Improving Patient Safety Through Proper Ordering and Administration of Andexanet Alfa.

Objective: To evaluate prescribing practices for the anti-Xa reversal agent, andexanet alfa, to identify challenges in ordering and administering this medication, and to offer recommendations to improve patient safety. Patients and Methods: This retrospective study reviewed all adult patients treated with andexanet alfa (AA) at a single institution between January 1, 2018, and March 31, 2020. We identified ordering and administration benchmarks based on recommendations from previous clinical trials on AA. We then reviewed these medical records to determine compliance with these benchmarks. We also collected data related to thrombotic complications and mortality. Results: Twenty-two AA dosing sets (loading and infusion dose) were given to 20 patients. Eight (36%) dosing sets met our ordering benchmarks regarding appropriate dose, time since last direct oral anticoagulants, urgency of administration, and documentation. Three (14%) dosing sets met the administrative benchmarks of being started within 30 minutes of the initial order, and 13 (59%) dosing sets had timely infusion of the infusion dose after the loading dose. No dosing set met all our administration benchmarks. There was 1 thrombotic event within 24 hours of the correct AA dose and 1 potential death related to AA. Conclusion: This study highlights challenges in ordering and administering AA at our institution and brings awareness to potential similar concerns at other institutions. These challenges also identified the need for optimized order sets, a streamlined administration process, and frequent provider education to improve patient safety.

Elderly Male With Epstein-Barr Virus (EBV)-Induced Pure Red Cell Aplasia.

Pure red cell aplasia (PRCA) is a rare hematologic disorder presenting with symptomatic normocytic anemia with preservation of other bone marrow cell lineages that may be acquired in adulthood due to malignancy, autoimmune disease, and infections. PRCA has been attributed to Epstein-Barr virus (EBV) in patients with underlying malignancy; however, we present a rare case of EBV-related PRCA in a previously healthy elderly male without an underlying malignancy who developed transfusion-dependent anemia that responded to glucocorticoids, rituximab, and intravenous immunoglobulins.

Successful treatment of severe passenger lymphocyte syndrome with efgartigimod synergy.

INTRODUCTION: This case describes passenger lymphocyte syndrome (PLS) generating human platelet antigen 1a (HPA-1a) alloantibodies against the recipient's platelets after liver transplant. Given the rarity of PLS, especially in liver transplant with HPA-1a alloantibodies, disease course and management options are poorly described. METHODS: The patient had cirrhosis secondary to nonalcoholic steatohepatitis complicated by hepatocellular carcinoma, encephalopathy, and severe ascites. The model for end-stage liver disease (MELD) score was 15 at presentation. The patient developed hepatic artery thrombosis after an orthotopic liver transplant and was relisted for transplant with a MELD score of 40. The patient received a hepatitis C virus antibody positive, hepatitis C virus nucleic amplification test positive donor liver on postoperative day (POD) 7 after first transplant. On POD 7 after the second transplant, the patient developed profound thrombocytopenia refractory to platelet infusion. They were found to have serum antibody to HPA-1a based upon serum platelet alloantibody testing. The donor was later found to be negative for HPA-1a by genetic testing. However, the patient's native platelets were HPA-1a positive. The patient was diagnosed with PLS. RESULTS: The patient's treatment course included 57 units of platelets transfused, emergency splenectomy, rituximab, plasma exchange, intravenous immunoglobulin (IVIG), eltrombopag, romiplostim, and efgartigimod. DISCUSSION: The synergistic effect of efgartigimod with eltrombopag and romiplostim most likely resolved the patient's thrombocytopenia. This case represents a novel use of efgartigimod in the treatment of passenger lymphocyte syndrome following liver transplant.

Severe Cytokine Release Syndrome and Hemophagocytic Lymphohistiocytosis (HLH)-Like Syndrome Following Administration of Combined Brentuximab Vedotin and Nivolumab for Recurrent Classical Hodgkin Lymphoma: A Case Report.

Brentuximab vedotin (BV) and nivolumab are increasingly utilized as a novel regimen in patients with relapsed/refractory classical Hodgkin lymphoma (cHL). A 26-year-old male presented to the hospital with refractory diabetic ketoacidosis and multiple electrolyte abnormalities, 9 days after the first dose of brentuximab vedotin and nivolumab for recurrent classical Hodgkin lymphoma. During his hospitalization, he developed multi-organ failure. His workup showed elevated cytokine levels concerning severe cytokine release syndrome (CRS) and hemophagocytic lymphohistiocytosis (HLH)-like syndrome. Despite treatment with CRS- and HLH-directed therapies, his clinical status deteriorated due to ongoing multifactorial shock and worsening multi-organ dysfunction, and comfort care measures were eventually pursued. To our knowledge, there have been no other cases reported of HLH-like syndrome after the combination of BV and nivolumab in patients with cHL. This case of a fatal adverse event following one dose of BV and nivolumab underscores the vital need for close monitoring of patients receiving this treatment regimen.

Acquired Factor VII Deficiency Associated With Chronic Myeloid Leukemia Blast Crisis.

Factor VII (FVII) is an important, vitamin K-dependent clotting factor. Acquired FVII deficiency is a rare entity that is associated with serious bleeding complications. We report a case of acquired FVII deficiency in a patient with recurrent chronic myeloid leukemia in blast crisis who developed bilateral retinal hemorrhages. The coagulopathy was corrected with the initiation of chemotherapy and subsequent reduction in peripheral blast count.

Resolution of acute pulmonary embolism using anticoagulation therapy alone in coronavirus disease 2019.

OBJECTIVE: To investigate the radiographic resolution of acute pulmonary embolism (PE) using contrast-enhanced computed tomography (CECT) examinations in patients diagnosed with acute PE while hospitalized with coronavirus disease 2019 (COVID-19) and to understand the mid-term and long-term implications of anticoagulation therapy. METHODS: We identified patients with acute PE per CECT and at least one follow-up CECT from March 11, 2020, to May 27, 2021, using a prospective registry of all hospitalized patients with COVID-19 infection receiving care within a multicenter Health System. Initial and follow-up CECT examinations were reviewed independently by two radiologists to evaluate for PE resolution. The Modified Miller Score was used to assess for thrombus burden at diagnosis and on follow-up. RESULTS: Of the 6070 hospitalized patients with COVID-19 infection, 5.7% (348/6070) were diagnosed with acute PE and 13.5% (47/348) had a follow-up CECT examination. The mean ± standard deviation time to follow-up imaging was 44 ± 48 days (range, 3-161 days). Of 47 patients, 47 (72.3%) had radiographic resolution of PE, with a mean time to follow-up of 48 ± 43 days (range, 6-239 days). All patients received anticoagulation monotherapy for a mean of 149 ± 95 days and this included apixaban (63.8%), warfarin (12.8%), and rivaroxaban (8.5%), among others. The mean Modified Miller Score at PE diagnosis and follow-up was 4.8 ± 4.2 (range, 1-14) and 1.4 ± 3.3 (range, 0-16; P < .0001), respectively. Nine patients (19%) died at a mean of 13 ± 8 days after follow-up CECT (range, 1-27 days) and at a mean of 28 ± 16 days after admission (range, 11-68 days). Seen of the nine deaths (78%) deaths were associated with progression of COVID-19 pneumonia. CONCLUSIONS: Hospitalized patients with COVID-19 have a clinically apparent 5.7% rate of developing PE. In patients with follow-up imaging, 72.3% had radiographic thrombus resolution at a mean of 44 days while on anticoagulation. Prospective studies of the natural history of PEs with COVID-19 that include systematic follow-up imaging are warranted to help guide anticoagulation recommendations.

Macrophage Activation Led Acute Heart Failure Managed Successfully with Immunosuppression.

Macrophage activation leading to multi-organ dysfunction/failure has been described in various hematologic disorders like hemophagocytic lympho-histiocytosis (HLH), also known as macrophage activation syndrome (MAS) and macrophage activation like syndrome (MALS). Congestive heart failure (CHF) appears to be an uncommon manifestation of macrophage activation. This novel entity of macrophage activation-associated cytokine-mediated CHF has not been well reported in the medical literature. We report two young female patients with acute CHF secondary to macrophage activation-associated cytokine storm. An extensive diagnostic workup was negative for other etiologies, such as ischemia, myocarditis, or infections. Their clinical, laboratory, and pathologic findings did not meet the diagnostic criteria for hemophagocytic syndrome (HPS)/MAS. However, both had laboratory and pathologic findings which were consistent with macrophage activation and cytokine storm. One patient met criteria for MALS. Therapeutically, our patients were promptly treated with steroids with or without anti-cytokine therapy with rapid restoration of cardiac function. Macrophage activation-induced disease may not always fulfil the diagnostic criteria for the currently known macrophage activation disorders. We suggest that markers of macrophage activation and cytokine levels should be part of the diagnostic workup in patients with otherwise unexplained acute CHF. Additional research is warranted to further elucidate the underlying mechanism of this disorder.

Deep vein thrombosis in the setting of Klippel-Trenaunay syndrome and sirolimus treatment.

Klippel-Trenaunay syndrome (KTS) is a congenital vascular disorder characterized by the triad of cutaneous capillary malformation, lymphatic and venous anomalies, and soft tissue and bone overgrowth. Sirolimus is a mechanistic target of rapamycin inhibitor used as an immunosuppressive drug. It has also been used to improve and treat vascular malformations that can predispose to intravascular coagulopathy. We have described the case of a patient with KTS receiving a therapeutic anticoagulation dose, for whom sirolimus was initiated, and who had presented with an extensive venous thromboembolism. Correlations between the use of sirolimus in patients with KTS are limited, and cautious use and monitoring could be necessary.

Radiotherapy in Early-stage Gastric MALT: Improved Survival Without Increased Cardiac Death.

PURPOSE: Radiotherapy (RT) is an effective treatment for localized gastric mucosa-associated lymphoid tissue (MALT) lymphomas unresponsive to antibiotic therapy; however, irradiating the stomach can result in significant radiation to the heart, a risk factor for cardiac disease. We analyzed the Surveillance, Epidemiology, and End Results database to evaluate outcomes related to cardiac disease among patients treated with RT for stage I gastric MALT. MATERIALS AND METHODS: We identified adult patients treated between 1993 and 2014. The relationship between treatment modality (RT, chemotherapy, combination, and no treatment) and overall survival (OS), mucosa-associated lymphoid tissue-specific survival (MSS), non-mucosa-associated lymphoid tissue-specific survival (non-MSS), and cardiac-specific survival (CSS) was assessed using the Kaplan-Meier estimator and Cox proportional hazards analyses. RESULTS: A total of 2996 patients (median follow-up, 5.6 y) were analyzed: 27.5% had received RT alone, 12.1% chemotherapy alone, 3.9% chemoradiotherapy, and 56.5% no/unknown treatment (including antibiotic therapy). Compared with RT alone, patients who received chemotherapy alone exhibited worse OS (hazard ratio [HR]: 1.67; 95% confidence interval [CI]: 1.32-2.10; P<0.001) and MSS (HR: 2.10; 95% CI: 1.36-3.23; P=0.001). Although CSS appeared worse in patients who received chemotherapy (HR: 1.56; 95% CI: 0.92-2.66; P=0.10), it was not statistically significant. When comparing orbital and gastric MALT patients, there was no significant difference in CSS (HR: 0.80; 95% CI: 0.49-1.31; P=0.38). CONCLUSIONS: RT improved survival among patients with stage I gastric MALT without increasing the risk of cardiac death. Those with gastric MALT exhibited similar CSS to those with orbital MALT. Although we cannot analyze nonfatal cardiac toxicity, these results suggest that, absent antibiotic therapy, RT should remain first-line treatment for early-stage gastric MALT.

A 5-Fluorouracil-Induced Hyperammonemic Encephalopathy Challenged with Capecitabine.

Cancer patients presenting with altered mental status demand a broad differential with early recognition of the etiology. Failure to do so is associated with increased morbidity and mortality. Causes that must be considered include organ involvement of the cancer, electrolytes abnormalities, and even chemotherapeutic agents. A 32-year-old female patient had been recently started on FOLFOX for metastatic colon cancer. Her initial treatments were uneventful, but she later developed encephalopathy during day three of cycle five. During her evaluation, she was found to have hyperammonemia (84 mcmol/L), without hepatic failure, that resolved with stopping chemotherapy and supportive care. After a trial of home infusion fluorouracil, she developed hyperammonemic encephalopathy again. During both admissions, her symptoms resolved with IV hydration and cessation of chemotherapy. She was then successfully challenged with capecitabine (1000 mg/m2 daily), and additional hydration, and continued chemotherapy without recurrence of symptoms. Hyperammonemia is associated with fluorouracil though the mechanism is unclear. Suspected etiologies include either elevated levels of the drug due to slower metabolism or accumulation of certain metabolites. Additionally, risk factors such urease-producing bacterial infections, dehydration, and increased catabolism are thought to increase the risk for hyperammonemia. This case demonstrates the need for greater awareness of fluorouracil as a cause of hyperammonemic encephalopathy. Knowledge of this may allow for earlier recognition and reduced unnecessary testing.

The Meaningless Meaning of Mean Heart Dose in Mediastinal Lymphoma in the Modern Radiation Therapy Era.

PURPOSE: Mean heart dose (MHD) correlates with late cardiac toxicity among survivors of lymphoma receiving involved-field radiation therapy (IFRT). We investigated MHD and cardiac substructure dose across older and newer radiation fields and techniques to understand the value of evaluating MHD alone. METHODS AND MATERIALS: After institutional review board approval, we developed a database of dosimetry plans for 40 patients with mediastinal lymphoma, which included IFRT (anterior-posterior and posterior-anterior), involved-site radiation therapy (ISRT) + 3-dimensional conformal radiation therapy (3DCRT), ISRT + intensity modulated radiation therapy, and ISRT + proton therapy plans for each patient. Each plan was evaluated for dose to the heart and cardiac substructures, including the right and left ventricles (RV, LV) and atria (RA, LA); tricuspid, mitral (MV), and aortic valves; and left anterior descending coronary artery (LAD). Correlation between MHD and cardiac substructure dose was assessed with linear regression. A correlation was considered very strong, strong, moderate, or weak if the r was ≥0.8, 0.6-0.79, 0.4-0.59, or <0.4, respectively. RESULTS: A very strong correlation was observed between MHD and the mean cardiac substructure dose for each plan as follows: IFRT-LV, RV, LA, MV and LAD; ISRT + 3DCRT-LV, RV, MV, TV, and LA; ISRT + intensity modulated radiation therapy-LV and RV; ISRT + proton therapy-none. The following strong correlations were observed: IFRT-RA; ISRT + 3DCRT-LAD, RA, AV; ISRT + IMRT-LA, RA, LAD, AV, TV, and MV; ISRT + proton therapy-LV only. CONCLUSIONS: In the management of mediastinal lymphoma, more conformal treatment techniques can lead to more heterogeneous dose distributions across the heart, which translate into weaker relationships between mean heart dose and mean cardiac substructure doses. Consequently, models for assessing the risk of cardiac toxicity after radiation therapy that rely on MHD can be misleading when using modern treatment fields and techniques. Contouring the cardiac substructures and evaluating their dose is important when using contemporary RT.

Temporality of heparin-induced antibodies: a retrospective study in outpatients undergoing hemodialysis on unfractionated heparin.

BACKGROUND: Heparin-induced antibodies (HIA) are responsible for causing heparin-induced thrombocytopenia and thrombosis. Research has shown that the temporality of heparin-induced antibodies does not follow the classic immunologic response. The immunobiology of HIA generation remains unclear with varying in vitro and in vivo data. Outpatients undergoing hemodialysis (HD) are exposed to heparin chronically. The HIA immune response can therefore be investigated in vivo in this population. METHODS: We examined the time between the start of HD using unfractionated heparin and HIA levels in 212 outpatients during a 6-year period. Antibodies were detected on enzyme-linked immunosorbent assay. HIA levels were analyzed to determine significance of the trend over time. HIA subgroups were also analyzed for correlation with subsequent thrombotic events and platelet count during follow up. RESULTS: Overall, the HIA response in HD was found to peak early with waning antibody response despite continued exposure to heparin. The peak prevalence of a strong immune response (optical density > 1.000) was early and short lived, while weaker immune response (optical density 0.400-1.000) persisted for the first 6 months then declined. The mean follow-up time per patient was 2.3 ± 1.4 years. Despite circulating HIA, including high titers, no patients developed HIT in this sample. There was no association between HIA and thrombocytopenia. There was increased incidence of thrombosis in patients with strong HIA compared to other groups, but this did not achieve statistical significance. CONCLUSIONS: The data suggest a significant temporal pattern of HIA in outpatients undergoing HD using unfractionated heparin. Positive HIA was not found to be significantly associated with thrombocytopenia or thrombosis risk in these patients. However, while not achieving statistical significance, subsequent thrombotic events occurred most frequently in the strong positive HIA group (optical density > 1.000). Further research into HIA and risk of thrombosis in this population is needed.

Fatal Type B Lactic Acidosis Associated With Metastatic Colorectal Cancer: A Case Report With Review of Literature, Pathogenesis, and Treatment.

Type B lactic acidosis associated with malignancy is a life-threatening complication and mostly seen in hematological malignancies but can also be seen in solid tumors. We report a rare case of a 64-year-old female diagnosed with metastatic adenocarcinoma of the colon with liver metastasis associated with severe type B lactic acidosis. We discuss pathophysiology, previously reported cases, and their outcomes. The most widely used therapies are bicarbonate infusion, thiamine supplementation, chemotherapy, and supportive care but is associated with poor outcomes, and no standard treatment recommendations are available. Early chemotherapy administration remains the only intervention that has shown some survival benefit. Physicians should be aware and proactive for early diagnosis and management of this condition with further research needed to guide optimal therapy.

A Rare Case of Erdheim-Chester Disease (Non-Langerhans Cell Histiocytosis) with Concurrent Langerhans Cell Histiocytosis: A Diagnostic and Therapeutic Challenge.

Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocyte disorder most commonly characterized by multifocal osteosclerotic lesions of the long bones demonstrating sheets of foamy histiocyte infiltrates on biopsy with or without histiocytic infiltration of extraskeletal tissues. ECD can be difficult to diagnose since it is a very rare disease that can affect many organ systems. Diagnosis is based on the pathologic evaluation of involved tissue interpreted within the clinical context. Patients who have the BRAF V600E mutation are treated first line with vemurafenib. For those without the mutation with symptomatic ECD, conventional or PEGylated interferon alpha is recommended. For patients who are either intolerant or nonresponsive to interferon alpha, systemic chemotherapy with or without corticosteroids can be used. We present a rare case of Erdheim-Chester disease with concurrent Langerhans cell histiocytosis which occurs in only one fifth of the cases and often presents as a diagnostic and therapeutic challenge.

Malignant Peripheral Nerve Sheath Tumors Masking as Ewing Sarcoma/Primitive Neuroectodermal Tumors.

Malignant peripheral nerve tumors, a small subset of soft tissue sarcomas, provide a unique diagnostic challenge. Although they may arise from peripheral nerves or from cells associated with nerve sheaths, malignant peripheral nerve tumors often present with diverse immunohistochemical features similar to those of other tumors. These features make MPNSTs difficult to diagnose and classify. We present a case of a 26-year-old female presenting with a rapidly growing soft tissue mass. The mass was excised and immunohistological staining suggested a Ewing's sarcoma/Primitive neuroectodermal tumor. Confirmational studies did not confirm this diagnosis and upon further review, the diagnosis was changed to a malignant peripheral nerve sheath tumor. We reviewed this case in the setting of the reported literature concerning MPNSTs with focus on the epidemiologic, diagnostic, and immunohistologic features that distinguish this tumor from other similar malignancies.