial:2 and venous:11), and atrial fibrillation (afib) (n=6; 31%). The median duration of DOAC therapy was 241.5 days (range 13-1879). Five patients were switched from warfarin to rivaroxaban (n=4) and apixaban (n=1) at patient and/or provider preference; the rest were initiated on the DOAC de novo based on provider preference. Of the 19 patients, one patient each experienced a major hemorrhagic and TE event. One patient with PV who was on rivaroxaban for afib required hospitalization for gastrointestinal hemorrhage due to gastritis; DOAC was discontinued following this episode. One other patient with PV had a non-ST elevation myocardial infarction while on rivaroxaban for afib and prior stroke; DOAC was continued. There were no deaths attributable to DOAC use. Discussion: Our limited data suggests that use of DOACs in patients with MPN is feasible with an acceptable balance between risk of hemorrhage and recurrent thrombosis. Additional data on long term outcomes of DOACs in MPNs are needed. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction: Though less commonly used than their anticoagulant counterparts, procoagulants have an important role in the reversal of anticoagulation. Four-factor prothrombin complex concentrate (4PCC) is now approved by the U.S. Food & Drug Administration (FDA) for the reversal of major bleeding associated with warfarin, and is often used off-label to reverse direct oral anticoagulants. Three-factor concentrate (3PCC) and off-label use of recombinant activated factor VII (rFVIIa) have filled this role in the past. Vitamin K is also used as a common antidote for warfarin-induced coagulopathy. Comparative data evaluating the safety profiles and relative thrombotic risks of the PCCs and rFVIIa is limited. In order to better evaluate their comparative safety we calculated the rate of adverse events reported to the FDA of each procoagulant. Methods: We evaluated the FDA Adverse Event Reporting System (FAERS) database, which compiles drug-related adverse events reported to the FDA from 1969 onwards, to assess the rate of adverse events reported with various procoagulants. Safety profiles were assessed using proportional reporting ratios (PRR) with the total number of reported cases as the denominator. Adverse events data for each drug (vitamin K, rFVIIa, 3PCC, 4PCC) was gathered from FAERS. Both generic and brand names were used to query the database. Adverse events data was filtered by including only events reported by healthcare professionals. Specific adverse events were chosen apriori based on hypothesized potential complications and included hemorrhagic and thrombotic complications. The PRR with 95% confidence interval was generated for each event, with a cut-off of 2 being used to identify associations. Results: As shown in Table 1 and Figure 1, rFVIIa was associated with increased reports of mortality while 4PCC was associated with ischemic stroke, and all but rFVIIa were associated with high INR. 3PCC displayed an increased association with reports of intracranial hemorrhage (ICH), although there was a low rate of reports for 3PCC. Lesser associations were found between rFVIIa and myocardial infarction (MI), 3PCC and deep-vein thrombosis (DVT), and 4PCC and DVT and ICH. In general, vitamin K had the weakest associations among adverse events. Conclusions: Our analysis found that the rate of reports of death and MI were higher with rFVIIa than other procoagulants, while reports of ischemic stroke and intracranial hemorrhage were more common with PCCs. rFVIIa has been associated with cardiovascular before, a finding reiterated by our study. There are notable limitations of this type of analysis, including the reliance on the accurate reporting of adverse events to the FDA, possibility of duplications of reports in the FAERS database, and the importance of not conflating correlation with causation as it relates to these events. The association between rFVIIa and increased death may be due to rFVIIa's history of off-label use in trauma patients and other patient groups at higher risk for mortality. While 4PCC may be the procoagulant of the present, it does not have a perfect safety profile, and further study is needed to better characterize the complications of 4PCC and ensure that it is used in such a way as to not under- or over-treat the condition. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction: Direct oral anticoagulants (DOACs) are being increasingly used due to their improved safety and efficacy as compared with warfarin. However, unlike warfarin, less is known regarding long-term and large-scale side effects of DOACs. In order to better evaluate the rates of DOAC-related adverse events on a population level we examined the rate of adverse events reported to the U.S. Food & Drug Administration (FDA) for three commonly used DOACs and warfarin. Methods: We evaluated the FDA Adverse Event Reporting System (FAERS) database, which compiles drug-related adverse events reported to the FDA from 1969 onwards. The safety profiles of warfarin and three DOACs were assessed by comparing adverse events per outpatient prescription and with proportional reporting ratios (PRR). Adverse event data for each drug (warfarin, dabigatran, rivaroxaban, apixaban) was gathered from FAERS. The generic name of each drug was used, and in the case of dabigatran and warfarin, dabigatran etexilate mesylate and warfarin sodium respectively were used to query the database. Adverse events data was filtered by including only those reported by healthcare professionals in the U.S. Specific adverse events were chosen apriori based on hypothesized potential hemorrhagic and thrombotic complications. Numbers of U.S. outpatient prescriptions were gathered from the ClinCalc DrugStats database using information from the Medical Expenditure Panel Survey (MEPS). Only adverse events data from years in which there was also prescription data were included in the study. PRR with 95% confidence interval was used to compare rates of DOAC adverse events, with warfarin being excluded to avoid the new-drug effect. A PRR of 2 or greater was considered significant. Results: As shown in Table 1, warfarin had the fewest reported adverse events per prescription for all categories save elevated international normalized ratio. Rivaroxaban had the highest proportion of reported adverse events, most notably the rate for breakthrough venous thromboembolism (VTE) was higher than for other DOACs. Dabigatran had the highest reported rated of ischemic stroke. When the DOAC data was analyzed using PRR, as seen in Figure 1, less difference was observed. Reported rates of pulmonary embolism (PE) and deep-vein thrombosis (DVT) were again higher with rivaroxaban while dabigatran again showed higher than expected rates of ischemic stroke and a slightly higher risk of myocardial infarction. Apixaban did not show higher than expected rates in any category. Reported rates of mortality did not significantly differ among the drugs. Conclusion: Our analysis found that among DOACs rates of breakthrough VTE were significantly higher with rivaroxaban, and that reported rates of ischemic stroke were significantly higher with dabigatran. While no DOACs have been compared against each other in prospective trials, post-marketing reports have suggested that different safety profiles exist among DOACs, a finding reiterated by our analysis. The significantly higher rate of VTE reported with rivaroxaban as compared to other DOACs has not previously been described to the best of our knowledge and deserves further analysis. The two methods of comparing the anticoagulants - reported event rate per prescription and PRR - show slightly different results, but the adverse findings reported with rivaroxaban and dabigatran remain consistent. Limitations of this study include the reliance on the accurate reporting of adverse events and reliability of the MEPS data, possible duplications in the FAERS database, and the importance of not conflating correlation with causation as it relates to these events. Considering both event rate per prescription and PRR, apixaban seems to offer the best safety profile of DOACs according to the FAERS data. Further study is needed to better characterize the comparative safety profiles of DOACs. Disclosures No relevant conflicts of interest to declare.

Abstract Introduction Varied presentations of vitamin B12 (B12) deficiency include hematologic (megaloblastic anemia) and neurologic (myelopathy, peripheral neuropathy). Delayed recognition and treatment may have serious consequences. Assessing B12 status can be challenging due to diverse laboratory assays and thresholds, resulting in a wide range of reported prevalence of B12 deficiency from 3-26%. Comorbidities may also spuriously elevate or suppress B12 levels. Methylmalonic acid (MMA) level, often used as a companion test to assess for B12 deficiency, may also be affected by differing laboratory thresholds and other medical comorbidities, such as renal dysfunction. Our institutional approach to B12 assessment, termed the pernicious anemia (PA) cascade, consists of reflexive testing to 1) document low B12 stores (B12 levels with or without MMA), and 2) diagnose pernicious anemia (intrinsic factor binding antibody [IFBA] with or without gastrin assay). In this study, our objectives were: (1) assess the usefulness of our B12 testing algorithm and associated laboratory thresholds for identifying B12 deficiency, and (2) evaluate clinical follow-up of test results as part of a quality project. Methods In this retrospective study, adult (age ≥18 years) inpatients who had B12 testing from 2007 to 2013 were identified. Medical records for those patients with B12 levels 150-400 ng/L were reviewed. Data abstracted included patient demographics, indication for B12 testing, B12 levels, results for MMA, IFBA, gastrin, serum creatinine, complete blood count, and clinical outpatient follow-up. The PA cascade algorithm is as follows: 1) for B12 <150 ng/L, IFBA is performed; 2) if IFBA is negative or indeterminate, then gastrin is performed; 3) for B12 150-400 ng/L, MMA is performed; 4) if MMA is >0.40 nmol/mL, then IFBA is performed. Reference range for B12 is 180-914 ng/L. Patients were determined to be B12 deficient if B12 level was <180 ng/L, or if B12 was 150-400 ng/L with elevated MMA and macrocytosis in the absence of significant renal dysfunction, defined as serum creatinine ≥2.0 mg/dL. Results Records of 326 patients (150 female) were reviewed. Indications for B12 testing were: hematologic, 175 patients (53.7%); neurologic, 127 patients (39.0 %), psychiatric, 18 patients (5.5%); other, 4 patients (1.2%). Fifty-nine of 326 (18.1%) patients were B12 deficient, of whom 17 of 59 (28.8%) had PA. There were 54 cases of elevated MMA, >0.40 nmol/mL, of which 30 cases had mildly elevated MMA, >0.40 nmol/mL and ≤0.60 nmol/mL, considered to be the MMA "gray zone". Thirty-two of the total 326 patients had serum creatinine ≥2.0 mg/dL, of which 23 patients also had elevated MMA. Elevated MMA in 13 of these 23 patients was more likely due to renal dysfunction than to B12 deficiency. B12 testing results were not mentioned in hospital discharge summaries for 173 patients, including 8 patients with B12 deficiency. For 22 B12-deficient patients, there was no documentation of B12 replacement. Conclusions The PA cascade detected B12 deficiency in a significant number of inpatients with low-normal B12 levels that might have otherwise been missed; 28.8% of this group had PA for whom long-term B12 replacement is indicated. As treatment for B12 deficiency is inexpensive, non-toxic, and non-invasive, it is reasonable to evaluate B12 status by cascade testing which may provide additional diagnostic data beyond B12 level. Notable clinical practice findings from this study include the lack of B12 results in 173 of 326 discharge summaries, and no record of B12 supplementation in 22 of 59 patients with B12 deficiency. These gaps in documentation and follow-up may be associated with the relatively long turnaround time of MMA testing. Efforts at improving documentation, communication, and treatment of B12 deficiency are ongoing. Disclosures No relevant conflicts of interest to declare.

AbstractAlthough anticoagulation without hemorrhage is a primary aim, this vision has remained as yet out of reach. Even despite the superior safety profile of the direct oral anticoagulants, hemorrhage remains a major risk of anticoagulation. Selective inhibition of the contact pathway of coagulation, specifically coagulation factor XI (FXI) and/or factor XII (FXII), has now substantial epidemiologic and preclinical data supporting the notion that these factors contribute to pathologic thrombosis and are yet primarily dispensable for in vivo hemostasis. In this way, targeting FXI and FXII may revolutionize the future anticoagulation landscape. Several drugs are under development for this purpose, including: ISIS 416858, a FXI antisense oligonucleotide which impairs hepatic synthesis of FXI; MAA868, a monoclonal antibody that binds the procoagulant enzymatic site of both zymogen and activated FXI (FXIa); BAY 1213790, a monoclonal antibody that binds the procoagulant enzymatic site of FXIa only; and AB023, a monoclonal antibody that inhibits activated FXII-mediated activation of FXI, along with two small molecules in clinical trials. Each of these drugs have demonstrated favorable safety profiles in their phases 1 and 2 studies to date, with preclinical data also supporting efficacy of abrogating thrombosis in various animal models. Other benefits of some of these drugs include once-monthly dosing and safety in patients with renal or hepatic impairment, while others offer quickly metabolized parenteral options, thus providing more convenient and widely available anticoagulation options. Though still far from the marketplace, drugs targeting FXI and FXII have the potential to usher in a new era of anticoagulation therapy.

The risks of systemic anti-coagulation or its reversal are well known but accepted as necessary under certain circumstances. However, particularly in the plastic surgical patient, systemic alteration to hemostasis is often unnecessary when local therapy could provide the needed adjustments. The aim of this review was to provide a summarized overview of the clinical applications of topical anti- and pro-coagulant therapy in plastic and reconstructive surgery. While not a robust field as of yet, local tranexamic acid (TXA) has shown promise in achieving hemostasis under various circumstances, hemostats are widely used to halt bleeding, and local anticoagulants such as heparin can improve flap survival. The main challenge to the advancement of local therapy is drug delivery. However, with increasingly promising innovations underway, the field will hopefully expand to the betterment of patient care.

AbstractIntroductionDirect oral anticoagulants (DOACs) are being increasingly used. However, unlike warfarin, less is known regarding their long‐term side effects. To better evaluate the rates of DOAC‐related adverse events (AEs) on a population level, we examined AEs reported to the FDA for three commonly used DOACs and warfarin.MethodsWe evaluated the FDA Adverse Event Reporting System (FAERS) database, which compiles reported drug‐related AEs from 1969 onwards. The safety profiles of the included drugs were assessed by comparing AEs per outpatient prescription and with proportional reporting ratios (PRR).ResultsRivaroxaban had the highest proportion of reported AEs. Most notably the rate for breakthrough venous thromboembolism (VTE) was higher than other DOACs. Dabigatran had the highest reported rates of ischemic stroke. When the DOAC data were analyzed using PRR, reported rates of VTE were again higher with rivaroxaban while dabigatran again showed slightly higher than expected rates of ischemic stroke. Apixaban did not show higher than expected rates in any category.ConclusionOur analysis found rates of reported breakthrough VTE were significantly higher with rivaroxaban, while apixaban had no higher than expected rates of any studied AEs.

AbstractAlthough popular for displaying dermatologic conditions before the advent of photography, the medical moulage has also illustrated injuries and accidents. Explored here are three farm accidents and the moulages based on them that occurred in rural Minnesota in the early 20th century. Besides being an object of historical interest, the medical moulage also provides a valuable learning and training opportunity, and can even be thought of as the predecessor of three dimensional printing.