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BACKGROUND The COVID-19 pandemic has extensively impacted the delivery of routine medical care including anticoagulation management. The Veterans Affairs Clinical Pharmacy Practice Office (VA CPPO) has provided guidance to assist anticoagulation clinic providers in developing action plans to determine the risk vs benefit of delaying routine monitoring to reduce patient risk of COVID-19 exposure in the health care system. Frequent laboratory monitoring of the International Normalized Ratio (INR) is needed to reduce the risk of bleeding and thromboembolic events for patients on warfarin. The Madison VA standard of care (SOC) includes routine INR monitoring at least every 6 weeks for stable patients taking warfarin. Alternatively, the benefit of routine laboratory monitoring for direct oral anticoagulants (DOACs) is less clear. Currently, the Madison VA recommends a complete blood count (CBC), serum creatinine (SCr), and liver function tests (LFTs) within 30 days prior to DOAC initiation, repeat CBC +/- SCr 1-3 months after DOAC initiation, then CBC/SCr every 6-12 months, monitored via the VA DOAC population management tool (PMT). Per the 2012 American Society of Hematology (ASH) and the American College of Chest Physicians (CHEST) guidelines, for warfarin, 12-week follow-up may be considered in patients with chronically stable INRs (Kearon et. al. Chest 2012). Additionally, the Madison VA completed a prior prospective study of 12-week INR follow-up for patients taking warfarin which demonstrated safety of extended follow-up intervals. However, the number of participants able to achieve (56%) and maintain (34%) a 12-week INR follow-up were lower than anticipated (Porter et. al. J Thromb Thrombolysis 2016). As of 3/30/2020, the Madison VA anticoagulation clinic followed 783 patients for warfarin management and 1742 patients for DOAC management. STUDY DESIGN AND METHODS A retrospective chart review to assess practice changes during the COVID-19 pandemic was conducted on anticoagulation patients with visits from 3/16/20 and 6/18/20 who were either on warfarin, transitioned to a DOAC, or newly initiated on DOAC therapy. For patients on warfarin with 2 therapeutic INRs obtained at least 4 weeks apart, follow-up was extended to 8-12 weeks. Conversion to a DOAC was considered for eligible warfarin patients, excluding presence of mechanical heart valves, moderate to severe mitral valve stenosis, significant liver disease (Child Pugh C), or pregnancy/breastfeeding. As there are no accepted standards for DOAC laboratory monitoring, per the VA CPPO, stable baseline labs within the prior 6-12 months were acceptable. Routine laboratory monitoring after initiation could also be deferred and patients were transitioned to the DOAC PMT. The data collected in the retrospective study was analyzed using descriptive statistics. OBJECTIVES The objective of this study was to assess patient safety and INR stability using the proposed COVID-19 extended follow-up parameters. If patient safety and stability could be maintained, it may lead to long term practice changes to extend follow-up and improve the anticoagulation clinic workload efficiency. ENDPOINTS The primary endpoint of the warfarin intervention was to determine the percentage of warfarin patients with therapeutic INRs after an extended interval. Secondary endpoints included the average length of the extended interval, bleeding or thromboembolic events during extended interval or within 30 days after the extended INR result. Other secondary endpoints included review of patient misadventures during the extended interval (e.g. patient taking incorrect warfarin doses), the percentage of patients with phone follow-up between extended INRs, and clinic time in therapeutic range (TTR). The primary endpoint of the DOAC transition intervention was to determine the percentage of warfarin patients transitioned to DOACs during the specified timeframe. Secondary endpoints included the average time since last CBC/SCr for those transitioning from warfarin or newly initiating DOAC, percentage of patients without an INR at time of transition, and bleeding or thromboembolic events within 30 days of transition. Disclosures No relevant conflicts of interest to declare.

Hemophilia B is an X-linked genetic deficiency of coagulation factor IX (FIX) activity associated with recurrent deep tissue and joint bleeding that may lead to long-term disability. FIX replacement therapy using plasma-derived protein or recombinant protein has significantly reduced bleeding and disability from hemophilia B, particularly when used in a prophylactic fashion. Although modern factor replacement has excellent efficacy and safety, barriers to the broader use of prophylaxis remain, including the need for intravenous (IV) access, frequent dosing, variability in individual pharmacokinetics, and cost. To overcome the requirement for frequent factor dosing, novel forms of recombinant FIX have been developed that possess extended terminal half-lives. Two of these products (FIXFc and rIX-FP) represent fusion proteins with the immunoglobulin G1 (IgG1) Fc domain and albumin, respectively, resulting in proteins that are recycled in vivo by the neonatal Fc receptor. The third product has undergone site-specific PEGylation on the activation peptide of FIX, similarly resulting in a long-lived FIX form. Clinical trials in previously treated hemophilia B patients have demonstrated excellent efficacy and confirmed less-frequent dosing requirements for the extended half-life forms. However, gaps in knowledge remain with regard to the risk of inhibitor formation and allergic reactions in previously untreated patient populations, safety in elderly patients with hemophilia, effects on in vivo FIX distribution, and cost-effectiveness. Additional strategies designed to rebalance hemostasis in hemophilia patients include monoclonal-antibody-mediated inhibition of tissue factor pathway inhibitor activity and siRNA-mediated reduction in antithrombin expression by the liver. Both of these approaches are long acting and potentially involve subcutaneous administration of the drug. In this review, we will discuss the biology of FIX, the evolution of FIX replacement therapy, the emerging FIX products possessing extended half-lives, and novel "rebalancing" approaches to hemophilia therapy.

Supplemental Digital Content is available in the text., Objectives: Microvascular thrombosis contributes to acute respiratory distress syndrome pathophysiology and has been demonstrated in coronavirus disease 2019-associated acute respiratory distress syndrome. Clinical laboratory measurements of coagulation and disseminated intravascular coagulation, such as coagulation factor function, platelet count, and fibrinogen, may not fully reflect the extent of microvascular thrombosis present in these patients. We investigated thromboelastography in patients with coronavirus disease 2019-associated acute respiratory distress syndrome with the objective of characterizing suspected coagulopathy and impaired fibrinolysis. Design: Retrospective observational cohort study. Setting: Single-center academic medical center. Patients: Ten patients with polymerase chain reaction-confirmed coronavirus disease 2019 disease complicated by acute respiratory distress syndrome. Interventions: Measurement of thromboelastography (n = 10) and thrombolysis with alteplase (n = 4). Measurements and Main Results: Hypercoagulability and decreased or absent fibrinolysis were demonstrated by thromboelastography. Thrombocytopenia and hypofibrinogenemia were not observed, while seven of 10 patients had elevated d-dimer values. For patients who received thrombolytic therapy, repeat thromboelastography demonstrated improvements in coagulation index and lysis at 30 minutes reflecting reduced hypercoagulability and increased fibrinolysis. One major bleeding complication was detected following thrombolysis. Eight of 10 patients survived and were successfully extubated, and six of 10 have since been discharged. Conclusions: In coronavirus disease 2019 patients with acute respiratory distress syndrome in whom thromboelastography was performed, hypercoagulability and impaired fibrinolysis were observed. In the context of autopsy studies demonstrating pulmonary microvascular thromboses in coronavirus disease 2019 patients, noninvasive detection of hypercoagulability and deficient fibrinolysis in coronavirus disease 2019 acute respiratory distress syndrome using thromboelastography could improve understanding and management of coronavirus disease 2019.

INTRODUCTION Bone marrow biopsy (BMB) is crucial for the diagnosis, staging, and monitoring of a variety of hematologic diseases. Obtaining an adequate BMB can be challenging given the need to balance patient comfort with acquisition of high quality specimens. We had observed variable BMB quality at our institution with poor quality specimens sometimes affecting diagnosis. We thus undertook this quality improvement (QI) project to improve the quality of diagnostic BMB specimens. METHODS We used an A3 QI process to identify factors possibly influencing BMB quality. We collected baseline data on 211 BMB, with short and long-term follow-up data on a further 382 cases. We used clinical conferences to discuss data, perform peer comparisons and identify strategies to create a sustainable improvement in BMB quality. RESULTS Baseline data showed that BMB length was influenced most by the individual performer, with some influence of needle gauge. Other factors such as sedation, BMB indication were noncontributory. BMB lengths improved following performer education and individual performer data comparisons (15.2 mm post vs 12.8 mm baseline, P

Background : AKT mediates signaling in the human epidermal growth factor receptor-2 (HER2) pathway. HER2 inhibition can result in feedback regulation of signaling, leading to high AKT activity. Preclinical studies demonstrate activity of combined HER2 and AKT inhibition. MK-2206 is an oral selective inhibitor of AKT. This study was designed to determine the maximum tolerated dose (MTD), dose limiting toxicities (DLTs), adverse events (AEs), clinical activity, pharmacokinetic (PK) parameters and explore potential biomarkers of the combination of MK-2206 with lapatinib. Methods : The dose escalation cohort included adult patients (pts) with solid tumors treated with MK-2206 (30-60 mg qod) and lapatinib (1000-1500 mg qd) continuously. Cycles were 28 days, except cycle 1 (35 days), due to a 1 week MK-2206 lead-in to evaluate for PK interactions. MK-2206 plasma concentrations were evaluated on day 1, 9 (steady state) and 15 (steady state in combination with lapatinib). Lapatinib plasma concentrations were evaluated on day 9 (first dose) and day 15 (steady state in combination with MK-2206). Both used a validated LC-MSMS assay. Pharmacokinetic parameters were calculated using non-compartmental methods with WinNonLin Phoenix version. The dose expansion cohort included women with advanced HER2+ breast cancer treated at the MTD. Peripheral blood mononuclear cells (PBMCs) and archived tumor samples were collected for all pts. Results : In the dose escalation cohort, 23 pts (median age 59 [range 22-72];15 female:8 male) were enrolled. Cancers were colorectal (8 pts), lung (4 pts), breast (3 pts) and other (8 pts). 19 evaluable pts were treated a median of 8 weeks (range 3-35). At dose level four, 1 pt had grade 4 hyponatremia, grade 3 rash and hypocalcemia and 1 pt had intolerable grade 2 mucositis with delivery of Conclusions : Continuous dosing of MK-2206 in combination with lapatinib is well-tolerated. Preliminary results of pharmacokinetic analysis indicate a potential for a drug interaction. Clinical benefit was seen in patients with HER2+ breast cancer. Citation Format: Moniba Nazeef, Amye J Tevaarwerk, Jens Eickhoff, Mark E Burkard, Jennifer Heideman, Glenn Liu, Chris Flynn, Jill M Kolesar, Kari B Wisinski. A phase I study of MK-2206 in combination with lapatinib in patients with advanced solid tumors followed by dose-expansion in advanced HER2+ breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P5-19-20.

Mantle cell lymphoma is a distinct subtype of non-Hodgkin’s lymphoma, which has historically been associated with a poor prognosis. It is now recognized as a heterogeneous disease with variable biologic and clinical behavior. Treatment paradigms have evolved along two lines. Younger, fit mantle cell lymphoma (MCL) patients are generally treated with intensive strategies and older less fit patients with non-intensive strategies. Most of the published literature has focused on intensive strategies, which appear to result in more durable remissions, but with an unclear impact on overall survival. The literature is more sparse for the roughly 50 % of patients who are not candidates for intensive strategies, and no “standard” approach has been established for this patient population. However, clues are emerging. Randomized clinical trials have (a) established that bendamustine-rituximab (BR) is more efficacious and less toxic than rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP); (b) established that bortezomib should replace vincristine if using an R-CHOP backbone; and (c) established that maintenance rituximab (MR) is beneficial after an R-CHOP induction. In our opinion, it is reasonable to extrapolate the data supporting MR after R-CHOP and apply MR after a BR induction. In our practice, we recommend BR followed by MR for 2 years to MCL patients not eligible for intensive therapy. An ongoing US intergroup trial is testing the addition of bortezomib to the BR backbone and the addition of lenalidomide to MR. This trial may establish a standard of care in the older MCL population. In addition, exciting options for relapsed MCL have emerged in the last few years, with the introduction of the Bruton tyrosine kinase (BTK) inhibitor ibrutinib and the development of the lenalidomide-rituximab combination. In this article, we will discuss the current available options for these older MCL patients and the evidence supporting those options.

Inferior vena cava (IVC) filters, first introduced in 1998, have been utilized to reduce risk of pulmonary embolism (PE) in the setting of an inability to anticoagulate patients. The use of IVC filters has increased and continues to rise, especially with the introduction of retrievable IVC filters. Since their initial introduction, guidelines have been developed on the appropriate use of IVC filters. According to the American College of Chest Physicians (ACCP), the use of an IVC filter is limited to patients with an absolute contraindication to therapeutic anticoagulation or failure or complication of anticoagulation in the setting an acute proximal venous thrombus. Relative indications for IVC filter placement include high clot burden in setting of low cardiopulmonary reserve, high risk patients, or severe trauma without documented thrombosis. In 2010, the FDA announced a safety communication recommending removal of retrievable IVC filters due to reports of several adverse clinical outcomes associated with retained filters including thrombus formation, recurrent PE, filter migration, erosion or perforation through the IVC wall, and filter fracture with fragment embolization. In 2014, the FDA recommended removal of the IVC filter within 2 months after filter placement if the patient's risk of thrombosis had passed. In this retrospective analysis of IVC filter management, we reviewed indications for placement according to current guidelines as set by the ACCP, initiation of appropriate anticoagulation, complication rates, and retrieval rates. In addition, we compared the data prior to the FDA recommendations in late 2014 and data after the recommendations to determine if there was a change in practice. After reviewing 179 patients, 89 patients in 2014 and 90 patients in 2015, who underwent IVC filter placement, only 81% (N=145) of patients had appropriate indications for IVC filter placement and 30% (N=54) of patients had inappropriate anticoagulation after IVC filter placement, given as prophylactic dosing of low molecular weight heparin. A comparison of retrieval rates prior to and after the FDA warning, showed a 19% (60% in 2014 vs 79% in 2015) improvement in IVC filter removals. There was an 11% complication rate, mainly related to IVC filter related acute DVT or IVC occlusion. A root cause analysis specifically for inappropriate IVC filter placement and appropriate anticoagulation and determined that familiarity of the guidelines and non-evidence based recommendations from consultants were major factors. Based on the analysis, we next plan to utilize the electronic health record system to help clinicians understand indications and when to initiate appropriate anticoagulation, with the opportunity for hematology consultants to be involved in situations that do not clearly fit within published guidelines. Disclosures No relevant conflicts of interest to declare.

Bone marrow biopsy (BMB) examination is an essential part of diagnosis for hematologic disorders. BMB length guidelines exist but are inconsistently followed; recommendations have included > 20mm for lymphoma (Cheson et al. JCO2014), 15 mm for myeloproliferative disease (Thiele et al. Haematologica 2005), 16 mm for malignant neoplasms in general (Bishop et al, J. Clin. Pathol. 1992). Poor BMB quality hinders pathology interpretation, may impact diagnosis, accurate lymphoma staging and may necessitate repeat procedure with associated patient anxiety and therapy delay. We had observed significant variation in BMB quality at our institution. We therefore undertook a quality improvement (QI) project to identify factors associated with suboptimal BMB and to implement strategies to improve overall BMB quality. Aim: To evaluate the proportion of our biopsies that meet above criteria and identify factors that contribute to suboptimal sampling. The ultimate goal is to improve the quality and length of BMB at our institution for better diagnostic accuracy. Methods: We collected data prospectively on 212 consecutive BMBs performed on adult patients at our institution for baseline evaluation. As BM performers knew about the project, we also collected retrospective data on BMB length to assess for a Hawthorne effect. We recorded the following BMB performance data: patient age, body mass index (BMI), clinic or inpatient setting, sedated or non-sedated procedure, needle gauge, use of trap, performing clinician and disease category. BMB performers included faculty, fellows and nurse practitioners. The BMB length, amount of marrow space, degree of crush and aspiration artifact and disease involvement were assessed in each case. We analyzed which BMB performance factors were associated with differences in BMB length and quality. QI intervention : We performed an email survey on perceived BMB adequacy criteria, discussed overall results and coded individual performance data at a meeting of all providers. We also presented the guidelines about recommended BM length. Individual data were revealed confidentially to each performer. Follow up : Data on BM length and performer were collected on 122 BMB following the intervention. Two-tailed Student t tests under the normality assumption were used to determine significance of differences in BM lengths between pre and post intervention biopsies. Results: Baseline BMB: 210 BMB samples from 24 performers were evaluated. Results were compared to 104 historical marrows to rule out observation bias (Hawthorne effect). No difference was seen in biopsy lengths before or after initiation of study. Median biopsy length was 12 mm (range 1-35 mm). There were no statistically significant differences in BM length depending on patient BMI, location (inpatient vs outpatient), sedation, diagnosis and needle gauge. However there was significant variation in biopsy lengths between performers varying from a mean of 8 to 23 mm (p Post QI intervention data: We evaluated a further 122 BMs from 15 performers. Median length increased from 12 mm to 15 mm (P Conclusions: BMB adequacy is highly dependent on the BMB performer. Other factors including BMI, disease, sedation and needle type do not significantly influence BM quality. Education on the value of adequate BM length and comparison between performers improves performance of some but not all clinicians. We plan to ask the clinicians whose BMB performance improved to discuss with our group to see if their experience can help others improve their BMB technique. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.