Hyperleukocytosis (Re)Visited- Is It Case Series Always Leukaemia: a Report of Two Pathology Section Cases and Review of Literature Short Communication
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Pathologic Rupture of the Spleen in a Patient with Acute Myelogenous Leukemia and Leukostasis
rev bras hematol hemoter. 2014;36(4):290–292 Revista Brasileira de Hematologia e Hemoterapia Brazilian Journal of Hematology and Hemotherapy www.rbhh.org Case report Pathologic rupture of the spleen in a patient with acute myelogenous leukemia and leukostasis Gil Cunha De Santis ∗, Luciana Correa Oliveira, Aline Fernanda Ramos, Nataly Dantas Fortes da Silva, Roberto Passetto Falcão Universidade de São Paulo (USP), Ribeirão Preto, SP, Brazil article info abstract Article history: Rupture of the spleen can be classified as spontaneous, traumatic, or pathologic. Patho- Received 14 October 2013 logic rupture has been reported in infectious diseases such as infectious mononucleosis, Accepted 14 January 2014 and hematologic malignancies such as acute and chronic leukemias. Splenomegaly is con- Available online 28 May 2014 sidered the most relevant factor that predisposes to splenic rupture. A 66-year-old man with acute myeloid leukemia evolved from an unclassified myeloproliferative neoplasm, Keywords: complaining of fatigue and mild upper left abdominal pain. He was pale and presented Splenomegaly fever and tachypnea. Laboratory analyses showed hemoglobin 8.3 g/dL, white blood cell 9 9 Leukemia count 278 × 10 /L, platelet count 367 × 10 /L, activated partial thromboplastin time (aPTT) Myeloid ratio 2.10, and international normalized ratio (INR) 1.60. A blood smear showed 62% of Acute myeloblasts. The immunophenotype of the blasts was positive for CD117, HLA-DR, CD13, Leukostasis CD56, CD64, CD11c and CD14. Lactate dehydrogenase was 2384 U/L and creatinine 2.4 mg/dL (normal range: 0.7–1.6 mg/dL). Two sessions of leukapheresis were performed. At the end of the second session, the patient presented hemodynamic instability that culminated in cir- culatory shock and death. -
My Beloved Neutrophil Dr Boxer 2014 Neutropenia Family Conference
The Beloved Neutrophil: Its Function in Health and Disease Stem Cell Multipotent Progenitor Myeloid Lymphoid CMP IL-3, SCF, GM-CSF CLP Committed Progenitor MEP GMP GM-CSF, IL-3, SCF EPO TPO G-CSF M-CSF IL-5 IL-3 SCF RBC Platelet Neutrophil Monocyte/ Basophil B-cells Macrophage Eosinophil T-Cells Mast cell NK cells Mature Cell Dendritic cells PRODUCTION AND KINETICS OF NEUTROPHILS CELLS % CELLS TIME Bone Marrow: Myeloblast 1 7 - 9 Mitotic Promyelocyte 4 Days Myelocyte 16 Maturation/ Metamyelocyte 22 3 – 7 Storage Band 30 Days Seg 21 Vascular: Peripheral Blood Seg 2 6 – 12 hours 3 Marginating Pool Apoptosis and ? Tissue clearance by 0 – 3 macrophages days PHAGOCYTOSIS 1. Mobilization 2. Chemotaxis 3. Recognition (Opsonization) 4. Ingestion 5. Degranulation 6. Peroxidation 7. Killing and Digestion 8. Net formation Adhesion: β 2 Integrins ▪ Heterodimer of a and b chain ▪ Tight adhesion, migration, ingestion, co- stimulation of other PMN responses LFA-1 Mac-1 (CR3) p150,95 a2b2 a CD11a CD11b CD11c CD11d b CD18 CD18 CD18 CD18 Cells All PMN, Dendritic Mac, mono, leukocytes mono/mac, PMN, T cell LGL Ligands ICAMs ICAM-1 C3bi, ICAM-3, C3bi other other Fibrinogen other GRANULOCYTE CHEMOATTRACTANTS Chemoattractants Source Activators Lipids PAF Neutrophils C5a, LPS, FMLP Endothelium LTB4 Neutrophils FMLP, C5a, LPS Chemokines (a) IL-8 Monocytes, endothelium LPS, IL-1, TNF, IL-3 other cells Gro a, b, g Monocytes, endothelium IL-1, TNF other cells NAP-2 Activated platelets Platelet activation Others FMLP Bacteria C5a Activation of complement Other Important Receptors on PMNs ñ Pattern recognition receptors – Detect microbes - Toll receptor family - Mannose receptor - bGlucan receptor – fungal cell walls ñ Cytokine receptors – enhance PMN function - G-CSF, GM-CSF - TNF Receptor ñ Opsonin receptors – trigger phagocytosis - FcgRI, II, III - Complement receptors – ñ Mac1/CR3 (CD11b/CD18) – C3bi ñ CR-1 – C3b, C4b, C3bi, C1q, Mannose binding protein From JG Hirsch, J Exp Med 116:827, 1962, with permission. -
Cells, Tissues and Organs of the Immune System
Immune Cells and Organs Bonnie Hylander, Ph.D. Aug 29, 2014 Dept of Immunology [email protected] Immune system Purpose/function? • First line of defense= epithelial integrity= skin, mucosal surfaces • Defense against pathogens – Inside cells= kill the infected cell (Viruses) – Systemic= kill- Bacteria, Fungi, Parasites • Two phases of response – Handle the acute infection, keep it from spreading – Prevent future infections We didn’t know…. • What triggers innate immunity- • What mediates communication between innate and adaptive immunity- Bruce A. Beutler Jules A. Hoffmann Ralph M. Steinman Jules A. Hoffmann Bruce A. Beutler Ralph M. Steinman 1996 (fruit flies) 1998 (mice) 1973 Discovered receptor proteins that can Discovered dendritic recognize bacteria and other microorganisms cells “the conductors of as they enter the body, and activate the first the immune system”. line of defense in the immune system, known DC’s activate T-cells as innate immunity. The Immune System “Although the lymphoid system consists of various separate tissues and organs, it functions as a single entity. This is mainly because its principal cellular constituents, lymphocytes, are intrinsically mobile and continuously recirculate in large number between the blood and the lymph by way of the secondary lymphoid tissues… where antigens and antigen-presenting cells are selectively localized.” -Masayuki, Nat Rev Immuno. May 2004 Not all who wander are lost….. Tolkien Lord of the Rings …..some are searching Overview of the Immune System Immune System • Cells – Innate response- several cell types – Adaptive (specific) response- lymphocytes • Organs – Primary where lymphocytes develop/mature – Secondary where mature lymphocytes and antigen presenting cells interact to initiate a specific immune response • Circulatory system- blood • Lymphatic system- lymph Cells= Leukocytes= white blood cells Plasma- with anticoagulant Granulocytes Serum- after coagulation 1. -
Novel Emergency Medicine Curriculum Utilizing Self- Directed Learning and the Flipped Classroom Method: Hematologic/Oncologic Emergencies Small Group
CURRICULUM Novel Emergency Medicine Curriculum Utilizing Self- Directed Learning and the Flipped Classroom Method: Hematologic/Oncologic Emergencies Small Group Module Michael G Barrie, MD*, Chad L Mayer, MD*, Colin Kaide, MD*, Emily Kauffman, DO*, Jennifer Mitzman, MD*, Matthew Malone, MD*, Daniel Bachmann, MD*, Ashish Panchal, MD*, Howard Werman, MD*, Benjamin Ostro, MD* and Andrew King, MD* *The Ohio State University Wexner Medical Center, Department of Emergency Medicine, Columbus, OH Correspondence should be addressed to Andrew King, MD, FACEP at [email protected], Twitter: @akingermd Submitted: August 6, 2018; Accepted: November 21, 2018; Electronically Published: January 15, 2019; https://doi.org/10.21980/J8VW56 Copyright: © 2019 Barrie, et al. This is an open access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 4.0) License. See: http://creativecommons.org/licenses/by/4.0/ ABSTRACT: Audience: This curriculum, created and implemented at The Ohio State University Wexner Medical Center, was designed to educate our emergency medicine (EM) residents, intern to senior resident level, as well as medical students and attending physicians. Introduction: Disorders of the hematologic system represent a wide spectrum of disease, including bleeding disorders, coagulopathies, blood cell disorders, and oncology related disorders. Hematologic related problems often complicate other disease processes, including malignancy. The number of patients diagnosed with malignancy is increasing due to many factors, including, but not limited to, an aging population and the increased ability for early detection.1 Patients with oncologic conditions can present in a variety of ways with a variety of complications,2 and understanding the steps in diagnosis and management are important components of any emergency physician’s training. -
Practice Parameter for the Diagnosis and Management of Primary Immunodeficiency
Practice parameter Practice parameter for the diagnosis and management of primary immunodeficiency Francisco A. Bonilla, MD, PhD, David A. Khan, MD, Zuhair K. Ballas, MD, Javier Chinen, MD, PhD, Michael M. Frank, MD, Joyce T. Hsu, MD, Michael Keller, MD, Lisa J. Kobrynski, MD, Hirsh D. Komarow, MD, Bruce Mazer, MD, Robert P. Nelson, Jr, MD, Jordan S. Orange, MD, PhD, John M. Routes, MD, William T. Shearer, MD, PhD, Ricardo U. Sorensen, MD, James W. Verbsky, MD, PhD, David I. Bernstein, MD, Joann Blessing-Moore, MD, David Lang, MD, Richard A. Nicklas, MD, John Oppenheimer, MD, Jay M. Portnoy, MD, Christopher R. Randolph, MD, Diane Schuller, MD, Sheldon L. Spector, MD, Stephen Tilles, MD, Dana Wallace, MD Chief Editor: Francisco A. Bonilla, MD, PhD Co-Editor: David A. Khan, MD Members of the Joint Task Force on Practice Parameters: David I. Bernstein, MD, Joann Blessing-Moore, MD, David Khan, MD, David Lang, MD, Richard A. Nicklas, MD, John Oppenheimer, MD, Jay M. Portnoy, MD, Christopher R. Randolph, MD, Diane Schuller, MD, Sheldon L. Spector, MD, Stephen Tilles, MD, Dana Wallace, MD Primary Immunodeficiency Workgroup: Chairman: Francisco A. Bonilla, MD, PhD Members: Zuhair K. Ballas, MD, Javier Chinen, MD, PhD, Michael M. Frank, MD, Joyce T. Hsu, MD, Michael Keller, MD, Lisa J. Kobrynski, MD, Hirsh D. Komarow, MD, Bruce Mazer, MD, Robert P. Nelson, Jr, MD, Jordan S. Orange, MD, PhD, John M. Routes, MD, William T. Shearer, MD, PhD, Ricardo U. Sorensen, MD, James W. Verbsky, MD, PhD GlaxoSmithKline, Merck, and Aerocrine; has received payment for lectures from Genentech/ These parameters were developed by the Joint Task Force on Practice Parameters, representing Novartis, GlaxoSmithKline, and Merck; and has received research support from Genentech/ the American Academy of Allergy, Asthma & Immunology; the American College of Novartis and Merck. -
Primary Immunodeficiency Disorders
ALLERGY AND IMMUNOLOGY 00954543 /98 $8.00 + .OO PRIMARY IMMUNODEFICIENCY DISORDERS Robert J. Mamlok, MD Immunodeficiency is a common thought among both patients and physicians when confronted with what is perceived as an excessive num- ber, duration, or severity of infections. Because of this, the starting point for evaluating patients for suspected immunodeficiency is based on what constitutes ”too many infections.” It generally is agreed that children with normal immune systems may have an average of 6 to 8 respiratory tract infections per year for the first decade of life. Even after a pattern of ab- normal infection is established, questions of secondary immunodeficiency should first be raised. The relatively uncommon primary immunodefi- ciency diseases are statistically dwarfed by secondary causes of recurrent infection, such as malnutrition, respiratory allergy, chronic cardiovascular, pulmonary, and renal disease, and environmental factors. On the other hand, a dizzying spiral of progress in our understanding of the genetics and immunology of primary immunodeficiency disease has resulted in improved diagnostic and therapeutic tools. Twenty-five newly recognized immunologic disease genes have been cloned in the last 5 ~ears.2~It has become arguably more important than ever for us to recognize the clinical and laboratory features of these relatively uncommon, but increasingly treatable, disorders. CLASSIFICATION The immune system has been classically divided into four separate arms: The B-cell system responsible for antibody formation, the T-cell sys- From the Division of Pediatric Allergy and Immunology, Texas Tech University Health Sci- ences Center, Lubbock, Texas PRIMARY CARE VOLUME 25 NUMBER 4 DECEMBER 1998 739 740 MAMLOK tem responsible for immune cellular regulation, the phagocytic (poly- morphonuclear and mononuclear) system and the complement (opsonic) system. -
Fracp Lecture 2010 Immune Deficiency 3
FRACP LECTURE 2010 IMMUNE DEFICIENCY 3 DR MARNIE ROBINSON PAEDIATRIC IMMUNOLOGIST/ALLERGIST IMMUNOLOGY LECTURE 3 • Neutrophil defects • INTERFERON –Y /IL‐12 pathway defect • Dysregulatory immune dfiideficienc ies NEUTROPHIL DEFECTS • Neutropaenia – Allo immune /au to immune – Kostmann, WHIM – cyclllical • Chronic granulomatous disease • Leukocyte adhesion deficiency • Neutrophil specific granule deficiency • Chediak –higashi syndrome AUTOIMMUNE NEUTROPAENIA • Antibodies against different neutrophil antigen • Aeitiology unknown • Slightly more common in females • Present with skin and upper respiratory tract infections (pneumonia /menin gitis /se psis less common) • Neutrophil count usually <0. 5 but may increase during infection • Treatment with G‐CSF (IVIG) • Usually remits spontaneously by <24 months ALLOIMMUNE NEUTROPAENIA • Caused by transplacental transfer of maternal against the FcyRIIIb isotypes of NA 1 and NA2 causing immune destruction of neutrophils • Incidence of 1/500 • Usually presents in first weeks of life • Present with omphalitis, cellulitis, pneumonia • Diagnosed by detection of neutrophil specific alloantibodies in maternal blood • Treat with G‐CSF • resolves with waning of maternal antibodies KOSTMANN’S SYNDROME • Bone marrow granulocyte arrest at promyeolocyte or myelocyte stage • Present early in life (usually <6 months) • Present with omphalitis , respiratory tract ifinfect ions, skin and liver abscesses • Increased susceptibility to AML • Treatment is with G‐CSF CYCLICAL NEUTROPAENIA • Defect in elastase 2 • Sporadic -
The Significance of Various Granulocytic Inclusions
4/8/19 THE SIGNIFICANCE OF VARIOUS DISCLOSURES GRANULOCYTIC INCLUSIONS ¡ No relevant financial interests to disclose. KRISTLE HABERICHTER, DO, FCAP GRAND TRAVERSE PATHOLOGY, PLLC OBJECTIVES GRANULOCYTES ¡ Innate immune system ¡ Travel to sites of infection, recognize and phagocytose pathogens ¡ Recognize common and uncommon granulocytic inclusions, including those associated with certain ¡ Utilize numerous cytotoxic mechanisms to kill pathogens inherited disorders and infectious etiologies ¡ Granulopoiesis occurs in the bone marrow ¡ Sufficient stem cells, adequate microenvironment, and regulatory factors ¡ Identify newly described green neutrophilic inclusions ¡ Granulocyte colony stimulating factor (G-CSF) → Granulocytes ¡ Monocyte colony stimulating factor (M-CSF) → Monocytes ¡ Understand the clinical significance and implications of various inclusions ¡ Granulocyte-monocytes colony stimulating factor (GM-CSF) → Granulocytes & Monocytes ¡ 1-3 weeks for complete granulopoiesis to occur ¡ Neutrophils only circulate for a few hours before migrating to the tissues Photo by K. Haberichter (Giemsa, 1000x) GRANULOCYTES INCLUSION CATEGORIES ¡ Primary granules → Myeloperoxidase Reactive/Acquired Changes Congenital Abnormalities Infectious Etiologies ¡ “Late” myeloblasts and promyelocytes ¡ To x ic G r a n u la t io n ¡ Chédiak-Higashi Syndrome ¡ Anaplasma ¡ Secondary granules → Leukocyte alkaline phosphatase ¡ Döhle Bodies ¡ Alder-Reilly Anomaly ¡ Ehrlichia ¡ Myelocytes, metamyelocytes, band and segmented neutrophils ¡ Cytokine Effect ¡ May-Hegglin -
Original Article Anemia, Leukocytosis and Eosinophilia in a Resource-Poor
Original Article Anemia, leukocytosis and eosinophilia in a resource-poor population with helmintho-ectoparasitic coinfection Daniel Pilger1, Jörg Heukelbach2, Alexander Diederichs1, Beate Schlosser1, Cinthya Pereira Leite Costa Araújo3, Anne Keysersa1, Oliver Liesenfeld1, Hermann Feldmeier1 1Charité - Universitätsmedizin Berlin, Campus Benjamin Franklin, Institute of Microbiology and Hygiene, D-12203 Berlin, Germany 2Department of Community Health, School of Medicine, Federal University of Ceará, Fortaleza, CE 60430-140, Brazil 3Department of Hematology, Estate University of Health Science of Alagoas, Alagoas, CEP 57010-300, Brazil Abstract Introduction: Eosinophilia and anemia are very common hematological alterations in the tropics but population-based studies scrutinizing their value for diagnosing parasitic infections are rare. Methodology: A cross-sectional study was conducted in a rural district in northeast Brazil where parasitic infections are common. Stool and blood samples were collected and individuals were clinically examined for the presence of ectoparasites. Results: In total, 874 individuals were examined. Infection with intestinal helminths occurred in 70% (95% CI 67 – 75), infestation with ectoparasites in 45% (95% CI 42 - 49) and co-infection with both helminths and ectoparasites was found in 33% (95% CI 29% - 36%) of all inhabitants. Eosinophil counts ranged from 40/µl to 13.800/µl (median: 900/µl). Haemoglobin levels ranged from 4.8 g/dl to 16.8 g/dl (median: 12.5 g/dl), and anemia was present in 24% of the participants. Leukocytosis was found in 13%, eosinophilia in 74%, and hypereosinophilia in 44% of the participants. Eosinophilia was more pronounced in individuals co-infected with intestinal helminths and ectoparasites (p < 0.001) and correctly predicted parasitic infection in 87% (95% CI 84%-90.7%) of all cases. -
Blood and Immunity
Chapter Ten BLOOD AND IMMUNITY Chapter Contents 10 Pretest Clinical Aspects of Immunity Blood Chapter Review Immunity Case Studies Word Parts Pertaining to Blood and Immunity Crossword Puzzle Clinical Aspects of Blood Objectives After study of this chapter you should be able to: 1. Describe the composition of the blood plasma. 7. Identify and use roots pertaining to blood 2. Describe and give the functions of the three types of chemistry. blood cells. 8. List and describe the major disorders of the blood. 3. Label pictures of the blood cells. 9. List and describe the major disorders of the 4. Explain the basis of blood types. immune system. 5. Define immunity and list the possible sources of 10. Describe the major tests used to study blood. immunity. 11. Interpret abbreviations used in blood studies. 6. Identify and use roots and suffixes pertaining to the 12. Analyse several case studies involving the blood. blood and immunity. Pretest 1. The scientific name for red blood cells 5. Substances produced by immune cells that is . counteract microorganisms and other foreign 2. The scientific name for white blood cells materials are called . is . 6. A deficiency of hemoglobin results in the disorder 3. Platelets, or thrombocytes, are involved in called . 7. A neoplasm involving overgrowth of white blood 4. The white blood cells active in adaptive immunity cells is called . are the . 225 226 ♦ PART THREE / Body Systems Other 1% Proteins 8% Plasma 55% Water 91% Whole blood Leukocytes and platelets Formed 0.9% elements 45% Erythrocytes 10 99.1% Figure 10-1 Composition of whole blood. -
Hemodialysis Leukopenia. Pulmonary Vascular Leukostasis Resulting from Complement Activation by Dialyzer Cellophane Membranes
Hemodialysis leukopenia. Pulmonary vascular leukostasis resulting from complement activation by dialyzer cellophane membranes. P R Craddock, … , K L Brighan, H S Jacob J Clin Invest. 1977;59(5):879-888. https://doi.org/10.1172/JCI108710. Research Article Acute leukopenia occurs in all patients during the first hour of hemodialysis with cellophanemembrane equipment. This transient cytopenia specifically involves granulocytes and monocytes, cells which share plasma membrane reactivity towards activated complement components. The present studies document that complement is activated during exposure of plasma to dialyzer cellophane, and that upon reinfusion of this plasma into the venous circulation, granulocyte and monocyte entrapment in the pulmonary vasculature is induced. During early dialysis, conversion of both C3 and factor B can be demonstrated in plasma as it leaves the dialyzer. Moreover, simple incubation of human plasma with dialyzer cellophane causes conversion of C3 and factor B, accompanied by depletion of total hemolytic complement and C3 but sparing of hemolytic C1. Reinfusion of autologous, cellophane-incubated plasma into rabbits produces selective granulocytopenia and monocytopenia identical to that seen in dialyzed patients. Lungs from such animals reveal striking pulmonary vessel engorgement with granulocytes. The activated complement component(s) responsible for leukostasis has an approximate molecular weight of 7,000-20,000 daltons. Since it is generated in C2-deficient plasma and is associated with factor B conversion, it is suggested that activation of complement by dialysis is predominantly through the altermative pathway. Find the latest version: https://jci.me/108710/pdf Hemodialysis Leukopenia PULMONARY VASCULAR LEUKOSTASIS RESULTING FROM COMPLEMENT ACTIVATION BY DIALYZER CELLOPHANE MEMBRANES PHILIP R. -
Statistical Analysis Plan
Cover Page for Statistical Analysis Plan Sponsor name: Novo Nordisk A/S NCT number NCT03061214 Sponsor trial ID: NN9535-4114 Official title of study: SUSTAINTM CHINA - Efficacy and safety of semaglutide once-weekly versus sitagliptin once-daily as add-on to metformin in subjects with type 2 diabetes Document date: 22 August 2019 Semaglutide s.c (Ozempic®) Date: 22 August 2019 Novo Nordisk Trial ID: NN9535-4114 Version: 1.0 CONFIDENTIAL Clinical Trial Report Status: Final Appendix 16.1.9 16.1.9 Documentation of statistical methods List of contents Statistical analysis plan...................................................................................................................... /LQN Statistical documentation................................................................................................................... /LQN Redacted VWDWLVWLFDODQDO\VLVSODQ Includes redaction of personal identifiable information only. Statistical Analysis Plan Date: 28 May 2019 Novo Nordisk Trial ID: NN9535-4114 Version: 1.0 CONFIDENTIAL UTN:U1111-1149-0432 Status: Final EudraCT No.:NA Page: 1 of 30 Statistical Analysis Plan Trial ID: NN9535-4114 Efficacy and safety of semaglutide once-weekly versus sitagliptin once-daily as add-on to metformin in subjects with type 2 diabetes Author Biostatistics Semaglutide s.c. This confidential document is the property of Novo Nordisk. No unpublished information contained herein may be disclosed without prior written approval from Novo Nordisk. Access to this document must be restricted to relevant parties.This