Combined preoperative plasma exchange and red blood cell exchange transfusion in a renal transplant patient with protein S deficiency and hemoglobin SC disease.

BACKGROUND: Protein S deficiency is associated with increased risk of venous thromboembolism, complicating the perioperative management of such patients. We present a patient with sickle cell disease (Hb SC genotype) and inherited protein S deficiency who underwent a living-donor renal transplant. To minimize thrombotic risk and sickle cell complications, both plasma exchange and red blood cell (RBC) exchange transfusion were performed pre-operatively. METHODS AND MATERIALS: Plasma exchange was utilized to increase protein S levels and to reduce the risk of post-operative venous thromboembolism, including allograft thrombosis, while RBC exchange was performed to reduce the risk of acute post-operative sickle cell disease complications. RESULTS: With the use of combined pre-operative plasma exchange and RBC exchange transfusion, this patient with protein S deficiency and Hb SC underwent a successful renal transplant without acute sickle cell complications or thrombotic complications. CONCLUSIONS: This case demonstrates the potential use of pre-operative plasma exchange in patients with protein S deficiency undergoing high thrombotic risk procedures.

Pharmacy hydroxyurea education materials for patients with sickle cell disease: An environmental scan and assessment of accuracy.

BACKGROUND: Hydroxyurea (HU) remains a cornerstone of sickle cell disease (SCD) therapy; however, its use is limited by poor patient adherence owing to concerns about side effects. Pharmacies routinely provide patients with handouts about HU, which, we hypothesized, contain inaccuracies that may contribute to negative patient perceptions of HU. METHODS: We used a systematic approach to collect and review patient information handouts (PIHs) on HU from pharmacies in Ontario, Canada. PIHs were evaluated according to: i. Number of inaccurate statements, ii. Percentage of essential statements based on comparison with a reference standard PIH developed by the Canadian Haemoglobinopathy Association (CanHaem), and iii. Reading level. RESULTS: PIHs were collected from 98% of chain and community pharmacies registered in Ontario. All PIHs contained inaccurate statements, most frequently relating to the risk of developing cancer. Only 33% of PIHs identified SCD as an indication for HU use. Pharmacy PIHs contained 45% of the essential statements present within the CanHaem HU PIH, neglecting to mention use of HU for management of SCD and benefits of HU in preventing SCD complications. Moreover, the reading level across pharmacy PIHs was 1.8 grades higher than that advised for written patient education materials. CONCLUSION: Patients who are prescribed HU are likely to be provided with PIHs that contain inaccuracies that are weighted toward the risks of HU therapy and run contrary to published literature. This study identifies a gap in the care of patients with SCD and an opportunity to improve the quality of HU PIHs to help patients make well-informed decisions about their health.

Primary Refractory Discordant Diffuse Large B-Cell and Classical Hodgkin Lymphoma.

Discordant lymphomas are defined as two or more distinct pathological lymphomas occurring in the same patient. Due to the rarity of discordant lymphomas, which is due in large part to the difficulty in establishing the diagnosis, the literature is limited to small case series and case reports. Consequently, guidelines on therapeutic strategies are lacking. This article presented a case of primary refractory discordant large B-cell lymphoma and classic Hodgkin lymphoma in a young man based on cervical node and mediastinal mass biopsy, respectively. This case illustrates the difficulty in establishing the diagnosis, which ultimately warranted a high index of clinical suspicion and pursuit of multiple sequential biopsies, as well as a novel treatment strategy using an immune checkpoint inhibitor.

Inferior vena cava filter use at a large community hospital: a retrospective cohort study.

Inferior vena cava (IVC) filters are considered when patients with venous thromboembolism (VTE) develop a contraindication to anticoagulation. Use of IVC filters is increasing, despite associated complications and lack of data on efficacy in reducing VTE-related mortality. We characterized the pattern of IVC filter use at a large community hospital between 2018 and 2022. Specifically, we assessed the indications for IVC filter insertion, filter removal rates, and filter-associated complications. Indications for IVC filters were compared to those outlined by current clinical practice guidelines. We reviewed 120 consecutive filter placement events. The most common indications included recent VTE and active bleeding (40.0%) or need for anticoagulation interruption for surgery (25.8%). Approximately one-third (30.0%) of IVC filters were inserted for indications either not supported or addressed by guidelines. Half (50.0%) of patients had successful removal of their IVC filter. At least 13 patients (10.8%) experienced a filter-related complication. In a large community-based practice, nearly one-third of IVC filters were inserted for indications not universally supported by current practice guidelines. Moreover, most IVC filters were not removed, raising the risk of filter-associated complications, and supporting the need for development of comprehensive guidelines addressing use of IVC filters, and post-insertion monitoring practices.

Interleukin-17A increases neurite outgrowth from adult postganglionic sympathetic neurons.

Inflammation can profoundly alter the structure and function of the nervous system. Interleukin (IL)-17 has been implicated in the pathogenesis of several inflammatory diseases associated with nervous system plasticity. However, the effects of IL-17 on the nervous system remain unexplored. Cell and explant culture techniques, immunohistochemistry, electrophysiology, and Ca2+ imaging were used to examine the impact of IL-17 on adult mouse sympathetic neurons. Receptors for IL-17 were present on postganglionic neurons from superior mesenteric ganglia (SMG). Supernatant from activated splenic T lymphocytes, which was abundant in IL-17, dramatically enhanced axonal length of SMG neurons. Importantly, IL-17-neutralizing antiserum abrogated the neurotrophic effect of splenocyte supernatant, and incubation of SMG neurons in IL-17 (1 ng/ml) significantly potentiated neurite outgrowth. The neurotrophic effect of IL-17 was accompanied by inhibition of voltage-dependent Ca2+ influx and was recapitulated by incubation of neurons in a blocker of N-type Ca2+ channels (ω-conotoxin GVIA; 30 nM). IL-17-induced neurite outgrowth in vitro appeared to be independent of glia, as treatment with a glial toxin (AraC; 5 µM) did not affect the outgrowth response to IL-17. Moreover, application of the cytokine to distal axons devoid of glial processes enhanced neurite extension. An inhibitor of the NF-κB pathway (SC-514; 20 µM) blocked the effects of IL-17. These data represent the first evidence that IL-17 can act on sympathetic somata and distal neurites to enhance neurite outgrowth, and identify a novel potential role for IL-17 in the neuroanatomical plasticity that accompanies inflammation.

Antithrombotic management of patients with deep vein thrombosis and venous stents: an international registry.

BACKGROUND: In patients with acute deep vein thrombosis (DVT) treated with catheter-based thrombolysis and venous stenting, poststenting anticoagulant management is uncertain. OBJECTIVES: To determine the type and duration of antithrombotic therapy used in patients who have received venous stents for treatment of acute lower extremity DVT. METHODS: We created an international registry of patients with leg DVT from 2005 to 2019 who received venous stents as part of their acute management. We collected data on baseline clinical characteristics and pre-venous and post-venous stent antithrombotic therapy. RESULTS: We studied 173 patients with venous stents: 101 (58%) were aged ≤50 years, 105 (61%) were female, and 128 (74%) had risk factors for thrombotic disease. DVT was iliofemoral in 150 (87%) patients, and catheter-based treatment was given within 7 days of diagnosis in 92 (53%) patients. After venous stenting, 109 (63%) patients received anticoagulant-only therapy with a direct oral anticoagulant (29%), warfarin (22%), or low-molecular-weight heparin (10%), and 59 (34%) received anticoagulant-antiplatelet therapy. In patients taking anticoagulant-only therapy, 29% received indefinite treatment; in patients on anticoagulant-antiplatelet therapy, 19% received indefinite treatment. Factors associated with combined anticoagulant-antiplatelet therapy vs anticoagulant-only therapy were use of thrombolytic, thrombectomy, and aspiration interventions (odds ratio [OR], 5.11; 95% CI, 1.45-18.05); use of balloon angioplasty (OR, 2.62; 95% CI, 1.20-5.76); and immediate stent restenosis (OR, 7.2; 95% CI, 1.45-5.89). CONCLUSION: Anticoagulant therapy without concomitant antiplatelet therapy appears to be the most common antithrombotic strategy in patients with DVT and venous stenting. More research is needed to determine outcomes of venous stenting in relation to antithrombotic therapy.

Management of major bleeds in patients with immune thrombocytopenia.

BACKGROUND: A standard approach to the recognition and management of major bleeding in immune thrombocytopenia (ITP) is lacking. METHODS: Retrospective cohort study of ITP patients presenting to the emergency department (ED) with severe thrombocytopenia (platelet count <20 × 109 /L) and bleeding in four academic hospitals from 2008 to 2016. We defined a major ITP bleed as a bleed at a critical site or causing hemodynamic instability. RESULTS: We identified 112 ITP patients (n = 141 visits) who presented to the ED with platelets <20 × 109 /L and bleeding. Twenty--nine patients (26%) had 32 ED visits with major bleeds. Risk factors for major bleeds were older age (odds ratio [OR] 1.03, 95% confidence interval [CI] 1.01-1.06), male sex (OR 3.25, 95% CI 1.22-9.32), and more prior ITP therapies (OR 1.42, 95% CI 1.10-1.87). Acute treatment of major bleeds required a median of three treatments (interquartile range [IQR] 2--4), which included intravenous immune globulin (91% of visits), corticosteroids (78% of visits), and platelet transfusions (75% of visits). Three patients (10%) died, nine (31%) developed recurrent bleeds, one (3%) developed arterial thrombosis, and one (3%) had permanent neurological disability. Six patients presented with minor bleeding and subsequently developed a major bleed after a median of 2 days (IQR 1-3). All six patients had oral purpura and four of six had gross hematuria preceding the major bleed. CONCLUSIONS: Major ITP bleeds are associated with significant morbidity and mortality. Oral purpura and hematuria often preceded major bleeds. Further research is needed to refine the definition of a major ITP bleed and develop evidence-based treatment strategies.

Landmark trials in thrombotic vascular disease: a critical appraisal of potential practice-changing trials in 2016-2017.

Recent years have witnessed an onslaught of large, multicenter, randomized controlled trials evaluating the prevention and management of thrombotic vascular diseases. While these trials have applied rigorous methodology to pragmatic and clinically relevant questions, several important gaps in knowledge remain. In this review, we critically appraise landmark studies in thrombosis published between 2016 and 2017 that address several ongoing areas of clinical uncertainty. Specifically, we review the role of endovascular therapy in the prevention of post-thrombotic syndrome following acute lower limb deep vein thrombosis (DVT) (ATTRACT trial), the efficacy of edoxaban as the first direct oral anticoagulant used for the treatment of cancer-associated thrombosis (HOKUSAI VTE-Cancer study), whether aspirin can be considered for thromboprophylaxis post-major orthopedic surgery (EPCAT-2 trial), and the need for anticoagulant therapy for treatment of isolated distal DVT (CACTUS trial). Using illustrative cases, we highlight the applicability of these trials to current practice and emphasize the unanswered questions that remain.

Andexanet alfa for the treatment of hemorrhage.

INTRODUCTION: While associated life-threatening and fatal bleeding events are less frequent with the direct factor Xa inhibitors compared to vitamin K antagonists, significant concern surrounding management of major bleeds and urgent periprocedural interruption of these agents exists among clinicians. Andexanet alfa is a recombinant human factor Xa decoy protein developed in response to this clinical gap in the care of patients receiving anticoagulation with factor Xa inhibitors. Areas covered: This paper reviews results from preclinical and healthy-volunteer studies demonstrating the ability of andexanet to rapidly and reliably normalize coagulation indices in patients treated with both direct and indirect factor Xa inhibitors. An interim analysis from an ongoing phase 3/4b clinical study assessing the efficacy and safety of andexanet in patients experiencing life-threatening hemorrhage in association with factor Xa inhibitors is discussed. It also provides an overview of the major safety concerns reported in these trials which include allergic and infusion reactions, development of anti-andexanet antibodies and, importantly, thrombosis. Expert commentary: While initial reports on restoration of hemostasis and safety are promising, further study of andexanet is required to gauge its efficacy and toxicity, including a potential prothrombotic effect. Further, its use in patients requiring urgent surgery should be studied.

ANCA-associated pauci-immune glomerulonephritis in a patient with bacterial endocarditis: a challenging clinical dilemma.

PURPOSE: We report the case of a 59-year-old man with chronic hepatitis B and C infection presenting with acute kidney injury and enterococcus faecalis-infective endocarditis (IE). An elevated proteinase-3 (PR3)-ANCA and pauci-immune glomerulonephritis (GN) on renal biopsy were discovered, corresponding to ANCA-mediated GN. We conducted a literature review to assess the role of ANCA in IE and treatment implications. METHODS: On systematic review of the literature, we found five previous cases whereby IE caused by streptococcus and bartonella species were related to ANCA vasculitis-associated GN. RESULTS: Most reports of IE-related GN are mediated by immune complex deposition and resolve following microbial clearance. Of the 5 cases of ANCA GN in the setting of IE, all had markedly elevated levels of PR3-ANCA with either a subacute or chronic course of infection. Patients were treated with a combination of steroids and cyclophosphamide (2/5), steroids and antibiotics alone (1/5), or with valvular replacement (2/5). Renal function was recovered in 4/5 patients. CONCLUSION: Infection is a major etiologic player in the formation of ANCA; however, the role of PR3-ANCA in IE remains unclear. Kidney biopsy is essential in differentiating IE-related GN due to infection and immune complex deposition versus ANCA-associated vasculitis. A paucity of reports on the development of GN in IE-associated ANCA vasculitis exists, highlighting the rarity of our case and lack of clear therapeutic strategies in a patient with active infection requiring immunosuppression. In this case, the patient's chronic hepatitis B and C coinfection presented a unique challenge.

Neural regulation of gastrointestinal inflammation: role of the sympathetic nervous system.

The sympathetic innervation of the gastrointestinal (GI) tract regulates motility, secretion and blood flow by inhibiting the activity of the enteric nervous system (ENS) and direct vasoconstrictor innervation of the gut microvasculature. In addition to these well-established roles, there is evidence that the sympathetic nervous system (SNS) can modulate GI inflammation. Postganglionic sympathetic neurons innervate lymphoid tissues and immune cells within the GI tract. Furthermore, innate and adaptive immune cells express receptors for sympathetic neurotransmitters. Activation of these receptors can affect a variety of important immune cell functions, including cytokine release and differentiation of helper T lymphocyte subsets. This review will consider the neuroanatomical evidence of GI immune cell innervation by sympathetic axons, the effects of blocking or enhancing SNS activity on GI inflammation, and the converse modulation of sympathetic neuroanatomy and function by GI inflammation.

Neural sensitivity to novel sounds in the rat's dorsal cortex of the inferior colliculus as revealed by evoked local field potentials.

Evoked local field potentials in response to contralaterally presented tone bursts were recorded from the rat's dorsal cortex of the inferior colliculus (ICd). An oddball stimulus paradigm was used to study the sensitivity of ensembles of neurons in the ICd to novel sounds. Our recordings indicate that neuron ensembles in the ICd display stimulus-specific adaptation when a large contrast in both frequency and probability of occurrence exists between the two tone bursts used for generating an oddball paradigm. A local field potential evoked by a tone burst presented as a deviant stimulus has a larger amplitude than that evoked by the same sound presented as a standard stimulus. The difference between the two responses occurs after the initial rising phases of their predominant deflections. The degree of stimulus-specific adaptation increases with the rate of sound presentation up to 8/s, the highest rate used in this study. A comparison between our results and those from previous studies suggests that differences exist between responses to oddball paradigms in the ICd and those in the primary auditory cortex, a major source of projection to the ICd. These differences suggest that local mechanisms exist in the ICd for suppressing neural responses to frequently presented sounds and enhancing responses to rarely presented sounds. Thus, the ICd may serve as an important component of an integrative circuit in the brain for detecting novel sounds in the acoustic environment.