Browse the corpus

Hematology Committee Senior Deputy Editor Karen Quillen, MD, MPH, Section Editor Patrick C. Alguire, MD, FACP Department of Hematologr/Oncologz, Atrius Health American College of Physicians Professor of Pathologz & Laboratory Medicine Philadelph ia. Pennsylvan ia Boston University School of Medicine Boston, Massachusetts Deputy Editor Jan Cerny, MD, PhD, EACP Richard S. Eisenstaedt, MD, MACP Associate Professor of Medicine Chair, Department of Medicine Division of Hematologr and Oncologz Abington Hospital, Jefferson Health Department of Medicine Abington, Pennsylvania Director, Leukemia Program Clinical Professor ol Medicine Co-Director of Blood and Bone Marrow Transplant Program Sidney Kimmel Medical College at Thomas Jefferson University University of Massachusetts Medical School Philadelph ia. Pennsylvan ia Associate Director, Cancer Research Office UMass Memorial Cancer Center North Worcester. Massachusetts Hematology Reviewers Randy L. Levine, MD Anna Rita Marcelli. MD Director. Transfusion Services Karen Seiter. MD Director. Out Patient Infusion Center Sanaa Rizk, MD, FACP Lenox Hill Hospital Hlaing Tint, MD, CMQ, FACP Associate Professor of Medicine, and Pathologr and James Gajewski, MD, MACP FRCP

Committee Senior Deputy Editor Karen Quillen, MD, MPH, Section Editor Patrick C. Alguire, MD, FACP Department of Hematologr/Oncologz, Atrius Health American College of Physicians Professor of Pathologz & Laboratory Medicine Philadelph ia. Pennsylvan ia Boston University School of Medicine Boston, Massachusetts Deputy Editor Jan Cerny, MD, PhD, EACP Richard S. Eisenstaedt, MD, MACP Associate Professor of Medicine Chair, Department of Medicine Division of Hematologr and Oncologz Abington Hospital, Jefferson Health Department of Medicine Abington, Pennsylvania Director, Leukemia Program Clinical Professor ol Medicine Co-Director of Blood and Bone Marrow Transplant Program Sidney Kimmel Medical College at Thomas Jefferson University University of Massachusetts Medical School Philadelph ia. Pennsylvan ia Associate Director, Cancer Research Office UMass Memorial Cancer Center North Worcester. Massachusetts Hematology Reviewers Randy L. Levine, MD Anna Rita Marcelli. MD Director. Transfusion Services Karen Seiter. MD Director. Out Patient Infusion Center Sanaa Rizk, MD, FACP Lenox Hill Hospital Hlaing Tint, MD, CMQ, FACP Associate Professor of Medicine, and Pathologr and James Gajewski, MD, MACP FRCP Laboratory Medicine Emmanuel Andes Fajardo, MD, FACP, FSHM Zucker School of Medicine at Hofstra Northwell Ming Y. Lim, MB BChir, MSCR New York. New York Steven L. Allen, MD, FACP Omar Castaneda Puglianini, MD Vinit K. Makkar, MD Staff Physician, Taussig Cancer Institute Cleveland Clinic Foundation Hospital Medicine Hematology Section Chiel Division of Hematologz Oncologr Reviewers Hillcrest Hospital, Cleveland Clinic Healthcare System Owhofasa Agbedia, MD, MPH Cleveland, Ohio Ronald E. Domen, MD, FCAP, FACP Musaberk Goksel, MD, FACP Brandon McMahon, MD Jessica SaIt, MD, MBE, FACP Associate Professor of Medicine University of Colorado School of Medicine Department of Medicine/Division of Hematologr Hematology ACP Editorial Staff Aurora. Colorado Linnea Donnarumma, Senior Medical Editor, Assessment and Education Programs Shayna Sarosiek, MD, MS Bedcy frrumm, Director, Assessment and Education Programs Division of Hematologic Malignancies Jackie Twomey, Managing Editor, Assessment and Dana Farber Cancer Institute Education Programs Boston. Massachusetts

Laboratory Medicine Emmanuel Andes Fajardo, MD, FACP, FSHM Zucker School of Medicine at Hofstra Northwell Ming Y. Lim, MB BChir, MSCR New York. New York Steven L. Allen, MD, FACP Omar Castaneda Puglianini, MD Vinit K. Makkar, MD Staff Physician, Taussig Cancer Institute Cleveland Clinic Foundation Hospital Medicine Hematology Section Chiel Division of Hematologz Oncologr Reviewers Hillcrest Hospital, Cleveland Clinic Healthcare System Owhofasa Agbedia, MD, MPH Cleveland, Ohio Ronald E. Domen, MD, FCAP, FACP Musaberk Goksel, MD, FACP Brandon McMahon, MD Jessica SaIt, MD, MBE, FACP Associate Professor of Medicine University of Colorado School of Medicine Department of Medicine/Division of Hematologr Hematology ACP Editorial Staff Aurora. Colorado Linnea Donnarumma, Senior Medical Editor, Assessment and Education Programs Shayna Sarosiek, MD, MS Bedcy frrumm, Director, Assessment and Education Programs Division of Hematologic Malignancies Jackie Twomey, Managing Editor, Assessment and Dana Farber Cancer Institute Education Programs Boston. Massachusetts ACP PrincipalStaff Editor-in-Chief Davoren Chick, MD, FACP Davoren Chick, MD, FACP Senior Vice President, Medical Education Senior Vice President. Medical Education American College of Physicians Tabassum Salam, MD, MBA, EACP Philadelphia, Pennsylvania Vice President, Medical Education ill

Margaret Wells, EdM Tabassum Salam, MD, MBA, FACP Vice President, Learning Assessment, Accreditation Consultontship and Research Johnson and Johnson Patrick C. Alguire, MD, EACP MKSAP Senior Deputy Editor Acknowledgments Becky Krumm The American College of Physicians (ACP) gratefully Director, Assessment and Education Programs acknowledges the special contributions to the development and production of the 19th edition of the Medical Jackie Twomey Knowledge Self-Assessment Program' (MKSAP' 19) made Managing Editor by the lollowing people: Julia Nawrocki Graphic Design: Barry Moshinski (Director, Graphic Services), D igital Co n ten t Asso ciate / Editor Raymond DeJohn (Designer, Graphic Services), Tom Malone Linnea Donnarumma (Print/Mail Production Manager, Graphic Services), Mike Senior Medicctl Editor Ripca (Technical Administrator, Graphic Services).

Patrick C. Alguire, MD, EACP MKSAP Senior Deputy Editor Acknowledgments Becky Krumm The American College of Physicians (ACP) gratefully Director, Assessment and Education Programs acknowledges the special contributions to the development and production of the 19th edition of the Medical Jackie Twomey Knowledge Self-Assessment Program' (MKSAP' 19) made Managing Editor by the lollowing people: Julia Nawrocki Graphic Design: Barry Moshinski (Director, Graphic Services), D igital Co n ten t Asso ciate / Editor Raymond DeJohn (Designer, Graphic Services), Tom Malone Linnea Donnarumma (Print/Mail Production Manager, Graphic Services), Mike Senior Medicctl Editor Ripca (Technical Administrator, Graphic Services). Amanda Cowley Production / Sustems: Dan Hoffmann (Vice President, Medical Editor Information Technology), Scott Hurd (Manager, Content Systems), Neil Kohl (Senior Architect), and Chris SandyCrump Patterson (Senior Architect). Medical Editor MKSAP 19 Digital: Under the leadership of Steven Spadt Georgette Forgione (Senior Vice President, Information Technology and Chief Medicol Editor Technology Officer), the development of the digital version Beth Goldner of MKSAP 19 was implemented by ACP's Digital Products Medical Editor and Services Department, directed and led by Brian Sweigard (Vice President, Digital Products and Services). Suzanne Meyers Other members of the team included Dan Barron (Senior Medical Editor Web Application Developer/Architect), Callie Cramer Elise Paxson (Data Visualization/Web Developer), Chris Forrest (Senior Medical Editor Web Application Developer), Kathleen Hoover (Manager, User Interface Design and Development), Kara Regis Chuck Graver (Director, Product Design and Development), Brad Lord F inance and Operations Administrator (Senior Web Application Developer/Architect), and John Kimberly Kerns McKnight (Senior Web Developer). Administ rat i u e Coordinator The College also wishes to acknowledge that many other persons, too numerous to mention, have contributed to Disclosures of relationships with any entity producing, the production of this program. Without their dedicated marketing, reselling, or distributing health care goods or efforts, this program would not have been possible. services consumed by, or used on, patients. Individuals not listed below have nothing to disclose.

Amanda Cowley Production / Sustems: Dan Hoffmann (Vice President, Medical Editor Information Technology), Scott Hurd (Manager, Content Systems), Neil Kohl (Senior Architect), and Chris SandyCrump Patterson (Senior Architect). Medical Editor MKSAP 19 Digital: Under the leadership of Steven Spadt Georgette Forgione (Senior Vice President, Information Technology and Chief Medicol Editor Technology Officer), the development of the digital version Beth Goldner of MKSAP 19 was implemented by ACP's Digital Products Medical Editor and Services Department, directed and led by Brian Sweigard (Vice President, Digital Products and Services). Suzanne Meyers Other members of the team included Dan Barron (Senior Medical Editor Web Application Developer/Architect), Callie Cramer Elise Paxson (Data Visualization/Web Developer), Chris Forrest (Senior Medical Editor Web Application Developer), Kathleen Hoover (Manager, User Interface Design and Development), Kara Regis Chuck Graver (Director, Product Design and Development), Brad Lord F inance and Operations Administrator (Senior Web Application Developer/Architect), and John Kimberly Kerns McKnight (Senior Web Developer). Administ rat i u e Coordinator The College also wishes to acknowledge that many other persons, too numerous to mention, have contributed to Disclosures of relationships with any entity producing, the production of this program. Without their dedicated marketing, reselling, or distributing health care goods or efforts, this program would not have been possible. services consumed by, or used on, patients. Individuals not listed below have nothing to disclose. Jan Cerny MKSAP Resource Page :

Amanda Cowley Production / Sustems: Dan Hoffmann (Vice President, Medical Editor Information Technology), Scott Hurd (Manager, Content Systems), Neil Kohl (Senior Architect), and Chris SandyCrump Patterson (Senior Architect). Medical Editor MKSAP 19 Digital: Under the leadership of Steven Spadt Georgette Forgione (Senior Vice President, Information Technology and Chief Medicol Editor Technology Officer), the development of the digital version Beth Goldner of MKSAP 19 was implemented by ACP's Digital Products Medical Editor and Services Department, directed and led by Brian Sweigard (Vice President, Digital Products and Services). Suzanne Meyers Other members of the team included Dan Barron (Senior Medical Editor Web Application Developer/Architect), Callie Cramer Elise Paxson (Data Visualization/Web Developer), Chris Forrest (Senior Medical Editor Web Application Developer), Kathleen Hoover (Manager, User Interface Design and Development), Kara Regis Chuck Graver (Director, Product Design and Development), Brad Lord F inance and Operations Administrator (Senior Web Application Developer/Architect), and John Kimberly Kerns McKnight (Senior Web Developer). Administ rat i u e Coordinator The College also wishes to acknowledge that many other persons, too numerous to mention, have contributed to Disclosures of relationships with any entity producing, the production of this program. Without their dedicated marketing, reselling, or distributing health care goods or efforts, this program would not have been possible. services consumed by, or used on, patients. Individuals not listed below have nothing to disclose. Jan Cerny MKSAP Resource Page : Consultontship The MKSAP Resource Page (wr,vlv.acponline.org/mksap19- Jazz Pharmaceuticals, Dalichi Sankyo, Pfizer Inc., Incyte resources) provides access to MKSAP 19 online answer sheets Inc., Amgen Inc. for transcribing answers from the print edition; access to l Stock Option s / Holdings Actinium Pharmaceuticals, Bluebird Bio, Dynavax MKSAP 19 Digital; Board Basics'; information on Continuing l Medical Education (CME), Maintenance of Certification (MOC), Technologies, aTyr Pharma, Gamida Cell, Viridian l and intemational Continuing Professional Development (CPD) Therapeutics, Mustang Bio, Novavax, Ovid Therapeutics, and MOC; errata; and other new information. ,t

Consultontship The MKSAP Resource Page (wr,vlv.acponline.org/mksap19- Jazz Pharmaceuticals, Dalichi Sankyo, Pfizer Inc., Incyte resources) provides access to MKSAP 19 online answer sheets Inc., Amgen Inc. for transcribing answers from the print edition; access to l Stock Option s / Holdings Actinium Pharmaceuticals, Bluebird Bio, Dynavax MKSAP 19 Digital; Board Basics'; information on Continuing l Medical Education (CME), Maintenance of Certification (MOC), Technologies, aTyr Pharma, Gamida Cell, Viridian l and intemational Continuing Professional Development (CPD) Therapeutics, Mustang Bio, Novavax, Ovid Therapeutics, and MOC; errata; and other new information. ,t Sorrento Therapeutics, TG Therapeutics, Vaxart, Veru Other (Data safety monitoring committee member) -. AlloVir lnternational MOC/CPD Brandon McMahon Information and instructions on submission of interna Consultontship tional MOC/CPD is available by accessing the CME/MOC/ t, Celgene, Rigel, Incyte Inc. CPD tab on the left navigation menu of MKSAP 19 Digital. : iv \

Hematology Approach to Nonmalignant bacterial and viral infections. Chronically low ALC and recur- rent infections should prompt evaluation for immunodeficiency Leukopenia and and measurement of immunoglobulin levels. Lymphopenia without clinical consequences or an associated illness does not Leukocytosis require treatment. Although leukopenia and leukocy.tosis may raise concem for an Neutropenia can result from impaired marrow produc- underlying hematologic malignanry, many causes are benign. tion, immune-mediated destruction, or cellular redistribution, Variability is expected in blood counts in the general population, especially to the spleen, as with portal hypertension due to with reference ranges spanning two standard deviations around cirrhosis or portal vein thrombosis. Effects depend on the the mean. Normal variation can sometimes explain aberrant degree of neutropenia, bone marrow reserve, and comorbid leukocyte counts, with 2.5% of persons falling above or below conditions. Severe neutropenia is classified as an ANC less than standard reference ranges. Some other common nonmalignant 500 cells/pl (0.5 x 10e/L). See Table l for some common causes. causes of quantitative abnormalities in the leukocyte count are Benign ethnic neutropenia (BEN) is a mild, chronically listed in Table 1. The basic elements of evaluation include per low ANC, typically 1000 to 1500 cells/pl (1 1.5 x 10e/L), sonal history and physical examination; family history; review of although it can be lower. BEN is more common among certain medication, supplements, and other drug use; complete blood demographics, including those of African descent. It has been count and differential; and peripheral blood smear. reported in 4.5% of Black and 0.8% of White persons in the United States. Myeloid progenitors are mildly reduced, with a smaller neutrophil reserve in the circulation and bone mar- Lymphopenia and Neutropenia row. However, myeloid maturation and function are normal. A decreased absolute lymphocyte count (ALC) can occur in BEN does not result in increased frequency or severity ofinfec- response to glucocorticoids, other medications, and various tions or other significant clinical consequences.

Approach to Nonmalignant bacterial and viral infections. Chronically low ALC and recur- rent infections should prompt evaluation for immunodeficiency Leukopenia and and measurement of immunoglobulin levels. Lymphopenia without clinical consequences or an associated illness does not Leukocytosis require treatment. Although leukopenia and leukocy.tosis may raise concem for an Neutropenia can result from impaired marrow produc- underlying hematologic malignanry, many causes are benign. tion, immune-mediated destruction, or cellular redistribution, Variability is expected in blood counts in the general population, especially to the spleen, as with portal hypertension due to with reference ranges spanning two standard deviations around cirrhosis or portal vein thrombosis. Effects depend on the the mean. Normal variation can sometimes explain aberrant degree of neutropenia, bone marrow reserve, and comorbid leukocyte counts, with 2.5% of persons falling above or below conditions. Severe neutropenia is classified as an ANC less than standard reference ranges. Some other common nonmalignant 500 cells/pl (0.5 x 10e/L). See Table l for some common causes. causes of quantitative abnormalities in the leukocyte count are Benign ethnic neutropenia (BEN) is a mild, chronically listed in Table 1. The basic elements of evaluation include per low ANC, typically 1000 to 1500 cells/pl (1 1.5 x 10e/L), sonal history and physical examination; family history; review of although it can be lower. BEN is more common among certain medication, supplements, and other drug use; complete blood demographics, including those of African descent. It has been count and differential; and peripheral blood smear. reported in 4.5% of Black and 0.8% of White persons in the United States. Myeloid progenitors are mildly reduced, with a smaller neutrophil reserve in the circulation and bone mar- Lymphopenia and Neutropenia row. However, myeloid maturation and function are normal. A decreased absolute lymphocyte count (ALC) can occur in BEN does not result in increased frequency or severity ofinfec- response to glucocorticoids, other medications, and various tions or other significant clinical consequences. TABI-[ 1 " Nonmalignant Causes of Abnormal Leukocyte Counts Neutropenia Lymphopenia Lymphocposis Neutrophilia (ANC <1500 cells/pl) (ALC <1OOO cells/pt) (ALC >4000 cells/IrL) (ANC >7700 cells/pt)

TABI-[ 1 " Nonmalignant Causes of Abnormal Leukocyte Counts Neutropenia Lymphopenia Lymphocposis Neutrophilia (ANC <1500 cells/pl) (ALC <1OOO cells/pt) (ALC >4000 cells/IrL) (ANC >7700 cells/pt) lnherited: Benign ethnic, cyclic, I nherited : mmunodeficiency I lnfections: Viral (EBV CMV HIV lnfections (especially bacterial) familial, congenital disorder influenza), bacterial (pertussis, Acute/ch ron ic nf lam matory i cat scratch disease, lnfections: Sepsis, HlV, EBV Infections: H lV, hepatitis, states: nflam matory bowel I Cl o stri d i oi d e s d iffi ci I e), other tuberculosis, typhoid, malaria, (tu bercu losis, syphilis, disease, rheu matologic Medications: Anti biotics measles, fungal (histoplasmosis) disorders (trimethopri m-su lfamethoxazole, babesiosis) dapsone, vancomycin), Medications: Glucocorticoids, Medications: Lithium, Monoclonal B-cell psychiatric (clozapine, tricyclic rituximab, immunosuppressants glucocorticoids, myeloid lymphocytosis antidepressants), growth factors, catecholamines Systemic disease: Autoim mu ne Asplenia immunomodulatory (SLE, rheumatoid arthritis), Asplenia (methotrexate, azathioprine, sarcoidosis, Cushing Cigarette smoking tacrolimus, mycophenolate, Cigarette smoking syndrome, aplastic anemia others), thyroid (methimazole, Drug hypersensitivity reaction propylthiou racil) Obesity Other: Alcohol, zinc deficiency, Hyperthyroidism protein-losing enteropathy Stressors (physical, emotional, Nutritional: Vitamin B12, folate, intense exercise) copper deficiencies Autoimmune: Primary autoimmune neutropenia, secondary to systemic process (SLE, rheumatoid arthritis)

lnherited: Benign ethnic, cyclic, I nherited : mmunodeficiency I lnfections: Viral (EBV CMV HIV lnfections (especially bacterial) familial, congenital disorder influenza), bacterial (pertussis, Acute/ch ron ic nf lam matory i cat scratch disease, lnfections: Sepsis, HlV, EBV Infections: H lV, hepatitis, states: nflam matory bowel I Cl o stri d i oi d e s d iffi ci I e), other tuberculosis, typhoid, malaria, (tu bercu losis, syphilis, disease, rheu matologic Medications: Anti biotics measles, fungal (histoplasmosis) disorders (trimethopri m-su lfamethoxazole, babesiosis) dapsone, vancomycin), Medications: Glucocorticoids, Medications: Lithium, Monoclonal B-cell psychiatric (clozapine, tricyclic rituximab, immunosuppressants glucocorticoids, myeloid lymphocytosis antidepressants), growth factors, catecholamines Systemic disease: Autoim mu ne Asplenia immunomodulatory (SLE, rheumatoid arthritis), Asplenia (methotrexate, azathioprine, sarcoidosis, Cushing Cigarette smoking tacrolimus, mycophenolate, Cigarette smoking syndrome, aplastic anemia others), thyroid (methimazole, Drug hypersensitivity reaction propylthiou racil) Obesity Other: Alcohol, zinc deficiency, Hyperthyroidism protein-losing enteropathy Stressors (physical, emotional, Nutritional: Vitamin B12, folate, intense exercise) copper deficiencies Autoimmune: Primary autoimmune neutropenia, secondary to systemic process (SLE, rheumatoid arthritis) Aplastic anemia Cellular redistribution (hypersplenism)

lnherited: Benign ethnic, cyclic, I nherited : mmunodeficiency I lnfections: Viral (EBV CMV HIV lnfections (especially bacterial) familial, congenital disorder influenza), bacterial (pertussis, Acute/ch ron ic nf lam matory i cat scratch disease, lnfections: Sepsis, HlV, EBV Infections: H lV, hepatitis, states: nflam matory bowel I Cl o stri d i oi d e s d iffi ci I e), other tuberculosis, typhoid, malaria, (tu bercu losis, syphilis, disease, rheu matologic Medications: Anti biotics measles, fungal (histoplasmosis) disorders (trimethopri m-su lfamethoxazole, babesiosis) dapsone, vancomycin), Medications: Glucocorticoids, Medications: Lithium, Monoclonal B-cell psychiatric (clozapine, tricyclic rituximab, immunosuppressants glucocorticoids, myeloid lymphocytosis antidepressants), growth factors, catecholamines Systemic disease: Autoim mu ne Asplenia immunomodulatory (SLE, rheumatoid arthritis), Asplenia (methotrexate, azathioprine, sarcoidosis, Cushing Cigarette smoking tacrolimus, mycophenolate, Cigarette smoking syndrome, aplastic anemia others), thyroid (methimazole, Drug hypersensitivity reaction propylthiou racil) Obesity Other: Alcohol, zinc deficiency, Hyperthyroidism protein-losing enteropathy Stressors (physical, emotional, Nutritional: Vitamin B12, folate, intense exercise) copper deficiencies Autoimmune: Primary autoimmune neutropenia, secondary to systemic process (SLE, rheumatoid arthritis) Aplastic anemia Cellular redistribution (hypersplenism) ALC = absolute leukocyte count; ANC = absolute neutrophil count; CMV = cytomegalovirus; EBV = Epstein Barr virus; SLE = systemic lupus erythematosus'

lnherited: Benign ethnic, cyclic, I nherited : mmunodeficiency I lnfections: Viral (EBV CMV HIV lnfections (especially bacterial) familial, congenital disorder influenza), bacterial (pertussis, Acute/ch ron ic nf lam matory i cat scratch disease, lnfections: Sepsis, HlV, EBV Infections: H lV, hepatitis, states: nflam matory bowel I Cl o stri d i oi d e s d iffi ci I e), other tuberculosis, typhoid, malaria, (tu bercu losis, syphilis, disease, rheu matologic Medications: Anti biotics measles, fungal (histoplasmosis) disorders (trimethopri m-su lfamethoxazole, babesiosis) dapsone, vancomycin), Medications: Glucocorticoids, Medications: Lithium, Monoclonal B-cell psychiatric (clozapine, tricyclic rituximab, immunosuppressants glucocorticoids, myeloid lymphocytosis antidepressants), growth factors, catecholamines Systemic disease: Autoim mu ne Asplenia immunomodulatory (SLE, rheumatoid arthritis), Asplenia (methotrexate, azathioprine, sarcoidosis, Cushing Cigarette smoking tacrolimus, mycophenolate, Cigarette smoking syndrome, aplastic anemia others), thyroid (methimazole, Drug hypersensitivity reaction propylthiou racil) Obesity Other: Alcohol, zinc deficiency, Hyperthyroidism protein-losing enteropathy Stressors (physical, emotional, Nutritional: Vitamin B12, folate, intense exercise) copper deficiencies Autoimmune: Primary autoimmune neutropenia, secondary to systemic process (SLE, rheumatoid arthritis) Aplastic anemia Cellular redistribution (hypersplenism) ALC = absolute leukocyte count; ANC = absolute neutrophil count; CMV = cytomegalovirus; EBV = Epstein Barr virus; SLE = systemic lupus erythematosus' 1

Hematopoietic Stem Cells and Their Disorders Many drugs can cause medication induced neutropenia, glucocorticoids. Cigarette smoking is another common cause, which results from impairment of normal granulopoiesis in although the mechanism is unknown, and these eflects often the bone marrow or through a drug dependent, antibody persist for a prolonged period after smoking cessation mediated immune destruction ol circulating neutrophils. sometimes for years. Obesity, especially in women, may be These effects are typically seen within the first 3 months of associated with neutrophilia. drug initiation and are often reversible. Medication induced Monocy'tosis accompanies some infections such as tuber neutropenia most often occurs in patients older than 50 years. culosis. Persistent monocytosis (fbr >6 months) without obvi Symptoms can include fever and oral ulcerations or may be ous infection, particularly when associated with cytopenias related to sites of infection. with complications more common (e.g., anemia or thrombocytoper.ria), should be referred for with lower ANCs. Treatment focuses on removing the off'end evaluation of possible hematopoietic stem cell disorders' ing agent, and symptoms often resolve within 1 to 3 weeks. I(EY POIilTS Granulocyte-colony stimulating factor can shorten recovery r Cigarette smoking is a common cause of chronic neu- time and may be used in patients with neutropenia and active trophilia; the mechanism is unknown, and neutro- inf'ection. philia may persist for a year or more following smoking Nutritional deficiencies can also cause neutropenia. cessation. Cobalamin and folate deficiencies can lower the ANC, often with concomitant macrocytic anemia and, at times, thrombo . Monoclonal B cell lymphocytosis occurs in generally cytopenia. Copper deficiency is a rare cause of neutropenia asymptomatic patients who lack other criteria for a and anemia that responds to copper supplementation. diagnosis of chronic lymphocytic leukemia. Autoimmune conditions such as systemic lupus erythe matosus can also be associated with isolated neutropenia.

Many drugs can cause medication induced neutropenia, glucocorticoids. Cigarette smoking is another common cause, which results from impairment of normal granulopoiesis in although the mechanism is unknown, and these eflects often the bone marrow or through a drug dependent, antibody persist for a prolonged period after smoking cessation mediated immune destruction ol circulating neutrophils. sometimes for years. Obesity, especially in women, may be These effects are typically seen within the first 3 months of associated with neutrophilia. drug initiation and are often reversible. Medication induced Monocy'tosis accompanies some infections such as tuber neutropenia most often occurs in patients older than 50 years. culosis. Persistent monocytosis (fbr >6 months) without obvi Symptoms can include fever and oral ulcerations or may be ous infection, particularly when associated with cytopenias related to sites of infection. with complications more common (e.g., anemia or thrombocytoper.ria), should be referred for with lower ANCs. Treatment focuses on removing the off'end evaluation of possible hematopoietic stem cell disorders' ing agent, and symptoms often resolve within 1 to 3 weeks. I(EY POIilTS Granulocyte-colony stimulating factor can shorten recovery r Cigarette smoking is a common cause of chronic neu- time and may be used in patients with neutropenia and active trophilia; the mechanism is unknown, and neutro- inf'ection. philia may persist for a year or more following smoking Nutritional deficiencies can also cause neutropenia. cessation. Cobalamin and folate deficiencies can lower the ANC, often with concomitant macrocytic anemia and, at times, thrombo . Monoclonal B cell lymphocytosis occurs in generally cytopenia. Copper deficiency is a rare cause of neutropenia asymptomatic patients who lack other criteria for a and anemia that responds to copper supplementation. diagnosis of chronic lymphocytic leukemia. Autoimmune conditions such as systemic lupus erythe matosus can also be associated with isolated neutropenia. xtY P0t1{rs Hematopoietic Stem Cells HVC . Lymphopenia without clinical consequences or an and Their Disorders associated illness does not require treatment. . Benign ethnic neutropenia results in a chronically Iow Overview absolute neutrophil count but without significant clinical Hematopoietic stem cells (HSCs) reside in the bone marrow. consequences. HSCs can self renew and. as multipotent cells, differentiate o Medication induced neutropenia occurs most often in into progenitor cells. which in turn produce leukocytes, er1.th patients older than 50 years during the first 3 months of rocytes. and platelets. This proliferation and differentiation to

xtY P0t1{rs Hematopoietic Stem Cells HVC . Lymphopenia without clinical consequences or an and Their Disorders associated illness does not require treatment. . Benign ethnic neutropenia results in a chronically Iow Overview absolute neutrophil count but without significant clinical Hematopoietic stem cells (HSCs) reside in the bone marrow. consequences. HSCs can self renew and. as multipotent cells, differentiate o Medication induced neutropenia occurs most often in into progenitor cells. which in turn produce leukocytes, er1.th patients older than 50 years during the first 3 months of rocytes. and platelets. This proliferation and differentiation to drug treatment; symptoms usually improve within 1to mature blood cells happens in an orderly manner called hematopoiesis, which is tightly regulated by multiple factors, 3 weeks of stopping the medication. including the bone marrow microenvironment and hemato poietic growth factors. For example, ery,,thropoietin stimulates ery,.throcytes; thrombopoietin stimulates platelet production; N eutrophilia, Lym phoqrtosis, and granulocyte colony stimulating factor (G-CSF) and and Monoqrtosis macrophage colony-stimulating factor stimulate granulocyte, Neutrophilia, lymphocl'tosis, and monocytosis are often reac monocyte, basophil, and eosinophil production. Disorders of tive secondary to infection or inflammation. Lymphocltosis hematopoiesis can occur at the HSC or progenitor cell level and occurs with many viral processes. Acute Epstein Barr virus can lead to underproduction or overproduction olblood cells. inlection can present with lymphadenopathy, hepatospleno- Disorders developing from early precursors are usually more megaly. and elevated ALC; atypical lymphocl,tes may be mis- aggressive than those developing from differentiated cells. taken for blasts. Monoclonal B cell lymphocytosis refers to a Bone marrow failure syndromes are characterized by the monoclonal population of B lymphocytes (<5000/pL [5 x 10e/L]) failure of hematopoiesis to keep up with physiologic demands that does not meet criteria for chronic lymphocl.tic leukemia for blood cell production (ineffective hematopoiesis), leading or lymphoproliferative malignancy; it is usually detected inci- to peripheral cytopenias. Rare inherited causes exist, but dentally in asymptomatic patients. Approximately 7'l,Io 2"1, of acquired disorders are more common and can occur second patients with a clone size greater than 2000 cells/pl (2 x 10,/L) ary to intrinsic bone marrow disorders such as myelodysplas evolve to meet criteria for chronic lymphocytic leukemia dur tic syndromes (MDS), or extrinsic disorders resulting from ing each year of follow-up; patients with a smaller clone size toxins or autoimmunity as in aplastic anemia (AA). have a much lower risk and normal longevity. No intervention Myeloproliferative neoplasms (MPNs) are characterized is required, but patients should be monitored periodically for by excessive clonal proliferation of myeloid precursors or signs ofprogression. HSCs, which is often driven by deregulation of a growth signal Neutrophilia frequently accompanies bacterial infec resulting from a specific mutation. The detection of clonal tions and can be caused by certain medications, including genetic abnormalities, such as BCR-ABL translocation and

drug treatment; symptoms usually improve within 1to mature blood cells happens in an orderly manner called hematopoiesis, which is tightly regulated by multiple factors, 3 weeks of stopping the medication. including the bone marrow microenvironment and hemato poietic growth factors. For example, ery,,thropoietin stimulates ery,.throcytes; thrombopoietin stimulates platelet production; N eutrophilia, Lym phoqrtosis, and granulocyte colony stimulating factor (G-CSF) and and Monoqrtosis macrophage colony-stimulating factor stimulate granulocyte, Neutrophilia, lymphocl'tosis, and monocytosis are often reac monocyte, basophil, and eosinophil production. Disorders of tive secondary to infection or inflammation. Lymphocltosis hematopoiesis can occur at the HSC or progenitor cell level and occurs with many viral processes. Acute Epstein Barr virus can lead to underproduction or overproduction olblood cells. inlection can present with lymphadenopathy, hepatospleno- Disorders developing from early precursors are usually more megaly. and elevated ALC; atypical lymphocl,tes may be mis- aggressive than those developing from differentiated cells. taken for blasts. Monoclonal B cell lymphocytosis refers to a Bone marrow failure syndromes are characterized by the monoclonal population of B lymphocytes (<5000/pL [5 x 10e/L]) failure of hematopoiesis to keep up with physiologic demands that does not meet criteria for chronic lymphocl.tic leukemia for blood cell production (ineffective hematopoiesis), leading or lymphoproliferative malignancy; it is usually detected inci- to peripheral cytopenias. Rare inherited causes exist, but dentally in asymptomatic patients. Approximately 7'l,Io 2"1, of acquired disorders are more common and can occur second patients with a clone size greater than 2000 cells/pl (2 x 10,/L) ary to intrinsic bone marrow disorders such as myelodysplas evolve to meet criteria for chronic lymphocytic leukemia dur tic syndromes (MDS), or extrinsic disorders resulting from ing each year of follow-up; patients with a smaller clone size toxins or autoimmunity as in aplastic anemia (AA). have a much lower risk and normal longevity. No intervention Myeloproliferative neoplasms (MPNs) are characterized is required, but patients should be monitored periodically for by excessive clonal proliferation of myeloid precursors or signs ofprogression. HSCs, which is often driven by deregulation of a growth signal Neutrophilia frequently accompanies bacterial infec resulting from a specific mutation. The detection of clonal tions and can be caused by certain medications, including genetic abnormalities, such as BCR-ABL translocation and 2

Hematopoietic Stem Cells and Their Disorders JAK2 (lAK2 V617Il mlulation, on peripheral blood testing can TABTE 2. Causes of Acquired Pure Red Cell Aplasia be used for diagnosis and disease monitoring. Parvovirus B1 9 infection Acute leukemias (myeloid or lymphoid) s1s eggressive clonal neoplasms in which cells also lose the capability to dif Thymoma ferentiate into mature cells (differentiation block). These dis Autoimmune disease orders usuaily require emergent evaluation and treatment. Lymphoid leukemias and lymphomas Solid tumors Bone Marrow Failure Syndromes Drugs (phenytoin, isoniazid) AplasticAnemia Pregnancy AA is an acquired HSC disorder characterized by severely Anti-EPO antibodies in patients receiving EPO decreased bone marrow cellularity and pancytopenia. EPO = erythropoietin. Although it is classified as a type of anemia, patients usually have a combination of anemia, neutropenia, and thrombocy- topenia (pancytopenia). Bone marrow cetlularity decreases Parvovirus B19 is cytotoxic to the erythrocyte precursors with age while the fat content of the marrow increases. These in the bone marrow Parvovirus infection is usually transient, changes are amplified in AA, which is categorized as severe or lasting 2 to 3 weeks, without typically causing clinically sig- very severe based on the degree of bone marrow cellularity nificant anemia in immunocompetent and otherwise healthy and the severity ol cytopenias. patients. However, patients with chronic hemolysis (such as AA is caused by a decrease in stem cells as a resuit of sickle cell anemia) who depend on increased erythrocyte autoimmunity, toxins, and infections. l\4edications, such as production can develop significant anemia with a decreased antithyroid medications (methimazole and propylthiouracil), reticuiocyte count. Immunocompromised patients can have p lactam antibiotics, sulfonamides, NSAIDs, anticonvulsants, sustained viremia leading to prolonged anemia requiring and gold salts, have also been associated with developing AA. intravenous immune globulin treatment to hasten viral Discontinuing the offending medication usually improves the clearance. AA, but it can take many weeks for cell counts to recover. Some patients with PRCA have an underlying occult thy Autoimmune injury to stem cells is important in the moma and can improve with thymectomy. Large granular pathogenesis of AA. In patients older than 50 years and in lymphocyte leukemia is a T cell lymphoproliferative disorder younger patients without a suitable stem celi donor, AA is that can be associated with PRCA. Flow cytometry of the treated by immunosuppression with antithymocyte globulin, peripheral blood can help identiSz this disorder. cyclosporine, prednisone, and eltrombopag. Younger patients A bone marrow biopsy specimen showing decreased with a suitable donor are usually treated with allogeneic ery4hrocyte precursors is required to diagnose PRCA. Idiopathic hematopoietic stem cell transplantation (HSCT). With advances PRCA is commonly immunologically mediated and treated in immunosuppression, bone marrow transplantation, and with immunosuppressive medications, such as prednisone, supportive care, the overall survival of young patients with a cyclosporine, and cyclophosphamide. good risk profile has reached greater than B0%. Asymptomatic I(EY POIilIS patients with mild to moderate AA can be ciosely monitored o Patients with aplastic anemia who are younger than without immediate treatment. 50 years are usually treated with allogeneic hematopoi- Patients with AA can develop a clone of paroxysmal noctur etic stem cell transplantation, whereas those without a nal hemoglobinuria cells, which lack complement stabilizing suitable stem cell donor or who are older than 50 years CD55 and CD59 proteins. However, identifying the paroxysmal should undergo immunosuppression with antithymo- nocturnal hemoglobinuria clone does not routinely change cyte globulin, cyclosporine, eltrombopag, and pred- treatment. AA can be difTerentiated from a hypoplastic variant nisone. of MDS with decreased bone marrow cellularity by finding dysplastic cells and cytogenetic abnormalities typical for MDS. . A bone marrow biopsy specimen showing a selective Patients with hypoplastic MDS are also often treated with decrease in erythrocyte precursors is required to diagnose immunosuppressive therapy. idiopathic pure red cell aplasia, which is then treated with immunosuppressive medications. Pure Red CellAplasia Pure red cell aplasia (PRCA) is characterized by normocytic or macrocytic anemia with decreased reticulocl.tes and absent or Myeloprol iferative N eoplasms decreased erythrocyte precursors in the bone marrow. The MPNs are a group of clonal stem cell disorders that share Leukocyte and platelet counts are normal. Several conditions several similar features. They are defined by specific, acquired have been implicated in the pathogenesis of PRCA, some of genetic mutational alleles resulting in overproduction of func which are listed in Table 2. tional, mature, differentiated myeloid elements (Figure 1).

JAK2 (lAK2 V617Il mlulation, on peripheral blood testing can TABTE 2. Causes of Acquired Pure Red Cell Aplasia be used for diagnosis and disease monitoring. Parvovirus B1 9 infection Acute leukemias (myeloid or lymphoid) s1s eggressive clonal neoplasms in which cells also lose the capability to dif Thymoma ferentiate into mature cells (differentiation block). These dis Autoimmune disease orders usuaily require emergent evaluation and treatment. Lymphoid leukemias and lymphomas Solid tumors Bone Marrow Failure Syndromes Drugs (phenytoin, isoniazid) AplasticAnemia Pregnancy AA is an acquired HSC disorder characterized by severely Anti-EPO antibodies in patients receiving EPO decreased bone marrow cellularity and pancytopenia. EPO = erythropoietin. Although it is classified as a type of anemia, patients usually have a combination of anemia, neutropenia, and thrombocy- topenia (pancytopenia). Bone marrow cetlularity decreases Parvovirus B19 is cytotoxic to the erythrocyte precursors with age while the fat content of the marrow increases. These in the bone marrow Parvovirus infection is usually transient, changes are amplified in AA, which is categorized as severe or lasting 2 to 3 weeks, without typically causing clinically sig- very severe based on the degree of bone marrow cellularity nificant anemia in immunocompetent and otherwise healthy and the severity ol cytopenias. patients. However, patients with chronic hemolysis (such as AA is caused by a decrease in stem cells as a resuit of sickle cell anemia) who depend on increased erythrocyte autoimmunity, toxins, and infections. l\4edications, such as production can develop significant anemia with a decreased antithyroid medications (methimazole and propylthiouracil), reticuiocyte count. Immunocompromised patients can have p lactam antibiotics, sulfonamides, NSAIDs, anticonvulsants, sustained viremia leading to prolonged anemia requiring and gold salts, have also been associated with developing AA. intravenous immune globulin treatment to hasten viral Discontinuing the offending medication usually improves the clearance. AA, but it can take many weeks for cell counts to recover. Some patients with PRCA have an underlying occult thy Autoimmune injury to stem cells is important in the moma and can improve with thymectomy. Large granular pathogenesis of AA. In patients older than 50 years and in lymphocyte leukemia is a T cell lymphoproliferative disorder younger patients without a suitable stem celi donor, AA is that can be associated with PRCA. Flow cytometry of the treated by immunosuppression with antithymocyte globulin, peripheral blood can help identiSz this disorder. cyclosporine, prednisone, and eltrombopag. Younger patients A bone marrow biopsy specimen showing decreased with a suitable donor are usually treated with allogeneic ery4hrocyte precursors is required to diagnose PRCA. Idiopathic hematopoietic stem cell transplantation (HSCT). With advances PRCA is commonly immunologically mediated and treated in immunosuppression, bone marrow transplantation, and with immunosuppressive medications, such as prednisone, supportive care, the overall survival of young patients with a cyclosporine, and cyclophosphamide. good risk profile has reached greater than B0%. Asymptomatic I(EY POIilIS patients with mild to moderate AA can be ciosely monitored o Patients with aplastic anemia who are younger than without immediate treatment. 50 years are usually treated with allogeneic hematopoi- Patients with AA can develop a clone of paroxysmal noctur etic stem cell transplantation, whereas those without a nal hemoglobinuria cells, which lack complement stabilizing suitable stem cell donor or who are older than 50 years CD55 and CD59 proteins. However, identifying the paroxysmal should undergo immunosuppression with antithymo- nocturnal hemoglobinuria clone does not routinely change cyte globulin, cyclosporine, eltrombopag, and pred- treatment. AA can be difTerentiated from a hypoplastic variant nisone. of MDS with decreased bone marrow cellularity by finding dysplastic cells and cytogenetic abnormalities typical for MDS. . A bone marrow biopsy specimen showing a selective Patients with hypoplastic MDS are also often treated with decrease in erythrocyte precursors is required to diagnose immunosuppressive therapy. idiopathic pure red cell aplasia, which is then treated with immunosuppressive medications. Pure Red CellAplasia Pure red cell aplasia (PRCA) is characterized by normocytic or macrocytic anemia with decreased reticulocl.tes and absent or Myeloprol iferative N eoplasms decreased erythrocyte precursors in the bone marrow. The MPNs are a group of clonal stem cell disorders that share Leukocyte and platelet counts are normal. Several conditions several similar features. They are defined by specific, acquired have been implicated in the pathogenesis of PRCA, some of genetic mutational alleles resulting in overproduction of func which are listed in Table 2. tional, mature, differentiated myeloid elements (Figure 1). 3